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[
"SLOS",
"SLOS",
"7-dehydrocholesterol reductase",
"DHCR7",
"Smith-Lemli-Opitz Syndrome"
] |
Smith-Lemli-Opitz Syndrome
|
Malgorzata JM Nowaczyk, Christopher A Wassif
|
Summary Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described. The diagnosis of SLOS is established in a proband with suggestive clinical features and elevated 7-dehydrocholesterol level and/or by identification of biallelic pathogenic variants in SLOS 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 detection is possible if the pathogenic variants in the family are known. Prenatal testing for a pregnancy at increased risk is possible using biochemical testing or molecular genetic testing if the pathogenic variants in the family are known.
|
## Diagnosis
Clinical diagnostic criteria for Smith-Lemli-Opitz syndrome (SLOS) have not been established.
Smith-Lemli-Opitz syndrome
Characteristic facial features (narrow forehead, epicanthal folds, ptosis, short mandible with preservation of jaw width, short nose, anteverted nares, and low-set ears)
2-3 syndactyly of the toes (minimal to Y-shaped)
Microcephaly
Growth restriction / short stature
Intellectual disability
Hypospadias in males
Cleft palate
Postaxial polydactyly
Elevated serum concentration of 7-dehydrocholesterol (7-DHC) as defined by the laboratory
Note: (1) 7-DHC concentration is usually measured in blood samples, but can be measured in other tissues. In rare instances, serum concentrations of 7-DHC and cholesterol can be in the normal ranges and a strong clinical suspicion of SLOS may require sterol analysis from cultured fibroblasts or confirmatory genetic testing [
Because normal serum concentrations of cholesterol change with age, values must be considered in the context of the individual.
Note: Serum concentration of cholesterol determined by the method employed in most hospital laboratories, which measures total cholesterol (cholesterol plus the precursors), does not identify all individuals with SLOS because total cholesterol levels can be in the normal range.
The diagnosis of Smith-Lemli-Opitz syndrome
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 Smith-Lemli-Opitz syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Smith-Lemli-Opitz syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Smith-Lemli-Opitz syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Smith-Lemli-Opitz 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
Most of the affected individuals studied have two detectable pathogenic variants; rare individuals had only one detectable pathogenic variant [
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.
• Characteristic facial features (narrow forehead, epicanthal folds, ptosis, short mandible with preservation of jaw width, short nose, anteverted nares, and low-set ears)
• 2-3 syndactyly of the toes (minimal to Y-shaped)
• Microcephaly
• Growth restriction / short stature
• Intellectual disability
• Hypospadias in males
• Cleft palate
• Postaxial polydactyly
• Elevated serum concentration of 7-dehydrocholesterol (7-DHC) as defined by the laboratory
• Note: (1) 7-DHC concentration is usually measured in blood samples, but can be measured in other tissues. In rare instances, serum concentrations of 7-DHC and cholesterol can be in the normal ranges and a strong clinical suspicion of SLOS may require sterol analysis from cultured fibroblasts or confirmatory genetic testing [
• Because normal serum concentrations of cholesterol change with age, values must be considered in the context of the individual.
• Note: Serum concentration of cholesterol determined by the method employed in most hospital laboratories, which measures total cholesterol (cholesterol plus the precursors), does not identify all individuals with SLOS because total cholesterol levels can be in the normal range.
• For an introduction to multigene panels click
## Suggestive Findings
Smith-Lemli-Opitz syndrome
Characteristic facial features (narrow forehead, epicanthal folds, ptosis, short mandible with preservation of jaw width, short nose, anteverted nares, and low-set ears)
2-3 syndactyly of the toes (minimal to Y-shaped)
Microcephaly
Growth restriction / short stature
Intellectual disability
Hypospadias in males
Cleft palate
Postaxial polydactyly
Elevated serum concentration of 7-dehydrocholesterol (7-DHC) as defined by the laboratory
Note: (1) 7-DHC concentration is usually measured in blood samples, but can be measured in other tissues. In rare instances, serum concentrations of 7-DHC and cholesterol can be in the normal ranges and a strong clinical suspicion of SLOS may require sterol analysis from cultured fibroblasts or confirmatory genetic testing [
Because normal serum concentrations of cholesterol change with age, values must be considered in the context of the individual.
Note: Serum concentration of cholesterol determined by the method employed in most hospital laboratories, which measures total cholesterol (cholesterol plus the precursors), does not identify all individuals with SLOS because total cholesterol levels can be in the normal range.
• Characteristic facial features (narrow forehead, epicanthal folds, ptosis, short mandible with preservation of jaw width, short nose, anteverted nares, and low-set ears)
• 2-3 syndactyly of the toes (minimal to Y-shaped)
• Microcephaly
• Growth restriction / short stature
• Intellectual disability
• Hypospadias in males
• Cleft palate
• Postaxial polydactyly
• Elevated serum concentration of 7-dehydrocholesterol (7-DHC) as defined by the laboratory
• Note: (1) 7-DHC concentration is usually measured in blood samples, but can be measured in other tissues. In rare instances, serum concentrations of 7-DHC and cholesterol can be in the normal ranges and a strong clinical suspicion of SLOS may require sterol analysis from cultured fibroblasts or confirmatory genetic testing [
• Because normal serum concentrations of cholesterol change with age, values must be considered in the context of the individual.
• Note: Serum concentration of cholesterol determined by the method employed in most hospital laboratories, which measures total cholesterol (cholesterol plus the precursors), does not identify all individuals with SLOS because total cholesterol levels can be in the normal range.
## Establishing the Diagnosis
The diagnosis of Smith-Lemli-Opitz syndrome
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 Smith-Lemli-Opitz syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Smith-Lemli-Opitz syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of Smith-Lemli-Opitz syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Smith-Lemli-Opitz 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
Most of the affected individuals studied have two detectable pathogenic variants; rare individuals had only one detectable pathogenic variant [
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
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Smith-Lemli-Opitz 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 diagnosis of Smith-Lemli-Opitz syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Smith-Lemli-Opitz 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
Most of the affected individuals studied have two detectable pathogenic variants; rare individuals had only one detectable pathogenic variant [
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
Severe Smith-Lemli-Opitz syndrome (SLOS) is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations including characteristic facial features, cleft palate, abnormal gingivae, cardiac defects, hypospadias, ambiguous genitalia (failure of masculinization of male genitalia), postaxial polydactyly, and 2-3 toe syndactyly [
Features of Smith-Lemli-Opitz Syndrome
Exact frequency unknown
Prematurity and breech presentation are common. Neonates frequently have poor suck, irritability, and failure to thrive.
Children and adults with SLOS are generally smaller than average with severe failure to thrive.
Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
Congenital, static microcephaly is also common.
In general, infants with more severe congenital anomalies have more feeding problems.
Constipation is a common problem and may be related to hypotonia, dysmotility, and/or hypomotility.
Gastroesophageal reflux is also common in infancy and improves with age in some individuals.
Liver disease is variable and can range from severe cholestasis (generally in those who are more severely affected) to mild/moderate stable elevation of serum amino transferases [
Pyloric stenosis and Hirschsprung disease are rare findings.
Cognitive function ranges from borderline intellectual capability to severe intellectual disability. Low normal intellectual function can be seen in individuals with mild forms of SLOS [
Behavior signs/symptoms include the following:
Sensory hyperreactivity
Irritability
Sleep cycle disturbance
Many individuals require very little sleep, often only a few hours per night [
Self-injurious behavior (hand biting and/or head banging)
Autism spectrum behaviors (46%-53%)
Temperament dysregulation
Social and communication deficits [
Depression and other psychiatric problems have been reported in older individuals.
Older children often exhibit hypertonia.
Seizures can occur, but are not more common than in the general population.
Abnormalities of myelination
Ventricular dilatation
Malformations of the corpus callosum and/or cerebellum
Dandy-Walker malformation and its variants
Holoprosencephaly (5%) [
Photosensitivity can be severe and can result from even brief exposure to sunlight.
Many individuals cannot tolerate any exposure to sunlight; others can tolerate varying periods of exposure if properly clothed and protected with a UVA- and UVB-protection sunscreen.
Because genital abnormalities are easier to recognize in males than females, males are more likely than females to be evaluated for a diagnosis of SLOS.
Hypospadias and/or bilateral cryptorchidism occurs in 50% of reported males with SLOS [
Bicornuate uterus and septate vagina have been noted in 46,XX females [
Other findings include:
Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
Precocious puberty in affected girls [Irons, unpublished].
Cleft palate is present in 40%-50% of affected individuals and may contribute to feeding and growth problems.
Dental anomalies include oligo- and polydontia, enamel hypoplasia, tooth crowding, agenesis of teeth, marked curve of Spee (occlusal curvature), and widely spaced incisors [
The ears are low set and posteriorly rotated, but can be otherwise normal [
The neck is often short with redundant skin at the nape.
The characteristic facial appearance may be subtle in some individuals, but when assessed objectively, is present even in the least severely affected individuals; the severity of the dysmorphic features correlates with the severity of both the biochemical and physical abnormalities [
Ptosis
Strabismus
Optic atrophy
Optic nerve hypoplasia
Abnormal pulmonary lobation and pulmonary hypoplasia are common in more severely affected individuals [
An increased frequency of upper- and/or lower-respiratory infections is seen, particularly in infancy and early childhood.
Postaxial, bilateral foot polydactyly is present in one quarter to one half of all affected individuals [
Less common findings include hypoplastic or short thumbs and thenar hypoplasia.
The index finger often has a subtle "zig-zag" appearance secondary to misalignment of the phalanges [
Less common are clinodactyly, hammer toes, and dorsiflexed halluces.
Adrenal insufficiency can result in severe electrolyte abnormalities [
Low serum concentrations of testosterone have been seen in severely affected males [
A strict genotype-phenotype correlation is difficult because most affected individuals are compound heterozygotes.
In general, individuals who are homozygous for two null alleles, such as the common
A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null variants or with two variants in loop 8-9 (amino acids 352-411), while those with one or two pathogenic variants in loop 1-2 (amino acids 59-94 and amino acids 119-151 respectively) or one pathogenic variant in the N-terminus (amino acids 1-37) have milder phenotypes [
However, the significant variation seen in severity, even among individuals with similar pathogenic variants, suggests influences on phenotype other than the
SLOS may also be referred to as RSH syndrome or SLO syndrome.
In North America, the birth prevalence of SLOS is estimated at 1:40,000 live births [
• Prematurity and breech presentation are common. Neonates frequently have poor suck, irritability, and failure to thrive.
• Children and adults with SLOS are generally smaller than average with severe failure to thrive.
• Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
• Congenital, static microcephaly is also common.
• Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
• Congenital, static microcephaly is also common.
• Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
• Congenital, static microcephaly is also common.
• In general, infants with more severe congenital anomalies have more feeding problems.
• Constipation is a common problem and may be related to hypotonia, dysmotility, and/or hypomotility.
• Gastroesophageal reflux is also common in infancy and improves with age in some individuals.
• Liver disease is variable and can range from severe cholestasis (generally in those who are more severely affected) to mild/moderate stable elevation of serum amino transferases [
• Pyloric stenosis and Hirschsprung disease are rare findings.
• Cognitive function ranges from borderline intellectual capability to severe intellectual disability. Low normal intellectual function can be seen in individuals with mild forms of SLOS [
• Behavior signs/symptoms include the following:
• Sensory hyperreactivity
• Irritability
• Sleep cycle disturbance
• Many individuals require very little sleep, often only a few hours per night [
• Self-injurious behavior (hand biting and/or head banging)
• Autism spectrum behaviors (46%-53%)
• Temperament dysregulation
• Social and communication deficits [
• Sensory hyperreactivity
• Irritability
• Sleep cycle disturbance
• Many individuals require very little sleep, often only a few hours per night [
• Self-injurious behavior (hand biting and/or head banging)
• Autism spectrum behaviors (46%-53%)
• Temperament dysregulation
• Social and communication deficits [
• Depression and other psychiatric problems have been reported in older individuals.
• Sensory hyperreactivity
• Irritability
• Sleep cycle disturbance
• Many individuals require very little sleep, often only a few hours per night [
• Self-injurious behavior (hand biting and/or head banging)
• Autism spectrum behaviors (46%-53%)
• Temperament dysregulation
• Social and communication deficits [
• Older children often exhibit hypertonia.
• Seizures can occur, but are not more common than in the general population.
• Abnormalities of myelination
• Ventricular dilatation
• Malformations of the corpus callosum and/or cerebellum
• Dandy-Walker malformation and its variants
• Holoprosencephaly (5%) [
• Photosensitivity can be severe and can result from even brief exposure to sunlight.
• Many individuals cannot tolerate any exposure to sunlight; others can tolerate varying periods of exposure if properly clothed and protected with a UVA- and UVB-protection sunscreen.
• Hypospadias and/or bilateral cryptorchidism occurs in 50% of reported males with SLOS [
• Bicornuate uterus and septate vagina have been noted in 46,XX females [
• Other findings include:
• Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
• Precocious puberty in affected girls [Irons, unpublished].
• Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
• Precocious puberty in affected girls [Irons, unpublished].
• Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
• Precocious puberty in affected girls [Irons, unpublished].
• Cleft palate is present in 40%-50% of affected individuals and may contribute to feeding and growth problems.
• Dental anomalies include oligo- and polydontia, enamel hypoplasia, tooth crowding, agenesis of teeth, marked curve of Spee (occlusal curvature), and widely spaced incisors [
• The ears are low set and posteriorly rotated, but can be otherwise normal [
• The neck is often short with redundant skin at the nape.
• Ptosis
• Strabismus
• Optic atrophy
• Optic nerve hypoplasia
• Abnormal pulmonary lobation and pulmonary hypoplasia are common in more severely affected individuals [
• An increased frequency of upper- and/or lower-respiratory infections is seen, particularly in infancy and early childhood.
• Postaxial, bilateral foot polydactyly is present in one quarter to one half of all affected individuals [
• Less common findings include hypoplastic or short thumbs and thenar hypoplasia.
• The index finger often has a subtle "zig-zag" appearance secondary to misalignment of the phalanges [
• Less common are clinodactyly, hammer toes, and dorsiflexed halluces.
• Adrenal insufficiency can result in severe electrolyte abnormalities [
• Low serum concentrations of testosterone have been seen in severely affected males [
• In general, individuals who are homozygous for two null alleles, such as the common
• A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null variants or with two variants in loop 8-9 (amino acids 352-411), while those with one or two pathogenic variants in loop 1-2 (amino acids 59-94 and amino acids 119-151 respectively) or one pathogenic variant in the N-terminus (amino acids 1-37) have milder phenotypes [
## Clinical Description
Severe Smith-Lemli-Opitz syndrome (SLOS) is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations including characteristic facial features, cleft palate, abnormal gingivae, cardiac defects, hypospadias, ambiguous genitalia (failure of masculinization of male genitalia), postaxial polydactyly, and 2-3 toe syndactyly [
Features of Smith-Lemli-Opitz Syndrome
Exact frequency unknown
Prematurity and breech presentation are common. Neonates frequently have poor suck, irritability, and failure to thrive.
Children and adults with SLOS are generally smaller than average with severe failure to thrive.
Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
Congenital, static microcephaly is also common.
In general, infants with more severe congenital anomalies have more feeding problems.
Constipation is a common problem and may be related to hypotonia, dysmotility, and/or hypomotility.
Gastroesophageal reflux is also common in infancy and improves with age in some individuals.
Liver disease is variable and can range from severe cholestasis (generally in those who are more severely affected) to mild/moderate stable elevation of serum amino transferases [
Pyloric stenosis and Hirschsprung disease are rare findings.
Cognitive function ranges from borderline intellectual capability to severe intellectual disability. Low normal intellectual function can be seen in individuals with mild forms of SLOS [
Behavior signs/symptoms include the following:
Sensory hyperreactivity
Irritability
Sleep cycle disturbance
Many individuals require very little sleep, often only a few hours per night [
Self-injurious behavior (hand biting and/or head banging)
Autism spectrum behaviors (46%-53%)
Temperament dysregulation
Social and communication deficits [
Depression and other psychiatric problems have been reported in older individuals.
Older children often exhibit hypertonia.
Seizures can occur, but are not more common than in the general population.
Abnormalities of myelination
Ventricular dilatation
Malformations of the corpus callosum and/or cerebellum
Dandy-Walker malformation and its variants
Holoprosencephaly (5%) [
Photosensitivity can be severe and can result from even brief exposure to sunlight.
Many individuals cannot tolerate any exposure to sunlight; others can tolerate varying periods of exposure if properly clothed and protected with a UVA- and UVB-protection sunscreen.
Because genital abnormalities are easier to recognize in males than females, males are more likely than females to be evaluated for a diagnosis of SLOS.
Hypospadias and/or bilateral cryptorchidism occurs in 50% of reported males with SLOS [
Bicornuate uterus and septate vagina have been noted in 46,XX females [
Other findings include:
Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
Precocious puberty in affected girls [Irons, unpublished].
Cleft palate is present in 40%-50% of affected individuals and may contribute to feeding and growth problems.
Dental anomalies include oligo- and polydontia, enamel hypoplasia, tooth crowding, agenesis of teeth, marked curve of Spee (occlusal curvature), and widely spaced incisors [
The ears are low set and posteriorly rotated, but can be otherwise normal [
The neck is often short with redundant skin at the nape.
The characteristic facial appearance may be subtle in some individuals, but when assessed objectively, is present even in the least severely affected individuals; the severity of the dysmorphic features correlates with the severity of both the biochemical and physical abnormalities [
Ptosis
Strabismus
Optic atrophy
Optic nerve hypoplasia
Abnormal pulmonary lobation and pulmonary hypoplasia are common in more severely affected individuals [
An increased frequency of upper- and/or lower-respiratory infections is seen, particularly in infancy and early childhood.
Postaxial, bilateral foot polydactyly is present in one quarter to one half of all affected individuals [
Less common findings include hypoplastic or short thumbs and thenar hypoplasia.
The index finger often has a subtle "zig-zag" appearance secondary to misalignment of the phalanges [
Less common are clinodactyly, hammer toes, and dorsiflexed halluces.
Adrenal insufficiency can result in severe electrolyte abnormalities [
Low serum concentrations of testosterone have been seen in severely affected males [
• Prematurity and breech presentation are common. Neonates frequently have poor suck, irritability, and failure to thrive.
• Children and adults with SLOS are generally smaller than average with severe failure to thrive.
• Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
• Congenital, static microcephaly is also common.
• Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
• Congenital, static microcephaly is also common.
• Growth parameters are typically 2 SD or more below the mean for age or, in less affected children, for family background.
• Congenital, static microcephaly is also common.
• In general, infants with more severe congenital anomalies have more feeding problems.
• Constipation is a common problem and may be related to hypotonia, dysmotility, and/or hypomotility.
• Gastroesophageal reflux is also common in infancy and improves with age in some individuals.
• Liver disease is variable and can range from severe cholestasis (generally in those who are more severely affected) to mild/moderate stable elevation of serum amino transferases [
• Pyloric stenosis and Hirschsprung disease are rare findings.
• Cognitive function ranges from borderline intellectual capability to severe intellectual disability. Low normal intellectual function can be seen in individuals with mild forms of SLOS [
• Behavior signs/symptoms include the following:
• Sensory hyperreactivity
• Irritability
• Sleep cycle disturbance
• Many individuals require very little sleep, often only a few hours per night [
• Self-injurious behavior (hand biting and/or head banging)
• Autism spectrum behaviors (46%-53%)
• Temperament dysregulation
• Social and communication deficits [
• Sensory hyperreactivity
• Irritability
• Sleep cycle disturbance
• Many individuals require very little sleep, often only a few hours per night [
• Self-injurious behavior (hand biting and/or head banging)
• Autism spectrum behaviors (46%-53%)
• Temperament dysregulation
• Social and communication deficits [
• Depression and other psychiatric problems have been reported in older individuals.
• Sensory hyperreactivity
• Irritability
• Sleep cycle disturbance
• Many individuals require very little sleep, often only a few hours per night [
• Self-injurious behavior (hand biting and/or head banging)
• Autism spectrum behaviors (46%-53%)
• Temperament dysregulation
• Social and communication deficits [
• Older children often exhibit hypertonia.
• Seizures can occur, but are not more common than in the general population.
• Abnormalities of myelination
• Ventricular dilatation
• Malformations of the corpus callosum and/or cerebellum
• Dandy-Walker malformation and its variants
• Holoprosencephaly (5%) [
• Photosensitivity can be severe and can result from even brief exposure to sunlight.
• Many individuals cannot tolerate any exposure to sunlight; others can tolerate varying periods of exposure if properly clothed and protected with a UVA- and UVB-protection sunscreen.
• Hypospadias and/or bilateral cryptorchidism occurs in 50% of reported males with SLOS [
• Bicornuate uterus and septate vagina have been noted in 46,XX females [
• Other findings include:
• Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
• Precocious puberty in affected girls [Irons, unpublished].
• Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
• Precocious puberty in affected girls [Irons, unpublished].
• Persistent urogenital sinus and posterior labial fusion without clitoromegaly in a female with an XX karyotype [
• Precocious puberty in affected girls [Irons, unpublished].
• Cleft palate is present in 40%-50% of affected individuals and may contribute to feeding and growth problems.
• Dental anomalies include oligo- and polydontia, enamel hypoplasia, tooth crowding, agenesis of teeth, marked curve of Spee (occlusal curvature), and widely spaced incisors [
• The ears are low set and posteriorly rotated, but can be otherwise normal [
• The neck is often short with redundant skin at the nape.
• Ptosis
• Strabismus
• Optic atrophy
• Optic nerve hypoplasia
• Abnormal pulmonary lobation and pulmonary hypoplasia are common in more severely affected individuals [
• An increased frequency of upper- and/or lower-respiratory infections is seen, particularly in infancy and early childhood.
• Postaxial, bilateral foot polydactyly is present in one quarter to one half of all affected individuals [
• Less common findings include hypoplastic or short thumbs and thenar hypoplasia.
• The index finger often has a subtle "zig-zag" appearance secondary to misalignment of the phalanges [
• Less common are clinodactyly, hammer toes, and dorsiflexed halluces.
• Adrenal insufficiency can result in severe electrolyte abnormalities [
• Low serum concentrations of testosterone have been seen in severely affected males [
## Genotype-Phenotype Correlations
A strict genotype-phenotype correlation is difficult because most affected individuals are compound heterozygotes.
In general, individuals who are homozygous for two null alleles, such as the common
A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null variants or with two variants in loop 8-9 (amino acids 352-411), while those with one or two pathogenic variants in loop 1-2 (amino acids 59-94 and amino acids 119-151 respectively) or one pathogenic variant in the N-terminus (amino acids 1-37) have milder phenotypes [
However, the significant variation seen in severity, even among individuals with similar pathogenic variants, suggests influences on phenotype other than the
• In general, individuals who are homozygous for two null alleles, such as the common
• A detailed evaluation of 207 individuals with SLOS showed that the most severe phenotypes were observed in individuals with two null variants or with two variants in loop 8-9 (amino acids 352-411), while those with one or two pathogenic variants in loop 1-2 (amino acids 59-94 and amino acids 119-151 respectively) or one pathogenic variant in the N-terminus (amino acids 1-37) have milder phenotypes [
## Nomenclature
SLOS may also be referred to as RSH syndrome or SLO syndrome.
## Prevalence
In North America, the birth prevalence of SLOS is estimated at 1:40,000 live births [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
Genes and Disorders of Interest in the Differential Diagnosis of Smith-Lemli-Opitz Syndrome
Cystic renal disease
Encephalocele
Broad posterior neck
Growth restriction
Hypospadias
Downslanting palpebral fissures
Pulmonic stenosis
Sterol metabolic disorder
Ambiguous genitalia
Cleft palate
Microcephaly
Total anomalous pulmonary venous drainage
Generalized osteosclerosis
Gingival nodules
Hypoplastic nasal bridge
Macrocephaly
Short limbs
Thick alveolar ridges
Sterol metabolic disorder
Midface hypoplasia
Narrow forehead
Ptosis
2-3 toe syndactyly
Postaxial polydactyly
4-5 finger syndactyly
Camptodactyly
Scoliosis
Hypopigmentation of the skin
2-3 toe syndactyly
DD & ID
Facial dysmorphism
Genital abnormalities
Structural brain malformations
Congenital heart defects
Autism
Normal 7-DHC
↑ plasma farnesol
Urine organic acids profile w/↑s in: methylsuccinate; mevalonate lactone; saturated & unsaturated branched-chain dicarboxylic acids
Sterol metabolic disorder
Cleft palate
2-3 toe syndactyly
Hepatic steatosis
Microcephaly
Narrow forehead
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GC-MS = gas chromatograph-mass spectroscopy; ID = intellectual disability; MOI = mode of inheritance; SLOS = Smith-Lemli-Opitz syndrome; XL = X-linked
Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in
Desmosterolosis may be associated with macrocephaly or microcephaly.
Squalene synthase deficiency is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to Smith-Lemli-Optiz syndrome.
Other disorders to consider in the differential diagnosis of SLOS include the following (shared clinical findings are indicated in parentheses):
Trisomy 13 syndrome (holoprosencephaly, cleft lip and cleft palate, cardiac defects, polydactyly)
Pseudotrisomy 13 syndrome (OMIM
Dubowitz syndrome (OMIM
Nguyen syndrome (OMIM
• Cystic renal disease
• Encephalocele
• Broad posterior neck
• Growth restriction
• Hypospadias
• Downslanting palpebral fissures
• Pulmonic stenosis
• Sterol metabolic disorder
• Ambiguous genitalia
• Cleft palate
• Microcephaly
• Total anomalous pulmonary venous drainage
• Generalized osteosclerosis
• Gingival nodules
• Hypoplastic nasal bridge
• Macrocephaly
• Short limbs
• Thick alveolar ridges
• Sterol metabolic disorder
• Midface hypoplasia
• Narrow forehead
• Ptosis
• 2-3 toe syndactyly
• Postaxial polydactyly
• 4-5 finger syndactyly
• Camptodactyly
• Scoliosis
• Hypopigmentation of the skin
• 2-3 toe syndactyly
• DD & ID
• Facial dysmorphism
• Genital abnormalities
• Structural brain malformations
• Congenital heart defects
• Autism
• Normal 7-DHC
• ↑ plasma farnesol
• Urine organic acids profile w/↑s in: methylsuccinate; mevalonate lactone; saturated & unsaturated branched-chain dicarboxylic acids
• Sterol metabolic disorder
• Cleft palate
• 2-3 toe syndactyly
• Hepatic steatosis
• Microcephaly
• Narrow forehead
• Trisomy 13 syndrome (holoprosencephaly, cleft lip and cleft palate, cardiac defects, polydactyly)
• Pseudotrisomy 13 syndrome (OMIM
• Dubowitz syndrome (OMIM
• Nguyen syndrome (OMIM
## Management
No consensus clinical management guidelines have been published.
To establish the extent of disease and needs in an individual diagnosed with Smith-Lemli-Opitz syndrome (SLOS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Smith-Lemli-Opitz Syndrome
Consider assessment for pyloric stenosis or gastroesophageal reflux in those w/suggestive symptoms.
Particular attention should be given to stooling pattern, abdominal distention, or other signs of possible bowel obstruction because of risk for Hirschsprung disease.
To incl motor, adaptive, cognitive, & speech-language evaluation
Evaluation for early intervention / special education
To assess for genital anomalies
If external genital anomalies are present, consider pelvic imaging to evaluate for internal structures (e.g., undescended gonads, müllerian structure).
To assess for congenital heart defect
Consider referral to cardiologist.
Syndactyly, polydactyly, & abnormalities of the toes
Gross motor & fine motor skills
Need for ankle-foot orthoses or other orthotics
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Use of community or online resources such as Parent to Parent;
Need for social work involvement for parental support;
Need for home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
In severely affected individuals, treatment with stress steroids in doses customarily used for children with congenital adrenal hyperplasia (see
Targeted Treatment of Manifestations in Individuals with Smith-Lemli-Opitz Syndrome
Including 7-dehydrocholesterol (7-DHC) and 8-DHC
Egg yolk or crystalline cholesterol in an oil-based or aqueous suspension
Dietary studies on cholesterol supplementation have not been conducted in a randomized fashion.
Dietary therapy does not appear to increase the levels of cholesterol in CSF [
Cholesterol supplementation should be considered in all individuals with SLOS because it may result in clinical improvement and has minimal side effects [
Documented improvements after institution of cholesterol supplementation include the following:
Improved growth
Reduced photosensitivity
Increased nerve conduction velocity
Improved tone
Achievement of ambulation
Developmental cognitive and behavioral changes
Note: A placebo-controlled trial of simvastatin [
Supportive Treatment of Manifestations in Individuals with Smith-Lemli-Opitz Syndrome
Haloperidol
Trazodone & apripiprazole (Abilify
Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; AFO = ankle-foot orthosis
Anesthetic problems including muscular rigidity and malignant hyperthermia have been reported [
Treatment with haloperidol may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms; see
One must weigh the benefit of such medications against the potential negative side effects; see
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
In severely affected individuals, treatment with stress steroids in doses customarily used for children with congenital adrenal hyperplasia (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.
Routine health supervision by a physician familiar with SLOS, its complications, and its treatment includes the following.
Recommended Surveillance for Individuals with Smith-Lemli-Opitz Syndrome
Measurement of growth parameters
Evaluation of nutritional status & safety of oral intake
At each visit
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, movement disorders.
Because children with SLOS have low muscle mass, careful monitoring of weight gain and growth is necessary so that overconsumption of calories does not lead to obesity.
In individuals who are on psychotropic drugs, close monitoring of clinical signs/symptoms and consideration of monitoring serum concentration of 7-DHC (depending on the drug that is prescribed) is recommended; see
Treatment with haloperidol, which has a high affinity for the DHCR7 substrate binding site, may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms. It is likely that other drugs in this class will cause the same change in sterol levels [
Other psychotropic drugs shown to elevate 7-DHC are trazodone and aripiprazole (Abilify
Photosensitivity can be severe and extended periods of sun exposure should be avoided, as severe sunburn can occur with only limited exposure; however, limited sun exposure is possible for some affected individuals as long as protective clothing is worn and a sunscreen with UVA and UVB properties is used.
It is appropriate to clarify the status of all sibs in order to identify as early as possible those who would benefit from prompt initiation of cholesterol supplementation. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Measurement of 7-DHC concentration in plasma or amniotic fluid (prenatally) if the pathogenic variants in the family are not known. In cases of borderline 7-DHC concentration, molecular genetic testing is indicated. Caution must be exercised in interpreting elevated 7-DHC concentration in individuals treated with haloperidol, aripiprazole, and trazodone [
See
No current guidelines exist for the management of pregnant women with SLOS, as to date only one affected woman with a successful pregnancy has been identified [
A study assessing the safety and therapeutic benefits of cholesterol supplementation and antioxidant medications is underway in Colorado (see
Search
For more severely affected infants with SLOS, the issues of surgical management of congenital anomalies such as cleft palate, congenital heart disease, and genital anomalies need to be considered as they would be in any other infant with a severe, usually lethal disorder.
Reassignment of sex of rearing for infants with a 46,XY karyotype and female genitalia may not always be appropriate because most will have early death, and the process of sex reassignment can be highly disruptive to a family already coping with the difficult issues of having a child with a genetic disorder characterized by life-threatening medical complications.
• Consider assessment for pyloric stenosis or gastroesophageal reflux in those w/suggestive symptoms.
• Particular attention should be given to stooling pattern, abdominal distention, or other signs of possible bowel obstruction because of risk for Hirschsprung disease.
• To incl motor, adaptive, cognitive, & speech-language evaluation
• Evaluation for early intervention / special education
• To assess for genital anomalies
• If external genital anomalies are present, consider pelvic imaging to evaluate for internal structures (e.g., undescended gonads, müllerian structure).
• To assess for congenital heart defect
• Consider referral to cardiologist.
• Syndactyly, polydactyly, & abnormalities of the toes
• Gross motor & fine motor skills
• Need for ankle-foot orthoses or other orthotics
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Use of community or online resources such as Parent to Parent;
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Improved growth
• Reduced photosensitivity
• Increased nerve conduction velocity
• Improved tone
• Achievement of ambulation
• Developmental cognitive and behavioral changes
• Haloperidol
• Trazodone & apripiprazole (Abilify
• Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• 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
• Evaluation of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, movement disorders.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Measurement of 7-DHC concentration in plasma or amniotic fluid (prenatally) if the pathogenic variants in the family are not known. In cases of borderline 7-DHC concentration, molecular genetic testing is indicated. Caution must be exercised in interpreting elevated 7-DHC concentration in individuals treated with haloperidol, aripiprazole, and trazodone [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Smith-Lemli-Opitz syndrome (SLOS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Smith-Lemli-Opitz Syndrome
Consider assessment for pyloric stenosis or gastroesophageal reflux in those w/suggestive symptoms.
Particular attention should be given to stooling pattern, abdominal distention, or other signs of possible bowel obstruction because of risk for Hirschsprung disease.
To incl motor, adaptive, cognitive, & speech-language evaluation
Evaluation for early intervention / special education
To assess for genital anomalies
If external genital anomalies are present, consider pelvic imaging to evaluate for internal structures (e.g., undescended gonads, müllerian structure).
To assess for congenital heart defect
Consider referral to cardiologist.
Syndactyly, polydactyly, & abnormalities of the toes
Gross motor & fine motor skills
Need for ankle-foot orthoses or other orthotics
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Use of community or online resources such as Parent to Parent;
Need for social work involvement for parental support;
Need for home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
In severely affected individuals, treatment with stress steroids in doses customarily used for children with congenital adrenal hyperplasia (see
• Consider assessment for pyloric stenosis or gastroesophageal reflux in those w/suggestive symptoms.
• Particular attention should be given to stooling pattern, abdominal distention, or other signs of possible bowel obstruction because of risk for Hirschsprung disease.
• To incl motor, adaptive, cognitive, & speech-language evaluation
• Evaluation for early intervention / special education
• To assess for genital anomalies
• If external genital anomalies are present, consider pelvic imaging to evaluate for internal structures (e.g., undescended gonads, müllerian structure).
• To assess for congenital heart defect
• Consider referral to cardiologist.
• Syndactyly, polydactyly, & abnormalities of the toes
• Gross motor & fine motor skills
• Need for ankle-foot orthoses or other orthotics
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Use of community or online resources such as Parent to Parent;
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Targeted Treatment of Manifestations in Individuals with Smith-Lemli-Opitz Syndrome
Including 7-dehydrocholesterol (7-DHC) and 8-DHC
Egg yolk or crystalline cholesterol in an oil-based or aqueous suspension
Dietary studies on cholesterol supplementation have not been conducted in a randomized fashion.
Dietary therapy does not appear to increase the levels of cholesterol in CSF [
Cholesterol supplementation should be considered in all individuals with SLOS because it may result in clinical improvement and has minimal side effects [
Documented improvements after institution of cholesterol supplementation include the following:
Improved growth
Reduced photosensitivity
Increased nerve conduction velocity
Improved tone
Achievement of ambulation
Developmental cognitive and behavioral changes
Note: A placebo-controlled trial of simvastatin [
Supportive Treatment of Manifestations in Individuals with Smith-Lemli-Opitz Syndrome
Haloperidol
Trazodone & apripiprazole (Abilify
Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; AFO = ankle-foot orthosis
Anesthetic problems including muscular rigidity and malignant hyperthermia have been reported [
Treatment with haloperidol may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms; see
One must weigh the benefit of such medications against the potential negative side effects; see
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
In severely affected individuals, treatment with stress steroids in doses customarily used for children with congenital adrenal hyperplasia (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.
• Improved growth
• Reduced photosensitivity
• Increased nerve conduction velocity
• Improved tone
• Achievement of ambulation
• Developmental cognitive and behavioral changes
• Haloperidol
• Trazodone & apripiprazole (Abilify
• Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• 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 attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Routine health supervision by a physician familiar with SLOS, its complications, and its treatment includes the following.
Recommended Surveillance for Individuals with Smith-Lemli-Opitz Syndrome
Measurement of growth parameters
Evaluation of nutritional status & safety of oral intake
At each visit
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, movement disorders.
Because children with SLOS have low muscle mass, careful monitoring of weight gain and growth is necessary so that overconsumption of calories does not lead to obesity.
In individuals who are on psychotropic drugs, close monitoring of clinical signs/symptoms and consideration of monitoring serum concentration of 7-DHC (depending on the drug that is prescribed) is recommended; see
• Measurement of growth parameters
• Evaluation of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, movement disorders.
## Agents/Circumstances to Avoid
Treatment with haloperidol, which has a high affinity for the DHCR7 substrate binding site, may exacerbate the biochemical sterol abnormalities in individuals with SLOS and cause an increase in symptoms. It is likely that other drugs in this class will cause the same change in sterol levels [
Other psychotropic drugs shown to elevate 7-DHC are trazodone and aripiprazole (Abilify
Photosensitivity can be severe and extended periods of sun exposure should be avoided, as severe sunburn can occur with only limited exposure; however, limited sun exposure is possible for some affected individuals as long as protective clothing is worn and a sunscreen with UVA and UVB properties is used.
## Evaluation of Relatives at Risk
It is appropriate to clarify the status of all sibs in order to identify as early as possible those who would benefit from prompt initiation of cholesterol supplementation. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Measurement of 7-DHC concentration in plasma or amniotic fluid (prenatally) if the pathogenic variants in the family are not known. In cases of borderline 7-DHC concentration, molecular genetic testing is indicated. Caution must be exercised in interpreting elevated 7-DHC concentration in individuals treated with haloperidol, aripiprazole, and trazodone [
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Measurement of 7-DHC concentration in plasma or amniotic fluid (prenatally) if the pathogenic variants in the family are not known. In cases of borderline 7-DHC concentration, molecular genetic testing is indicated. Caution must be exercised in interpreting elevated 7-DHC concentration in individuals treated with haloperidol, aripiprazole, and trazodone [
## Pregnancy Management
No current guidelines exist for the management of pregnant women with SLOS, as to date only one affected woman with a successful pregnancy has been identified [
## Therapies Under Investigation
A study assessing the safety and therapeutic benefits of cholesterol supplementation and antioxidant medications is underway in Colorado (see
Search
## Other
For more severely affected infants with SLOS, the issues of surgical management of congenital anomalies such as cleft palate, congenital heart disease, and genital anomalies need to be considered as they would be in any other infant with a severe, usually lethal disorder.
Reassignment of sex of rearing for infants with a 46,XY karyotype and female genitalia may not always be appropriate because most will have early death, and the process of sex reassignment can be highly disruptive to a family already coping with the difficult issues of having a child with a genetic disorder characterized by life-threatening medical complications.
## Genetic Counseling
Smith-Lemli-Opitz syndrome (SLOS) 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 SLOS.
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.
Intrafamilial variability has been observed in SLOS but, in general, the severity of manifestations in the proband can be used to predict the clinical outcome in a sib with the same pathogenic variants.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing SLOS.
Individuals with severe SLOS have not been reported to reproduce.
Fertility does not appear to be reduced in mildly affected individuals with SLOS. A woman with SLOS who was not diagnosed until her pregnancy as having SLOS gave birth to a normal child [
Note: Because of considerable overlap between the ranges of serum concentration of cholesterol and 7-DHC in carriers and non-carriers, carrier status cannot be determined by measuring the serum concentration of either compound.
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 carriers, or are at risk of being carriers.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
In pregnancies in which no family history of SLOS exists, certain fetal ultrasound findings could prompt consideration of SLOS. Prenatal findings of SLOS may include IUGR; major malformations of the brain, heart, kidneys, or limbs; and ambiguous genitalia, especially female-appearing genitalia or severe hypospadias in an XY fetus. Other nonspecific findings may include increased nuchal translucency, cystic hygroma, nonimmune hydrops, and cleft palate. However, although abnormal findings on ultrasound examination can be seen in fetuses with SLOS, no pattern is pathognomonic. Furthermore, ultrasound examination may be normal.
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 SLOS.
• 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.
• Intrafamilial variability has been observed in SLOS but, in general, the severity of manifestations in the proband can be used to predict the clinical outcome in a sib with the same pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing SLOS.
• Individuals with severe SLOS have not been reported to reproduce.
• Fertility does not appear to be reduced in mildly affected individuals with SLOS. A woman with SLOS who was not diagnosed until her pregnancy as having SLOS gave birth to a normal child [
• 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 carriers, or are at risk of being carriers.
## Mode of Inheritance
Smith-Lemli-Opitz syndrome (SLOS) 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 SLOS.
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.
Intrafamilial variability has been observed in SLOS but, in general, the severity of manifestations in the proband can be used to predict the clinical outcome in a sib with the same pathogenic variants.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing SLOS.
Individuals with severe SLOS have not been reported to reproduce.
Fertility does not appear to be reduced in mildly affected individuals with SLOS. A woman with SLOS who was not diagnosed until her pregnancy as having SLOS gave birth to a normal child [
• 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 SLOS.
• 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.
• Intrafamilial variability has been observed in SLOS but, in general, the severity of manifestations in the proband can be used to predict the clinical outcome in a sib with the same pathogenic variants.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing SLOS.
• Individuals with severe SLOS have not been reported to reproduce.
• Fertility does not appear to be reduced in mildly affected individuals with SLOS. A woman with SLOS who was not diagnosed until her pregnancy as having SLOS gave birth to a normal child [
## Carrier Detection
Note: Because of considerable overlap between the ranges of serum concentration of cholesterol and 7-DHC in carriers and non-carriers, carrier status cannot be determined by measuring the serum concentration of either compound.
## 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 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 carriers, or are at risk of being carriers.
## 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.
In pregnancies in which no family history of SLOS exists, certain fetal ultrasound findings could prompt consideration of SLOS. Prenatal findings of SLOS may include IUGR; major malformations of the brain, heart, kidneys, or limbs; and ambiguous genitalia, especially female-appearing genitalia or severe hypospadias in an XY fetus. Other nonspecific findings may include increased nuchal translucency, cystic hygroma, nonimmune hydrops, and cleft palate. However, although abnormal findings on ultrasound examination can be seen in fetuses with SLOS, no pattern is pathognomonic. Furthermore, ultrasound examination may be normal.
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.
## High-Risk Pregnancies
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
## Low-Risk Pregnancies
In pregnancies in which no family history of SLOS exists, certain fetal ultrasound findings could prompt consideration of SLOS. Prenatal findings of SLOS may include IUGR; major malformations of the brain, heart, kidneys, or limbs; and ambiguous genitalia, especially female-appearing genitalia or severe hypospadias in an XY fetus. Other nonspecific findings may include increased nuchal translucency, cystic hygroma, nonimmune hydrops, and cleft palate. However, although abnormal findings on ultrasound examination can be seen in fetuses with SLOS, no pattern is pathognomonic. Furthermore, ultrasound examination may be normal.
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 212
Georgetown MA 01833
•
•
•
• PO Box 212
• Georgetown MA 01833
•
•
•
## Molecular Genetics
Smith-Lemli-Opitz Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Smith-Lemli-Opitz Syndrome (
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Christopher M Cunniff, MD, FACMG; University of Arizona Colleges of Medicine and Science (1998-2007)Mira Irons, MD, FACMG, FAAP; Harvard Medical School (2007-2013)Tracey L Kurtzman; University of Arizona College of Medicine (1998-2001)Malgorzata JM Nowaczyk, MD, FRCPC, FCCMG, FACMG (2013-present)Christopher A Wassif, PhD (2020-present)
30 January 2020 (ma) Comprehensive update posted live
20 June 2013 (me) Comprehensive update posted live
24 October 2007 (me) Comprehensive update posted live
11 February 2004 (me) Comprehensive update posted live
6 November 2001 (me) Comprehensive update posted live
13 November 1998 (pb) Review posted live
20 April 1998 (cc) Original submission by TL Kurtzman, BA and C Cunniff, MD
• 30 January 2020 (ma) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 24 October 2007 (me) Comprehensive update posted live
• 11 February 2004 (me) Comprehensive update posted live
• 6 November 2001 (me) Comprehensive update posted live
• 13 November 1998 (pb) Review posted live
• 20 April 1998 (cc) Original submission by TL Kurtzman, BA and C Cunniff, MD
## Author History
Christopher M Cunniff, MD, FACMG; University of Arizona Colleges of Medicine and Science (1998-2007)Mira Irons, MD, FACMG, FAAP; Harvard Medical School (2007-2013)Tracey L Kurtzman; University of Arizona College of Medicine (1998-2001)Malgorzata JM Nowaczyk, MD, FRCPC, FCCMG, FACMG (2013-present)Christopher A Wassif, PhD (2020-present)
## Revision History
30 January 2020 (ma) Comprehensive update posted live
20 June 2013 (me) Comprehensive update posted live
24 October 2007 (me) Comprehensive update posted live
11 February 2004 (me) Comprehensive update posted live
6 November 2001 (me) Comprehensive update posted live
13 November 1998 (pb) Review posted live
20 April 1998 (cc) Original submission by TL Kurtzman, BA and C Cunniff, MD
• 30 January 2020 (ma) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 24 October 2007 (me) Comprehensive update posted live
• 11 February 2004 (me) Comprehensive update posted live
• 6 November 2001 (me) Comprehensive update posted live
• 13 November 1998 (pb) Review posted live
• 20 April 1998 (cc) Original submission by TL Kurtzman, BA and C Cunniff, MD
## References
## Literature Cited
|
[] |
13/11/1998
|
30/1/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sma-xli
|
sma-xli
|
[
"SMAX2",
"XL-SMA",
"XL-SMA",
"Ubiquitin-like modifier-activating enzyme 1",
"UBA1",
"Spinal Muscular Atrophy, X-Linked Infantile"
] |
Spinal Muscular Atrophy, X-Linked Infantile
|
Lisa Baumbach-Reardon, JM Hunter, Mary Ellen Ahearn, Miranda Pfautsch
|
Summary X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem. Often congenital contractures and/or fractures are present. Intellect is normal. Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement. The diagnosis of X-linked infantile spinal muscular atrophy is established in a male proband with suggestive clinical features and a hemizygous pathogenic variant in By definition, XL-SMA is inherited in an X-linked manner. Heterozygous females have a 50% chance of transmitting the pathogenic variant with each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected. Once the
|
## Diagnosis
While suggestive diagnostic criteria were proposed by
X-linked infantile spinal muscular atrophy
Congenital hypotonia and areflexia on physical examination
Congenital contractures and/or fractures
Digital contractures at birth. These usually remain throughout the individual's life.
The diagnosis of X-linked infantile spinal muscular atrophy
Note: (1) Female carriers of XL-SMA are usually unaffected. (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 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 X-linked infantile spinal muscular atrophy is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of X-linked infantile spinal muscular atrophy, molecular genetic testing approaches can include
Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. However, no deletions or duplications involving this gene have been reported as a cause of X-linked infantile SMA and some studies suggest that deletion of this gene in a male may be embryonic lethal.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by hypotonia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Infantile Spinal Muscular Atrophy
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
To date, eight families and one simplex individual have been detected 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available. To date, all pathogenic variants reported have been missense variants [
• Congenital hypotonia and areflexia on physical examination
• Congenital contractures and/or fractures
• Digital contractures at birth. These usually remain throughout the individual's life.
• Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. However, no deletions or duplications involving this gene have been reported as a cause of X-linked infantile SMA and some studies suggest that deletion of this gene in a male may be embryonic lethal.
• For an introduction to multigene panels click
## Suggestive Findings
X-linked infantile spinal muscular atrophy
Congenital hypotonia and areflexia on physical examination
Congenital contractures and/or fractures
Digital contractures at birth. These usually remain throughout the individual's life.
• Congenital hypotonia and areflexia on physical examination
• Congenital contractures and/or fractures
• Digital contractures at birth. These usually remain throughout the individual's life.
## Establishing the Diagnosis
The diagnosis of X-linked infantile spinal muscular atrophy
Note: (1) Female carriers of XL-SMA are usually unaffected. (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 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 X-linked infantile spinal muscular atrophy is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of X-linked infantile spinal muscular atrophy, molecular genetic testing approaches can include
Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. However, no deletions or duplications involving this gene have been reported as a cause of X-linked infantile SMA and some studies suggest that deletion of this gene in a male may be embryonic lethal.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by hypotonia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Infantile Spinal Muscular Atrophy
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
To date, eight families and one simplex individual have been detected 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available. To date, all pathogenic variants reported have been missense variants [
• Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. However, no deletions or duplications involving this gene have been reported as a cause of X-linked infantile SMA and some studies suggest that deletion of this gene in a male may be embryonic lethal.
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of X-linked infantile spinal muscular atrophy, molecular genetic testing approaches can include
Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. However, no deletions or duplications involving this gene have been reported as a cause of X-linked infantile SMA and some studies suggest that deletion of this gene in a male may be embryonic lethal.
For an introduction to multigene panels click
• Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis. However, no deletions or duplications involving this gene have been reported as a cause of X-linked infantile SMA and some studies suggest that deletion of this gene in a male may be embryonic lethal.
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by hypotonia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Infantile Spinal Muscular Atrophy
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
To date, eight families and one simplex individual have been detected 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available. To date, all pathogenic variants reported have been missense variants [
## Clinical Characteristics
X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by severe hypotonia and areflexia with loss of anterior horn cells in the spinal cord (i.e., lower motor neurons). The disease course is similar to that of the most severe forms of classic autosomal recessive SMA (when supportive care only is given) caused by biallelic pathogenic variants in
The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.
The weakness in XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.
Most children affected with XL-SMA have severe respiratory issues, due to weakness of muscles in the respiratory system.
The majority of children have succumbed due to complications of upper respiratory tract infections or pneumonia, and thus it is advisable to consider noninvasive ventilation and/or tracheostomy shortly after birth (see
During the neonatal period, affected individuals typically have poor suck-and-swallow responses.
Placement of a gastrostomy tube to avoid aspiration and to provide proper nutrition is often necessary (see
Mild micrognathia
Kyphosis
Scoliosis
Cryptorchidism
Note: Individuals with a clinical picture consistent with SMA type II or type III have not been tested for pathogenic variants in
Female carriers of XL-SMA are usually unaffected.
No genotype-phenotype correlations have been identified.
XL-SMA has also been called:
X-linked lethal infantile SMA
Infantile X-linked SMA
X-linked arthrogryposis multiplex congenita
Distal X-linked AMC
X-linked arthrogryposis type I, AMCX1
Note: SMAX1 is Kennedy disease (
The prevalence of XL-SMA is unknown. To date, 14 multigenerational families with affected family members have been identified throughout North America, Europe, Mexico, and Thailand [Author, personal observation]. This includes the family described by
• The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.
• The weakness in XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.
• Most children affected with XL-SMA have severe respiratory issues, due to weakness of muscles in the respiratory system.
• The majority of children have succumbed due to complications of upper respiratory tract infections or pneumonia, and thus it is advisable to consider noninvasive ventilation and/or tracheostomy shortly after birth (see
• During the neonatal period, affected individuals typically have poor suck-and-swallow responses.
• Placement of a gastrostomy tube to avoid aspiration and to provide proper nutrition is often necessary (see
• Mild micrognathia
• Kyphosis
• Scoliosis
• Cryptorchidism
• X-linked lethal infantile SMA
• Infantile X-linked SMA
• X-linked arthrogryposis multiplex congenita
• Distal X-linked AMC
• X-linked arthrogryposis type I, AMCX1
## Clinical Description
X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by severe hypotonia and areflexia with loss of anterior horn cells in the spinal cord (i.e., lower motor neurons). The disease course is similar to that of the most severe forms of classic autosomal recessive SMA (when supportive care only is given) caused by biallelic pathogenic variants in
The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.
The weakness in XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.
Most children affected with XL-SMA have severe respiratory issues, due to weakness of muscles in the respiratory system.
The majority of children have succumbed due to complications of upper respiratory tract infections or pneumonia, and thus it is advisable to consider noninvasive ventilation and/or tracheostomy shortly after birth (see
During the neonatal period, affected individuals typically have poor suck-and-swallow responses.
Placement of a gastrostomy tube to avoid aspiration and to provide proper nutrition is often necessary (see
Mild micrognathia
Kyphosis
Scoliosis
Cryptorchidism
Note: Individuals with a clinical picture consistent with SMA type II or type III have not been tested for pathogenic variants in
Female carriers of XL-SMA are usually unaffected.
• The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.
• The weakness in XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.
• Most children affected with XL-SMA have severe respiratory issues, due to weakness of muscles in the respiratory system.
• The majority of children have succumbed due to complications of upper respiratory tract infections or pneumonia, and thus it is advisable to consider noninvasive ventilation and/or tracheostomy shortly after birth (see
• During the neonatal period, affected individuals typically have poor suck-and-swallow responses.
• Placement of a gastrostomy tube to avoid aspiration and to provide proper nutrition is often necessary (see
• Mild micrognathia
• Kyphosis
• Scoliosis
• Cryptorchidism
## Males
X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by severe hypotonia and areflexia with loss of anterior horn cells in the spinal cord (i.e., lower motor neurons). The disease course is similar to that of the most severe forms of classic autosomal recessive SMA (when supportive care only is given) caused by biallelic pathogenic variants in
The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.
The weakness in XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.
Most children affected with XL-SMA have severe respiratory issues, due to weakness of muscles in the respiratory system.
The majority of children have succumbed due to complications of upper respiratory tract infections or pneumonia, and thus it is advisable to consider noninvasive ventilation and/or tracheostomy shortly after birth (see
During the neonatal period, affected individuals typically have poor suck-and-swallow responses.
Placement of a gastrostomy tube to avoid aspiration and to provide proper nutrition is often necessary (see
Mild micrognathia
Kyphosis
Scoliosis
Cryptorchidism
Note: Individuals with a clinical picture consistent with SMA type II or type III have not been tested for pathogenic variants in
• The most consistent features of XL-SMA are anterior horn cell disease and contractures (especially digital contractures) with or without fractures.
• The weakness in XL-SMA is progressive. Affected infants may achieve some early motor milestones, but the extent varies among families.
• Most children affected with XL-SMA have severe respiratory issues, due to weakness of muscles in the respiratory system.
• The majority of children have succumbed due to complications of upper respiratory tract infections or pneumonia, and thus it is advisable to consider noninvasive ventilation and/or tracheostomy shortly after birth (see
• During the neonatal period, affected individuals typically have poor suck-and-swallow responses.
• Placement of a gastrostomy tube to avoid aspiration and to provide proper nutrition is often necessary (see
• Mild micrognathia
• Kyphosis
• Scoliosis
• Cryptorchidism
## Females
Female carriers of XL-SMA are usually unaffected.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
XL-SMA has also been called:
X-linked lethal infantile SMA
Infantile X-linked SMA
X-linked arthrogryposis multiplex congenita
Distal X-linked AMC
X-linked arthrogryposis type I, AMCX1
Note: SMAX1 is Kennedy disease (
• X-linked lethal infantile SMA
• Infantile X-linked SMA
• X-linked arthrogryposis multiplex congenita
• Distal X-linked AMC
• X-linked arthrogryposis type I, AMCX1
## Prevalence
The prevalence of XL-SMA is unknown. To date, 14 multigenerational families with affected family members have been identified throughout North America, Europe, Mexico, and Thailand [Author, personal observation]. This includes the family described by
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Somatic (i.e., mosaic or postzygotic)
## Differential Diagnosis
The differential diagnosis of X-linked infantile spinal muscular atrophy (XL-SMA) caused by mutation of
Disorders with Spinal Muscular Atrophy and/or Contractures in the Differential Diagnosis of X-Linked Infantile Spinal Muscular Atrophy
= feature that is present in persons with this disorder; ± = feature that may or may not be present in persons with this disorder AD = autosomal dominant; AHC= anterior horn cell loss; AR = autosomal recessive; EMG = electromyogram; MOI = mode of inheritance; NA= not applicable or not available; NR = feature not reported in persons with this disorder; SMA = spinal muscular atrophy: XL = X-linked
Following XL-SMA, disorders are ordered alphabetically by gene within inheritance groups.
See following Note on arthrogryposis.
Hyperextensibility of finger joints is often found, despite reports of limited elbow and knee extensions.
Often associated with prenatal death
Two boys with clinical findings identical to those associated with XL-SMA were found to have biallelic
Most die of respiratory failure in the first year of life. Survivors have failure to thrive and intellectual disability.
The highest prevalence is in Finland (OMIM
Note: Arthrogryposis (defined as multiple congenital contractures in multiple body areas) is etiologically heterogeneous: underlying etiologies include central nervous system causes, neurogenic effects, fetal constraint, and intrauterine vascular disruption (e.g., amyoplasia).
For a detailed review of X-linked syndromes with arthrogryposis or early contractures, see
## Management
To establish the extent of disease and needs in an individual diagnosed with X-linked infantile spinal muscular atrophy (XL-SMA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with X-Linked Infantile Spinal Muscular Atrophy
To incl eval of aspiration risk, fatigue during feeding, GERD, & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk &/or poor oral intake.
Orthopedist;
PT for flexion contractures.
Community or
Social work involvement for parental support;
Home nursing referral.
GERD = gastroesophageal reflux disease; PT = physical therapist
Treatment of Manifestations in Individuals with X-Linked Infantile Spinal Muscular Atrophy
For affected males who survive newborn period
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or weak suck
Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, esp during acute illness.
Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/XL-SMA) appears to ↓ pulmonary complications.
For hypoventilation as demonstrated by ↓ oxygen saturation by pulse oximetry or by obstructive sleep apnea
BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Including higher-calorie feeds and fat supplementation
Options should be discussed with the parents/care providers before respiratory failure occurs.
The type of respiratory support is dependent on the individual's respiratory status, quality-of-life goals, and reduction in respiratory complications.
Discuss "do not attempt to resuscitate" status with the family before respiratory failure occurs. This discussion may begin early but is appropriate when abdominal breathing is present and/or the forced vital capacity is less than 30%.
Noninvasive pulmonary intervention should be incorporated into the management of all affected individuals.
Individuals with XL-SMA should be followed regularly by a physician familiar with this condition (e.g., a clinical geneticist). Other subspecialists involved in ongoing care include a neurologist, pulmonologist, orthopedist, physical and occupational therapists, nutritionist, and gastroenterologist as needed.
Affected children should be followed at least monthly until the severity and disease course are more clearly delineated. Affected children frequently die in infancy or early childhood; their clinical status should be followed closely to optimize management, and to assure that the family has a good understanding of the progression and can make informed decisions.
Recommended Surveillance for Individuals with X-Linked Infantile Spinal Muscular Atrophy
Referral to a pulmonologist is recommended.
See
Search
• To incl eval of aspiration risk, fatigue during feeding, GERD, & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk &/or poor oral intake.
• Orthopedist;
• PT for flexion contractures.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• For affected males who survive newborn period
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or weak suck
• Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, esp during acute illness.
• Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/XL-SMA) appears to ↓ pulmonary complications.
• For hypoventilation as demonstrated by ↓ oxygen saturation by pulse oximetry or by obstructive sleep apnea
• BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with X-linked infantile spinal muscular atrophy (XL-SMA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with X-Linked Infantile Spinal Muscular Atrophy
To incl eval of aspiration risk, fatigue during feeding, GERD, & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk &/or poor oral intake.
Orthopedist;
PT for flexion contractures.
Community or
Social work involvement for parental support;
Home nursing referral.
GERD = gastroesophageal reflux disease; PT = physical therapist
• To incl eval of aspiration risk, fatigue during feeding, GERD, & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk &/or poor oral intake.
• Orthopedist;
• PT for flexion contractures.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with X-Linked Infantile Spinal Muscular Atrophy
For affected males who survive newborn period
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or weak suck
Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, esp during acute illness.
Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/XL-SMA) appears to ↓ pulmonary complications.
For hypoventilation as demonstrated by ↓ oxygen saturation by pulse oximetry or by obstructive sleep apnea
BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Including higher-calorie feeds and fat supplementation
Options should be discussed with the parents/care providers before respiratory failure occurs.
The type of respiratory support is dependent on the individual's respiratory status, quality-of-life goals, and reduction in respiratory complications.
Discuss "do not attempt to resuscitate" status with the family before respiratory failure occurs. This discussion may begin early but is appropriate when abdominal breathing is present and/or the forced vital capacity is less than 30%.
Noninvasive pulmonary intervention should be incorporated into the management of all affected individuals.
• For affected males who survive newborn period
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or weak suck
• Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, esp during acute illness.
• Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/XL-SMA) appears to ↓ pulmonary complications.
• For hypoventilation as demonstrated by ↓ oxygen saturation by pulse oximetry or by obstructive sleep apnea
• BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
## Surveillance
Individuals with XL-SMA should be followed regularly by a physician familiar with this condition (e.g., a clinical geneticist). Other subspecialists involved in ongoing care include a neurologist, pulmonologist, orthopedist, physical and occupational therapists, nutritionist, and gastroenterologist as needed.
Affected children should be followed at least monthly until the severity and disease course are more clearly delineated. Affected children frequently die in infancy or early childhood; their clinical status should be followed closely to optimize management, and to assure that the family has a good understanding of the progression and can make informed decisions.
Recommended Surveillance for Individuals with X-Linked Infantile Spinal Muscular Atrophy
Referral to a pulmonologist is recommended.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
By definition, X-linked infantile spinal muscular atrophy (XL-SMA) 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
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
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Males with a severe phenotype do not generally survive.
Males with milder phenotypes transmit the
All of their daughters, who will be heterozygotes and will usually not be affected;
None of their sons.
Carrier testing for at risk female relatives requires prior identification of the
Note: Females who are heterozygous for this X-linked disorder will usually not be 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 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 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 a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males with a severe phenotype do not generally survive.
• Males with milder phenotypes transmit the
• All of their daughters, who will be heterozygotes and will usually not be affected;
• None of their sons.
• All of their daughters, who will be heterozygotes and will usually not be affected;
• None of their sons.
• All of their daughters, who will be heterozygotes and will usually not be affected;
• 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
By definition, X-linked infantile spinal muscular atrophy (XL-SMA) 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
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
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Males with a severe phenotype do not generally survive.
Males with milder phenotypes transmit the
All of their daughters, who will be heterozygotes and will usually not be affected;
None of their sons.
• 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 a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males with a severe phenotype do not generally survive.
• Males with milder phenotypes transmit the
• All of their daughters, who will be heterozygotes and will usually not be affected;
• None of their sons.
• All of their daughters, who will be heterozygotes and will usually not be affected;
• None of their sons.
• All of their daughters, who will be heterozygotes and will usually not be affected;
• None of their sons.
## Heterozygote (Carrier) Detection
Carrier testing for at risk female relatives requires prior identification of the
Note: Females who are heterozygous for this X-linked disorder will usually not be affected.
## 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 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
P.O. Box 6291
Spartanburg SC 29304
8201 Corporate Drive
Suite 600
Landover MD 20785
•
•
•
•
•
• P.O. Box 6291
• Spartanburg SC 29304
•
•
•
•
•
•
•
• 8201 Corporate Drive
• Suite 600
• Landover MD 20785
•
## Molecular Genetics
Spinal Muscular Atrophy, X-Linked Infantile: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinal Muscular Atrophy, X-Linked Infantile (
## Molecular Pathogenesis
## Chapter Notes
The authors are grateful to the numerous clinicians and families who have supported XL-SMA disease gene discovery efforts through their cooperation throughout the years (especially Dr Louis Elsas), as well as to the laboratories of Drs Alfons Meindl and Eric Hoffman, who share in the XL-SMA disease gene discovery. The senior author is also extremely grateful to Dr Judith Hall for her expert review of this document. This work was supported in the United States by funds from the Dr John T Macdonald Center for Medical Genetics at the University of Miami Miller School of Medicine, the University of Miami Miller School of Medicine, Peyton's Pals, the national Muscular Dystrophy Association, the Families of SMA, TGEN, Flinn Foundation of Research Arizona, and the Arizona Biomedical Commission for Research; and in Europe, by the German Ministry for Research and Education grant and FAZIT-Stiftung, Frankfurt/Main, Germany. The authors would like to dedicate this review in memory of four human geneticists who were fundamental to the early days of this research project: Dr Frank Greenberg, Dr Ronald Haun, Dr Emmanuel Shapira, and especially Dr Victor McKusick, who thought every inherited disorder, common or rare, was worth recognition and further investigation.
Mary Ellen Ahearn, MS (2008-present)Lisa Baumbach-Reardon, PhD, FACMG (2008-present)JM Hunter, PhD, FACMG (2021-present)Miranda Pfautsch (2021-present)Stephanie J Sacharow, MD; Boston Children's Hospital (2008-2021)
9 May 2024 (ma) Revision: VEXAS syndrome added to
29 July 2021 (ma) Comprehensive update posted live
13 September 2012 (me) Comprehensive update posted live
30 October 2008 (me) Review posted live
10 July 2008 (lbr) Original submission
• 9 May 2024 (ma) Revision: VEXAS syndrome added to
• 29 July 2021 (ma) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 30 October 2008 (me) Review posted live
• 10 July 2008 (lbr) Original submission
## Acknowledgments
The authors are grateful to the numerous clinicians and families who have supported XL-SMA disease gene discovery efforts through their cooperation throughout the years (especially Dr Louis Elsas), as well as to the laboratories of Drs Alfons Meindl and Eric Hoffman, who share in the XL-SMA disease gene discovery. The senior author is also extremely grateful to Dr Judith Hall for her expert review of this document. This work was supported in the United States by funds from the Dr John T Macdonald Center for Medical Genetics at the University of Miami Miller School of Medicine, the University of Miami Miller School of Medicine, Peyton's Pals, the national Muscular Dystrophy Association, the Families of SMA, TGEN, Flinn Foundation of Research Arizona, and the Arizona Biomedical Commission for Research; and in Europe, by the German Ministry for Research and Education grant and FAZIT-Stiftung, Frankfurt/Main, Germany. The authors would like to dedicate this review in memory of four human geneticists who were fundamental to the early days of this research project: Dr Frank Greenberg, Dr Ronald Haun, Dr Emmanuel Shapira, and especially Dr Victor McKusick, who thought every inherited disorder, common or rare, was worth recognition and further investigation.
## Author History
Mary Ellen Ahearn, MS (2008-present)Lisa Baumbach-Reardon, PhD, FACMG (2008-present)JM Hunter, PhD, FACMG (2021-present)Miranda Pfautsch (2021-present)Stephanie J Sacharow, MD; Boston Children's Hospital (2008-2021)
## Revision History
9 May 2024 (ma) Revision: VEXAS syndrome added to
29 July 2021 (ma) Comprehensive update posted live
13 September 2012 (me) Comprehensive update posted live
30 October 2008 (me) Review posted live
10 July 2008 (lbr) Original submission
• 9 May 2024 (ma) Revision: VEXAS syndrome added to
• 29 July 2021 (ma) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 30 October 2008 (me) Review posted live
• 10 July 2008 (lbr) Original submission
## References
## Literature Cited
|
[] |
30/10/2008
|
29/7/2021
|
9/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sma
|
sma
|
[
"SMA",
"Spinal Muscular Atrophy I",
"Spinal Muscular Atrophy II",
"Spinal Muscular Atrophy 0",
"Spinal Muscular Atrophy III",
"Spinal Muscular Atrophy IV",
"Survival motor neuron protein",
"SMN1",
"SMN2",
"Spinal Muscular Atrophy"
] |
Spinal Muscular Atrophy
|
Thomas W Prior, Meganne E Leach, Erika L Finanger
|
Summary Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal greater than distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of The diagnosis of SMA is established in a proband with a history of motor difficulties or regression, proximal muscle weakness, reduced/absent deep tendon reflexes, evidence of motor unit disease, and/or biallelic pathogenic variants in SMA is inherited in an autosomal recessive manner. Each pregnancy of a couple who have had a child with SMA has an approximately 25% chance of producing an affected child, an approximately 50% chance of producing an asymptomatic carrier, and an approximately 25% chance of producing an unaffected child who is not a carrier. These recurrence risks deviate slightly from the norm for autosomal recessive inheritance because about 2% of affected individuals have a
|
Spinal muscular atrophy 0
Spinal muscular atrophy I
Spinal muscular atrophy II
Spinal muscular atrophy III
Spinal muscular atrophy IV
For synonyms and outdated names see
Note: This review is restricted to the discussion of
• Spinal muscular atrophy 0
• Spinal muscular atrophy I
• Spinal muscular atrophy II
• Spinal muscular atrophy III
• Spinal muscular atrophy IV
## Diagnosis
A consensus document on the diagnosis of children with spinal muscular atrophy (SMA) was initially developed by
NBS for spinal muscular atrophy (SMA) is primarily based on real-time PCR that detects the common
Follow-up molecular genetic testing confirmation of a positive NBS result is recommended (see
History of motor difficulties, especially with loss of skills
Proximal greater than distal muscle weakness
Hypotonia
Areflexia/hyporeflexia
Tongue fasciculations
Hand tremor
Recurrent lower respiratory tract infections or severe bronchiolitis in the first few months of life
Evidence of motor unit disease on electromyogram
The diagnosis of SMA
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
Establish that the inactivating variant has previously been reported in
Sequence a long-range PCR product or a subclone of
Note: (1) Gene-targeted deletion/duplication analysis to determine
See
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinal Muscular Atrophy
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 and multiplex ligation-dependent probe amplification (MLPA) to detect single-exon deletions or duplications. Note that
Detects the 2%-5% of individuals who are compound heterozygous for an intragenic pathogenic variant and an
False negatives may occur because about 5%-8% of the population have two copies of
Gene-targeted deletion/duplication analysis of
• NBS for spinal muscular atrophy (SMA) is primarily based on real-time PCR that detects the common
• Follow-up molecular genetic testing confirmation of a positive NBS result is recommended (see
• History of motor difficulties, especially with loss of skills
• Proximal greater than distal muscle weakness
• Hypotonia
• Areflexia/hyporeflexia
• Tongue fasciculations
• Hand tremor
• Recurrent lower respiratory tract infections or severe bronchiolitis in the first few months of life
• Evidence of motor unit disease on electromyogram
• Establish that the inactivating variant has previously been reported in
• Sequence a long-range PCR product or a subclone of
## Suggestive Findings
NBS for spinal muscular atrophy (SMA) is primarily based on real-time PCR that detects the common
Follow-up molecular genetic testing confirmation of a positive NBS result is recommended (see
History of motor difficulties, especially with loss of skills
Proximal greater than distal muscle weakness
Hypotonia
Areflexia/hyporeflexia
Tongue fasciculations
Hand tremor
Recurrent lower respiratory tract infections or severe bronchiolitis in the first few months of life
Evidence of motor unit disease on electromyogram
• NBS for spinal muscular atrophy (SMA) is primarily based on real-time PCR that detects the common
• Follow-up molecular genetic testing confirmation of a positive NBS result is recommended (see
• History of motor difficulties, especially with loss of skills
• Proximal greater than distal muscle weakness
• Hypotonia
• Areflexia/hyporeflexia
• Tongue fasciculations
• Hand tremor
• Recurrent lower respiratory tract infections or severe bronchiolitis in the first few months of life
• Evidence of motor unit disease on electromyogram
## Establishing the Diagnosis
The diagnosis of SMA
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
Establish that the inactivating variant has previously been reported in
Sequence a long-range PCR product or a subclone of
Note: (1) Gene-targeted deletion/duplication analysis to determine
See
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinal Muscular Atrophy
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 and multiplex ligation-dependent probe amplification (MLPA) to detect single-exon deletions or duplications. Note that
Detects the 2%-5% of individuals who are compound heterozygous for an intragenic pathogenic variant and an
False negatives may occur because about 5%-8% of the population have two copies of
Gene-targeted deletion/duplication analysis of
• Establish that the inactivating variant has previously been reported in
• Sequence a long-range PCR product or a subclone of
## Molecular Genetic Testing Approaches
Because
Establish that the inactivating variant has previously been reported in
Sequence a long-range PCR product or a subclone of
Note: (1) Gene-targeted deletion/duplication analysis to determine
See
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinal Muscular Atrophy
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 and multiplex ligation-dependent probe amplification (MLPA) to detect single-exon deletions or duplications. Note that
Detects the 2%-5% of individuals who are compound heterozygous for an intragenic pathogenic variant and an
False negatives may occur because about 5%-8% of the population have two copies of
Gene-targeted deletion/duplication analysis of
• Establish that the inactivating variant has previously been reported in
• Sequence a long-range PCR product or a subclone of
## Clinical Characteristics
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal greater than distal, and progressive.
Before the advent of molecular diagnosis, attempts were made to classify SMA into discrete subtypes; however, it is now apparent that the phenotype of SMA associated with
Spinal Muscular Atrophy: Spectrum of Phenotypes at Presentation
Severe neonatal hypotonia
Severe weakness
Areflexia
Respiratory failure at birth
Facial diplegia
↓ fetal movements
Atrial septal defects
Arthrogryposis
Loss of head control
Mild joint contractures
Normal or minimal facial weakness
Variable suck & swallow difficulties
Developmental delay w/loss of motor skills
↓ or absent deep tendon reflexes
Proximal muscle weakness
Postural tremor of fingers
Proximal muscle weakness (i.e., difficulty w/stairs, running)
Loss of motor skills
Fatigue
Postural tremor of fingers
Loss of patellar reflexes
Fatigue
Proximal muscle weakness
With supportive care only
With supportive care only, fasciculation of the tongue is seen in most but not all infants. While the muscles of the face are relatively spared at initial presentation, bulbar weakness is present in the neonatal period or during the first few months, and infants develop problems sucking or swallowing, leading to growth failure and recurrent aspiration. Weakness of the intercostal respiratory muscles with relative preservation of diaphragm musculature leads to characteristic "bell-shaped" chest and paradoxic respiration (abdominal breathing). The diaphragm is not involved until late in the course of disease. In the past, cognitive function was thought to be normal, but with newer disease-modifying therapies, this premise does not always seem to be true and is being actively investigated. Severe symptomatic bradycardia has been noted in a study of the long-term survival of ventilator-dependent individuals with SMA I [
With supportive care only, prospective studies of children with SMA I have shown median survival of 24 months [
With supportive care only, the life expectancy of persons with SMA II is not known with certainty. A review of life expectancy of 240 individuals with SMA II from Germany and Poland found that 68% of individuals with SMA II were alive at age 25 years [
Most children with SMA III treated only with supportive care make gains in their motor function until about age six years and then experience a slow decline in function until about puberty. Puberty may be associated with a more rapid decline in function for adolescents with SMA III.
With supportive care only, adulthood is then associated with another, much slower decline in function [
Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications of SMA in those who receive supportive care only. At this time, it is unknown what long-term manifestations may arise in individuals who receive early and/or presymptomatic targeted treatment (see
Bulbar dysfunction is universal in individuals with SMA I; the bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III.
Gastrointestinal issues may include constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux with aspiration.
Growth failure can be addressed with gastrostomy tube placement as needed (see
Nonambulatory individuals with SMA II and III are at risk of developing obesity [
Respiratory failure is the most common cause of death in SMA I and II.
Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.
Noninvasive ventilation such as bilevel positive airway pressure and airway clearance techniques are commonly used to improve respiratory insufficiency in those with SMA (see
Approximately 50% of affected children (especially those who are nonambulatory) develop spinal curvatures of more than 50 degrees (which require surgery) before age ten years.
Later in the disease course, nonambulatory individuals can develop thoracic kyphosis [
Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown.
Although the etiology of these metabolic derangements remains unknown, one report suggests that aberrant glucose metabolism may play a role [
Prolonged fasting should be avoided (see
The availability of disease-modifying treatment options (see
Spinal Muscular Atrophy:
Adapted from
Clinical phenotype with supportive care only
With supportive care only, the maximum motor function achieved is sitting.
With supportive care only, ambulation is achieved but may not be maintained.
A single-base substitution – c.859G>C (p.Gly287Arg) – in exon 7 of
In some rare families with unaffected females who have biallelic
SMA I was previously known as Werdnig-Hoffmann disease or acute SMA [
SMA II was called chronic SMA or Dubowitz disease prior to the current classification.
SMA III has had the eponym "Kugelberg-Welander disease" and has also been referred to as juvenile SMA [
SMA IV may also be referred to as adolescent- or adult-onset SMA.
The exact prevalence of SMA is unknown. Historical studies evaluating the prevalence of SMA were limited by lack of genetic confirmation and may underestimate the prevalence of more severe phenotypes due to the shortened life span. It has been suggested that the overall prevalence of SMA is between one and two in 100,000 people [
Spinal Muscular Atrophy: Carrier Frequency and Incidence
Adapted from
• Severe neonatal hypotonia
• Severe weakness
• Areflexia
• Respiratory failure at birth
• Facial diplegia
• ↓ fetal movements
• Atrial septal defects
• Arthrogryposis
• Loss of head control
• Mild joint contractures
• Normal or minimal facial weakness
• Variable suck & swallow difficulties
• Developmental delay w/loss of motor skills
• ↓ or absent deep tendon reflexes
• Proximal muscle weakness
• Postural tremor of fingers
• Proximal muscle weakness (i.e., difficulty w/stairs, running)
• Loss of motor skills
• Fatigue
• Postural tremor of fingers
• Loss of patellar reflexes
• Fatigue
• Proximal muscle weakness
• Bulbar dysfunction is universal in individuals with SMA I; the bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III.
• Gastrointestinal issues may include constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux with aspiration.
• Growth failure can be addressed with gastrostomy tube placement as needed (see
• Nonambulatory individuals with SMA II and III are at risk of developing obesity [
• Respiratory failure is the most common cause of death in SMA I and II.
• Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.
• Noninvasive ventilation such as bilevel positive airway pressure and airway clearance techniques are commonly used to improve respiratory insufficiency in those with SMA (see
• Approximately 50% of affected children (especially those who are nonambulatory) develop spinal curvatures of more than 50 degrees (which require surgery) before age ten years.
• Later in the disease course, nonambulatory individuals can develop thoracic kyphosis [
• Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown.
• Although the etiology of these metabolic derangements remains unknown, one report suggests that aberrant glucose metabolism may play a role [
• Prolonged fasting should be avoided (see
• A single-base substitution – c.859G>C (p.Gly287Arg) – in exon 7 of
• In some rare families with unaffected females who have biallelic
## Clinical Description
Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal greater than distal, and progressive.
Before the advent of molecular diagnosis, attempts were made to classify SMA into discrete subtypes; however, it is now apparent that the phenotype of SMA associated with
Spinal Muscular Atrophy: Spectrum of Phenotypes at Presentation
Severe neonatal hypotonia
Severe weakness
Areflexia
Respiratory failure at birth
Facial diplegia
↓ fetal movements
Atrial septal defects
Arthrogryposis
Loss of head control
Mild joint contractures
Normal or minimal facial weakness
Variable suck & swallow difficulties
Developmental delay w/loss of motor skills
↓ or absent deep tendon reflexes
Proximal muscle weakness
Postural tremor of fingers
Proximal muscle weakness (i.e., difficulty w/stairs, running)
Loss of motor skills
Fatigue
Postural tremor of fingers
Loss of patellar reflexes
Fatigue
Proximal muscle weakness
With supportive care only
With supportive care only, fasciculation of the tongue is seen in most but not all infants. While the muscles of the face are relatively spared at initial presentation, bulbar weakness is present in the neonatal period or during the first few months, and infants develop problems sucking or swallowing, leading to growth failure and recurrent aspiration. Weakness of the intercostal respiratory muscles with relative preservation of diaphragm musculature leads to characteristic "bell-shaped" chest and paradoxic respiration (abdominal breathing). The diaphragm is not involved until late in the course of disease. In the past, cognitive function was thought to be normal, but with newer disease-modifying therapies, this premise does not always seem to be true and is being actively investigated. Severe symptomatic bradycardia has been noted in a study of the long-term survival of ventilator-dependent individuals with SMA I [
With supportive care only, prospective studies of children with SMA I have shown median survival of 24 months [
With supportive care only, the life expectancy of persons with SMA II is not known with certainty. A review of life expectancy of 240 individuals with SMA II from Germany and Poland found that 68% of individuals with SMA II were alive at age 25 years [
Most children with SMA III treated only with supportive care make gains in their motor function until about age six years and then experience a slow decline in function until about puberty. Puberty may be associated with a more rapid decline in function for adolescents with SMA III.
With supportive care only, adulthood is then associated with another, much slower decline in function [
Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications of SMA in those who receive supportive care only. At this time, it is unknown what long-term manifestations may arise in individuals who receive early and/or presymptomatic targeted treatment (see
Bulbar dysfunction is universal in individuals with SMA I; the bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III.
Gastrointestinal issues may include constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux with aspiration.
Growth failure can be addressed with gastrostomy tube placement as needed (see
Nonambulatory individuals with SMA II and III are at risk of developing obesity [
Respiratory failure is the most common cause of death in SMA I and II.
Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.
Noninvasive ventilation such as bilevel positive airway pressure and airway clearance techniques are commonly used to improve respiratory insufficiency in those with SMA (see
Approximately 50% of affected children (especially those who are nonambulatory) develop spinal curvatures of more than 50 degrees (which require surgery) before age ten years.
Later in the disease course, nonambulatory individuals can develop thoracic kyphosis [
Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown.
Although the etiology of these metabolic derangements remains unknown, one report suggests that aberrant glucose metabolism may play a role [
Prolonged fasting should be avoided (see
The availability of disease-modifying treatment options (see
• Severe neonatal hypotonia
• Severe weakness
• Areflexia
• Respiratory failure at birth
• Facial diplegia
• ↓ fetal movements
• Atrial septal defects
• Arthrogryposis
• Loss of head control
• Mild joint contractures
• Normal or minimal facial weakness
• Variable suck & swallow difficulties
• Developmental delay w/loss of motor skills
• ↓ or absent deep tendon reflexes
• Proximal muscle weakness
• Postural tremor of fingers
• Proximal muscle weakness (i.e., difficulty w/stairs, running)
• Loss of motor skills
• Fatigue
• Postural tremor of fingers
• Loss of patellar reflexes
• Fatigue
• Proximal muscle weakness
• Bulbar dysfunction is universal in individuals with SMA I; the bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III.
• Gastrointestinal issues may include constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux with aspiration.
• Growth failure can be addressed with gastrostomy tube placement as needed (see
• Nonambulatory individuals with SMA II and III are at risk of developing obesity [
• Respiratory failure is the most common cause of death in SMA I and II.
• Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.
• Noninvasive ventilation such as bilevel positive airway pressure and airway clearance techniques are commonly used to improve respiratory insufficiency in those with SMA (see
• Approximately 50% of affected children (especially those who are nonambulatory) develop spinal curvatures of more than 50 degrees (which require surgery) before age ten years.
• Later in the disease course, nonambulatory individuals can develop thoracic kyphosis [
• Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown.
• Although the etiology of these metabolic derangements remains unknown, one report suggests that aberrant glucose metabolism may play a role [
• Prolonged fasting should be avoided (see
## SMA Subtypes
With supportive care only, fasciculation of the tongue is seen in most but not all infants. While the muscles of the face are relatively spared at initial presentation, bulbar weakness is present in the neonatal period or during the first few months, and infants develop problems sucking or swallowing, leading to growth failure and recurrent aspiration. Weakness of the intercostal respiratory muscles with relative preservation of diaphragm musculature leads to characteristic "bell-shaped" chest and paradoxic respiration (abdominal breathing). The diaphragm is not involved until late in the course of disease. In the past, cognitive function was thought to be normal, but with newer disease-modifying therapies, this premise does not always seem to be true and is being actively investigated. Severe symptomatic bradycardia has been noted in a study of the long-term survival of ventilator-dependent individuals with SMA I [
With supportive care only, prospective studies of children with SMA I have shown median survival of 24 months [
With supportive care only, the life expectancy of persons with SMA II is not known with certainty. A review of life expectancy of 240 individuals with SMA II from Germany and Poland found that 68% of individuals with SMA II were alive at age 25 years [
Most children with SMA III treated only with supportive care make gains in their motor function until about age six years and then experience a slow decline in function until about puberty. Puberty may be associated with a more rapid decline in function for adolescents with SMA III.
With supportive care only, adulthood is then associated with another, much slower decline in function [
## Potential Complications of SMA
Poor weight gain with growth failure, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications of SMA in those who receive supportive care only. At this time, it is unknown what long-term manifestations may arise in individuals who receive early and/or presymptomatic targeted treatment (see
Bulbar dysfunction is universal in individuals with SMA I; the bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III.
Gastrointestinal issues may include constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux with aspiration.
Growth failure can be addressed with gastrostomy tube placement as needed (see
Nonambulatory individuals with SMA II and III are at risk of developing obesity [
Respiratory failure is the most common cause of death in SMA I and II.
Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.
Noninvasive ventilation such as bilevel positive airway pressure and airway clearance techniques are commonly used to improve respiratory insufficiency in those with SMA (see
Approximately 50% of affected children (especially those who are nonambulatory) develop spinal curvatures of more than 50 degrees (which require surgery) before age ten years.
Later in the disease course, nonambulatory individuals can develop thoracic kyphosis [
Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown.
Although the etiology of these metabolic derangements remains unknown, one report suggests that aberrant glucose metabolism may play a role [
Prolonged fasting should be avoided (see
• Bulbar dysfunction is universal in individuals with SMA I; the bulbar dysfunction eventually becomes a serious problem for persons with SMA II and only very late in the course of disease for those with SMA III.
• Gastrointestinal issues may include constipation, delayed gastric emptying, and potentially life-threatening gastroesophageal reflux with aspiration.
• Growth failure can be addressed with gastrostomy tube placement as needed (see
• Nonambulatory individuals with SMA II and III are at risk of developing obesity [
• Respiratory failure is the most common cause of death in SMA I and II.
• Decreased respiratory function leads to impaired cough with inadequate clearance of lower airway secretions, hypoventilation during sleep, and recurrent pneumonia.
• Noninvasive ventilation such as bilevel positive airway pressure and airway clearance techniques are commonly used to improve respiratory insufficiency in those with SMA (see
• Approximately 50% of affected children (especially those who are nonambulatory) develop spinal curvatures of more than 50 degrees (which require surgery) before age ten years.
• Later in the disease course, nonambulatory individuals can develop thoracic kyphosis [
• Whether these metabolic abnormalities are primary or secondary to the underlying defect in SMA is unknown.
• Although the etiology of these metabolic derangements remains unknown, one report suggests that aberrant glucose metabolism may play a role [
• Prolonged fasting should be avoided (see
## Prognosis
The availability of disease-modifying treatment options (see
## Genotype-Phenotype Correlations
Spinal Muscular Atrophy:
Adapted from
Clinical phenotype with supportive care only
With supportive care only, the maximum motor function achieved is sitting.
With supportive care only, ambulation is achieved but may not be maintained.
A single-base substitution – c.859G>C (p.Gly287Arg) – in exon 7 of
In some rare families with unaffected females who have biallelic
• A single-base substitution – c.859G>C (p.Gly287Arg) – in exon 7 of
• In some rare families with unaffected females who have biallelic
## Nomenclature
SMA I was previously known as Werdnig-Hoffmann disease or acute SMA [
SMA II was called chronic SMA or Dubowitz disease prior to the current classification.
SMA III has had the eponym "Kugelberg-Welander disease" and has also been referred to as juvenile SMA [
SMA IV may also be referred to as adolescent- or adult-onset SMA.
## Prevalence
The exact prevalence of SMA is unknown. Historical studies evaluating the prevalence of SMA were limited by lack of genetic confirmation and may underestimate the prevalence of more severe phenotypes due to the shortened life span. It has been suggested that the overall prevalence of SMA is between one and two in 100,000 people [
Spinal Muscular Atrophy: Carrier Frequency and Incidence
Adapted from
## Genetically Related (Allelic) Disorders
No phenotypes other than those described in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Spinal Muscular Atrophy
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; SMARD = spinal muscular atrophy with respiratory distress; XL = X-linked
SMARD spans a phenotypic spectrum [
Pathogenic variants in
Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS / Angelman syndrome region (15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and, rarely, an imprinting defect). 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.
Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include those listed in the table (see
Congenital myopathies: see
Metabolic/mitochondrial myopathies: see glycogen storage diseases (
Peripheral neuropathies: see
Muscular dystrophies: see
See
## Management
Detailed recommendations on management of care in individuals with spinal muscular atrophy (SMA) have been published; see
To establish the extent of disease and needs in an individual diagnosed with SMA, the affected individual should be referred to a multidisciplinary clinic. Regardless of SMA subtype, clinical care should be based on an individual's current functional status. Issues to consider are listed in
Spinal Muscular Atrophy: Evaluations to Consider Following Initial Diagnosis
Incl evaluation of aspiration risk,
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
In children age >4-6 yrs, a handheld spirometer is accurate.
Greater reduction in FVC is assoc w/↑ risk of decompensation during respiratory infection.
Gross motor & fine motor skills
Contractures, hip dislocation, & 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
ADL = activities of daily living; FVC = forced vital capacity; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy; SMA = spinal muscular atrophy
Including consideration of a formal videofluoroscopic swallowing study
Assess equipment needed for safety (car seat / car bed) and independence, such as power chair and other equipment in the home, to improve the quality of life for the affected individual and the caregiver.
Currently, there is no cure for SMA.
Three treatment options that are targeted to the underlying mechanism that leads to SMA are available and have a positive effect on disease progression (see
The decision of when to initiate targeted therapy after detection of an affected individual via newborn screening relies on genotype and presence of symptoms [
Targeted treatment is recommended for all individuals who have two, three, or four copies of
For individuals who have one copy of
For individuals with five copies of
Spinal Muscular Atrophy: Targeted Treatment
Age <2 mos: 0.15 mg/kg
Age 2 mos to <2 yrs: 0.2 mg/kg
Age ≥2 yrs w/weight <20 kg: 0.25 mg/kg
Age ≥2 yrs w/weight>20 kg: 5 mg
Evrysdi
In animal studies, use during pregnancy resulted in teratogenic effects, incl fetal demise & reproductive impairment in offspring.
12 mg per dose
Intrathecal loading doses every 14 days for total of 3 loading doses
4th loading dose 30 days after 3rd dose
Then, maintenance doses every 4 mos
Side effects are primarily related to mode of delivery (lumbar puncture).
Monitor for thrombocytopenia/coagulation abnormalities & renal toxicity.
Assessment of liver function prior to infusion is recommended.
Care should be taken in providing this therapy to persons w/pre-existing liver impairment.
This is also referred to as disease-modifying therapy (DMT).
Treatments discussed in this table are targeted to address the underlying mechanism of disease causation and not specifically the signs and symptoms experienced by an affected individual (see
The antisense oligonucleotide is a single-stranded RNA molecule that is specifically designed to bind to the ISS-N1 regulatory motif in the intron downstream of exon 7 in the
In a double-blind, sham-controlled Phase III clinical trial of nusinersen in 121 infants with SMA I, 51% of treated infants showed acquisition of a new motor milestone as assessed by the Hammersmith Infant Neurological Examination (HINE) compared with 0% of controls. Further, event-free survival ("event" = death or need for permanent ventilator assistance) was higher in the nusinersen group than in the control group (hazard ratio 0.53; P=0.005), as was the likelihood of overall survival (hazard ratio 0.37; P=0.004) [
In a parallel double-blind, sham-controlled, Phase III trial including 126 children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group [
The efficacy of treatment with nusinersen in those who already have symptoms is not completely understood [
A Phase I trial in 15 individuals with SMA I showed event-free survival ("event" = death or need for permanent ventilator assistance) at age 20 months in all 15 individuals, compared with only 8% of historical controls. Treated individuals showed an improvement in motor milestones and an increase from baseline in objective motor function scales [
Supportive treatment of children with SMA is guided by the underlying subtype but should be individualized to the affected person and their current functional status (nonsitter, sitter, or walker) [
Spinal Muscular Atrophy: Treatment of Manifestations
Most untreated persons w/SMA I have a gastrostomy tube by age 12 mos.
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or bulbar dysfunction
Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, particularly during acute illness
Suctioning of secretions, careful use of medications
Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/SMA) appears to ↓ pulmonary complications.
For hypoventilation as demonstrated by hypercarbia or on sleep study
Has been shown to improve sleep breathing parameters in those w/SMA I & II
BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
Use of spinal orthosis for curvatures >20 degrees prior to surgical intervention is common.
Important consideration in spinal surgery: leave a window for possibility of intrathecal administration of future treatments.
For gradual outpatient distractions controlled by an external remote device
May ↓ need for repeated surgery
BiPAP = bilevel positive airway pressure; IV = intravenous; SMA = spinal muscular atrophy
In those who receive supportive care only [
See
Options should be discussed with parents/caregivers before respiratory failure occurs.
The type of respiratory support is dependent on the individual's respiratory status, quality-of-life goals, and access to equipment.
Noninvasive pulmonary intervention should be incorporated into the management of all types of SMA.
There is insufficient evidence that spinal orthotics alter scoliosis in SMA.
A small case series of individuals with neuromuscular disorders (2 of whom had SMA) evaluated magnetically controlled growing rods and pulmonary function. Affected individuals showed an improvement in forced vital capacity and forced expired volume in 1 second postoperatively with spinal deformity correction, with very few complications [
Where available, targeted therapy should be initiated as soon as possible for eligible individuals. A treatment algorithm for the evaluation of presymptomatic infants has been published [
For those who are receiving a targeted therapy, review of prescribing information and the package insert is suggested, as recommendations for ongoing surveillance are changing rapidly for each targeted therapy. Both potential side effects and new phenotypes associated with targeted treatments continue to emerge.
Individuals with SMA are evaluated at least every six months; weaker children are evaluated more frequently.
Multidisciplinary surveillance at each visit includes assessments of nutritional state, respiratory function, motor function, and orthopedic status (spine, hips, and joint range of motion) to help determine appropriate interventions.
Prolonged fasting should be avoided, particularly in the acutely ill infant with SMA [
It is appropriate to determine the genetic status of younger, apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted treatment and preventive measures.
See
There have been several published studies surveying the pregnancy experience of women with SMA [
There are no adequate data on the developmental risk associated with the use of nusinersen in pregnant women. When nusinersen was administered by subcutaneous injection to mice throughout pregnancy and lactation, developmental toxicity (long-term neurobehavioral impairment) was observed at all doses tested. There has been one reported case of a pregnancy that occurred during treatment with nusinersen [
No human pregnancies have been reported to have occurred during/after treatment with risdiplam. Teratogenic effects have been seen in studies of pregnant animals, including fetal demise, malformations, and reproductive impairments in the surviving offspring. Based on the results from animal studies, risdiplam use should be avoided in pregnant women. It is unknown if risdiplam is excreted in human breast milk, but it is excreted in the milk of lactating animals.
There have not been any reported cases of pregnant women with SMA treated with onasemnogene abeparvovec-xioi. No animal studies have been performed evaluating the reproductive risks or possible fetal toxicity of use of onasemnogene abeparvovec-xioi in pregnancy.
A number of different therapeutic approaches are in development, including further studies on the approved therapeutics discussed above. See the
Reldesemtiv is a tropinin complex activator proposed to cause increased muscle force output [
At least three myostatin inhibitor agents are currently in clinical trials for use in SMA. Results have not been published, but long-term extension studies are under way.
Search
• Incl evaluation of aspiration risk,
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• In children age >4-6 yrs, a handheld spirometer is accurate.
• Greater reduction in FVC is assoc w/↑ risk of decompensation during respiratory infection.
• Gross motor & fine motor skills
• Contractures, hip dislocation, & 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
• Targeted treatment is recommended for all individuals who have two, three, or four copies of
• For individuals who have one copy of
• For individuals with five copies of
• Age <2 mos: 0.15 mg/kg
• Age 2 mos to <2 yrs: 0.2 mg/kg
• Age ≥2 yrs w/weight <20 kg: 0.25 mg/kg
• Age ≥2 yrs w/weight>20 kg: 5 mg
• Evrysdi
• In animal studies, use during pregnancy resulted in teratogenic effects, incl fetal demise & reproductive impairment in offspring.
• 12 mg per dose
• Intrathecal loading doses every 14 days for total of 3 loading doses
• 4th loading dose 30 days after 3rd dose
• Then, maintenance doses every 4 mos
• Side effects are primarily related to mode of delivery (lumbar puncture).
• Monitor for thrombocytopenia/coagulation abnormalities & renal toxicity.
• Assessment of liver function prior to infusion is recommended.
• Care should be taken in providing this therapy to persons w/pre-existing liver impairment.
• Most untreated persons w/SMA I have a gastrostomy tube by age 12 mos.
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or bulbar dysfunction
• Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, particularly during acute illness
• Suctioning of secretions, careful use of medications
• Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/SMA) appears to ↓ pulmonary complications.
• For hypoventilation as demonstrated by hypercarbia or on sleep study
• Has been shown to improve sleep breathing parameters in those w/SMA I & II
• BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
• Use of spinal orthosis for curvatures >20 degrees prior to surgical intervention is common.
• Important consideration in spinal surgery: leave a window for possibility of intrathecal administration of future treatments.
• For gradual outpatient distractions controlled by an external remote device
• May ↓ need for repeated surgery
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SMA, the affected individual should be referred to a multidisciplinary clinic. Regardless of SMA subtype, clinical care should be based on an individual's current functional status. Issues to consider are listed in
Spinal Muscular Atrophy: Evaluations to Consider Following Initial Diagnosis
Incl evaluation of aspiration risk,
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
In children age >4-6 yrs, a handheld spirometer is accurate.
Greater reduction in FVC is assoc w/↑ risk of decompensation during respiratory infection.
Gross motor & fine motor skills
Contractures, hip dislocation, & 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
ADL = activities of daily living; FVC = forced vital capacity; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy; SMA = spinal muscular atrophy
Including consideration of a formal videofluoroscopic swallowing study
Assess equipment needed for safety (car seat / car bed) and independence, such as power chair and other equipment in the home, to improve the quality of life for the affected individual and the caregiver.
• Incl evaluation of aspiration risk,
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• In children age >4-6 yrs, a handheld spirometer is accurate.
• Greater reduction in FVC is assoc w/↑ risk of decompensation during respiratory infection.
• Gross motor & fine motor skills
• Contractures, hip dislocation, & 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
Currently, there is no cure for SMA.
Three treatment options that are targeted to the underlying mechanism that leads to SMA are available and have a positive effect on disease progression (see
The decision of when to initiate targeted therapy after detection of an affected individual via newborn screening relies on genotype and presence of symptoms [
Targeted treatment is recommended for all individuals who have two, three, or four copies of
For individuals who have one copy of
For individuals with five copies of
Spinal Muscular Atrophy: Targeted Treatment
Age <2 mos: 0.15 mg/kg
Age 2 mos to <2 yrs: 0.2 mg/kg
Age ≥2 yrs w/weight <20 kg: 0.25 mg/kg
Age ≥2 yrs w/weight>20 kg: 5 mg
Evrysdi
In animal studies, use during pregnancy resulted in teratogenic effects, incl fetal demise & reproductive impairment in offspring.
12 mg per dose
Intrathecal loading doses every 14 days for total of 3 loading doses
4th loading dose 30 days after 3rd dose
Then, maintenance doses every 4 mos
Side effects are primarily related to mode of delivery (lumbar puncture).
Monitor for thrombocytopenia/coagulation abnormalities & renal toxicity.
Assessment of liver function prior to infusion is recommended.
Care should be taken in providing this therapy to persons w/pre-existing liver impairment.
This is also referred to as disease-modifying therapy (DMT).
Treatments discussed in this table are targeted to address the underlying mechanism of disease causation and not specifically the signs and symptoms experienced by an affected individual (see
The antisense oligonucleotide is a single-stranded RNA molecule that is specifically designed to bind to the ISS-N1 regulatory motif in the intron downstream of exon 7 in the
In a double-blind, sham-controlled Phase III clinical trial of nusinersen in 121 infants with SMA I, 51% of treated infants showed acquisition of a new motor milestone as assessed by the Hammersmith Infant Neurological Examination (HINE) compared with 0% of controls. Further, event-free survival ("event" = death or need for permanent ventilator assistance) was higher in the nusinersen group than in the control group (hazard ratio 0.53; P=0.005), as was the likelihood of overall survival (hazard ratio 0.37; P=0.004) [
In a parallel double-blind, sham-controlled, Phase III trial including 126 children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group [
The efficacy of treatment with nusinersen in those who already have symptoms is not completely understood [
A Phase I trial in 15 individuals with SMA I showed event-free survival ("event" = death or need for permanent ventilator assistance) at age 20 months in all 15 individuals, compared with only 8% of historical controls. Treated individuals showed an improvement in motor milestones and an increase from baseline in objective motor function scales [
Supportive treatment of children with SMA is guided by the underlying subtype but should be individualized to the affected person and their current functional status (nonsitter, sitter, or walker) [
Spinal Muscular Atrophy: Treatment of Manifestations
Most untreated persons w/SMA I have a gastrostomy tube by age 12 mos.
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or bulbar dysfunction
Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, particularly during acute illness
Suctioning of secretions, careful use of medications
Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/SMA) appears to ↓ pulmonary complications.
For hypoventilation as demonstrated by hypercarbia or on sleep study
Has been shown to improve sleep breathing parameters in those w/SMA I & II
BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
Use of spinal orthosis for curvatures >20 degrees prior to surgical intervention is common.
Important consideration in spinal surgery: leave a window for possibility of intrathecal administration of future treatments.
For gradual outpatient distractions controlled by an external remote device
May ↓ need for repeated surgery
BiPAP = bilevel positive airway pressure; IV = intravenous; SMA = spinal muscular atrophy
In those who receive supportive care only [
See
Options should be discussed with parents/caregivers before respiratory failure occurs.
The type of respiratory support is dependent on the individual's respiratory status, quality-of-life goals, and access to equipment.
Noninvasive pulmonary intervention should be incorporated into the management of all types of SMA.
There is insufficient evidence that spinal orthotics alter scoliosis in SMA.
A small case series of individuals with neuromuscular disorders (2 of whom had SMA) evaluated magnetically controlled growing rods and pulmonary function. Affected individuals showed an improvement in forced vital capacity and forced expired volume in 1 second postoperatively with spinal deformity correction, with very few complications [
• Targeted treatment is recommended for all individuals who have two, three, or four copies of
• For individuals who have one copy of
• For individuals with five copies of
• Age <2 mos: 0.15 mg/kg
• Age 2 mos to <2 yrs: 0.2 mg/kg
• Age ≥2 yrs w/weight <20 kg: 0.25 mg/kg
• Age ≥2 yrs w/weight>20 kg: 5 mg
• Evrysdi
• In animal studies, use during pregnancy resulted in teratogenic effects, incl fetal demise & reproductive impairment in offspring.
• 12 mg per dose
• Intrathecal loading doses every 14 days for total of 3 loading doses
• 4th loading dose 30 days after 3rd dose
• Then, maintenance doses every 4 mos
• Side effects are primarily related to mode of delivery (lumbar puncture).
• Monitor for thrombocytopenia/coagulation abnormalities & renal toxicity.
• Assessment of liver function prior to infusion is recommended.
• Care should be taken in providing this therapy to persons w/pre-existing liver impairment.
• Most untreated persons w/SMA I have a gastrostomy tube by age 12 mos.
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or bulbar dysfunction
• Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, particularly during acute illness
• Suctioning of secretions, careful use of medications
• Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/SMA) appears to ↓ pulmonary complications.
• For hypoventilation as demonstrated by hypercarbia or on sleep study
• Has been shown to improve sleep breathing parameters in those w/SMA I & II
• BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
• Use of spinal orthosis for curvatures >20 degrees prior to surgical intervention is common.
• Important consideration in spinal surgery: leave a window for possibility of intrathecal administration of future treatments.
• For gradual outpatient distractions controlled by an external remote device
• May ↓ need for repeated surgery
## Targeted Therapies
Three treatment options that are targeted to the underlying mechanism that leads to SMA are available and have a positive effect on disease progression (see
The decision of when to initiate targeted therapy after detection of an affected individual via newborn screening relies on genotype and presence of symptoms [
Targeted treatment is recommended for all individuals who have two, three, or four copies of
For individuals who have one copy of
For individuals with five copies of
Spinal Muscular Atrophy: Targeted Treatment
Age <2 mos: 0.15 mg/kg
Age 2 mos to <2 yrs: 0.2 mg/kg
Age ≥2 yrs w/weight <20 kg: 0.25 mg/kg
Age ≥2 yrs w/weight>20 kg: 5 mg
Evrysdi
In animal studies, use during pregnancy resulted in teratogenic effects, incl fetal demise & reproductive impairment in offspring.
12 mg per dose
Intrathecal loading doses every 14 days for total of 3 loading doses
4th loading dose 30 days after 3rd dose
Then, maintenance doses every 4 mos
Side effects are primarily related to mode of delivery (lumbar puncture).
Monitor for thrombocytopenia/coagulation abnormalities & renal toxicity.
Assessment of liver function prior to infusion is recommended.
Care should be taken in providing this therapy to persons w/pre-existing liver impairment.
This is also referred to as disease-modifying therapy (DMT).
Treatments discussed in this table are targeted to address the underlying mechanism of disease causation and not specifically the signs and symptoms experienced by an affected individual (see
The antisense oligonucleotide is a single-stranded RNA molecule that is specifically designed to bind to the ISS-N1 regulatory motif in the intron downstream of exon 7 in the
In a double-blind, sham-controlled Phase III clinical trial of nusinersen in 121 infants with SMA I, 51% of treated infants showed acquisition of a new motor milestone as assessed by the Hammersmith Infant Neurological Examination (HINE) compared with 0% of controls. Further, event-free survival ("event" = death or need for permanent ventilator assistance) was higher in the nusinersen group than in the control group (hazard ratio 0.53; P=0.005), as was the likelihood of overall survival (hazard ratio 0.37; P=0.004) [
In a parallel double-blind, sham-controlled, Phase III trial including 126 children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group [
The efficacy of treatment with nusinersen in those who already have symptoms is not completely understood [
A Phase I trial in 15 individuals with SMA I showed event-free survival ("event" = death or need for permanent ventilator assistance) at age 20 months in all 15 individuals, compared with only 8% of historical controls. Treated individuals showed an improvement in motor milestones and an increase from baseline in objective motor function scales [
• Targeted treatment is recommended for all individuals who have two, three, or four copies of
• For individuals who have one copy of
• For individuals with five copies of
• Age <2 mos: 0.15 mg/kg
• Age 2 mos to <2 yrs: 0.2 mg/kg
• Age ≥2 yrs w/weight <20 kg: 0.25 mg/kg
• Age ≥2 yrs w/weight>20 kg: 5 mg
• Evrysdi
• In animal studies, use during pregnancy resulted in teratogenic effects, incl fetal demise & reproductive impairment in offspring.
• 12 mg per dose
• Intrathecal loading doses every 14 days for total of 3 loading doses
• 4th loading dose 30 days after 3rd dose
• Then, maintenance doses every 4 mos
• Side effects are primarily related to mode of delivery (lumbar puncture).
• Monitor for thrombocytopenia/coagulation abnormalities & renal toxicity.
• Assessment of liver function prior to infusion is recommended.
• Care should be taken in providing this therapy to persons w/pre-existing liver impairment.
## Supportive Care
Supportive treatment of children with SMA is guided by the underlying subtype but should be individualized to the affected person and their current functional status (nonsitter, sitter, or walker) [
Spinal Muscular Atrophy: Treatment of Manifestations
Most untreated persons w/SMA I have a gastrostomy tube by age 12 mos.
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or bulbar dysfunction
Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, particularly during acute illness
Suctioning of secretions, careful use of medications
Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/SMA) appears to ↓ pulmonary complications.
For hypoventilation as demonstrated by hypercarbia or on sleep study
Has been shown to improve sleep breathing parameters in those w/SMA I & II
BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
Use of spinal orthosis for curvatures >20 degrees prior to surgical intervention is common.
Important consideration in spinal surgery: leave a window for possibility of intrathecal administration of future treatments.
For gradual outpatient distractions controlled by an external remote device
May ↓ need for repeated surgery
BiPAP = bilevel positive airway pressure; IV = intravenous; SMA = spinal muscular atrophy
In those who receive supportive care only [
See
Options should be discussed with parents/caregivers before respiratory failure occurs.
The type of respiratory support is dependent on the individual's respiratory status, quality-of-life goals, and access to equipment.
Noninvasive pulmonary intervention should be incorporated into the management of all types of SMA.
There is insufficient evidence that spinal orthotics alter scoliosis in SMA.
A small case series of individuals with neuromuscular disorders (2 of whom had SMA) evaluated magnetically controlled growing rods and pulmonary function. Affected individuals showed an improvement in forced vital capacity and forced expired volume in 1 second postoperatively with spinal deformity correction, with very few complications [
• Most untreated persons w/SMA I have a gastrostomy tube by age 12 mos.
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia &/or bulbar dysfunction
• Incl mechanical in-exsufflator in conjunction w/suctioning & chest physiotherapy, particularly during acute illness
• Suctioning of secretions, careful use of medications
• Use of mechanical in-exsufflation in treatment of children w/neuromuscular diseases (incl those w/SMA) appears to ↓ pulmonary complications.
• For hypoventilation as demonstrated by hypercarbia or on sleep study
• Has been shown to improve sleep breathing parameters in those w/SMA I & II
• BiPAP may improve chest wall & lung development, which may ↓ lung infections & pulmonary comorbidity.
• Use of spinal orthosis for curvatures >20 degrees prior to surgical intervention is common.
• Important consideration in spinal surgery: leave a window for possibility of intrathecal administration of future treatments.
• For gradual outpatient distractions controlled by an external remote device
• May ↓ need for repeated surgery
## Surveillance
Where available, targeted therapy should be initiated as soon as possible for eligible individuals. A treatment algorithm for the evaluation of presymptomatic infants has been published [
For those who are receiving a targeted therapy, review of prescribing information and the package insert is suggested, as recommendations for ongoing surveillance are changing rapidly for each targeted therapy. Both potential side effects and new phenotypes associated with targeted treatments continue to emerge.
Individuals with SMA are evaluated at least every six months; weaker children are evaluated more frequently.
Multidisciplinary surveillance at each visit includes assessments of nutritional state, respiratory function, motor function, and orthopedic status (spine, hips, and joint range of motion) to help determine appropriate interventions.
## Agents/Circumstances to Avoid
Prolonged fasting should be avoided, particularly in the acutely ill infant with SMA [
## Evaluation of Relatives at Risk
It is appropriate to determine the genetic status of younger, apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of targeted treatment and preventive measures.
See
## Pregnancy Management
There have been several published studies surveying the pregnancy experience of women with SMA [
There are no adequate data on the developmental risk associated with the use of nusinersen in pregnant women. When nusinersen was administered by subcutaneous injection to mice throughout pregnancy and lactation, developmental toxicity (long-term neurobehavioral impairment) was observed at all doses tested. There has been one reported case of a pregnancy that occurred during treatment with nusinersen [
No human pregnancies have been reported to have occurred during/after treatment with risdiplam. Teratogenic effects have been seen in studies of pregnant animals, including fetal demise, malformations, and reproductive impairments in the surviving offspring. Based on the results from animal studies, risdiplam use should be avoided in pregnant women. It is unknown if risdiplam is excreted in human breast milk, but it is excreted in the milk of lactating animals.
There have not been any reported cases of pregnant women with SMA treated with onasemnogene abeparvovec-xioi. No animal studies have been performed evaluating the reproductive risks or possible fetal toxicity of use of onasemnogene abeparvovec-xioi in pregnancy.
## Therapies Under Investigation
A number of different therapeutic approaches are in development, including further studies on the approved therapeutics discussed above. See the
Reldesemtiv is a tropinin complex activator proposed to cause increased muscle force output [
At least three myostatin inhibitor agents are currently in clinical trials for use in SMA. Results have not been published, but long-term extension studies are under way.
Search
## Genetic Counseling
Spinal muscular atrophy is inherited in an autosomal recessive manner.
Approximately 98% of parents of an affected child are heterozygotes (i.e., carriers of one
About 2% of parents are not carriers of an
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has an approximately 25% chance of being affected, an approximately 50% chance of being an asymptomatic carrier, and an approximately 25% chance of being unaffected and not a carrier.
Note: Recurrence risk in sibs is the same (i.e., ~25%) if one parent of the proband has a [2+0]
Recurrence risk in sibs of a proband with one pathogenic variant known to have been inherited from a carrier parent and one apparently
The offspring of an individual with SMA are obligate heterozygotes (carriers) for an
The reproductive partner of an individual with SMA should be offered carrier testing. If the partner shows at least two
Molecular genetic testing to determine carrier status is recommended for:
Parents of more than one child with molecularly confirmed SMA;
Parents of a child with molecularly confirmed SMA who represents a simplex case (i.e., a single occurrence in a family);
Parents of a child with suspected but not molecularly confirmed SMA;
Persons not known to have a family history of SMA (see
Note: Preconception carrier screening for SMA in individuals with and without a family history of SMA has been recommended by the
About 4% of carriers have two copies of
In the United States pan ethnic population, the calculated a priori carrier frequency is 1/54 with a detection rate of 91.2%. Therefore, an individual from this pan ethnic population with normal
If exon 7 is found to be deleted from one copy of
If exon 7 is found to be deleted from one copy of
The parent in whom the exon 7
Note: (1) Testing additional family members of the parent with the [2+0]
The child may have a
Non-paternity
If the child is confirmed to have exon 7 deleted from one copy of
Typically, one parent is found to have the
Molecular genetic testing for the intragenic
If the intragenic
If the intragenic
A
Gonadal mosaicism for the intragenic
Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
If DNA is not available, perform
If exon 7 is found to be deleted from one copy of
If exon 7 is found to be deleted from one copy of
If exon 7 is not found to be deleted from one copy of
Preconception carrier screening for SMA in individuals not known to have a family history of SMA has been recommended by multiple national physician organizations. Carrier screening for persons not known to have a family history of SMA requires
Note: In the general population most people have one copy of
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.
Note: Interpretation of test results and prediction of clinical findings in an affected child may be difficult and should be done in the context of formal genetic counseling.
• Approximately 98% of parents of an affected child are heterozygotes (i.e., carriers of one
• About 2% of parents are not carriers of an
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has an approximately 25% chance of being affected, an approximately 50% chance of being an asymptomatic carrier, and an approximately 25% chance of being unaffected and not a carrier.
• Note: Recurrence risk in sibs is the same (i.e., ~25%) if one parent of the proband has a [2+0]
• Recurrence risk in sibs of a proband with one pathogenic variant known to have been inherited from a carrier parent and one apparently
• The offspring of an individual with SMA are obligate heterozygotes (carriers) for an
• The reproductive partner of an individual with SMA should be offered carrier testing. If the partner shows at least two
• Parents of more than one child with molecularly confirmed SMA;
• Parents of a child with molecularly confirmed SMA who represents a simplex case (i.e., a single occurrence in a family);
• Parents of a child with suspected but not molecularly confirmed SMA;
• Persons not known to have a family history of SMA (see
• About 4% of carriers have two copies of
• In the United States pan ethnic population, the calculated a priori carrier frequency is 1/54 with a detection rate of 91.2%. Therefore, an individual from this pan ethnic population with normal
• If exon 7 is found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• Typically, one parent is found to have the
• Molecular genetic testing for the intragenic
• If the intragenic
• If the intragenic
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• If exon 7 is found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• If exon 7 is not found to be deleted from one copy of
• 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
Spinal muscular atrophy is inherited in an autosomal recessive manner.
## Risk to Family Members
Approximately 98% of parents of an affected child are heterozygotes (i.e., carriers of one
About 2% of parents are not carriers of an
Heterozygotes are asymptomatic and are not at risk of developing the disorder.
At conception, each sib of an affected individual has an approximately 25% chance of being affected, an approximately 50% chance of being an asymptomatic carrier, and an approximately 25% chance of being unaffected and not a carrier.
Note: Recurrence risk in sibs is the same (i.e., ~25%) if one parent of the proband has a [2+0]
Recurrence risk in sibs of a proband with one pathogenic variant known to have been inherited from a carrier parent and one apparently
The offspring of an individual with SMA are obligate heterozygotes (carriers) for an
The reproductive partner of an individual with SMA should be offered carrier testing. If the partner shows at least two
• Approximately 98% of parents of an affected child are heterozygotes (i.e., carriers of one
• About 2% of parents are not carriers of an
• Heterozygotes are asymptomatic and are not at risk of developing the disorder.
• At conception, each sib of an affected individual has an approximately 25% chance of being affected, an approximately 50% chance of being an asymptomatic carrier, and an approximately 25% chance of being unaffected and not a carrier.
• Note: Recurrence risk in sibs is the same (i.e., ~25%) if one parent of the proband has a [2+0]
• Recurrence risk in sibs of a proband with one pathogenic variant known to have been inherited from a carrier parent and one apparently
• The offspring of an individual with SMA are obligate heterozygotes (carriers) for an
• The reproductive partner of an individual with SMA should be offered carrier testing. If the partner shows at least two
## Carrier Detection
Molecular genetic testing to determine carrier status is recommended for:
Parents of more than one child with molecularly confirmed SMA;
Parents of a child with molecularly confirmed SMA who represents a simplex case (i.e., a single occurrence in a family);
Parents of a child with suspected but not molecularly confirmed SMA;
Persons not known to have a family history of SMA (see
Note: Preconception carrier screening for SMA in individuals with and without a family history of SMA has been recommended by the
About 4% of carriers have two copies of
In the United States pan ethnic population, the calculated a priori carrier frequency is 1/54 with a detection rate of 91.2%. Therefore, an individual from this pan ethnic population with normal
If exon 7 is found to be deleted from one copy of
If exon 7 is found to be deleted from one copy of
The parent in whom the exon 7
Note: (1) Testing additional family members of the parent with the [2+0]
The child may have a
Non-paternity
If the child is confirmed to have exon 7 deleted from one copy of
Typically, one parent is found to have the
Molecular genetic testing for the intragenic
If the intragenic
If the intragenic
A
Gonadal mosaicism for the intragenic
Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
If DNA is not available, perform
If exon 7 is found to be deleted from one copy of
If exon 7 is found to be deleted from one copy of
If exon 7 is not found to be deleted from one copy of
Preconception carrier screening for SMA in individuals not known to have a family history of SMA has been recommended by multiple national physician organizations. Carrier screening for persons not known to have a family history of SMA requires
Note: In the general population most people have one copy of
• Parents of more than one child with molecularly confirmed SMA;
• Parents of a child with molecularly confirmed SMA who represents a simplex case (i.e., a single occurrence in a family);
• Parents of a child with suspected but not molecularly confirmed SMA;
• Persons not known to have a family history of SMA (see
• About 4% of carriers have two copies of
• In the United States pan ethnic population, the calculated a priori carrier frequency is 1/54 with a detection rate of 91.2%. Therefore, an individual from this pan ethnic population with normal
• If exon 7 is found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• Typically, one parent is found to have the
• Molecular genetic testing for the intragenic
• If the intragenic
• If the intragenic
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• If exon 7 is found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• If exon 7 is not found to be deleted from one copy of
## Determining Carrier Status
If exon 7 is found to be deleted from one copy of
If exon 7 is found to be deleted from one copy of
The parent in whom the exon 7
Note: (1) Testing additional family members of the parent with the [2+0]
The child may have a
Non-paternity
If the child is confirmed to have exon 7 deleted from one copy of
Typically, one parent is found to have the
Molecular genetic testing for the intragenic
If the intragenic
If the intragenic
A
Gonadal mosaicism for the intragenic
Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
If DNA is not available, perform
If exon 7 is found to be deleted from one copy of
If exon 7 is found to be deleted from one copy of
If exon 7 is not found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• The parent in whom the exon 7
• Note: (1) Testing additional family members of the parent with the [2+0]
• The child may have a
• Non-paternity
• Typically, one parent is found to have the
• Molecular genetic testing for the intragenic
• If the intragenic
• If the intragenic
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• A
• Gonadal mosaicism for the intragenic
• Non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption.
• If exon 7 is found to be deleted from one copy of
• If exon 7 is found to be deleted from one copy of
• If exon 7 is not found to be deleted from one copy of
## Population Screening
Preconception carrier screening for SMA in individuals not known to have a family history of SMA has been recommended by multiple national physician organizations. Carrier screening for persons not known to have a family history of SMA requires
Note: In the general population most people have one copy of
## 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
Note: Interpretation of test results and prediction of clinical findings in an affected child may be difficult and should be done in the context of formal genetic counseling.
## Resources
Health Resources & Services Administration
•
•
•
•
•
•
•
•
•
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Spinal Muscular Atrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinal Muscular Atrophy (
SMN protein is localized to novel nuclear structures called "gems"; gems appear similar to (and possibly interact with) coiled bodies, which are thought to play a role in the processing and metabolism of small nuclear RNAs [
SMN protein has also been reported to influence other cellular activities such as apoptosis and translational regulation [
Spinal muscular atrophy (SMA) may be the result of a genetic defect in the biogenesis and trafficking of the spliceosomal snRNP complexes. Mutated SMN protein, such as that found in individuals with SMA, lacks the splicing-regeneration activity of wild type SMN protein. Reduced SMN protein lowers the capacity of cells to assemble the snRNPs, which leads to altered levels of spliceosomal components and defects in splicing, and impaired capacity to produce specific mRNAs and their encoded proteins that are necessary for cellular growth and function. It remains unclear how a defect of splicing results in a motor neuron-specific disorder [
SMA is caused by loss of
Other terms that have been used to identify
Other terms that have been used to identify
For a detailed summary of gene and protein information, see
• Other terms that have been used to identify
• Other terms that have been used to identify
## Molecular Pathogenesis
SMN protein is localized to novel nuclear structures called "gems"; gems appear similar to (and possibly interact with) coiled bodies, which are thought to play a role in the processing and metabolism of small nuclear RNAs [
SMN protein has also been reported to influence other cellular activities such as apoptosis and translational regulation [
Spinal muscular atrophy (SMA) may be the result of a genetic defect in the biogenesis and trafficking of the spliceosomal snRNP complexes. Mutated SMN protein, such as that found in individuals with SMA, lacks the splicing-regeneration activity of wild type SMN protein. Reduced SMN protein lowers the capacity of cells to assemble the snRNPs, which leads to altered levels of spliceosomal components and defects in splicing, and impaired capacity to produce specific mRNAs and their encoded proteins that are necessary for cellular growth and function. It remains unclear how a defect of splicing results in a motor neuron-specific disorder [
SMA is caused by loss of
Other terms that have been used to identify
Other terms that have been used to identify
For a detailed summary of gene and protein information, see
• Other terms that have been used to identify
• Other terms that have been used to identify
## Chapter Notes
Erika L Finanger, MD (2016-present)Meganne E Leach, MSN, PNP (2019-present)Thomas W Prior, PhD, FACMG (2000-present)Barry S Russman, MD; Oregon Health and Science University (2000-2016)
19 September 2024 (ma) Comprehensive update posted live
14 November 2019 (ma) Comprehensive update posted live
22 December 2016 (sw) Comprehensive update posted live
14 November 2013 (me) Comprehensive update posted live
27 January 2011 (me) Comprehensive update posted live
3 April 2006 (me) Comprehensive update posted live
17 October 2003 (me) Comprehensive update posted live
24 February 2000 (me) Review posted live
28 February 1999 (br) Original submission
• 19 September 2024 (ma) Comprehensive update posted live
• 14 November 2019 (ma) Comprehensive update posted live
• 22 December 2016 (sw) Comprehensive update posted live
• 14 November 2013 (me) Comprehensive update posted live
• 27 January 2011 (me) Comprehensive update posted live
• 3 April 2006 (me) Comprehensive update posted live
• 17 October 2003 (me) Comprehensive update posted live
• 24 February 2000 (me) Review posted live
• 28 February 1999 (br) Original submission
## Author History
Erika L Finanger, MD (2016-present)Meganne E Leach, MSN, PNP (2019-present)Thomas W Prior, PhD, FACMG (2000-present)Barry S Russman, MD; Oregon Health and Science University (2000-2016)
## Revision History
19 September 2024 (ma) Comprehensive update posted live
14 November 2019 (ma) Comprehensive update posted live
22 December 2016 (sw) Comprehensive update posted live
14 November 2013 (me) Comprehensive update posted live
27 January 2011 (me) Comprehensive update posted live
3 April 2006 (me) Comprehensive update posted live
17 October 2003 (me) Comprehensive update posted live
24 February 2000 (me) Review posted live
28 February 1999 (br) Original submission
• 19 September 2024 (ma) Comprehensive update posted live
• 14 November 2019 (ma) Comprehensive update posted live
• 22 December 2016 (sw) Comprehensive update posted live
• 14 November 2013 (me) Comprehensive update posted live
• 27 January 2011 (me) Comprehensive update posted live
• 3 April 2006 (me) Comprehensive update posted live
• 17 October 2003 (me) Comprehensive update posted live
• 24 February 2000 (me) Review posted live
• 28 February 1999 (br) Original submission
## Key Sections in This
## References
Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28:197-207. [
Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis 2018;5:145-58. [
Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103-115. [
• Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28:197-207. [
• Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis 2018;5:145-58. [
• Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103-115. [
## Published Guidelines / Consensus Statements
Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28:197-207. [
Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis 2018;5:145-58. [
Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103-115. [
• Finkel RS, Mercuri E, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 2: pulmonary acute care; medications, supplements and immunizations; other organ systems; and ethics. Neuromuscul Disord. 2018;28:197-207. [
• Glascock J, Sampson J, Haidet-Phillips A, Connolly A, Darras B, Day J, Finkel R, Howell RR, Klinger K, Kuntz N, Prior T, Shieh PB, Crawford TO, Kerr D, Jarecki J. Treatment algorithm for infants diagnosed with spinal muscular atrophy through newborn screening. J Neuromuscul Dis 2018;5:145-58. [
• Mercuri E, Finkel RS, Muntoni F, Wirth B, Montes J, Main M, Mazzone ES, Vitale M, Snyder B, Quijano-Roy S, Bertini E, Davis RH, Meyer OH, Simonds AK, Schroth MK, Graham RJ, Kirschner J, Iannaccone ST, Crawford TO, Woods S, Qian Y, Sejersen T; SMA Care Group. Diagnosis and management of spinal muscular atrophy: part 1: recommendations for diagnosis, rehabilitation, orthopedic and nutritional care. Neuromuscul Disord. 2018;28:103-115. [
## Literature Cited
Diagnostic algorithm for spinal muscular atrophy
CK = creatine kinase; EMG = electromyography; MLPA = multiplex ligation-dependent probe amplification; NCV = nerve conduction velocity; NMD = neuromuscular disorder; SMA = spinal muscular atrophy; qPCR = quantitative polymerase chain reaction; WES = whole-exome sequencing; WGS = whole-genome sequencing
|
[] |
24/2/2000
|
19/9/2024
|
3/12/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
smdcf
|
smdcf
|
[
"Spondylometaphyseal Dysplasia Sutcliffe",
"Spondylometaphyseal Dysplasia Sutcliffe",
"Collagen alpha-1(II) chain",
"Fibronectin",
"COL2A1",
"FN1",
"Spondylometaphyseal Dysplasia, Corner Fracture Type"
] |
Spondylometaphyseal Dysplasia, Corner Fracture Type
|
Jade England, Philippe M Campeau
|
Summary Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is a skeletal dysplasia characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Radiographic features include enlargement and corner fracture-like lesions of the metaphyses, developmental coxa vara, shortened long bones, scoliosis, and vertebral anomalies. Limited joint mobility and chronic pain are common. Vision impairment and glaucoma have been reported. The diagnosis of SMDCF is established in a proband with characteristic clinical and radiographic features including short stature, corner fracture-like lesions, developmental coxa vara, and vertebral anomalies. Identification of a heterozygous pathogenic variant in SMDCF is inherited in an autosomal dominant manner. An individual with SMDCF may have an affected parent or, somewhat more frequently, may have the disorder as the result of a
|
## Diagnosis
Formal diagnostic criteria for spondylometaphyseal dysplasia, corner fracture type (SMDCF) have not been established.
SMDCF
Mild-to-moderate short stature noted at birth in some individuals with short lower extremities and/or short trunk
Mild-to-severe scoliosis
Genu varum or valgum
Pectus carinatum
Limited mobility and/or musculoskeletal pain
Vision impairment (e.g., myopia, borderline increased intraocular pressure, Brown syndrome [strabismus caused by dysfunction of the superior oblique muscle])
Normal hearing
Normal intelligence
Irregular metaphyses
Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
Enlargement of the metaphyses of the long bones
Developmental coxa vara (i.e., varus deformity of the proximal femora that develops during early childhood) is typically identified by age six years and was described in one individual at birth [
Scoliosis
Vertebral anomalies (platyspondyly, hypoplasia, ovoid vertebral bodies, biconcave vertebral bodies, anterior wedging, biconvex vertebral bodies, irregular vertebral bodies, hypoplasia, narrow intervertebral spaces, vertebral fusion)
Shortening of the long bones. This finding can be detected on prenatal ultrasound in some individuals.
Leg length discrepancy
Bowing of the tibia
Epiphyses are usually normal.
The diagnosis of SMDCF
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 clinical and radiographic findings suggest the diagnosis of SMDCF, 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 spondylometaphyseal dysplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spondylometaphyseal Dysplasia, Corner Fracture Type
NA = not applicable; SMDCF = spondylometaphyseal dysplasia, corner fracture type
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.
There is evidence of locus heterogeneity (i.e., this disorder can be caused by pathogenic variant[s] in other as-yet-unidentified genes) [
• Mild-to-moderate short stature noted at birth in some individuals with short lower extremities and/or short trunk
• Mild-to-severe scoliosis
• Genu varum or valgum
• Pectus carinatum
• Limited mobility and/or musculoskeletal pain
• Vision impairment (e.g., myopia, borderline increased intraocular pressure, Brown syndrome [strabismus caused by dysfunction of the superior oblique muscle])
• Normal hearing
• Normal intelligence
• Irregular metaphyses
• Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
• Enlargement of the metaphyses of the long bones
• Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
• Enlargement of the metaphyses of the long bones
• Developmental coxa vara (i.e., varus deformity of the proximal femora that develops during early childhood) is typically identified by age six years and was described in one individual at birth [
• Scoliosis
• Vertebral anomalies (platyspondyly, hypoplasia, ovoid vertebral bodies, biconcave vertebral bodies, anterior wedging, biconvex vertebral bodies, irregular vertebral bodies, hypoplasia, narrow intervertebral spaces, vertebral fusion)
• Shortening of the long bones. This finding can be detected on prenatal ultrasound in some individuals.
• Leg length discrepancy
• Bowing of the tibia
• Epiphyses are usually normal.
• Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
• Enlargement of the metaphyses of the long bones
• For an introduction to multigene panels click
## Suggestive Findings
SMDCF
Mild-to-moderate short stature noted at birth in some individuals with short lower extremities and/or short trunk
Mild-to-severe scoliosis
Genu varum or valgum
Pectus carinatum
Limited mobility and/or musculoskeletal pain
Vision impairment (e.g., myopia, borderline increased intraocular pressure, Brown syndrome [strabismus caused by dysfunction of the superior oblique muscle])
Normal hearing
Normal intelligence
Irregular metaphyses
Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
Enlargement of the metaphyses of the long bones
Developmental coxa vara (i.e., varus deformity of the proximal femora that develops during early childhood) is typically identified by age six years and was described in one individual at birth [
Scoliosis
Vertebral anomalies (platyspondyly, hypoplasia, ovoid vertebral bodies, biconcave vertebral bodies, anterior wedging, biconvex vertebral bodies, irregular vertebral bodies, hypoplasia, narrow intervertebral spaces, vertebral fusion)
Shortening of the long bones. This finding can be detected on prenatal ultrasound in some individuals.
Leg length discrepancy
Bowing of the tibia
Epiphyses are usually normal.
• Mild-to-moderate short stature noted at birth in some individuals with short lower extremities and/or short trunk
• Mild-to-severe scoliosis
• Genu varum or valgum
• Pectus carinatum
• Limited mobility and/or musculoskeletal pain
• Vision impairment (e.g., myopia, borderline increased intraocular pressure, Brown syndrome [strabismus caused by dysfunction of the superior oblique muscle])
• Normal hearing
• Normal intelligence
• Irregular metaphyses
• Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
• Enlargement of the metaphyses of the long bones
• Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
• Enlargement of the metaphyses of the long bones
• Developmental coxa vara (i.e., varus deformity of the proximal femora that develops during early childhood) is typically identified by age six years and was described in one individual at birth [
• Scoliosis
• Vertebral anomalies (platyspondyly, hypoplasia, ovoid vertebral bodies, biconcave vertebral bodies, anterior wedging, biconvex vertebral bodies, irregular vertebral bodies, hypoplasia, narrow intervertebral spaces, vertebral fusion)
• Shortening of the long bones. This finding can be detected on prenatal ultrasound in some individuals.
• Leg length discrepancy
• Bowing of the tibia
• Epiphyses are usually normal.
• Corner fracture-like lesions. The lesions can be asymmetric and are most often seen at the proximal and distal tibiae, distal radii, proximal humeri, and distal femora. These are thought to be irregular ossification centers and/or secondary ossification centers. They tend to enlarge in infancy and then disappear once the growth plates fuse at the time of skeletal maturation. Fusion of the growth plates occurs between age 12 and 16 years in females and age 14 and 19 years in males [
• Enlargement of the metaphyses of the long bones
## Establishing the Diagnosis
The diagnosis of SMDCF
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 clinical and radiographic findings suggest the diagnosis of SMDCF, 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 spondylometaphyseal dysplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spondylometaphyseal Dysplasia, Corner Fracture Type
NA = not applicable; SMDCF = spondylometaphyseal dysplasia, corner fracture type
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.
There is evidence of locus heterogeneity (i.e., this disorder can be caused by pathogenic variant[s] in other as-yet-unidentified genes) [
• For an introduction to multigene panels click
## Option 1
When the clinical and radiographic findings suggest the diagnosis of SMDCF, 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 spondylometaphyseal dysplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spondylometaphyseal Dysplasia, Corner Fracture Type
NA = not applicable; SMDCF = spondylometaphyseal dysplasia, corner fracture type
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.
There is evidence of locus heterogeneity (i.e., this disorder can be caused by pathogenic variant[s] in other as-yet-unidentified genes) [
## Clinical Characteristics
Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Complications include coxa vara, scoliosis, and chronic pain. Some individuals have ocular manifestations. To date, approximately 50 individuals with spondylometaphyseal dysplasia, corner fracture type (SMDCF) have been reported. A heterozygous
Spondylometaphyseal Dysplasia, Corner Fracture Type: Frequency of Select Features
SMDCF = spondylometaphyseal dysplasia, corner fracture type
Almost half of the individuals were born premature.
Because of the association of SMDCF with scoliosis and short stature, there is a risk for chest deformity; pectus carinatum is reported. One individual with
Genu valgum and genu varum are both described and may require surgical treatment [
There have been reports of chronic pain, especially in the legs, in individuals with SMDCF. All individuals described were ambulatory except for one individual who became wheelchair bound in adulthood because of painful joint limitations [
No clinically relevant genotype-phenotype correlations for
Penetrance is 100%.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
SMDCF is a rare disorder. Approximately 50 individuals have been described in the literature [
## Clinical Description
Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is characterized by short stature and a waddling gait in early childhood. Short stature may be present at birth or develop in early infancy. Individuals may present with short limbs and/or short trunk. Complications include coxa vara, scoliosis, and chronic pain. Some individuals have ocular manifestations. To date, approximately 50 individuals with spondylometaphyseal dysplasia, corner fracture type (SMDCF) have been reported. A heterozygous
Spondylometaphyseal Dysplasia, Corner Fracture Type: Frequency of Select Features
SMDCF = spondylometaphyseal dysplasia, corner fracture type
Almost half of the individuals were born premature.
Because of the association of SMDCF with scoliosis and short stature, there is a risk for chest deformity; pectus carinatum is reported. One individual with
Genu valgum and genu varum are both described and may require surgical treatment [
There have been reports of chronic pain, especially in the legs, in individuals with SMDCF. All individuals described were ambulatory except for one individual who became wheelchair bound in adulthood because of painful joint limitations [
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations for
## Penetrance
Penetrance is 100%.
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
SMDCF is a rare disorder. Approximately 50 individuals have been described in the literature [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Note: Type II collagen disorders are typically inherited in an autosomal dominant manner; however, autosomal recessive inheritance of type II collagen disorders has been reported in several families to date.
Odontoid hypoplasia
Myopia
Pectus carinatum
Platyspondyly
Scoliosis
Short trunk
Metaphyseal irregularity: corner fracture-like lesions
Coxa vara
Genu valgum
Cleft palate
Splayed ribs
Epiphyseal delay
Myopia
Platyspondyly
Short trunk
Coxa vara
Cataracts
Retinal detachment
Cleft palate
Conductive hearing loss
Delayed epiphyseal ossification
Abnormal epiphyses
Pectus carinatum
Platyspondyly
Short stature
Sensorineural hearing loss
Absent styloid processes
Hand & foot abnormalities
Short ulna
Myopia
Odontoid hypoplasia
Pectus carinatum
Ovoid vertebral bodies
Platyspondyly
Scoliosis
Short trunk
Coxa vara
Retinal detachment
Vitreoretinal degeneration
Cleft palate
Cervical myelopathy
Hypotonia
Flattened epiphyses
Talipes equinovarus
Platyspondyly
Scoliosis
Coxa vara
Normal stature
Short metacarpals
Hypoplastic/dysplastic toes & metatarsals
SMDCF = spondylometaphyseal dysplasia, corner fracture type
Note: In the 2023 Nosology of Genetic Skeletal Disorders [
Allelic Disorders Not in the Differential Diagnosis of Spondylometaphyseal Dysplasia, Corner Fracture Type
Note:
• Odontoid hypoplasia
• Myopia
• Pectus carinatum
• Platyspondyly
• Scoliosis
• Short trunk
• Metaphyseal irregularity: corner fracture-like lesions
• Coxa vara
• Genu valgum
• Cleft palate
• Splayed ribs
• Epiphyseal delay
• Myopia
• Platyspondyly
• Short trunk
• Coxa vara
• Cataracts
• Retinal detachment
• Cleft palate
• Conductive hearing loss
• Delayed epiphyseal ossification
• Abnormal epiphyses
• Pectus carinatum
• Platyspondyly
• Short stature
• Sensorineural hearing loss
• Absent styloid processes
• Hand & foot abnormalities
• Short ulna
• Myopia
• Odontoid hypoplasia
• Pectus carinatum
• Ovoid vertebral bodies
• Platyspondyly
• Scoliosis
• Short trunk
• Coxa vara
• Retinal detachment
• Vitreoretinal degeneration
• Cleft palate
• Cervical myelopathy
• Hypotonia
• Flattened epiphyses
• Talipes equinovarus
• Platyspondyly
• Scoliosis
• Coxa vara
• Normal stature
• Short metacarpals
• Hypoplastic/dysplastic toes & metatarsals
## Differential Diagnosis
Genetic disorders with overlapping clinical and radiographic features of spondylometaphyseal dysplasia, corner fracture type (SMDCF) include those listed in
Genes of Interest in the Differential Diagnosis of Spondylometaphyseal Dysplasia, Corner Fracture Type
Short stature
Corner fractures, osteoporosis
Microcephaly, kinky & sparse hair, skin hypopigmentation, skin/joint laxity, neurologic degeneration, low serum copper & ceruloplasmin concentration
Wormian bones
Note: Subcutaneous injections of copper histidinate beginning by age 28 days
Short stature, short limbs
Platyspondyly, coxa vara, metaphyseal dysplasia, short metacarpals
Retinal abnormalities, progressive retinal degeneration, optic atrophy, cone-rod dystrophy, nystagmus, splenomegaly
Small thorax & thoracic deformation, lacy iliac wings, narrow sacrosciatic notch, short femoral neck
Short stature
Platyspondyly, corner fracture-like lesions, metaphyseal abnormalities, coxa vara, genu varum
Short stature, scoliosis, short trunk, pectus carinatum, joint pain, normal intelligence
Odontoid hypoplasia, platyspondyly, widened metaphyses, genu valgum
Coarse facial features, corneal opacities, hearing loss, hepatomegaly, hypermobile joints, abnormal glycosaminoglycan excretion in urine
Cervical subluxation, rib abnormalities, compression of spinal cord, epiphyseal involvement, coxa valga, hip dislocation, ulnar deviation of wrists
Short stature, scoliosis, short limbs
Ovoid vertebral bodies, platyspondyly, coxa vara, metaphyseal involvement, tibial & femoral bowing
Cone-rod dystrophy, macular involvement, nystagmus
Rib cupping, flat acetabuli, hypoplastic inferior ilia, narrow sacrosciatic notch, brachydactyly, short metacarpals
Short stature, facial dysmorphism
Corner fracture-like lesions, osteopenia
50% of affected children are below 3rd centile for height.
Ovoid vertebral bodies, coxa vara, metaphyseal dysplasia of long bones, osteoporosis
Small head circumference, poor weight gain, exocrine pancreatic deficiency, bone marrow failure, cognitive &/or behavioral impairment
Narrow thorax & costal abnormalities, narrow sacroiliac notch, delayed skeletal maturation
Short trunk, pectus carinatum, scoliosis
Odontoid hypoplasia, irregular metaphyses, coxa vara
Marked platyspondyly & kyphoscoliosis, severe involvement of short tubular bones, hand/carpal/foot abnormalities
Not assoc w/corner fractures
Short trunk, scoliosis
Platyspondyly, proximal femoral metaphyseal dysplasia
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; SMDCF = spondylometaphyseal dysplasia, corner fracture type; XL = X-linked
Corrected for prematurity/gestational age
Pathogenic variants in
SDS caused by pathogenic variants in
Unlike SMDCF, SMD, Duetting type is also characterized by bipartite trochlea, brachydactyly, coxa valga, dolichocephaly, irregular patellar margins, osteoporotic tarsals and metatarsals, sclerotic costochondral joints, severe metaphyseal changes of the femoral neck, and tongue-like deformity of the vertebral bodies.
• Short stature
• Corner fractures, osteoporosis
• Microcephaly, kinky & sparse hair, skin hypopigmentation, skin/joint laxity, neurologic degeneration, low serum copper & ceruloplasmin concentration
• Wormian bones
• Note: Subcutaneous injections of copper histidinate beginning by age 28 days
• Short stature, short limbs
• Platyspondyly, coxa vara, metaphyseal dysplasia, short metacarpals
• Retinal abnormalities, progressive retinal degeneration, optic atrophy, cone-rod dystrophy, nystagmus, splenomegaly
• Small thorax & thoracic deformation, lacy iliac wings, narrow sacrosciatic notch, short femoral neck
• Short stature
• Platyspondyly, corner fracture-like lesions, metaphyseal abnormalities, coxa vara, genu varum
• Short stature, scoliosis, short trunk, pectus carinatum, joint pain, normal intelligence
• Odontoid hypoplasia, platyspondyly, widened metaphyses, genu valgum
• Coarse facial features, corneal opacities, hearing loss, hepatomegaly, hypermobile joints, abnormal glycosaminoglycan excretion in urine
• Cervical subluxation, rib abnormalities, compression of spinal cord, epiphyseal involvement, coxa valga, hip dislocation, ulnar deviation of wrists
• Short stature, scoliosis, short limbs
• Ovoid vertebral bodies, platyspondyly, coxa vara, metaphyseal involvement, tibial & femoral bowing
• Cone-rod dystrophy, macular involvement, nystagmus
• Rib cupping, flat acetabuli, hypoplastic inferior ilia, narrow sacrosciatic notch, brachydactyly, short metacarpals
• Short stature, facial dysmorphism
• Corner fracture-like lesions, osteopenia
• 50% of affected children are below 3rd centile for height.
• Ovoid vertebral bodies, coxa vara, metaphyseal dysplasia of long bones, osteoporosis
• Small head circumference, poor weight gain, exocrine pancreatic deficiency, bone marrow failure, cognitive &/or behavioral impairment
• Narrow thorax & costal abnormalities, narrow sacroiliac notch, delayed skeletal maturation
• Short trunk, pectus carinatum, scoliosis
• Odontoid hypoplasia, irregular metaphyses, coxa vara
• Marked platyspondyly & kyphoscoliosis, severe involvement of short tubular bones, hand/carpal/foot abnormalities
• Not assoc w/corner fractures
• Short trunk, scoliosis
• Platyspondyly, proximal femoral metaphyseal dysplasia
• Unlike SMDCF, SMD, Duetting type is also characterized by bipartite trochlea, brachydactyly, coxa valga, dolichocephaly, irregular patellar margins, osteoporotic tarsals and metatarsals, sclerotic costochondral joints, severe metaphyseal changes of the femoral neck, and tongue-like deformity of the vertebral bodies.
## Management
No clinical practice guidelines for spondylometaphyseal dysplasia, corner fracture type (SMDCF) 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 SMDCF, the evaluations summarized in
Spondylometaphyseal Dysplasia, Corner Fracture Type: Recommended Evaluations Following Initial Diagnosis
To evaluate for cervical instability
If atlantoaxial instability is present, eval by anesthesiologist & pulmonary assessment (when indicated) prior to any surgery
MOI = mode of inheritance; PT = physical therapist; SMDCF = spondylometaphyseal dysplasia, corner fracture type
Recommendations are based on two individuals reported with this feature.
Recommendations are based on one individual reported with this feature.
Recommendations are based on the best practice guidelines regarding diagnosis and management of individuals with type II collagen disorders [
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
Spondylometaphyseal Dysplasia, Corner Fracture Type: Treatment of Manifestations
PT = physical therapist
Recommendations are based on a single individual reported with this feature.
Note: For individuals with
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Spondylometaphyseal Dysplasia, Corner Fracture Type: Recommended Surveillance
Recommendations are based on a single individual reported with this feature.
Avoid contact sports if atlantoaxial instability is present.
For individuals with joint pain, avoid activities that strain joints; instead, favor joint-friendly activities (e.g., swimming, cycling).
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 treatment for orthopedic and ophthalmologic complications. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Measurement of height, physical examination, and radiographs of the spine and limbs if the pathogenic variant in the family is not known.
See
Search
• To evaluate for cervical instability
• If atlantoaxial instability is present, eval by anesthesiologist & pulmonary assessment (when indicated) prior to any surgery
• Molecular genetic testing if the pathogenic variant in the family is known;
• Measurement of height, physical examination, and radiographs of the spine and limbs 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 SMDCF, the evaluations summarized in
Spondylometaphyseal Dysplasia, Corner Fracture Type: Recommended Evaluations Following Initial Diagnosis
To evaluate for cervical instability
If atlantoaxial instability is present, eval by anesthesiologist & pulmonary assessment (when indicated) prior to any surgery
MOI = mode of inheritance; PT = physical therapist; SMDCF = spondylometaphyseal dysplasia, corner fracture type
Recommendations are based on two individuals reported with this feature.
Recommendations are based on one individual reported with this feature.
Recommendations are based on the best practice guidelines regarding diagnosis and management of individuals with type II collagen disorders [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To evaluate for cervical instability
• If atlantoaxial instability is present, eval by anesthesiologist & pulmonary assessment (when indicated) prior to any surgery
## 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
Spondylometaphyseal Dysplasia, Corner Fracture Type: Treatment of Manifestations
PT = physical therapist
Recommendations are based on a single individual reported with this feature.
Note: For individuals with
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Spondylometaphyseal Dysplasia, Corner Fracture Type: Recommended Surveillance
Recommendations are based on a single individual reported with this feature.
## Agents/Circumstances to Avoid
Avoid contact sports if atlantoaxial instability is present.
For individuals with joint pain, avoid activities that strain joints; instead, favor joint-friendly activities (e.g., swimming, cycling).
## 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 treatment for orthopedic and ophthalmologic complications. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known;
Measurement of height, physical examination, and radiographs of the spine and limbs if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• Measurement of height, physical examination, and radiographs of the spine and limbs if the pathogenic variant in the family is not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is inherited in an autosomal dominant manner.
An individual with a clinical and/or molecular diagnosis of SMDCF may have an affected parent.
Somewhat more frequently, an individual diagnosed with SMDCF represents a simplex case (i.e., the only family member known to be affected). In 15 families in which the parents of a proband with
In ten of 14 evaluated families, the
In a single evaluated family, the
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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation [
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 SMDCF-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Phenotypic variability within families has been reported [
If the proband has a known SMDCF-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are unaffected based on appropriate clinical evaluation but their genetic status is unknown, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
Each child of an individual with SMDCF has a 50% risk of having SMDCF.
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMDCF 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 may suffer from serious sequelae and poor outcomes [
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.
Once the SMDCF-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 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.
• An individual with a clinical and/or molecular diagnosis of SMDCF may have an affected parent.
• Somewhat more frequently, an individual diagnosed with SMDCF represents a simplex case (i.e., the only family member known to be affected). In 15 families in which the parents of a proband with
• In ten of 14 evaluated families, the
• In a single evaluated family, the
• In ten of 14 evaluated families, the
• In a single evaluated family, the
• 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation [
• 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.
• In ten of 14 evaluated families, the
• In a single evaluated family, 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.
• If a parent of the proband is affected and/or is known to have the SMDCF-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Phenotypic variability within families has been reported [
• If the proband has a known SMDCF-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are unaffected based on appropriate clinical evaluation but their genetic status is unknown, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• Each child of an individual with SMDCF has a 50% risk of having SMDCF.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMDCF 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 may suffer from 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
Spondylometaphyseal dysplasia, corner fracture type (SMDCF) is inherited in an autosomal dominant manner.
## Risk to Family Members
An individual with a clinical and/or molecular diagnosis of SMDCF may have an affected parent.
Somewhat more frequently, an individual diagnosed with SMDCF represents a simplex case (i.e., the only family member known to be affected). In 15 families in which the parents of a proband with
In ten of 14 evaluated families, the
In a single evaluated family, the
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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation [
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 SMDCF-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Phenotypic variability within families has been reported [
If the proband has a known SMDCF-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are unaffected based on appropriate clinical evaluation but their genetic status is unknown, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
Each child of an individual with SMDCF has a 50% risk of having SMDCF.
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMDCF 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 may suffer from serious sequelae and poor outcomes [
• An individual with a clinical and/or molecular diagnosis of SMDCF may have an affected parent.
• Somewhat more frequently, an individual diagnosed with SMDCF represents a simplex case (i.e., the only family member known to be affected). In 15 families in which the parents of a proband with
• In ten of 14 evaluated families, the
• In a single evaluated family, the
• In ten of 14 evaluated families, the
• In a single evaluated family, the
• 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. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members due to a milder phenotypic presentation [
• 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.
• In ten of 14 evaluated families, the
• In a single evaluated family, 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.
• If a parent of the proband is affected and/or is known to have the SMDCF-related pathogenic variant identified in the proband, the risk to the sibs is 50%. Phenotypic variability within families has been reported [
• If the proband has a known SMDCF-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent and/or the parents are unaffected based on appropriate clinical evaluation but their genetic status is unknown, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [
• Each child of an individual with SMDCF has a 50% risk of having SMDCF.
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMDCF 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 may suffer from serious sequelae and poor outcomes [
## 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
Once the SMDCF-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 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
Spondylometaphyseal Dysplasia, Corner Fracture Type: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spondylometaphyseal Dysplasia, Corner Fracture Type (
The formation of fibronectin depends on
Pathogenic variants in the N-terminal assembly domain, necessary for fibronectin interaction to form fibrils, affect the assembly of the cell and lower the number of fibrils in the cell matrix [
Pathogenic variants in the III-2 domain, necessary for the assembly of fibronectin, result in similar levels of mutated mRNA and wild type mRNA but greatly reduced secretion of the abnormal protein [
Fibronectin is secreted by the liver; levels in the plasma of affected individuals is reduced [
Mutated fibronectin is exported from rough endoplasmic reticulum into vesicles and accumulates in mutated cells. There is an increase in intracellular fibronectin and a decrease in extracellular fibronectin levels. This impairs stem cell proliferation, mesenchymal condensation, and the differentiation of mesenchymal stem cells into chondrocytes [
Spondylometaphyseal Dysplasia, Corner Fracture Type: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
• Pathogenic variants in the N-terminal assembly domain, necessary for fibronectin interaction to form fibrils, affect the assembly of the cell and lower the number of fibrils in the cell matrix [
• Pathogenic variants in the III-2 domain, necessary for the assembly of fibronectin, result in similar levels of mutated mRNA and wild type mRNA but greatly reduced secretion of the abnormal protein [
• Fibronectin is secreted by the liver; levels in the plasma of affected individuals is reduced [
## Molecular Pathogenesis
The formation of fibronectin depends on
Pathogenic variants in the N-terminal assembly domain, necessary for fibronectin interaction to form fibrils, affect the assembly of the cell and lower the number of fibrils in the cell matrix [
Pathogenic variants in the III-2 domain, necessary for the assembly of fibronectin, result in similar levels of mutated mRNA and wild type mRNA but greatly reduced secretion of the abnormal protein [
Fibronectin is secreted by the liver; levels in the plasma of affected individuals is reduced [
Mutated fibronectin is exported from rough endoplasmic reticulum into vesicles and accumulates in mutated cells. There is an increase in intracellular fibronectin and a decrease in extracellular fibronectin levels. This impairs stem cell proliferation, mesenchymal condensation, and the differentiation of mesenchymal stem cells into chondrocytes [
Spondylometaphyseal Dysplasia, Corner Fracture Type: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes from
• Pathogenic variants in the N-terminal assembly domain, necessary for fibronectin interaction to form fibrils, affect the assembly of the cell and lower the number of fibrils in the cell matrix [
• Pathogenic variants in the III-2 domain, necessary for the assembly of fibronectin, result in similar levels of mutated mRNA and wild type mRNA but greatly reduced secretion of the abnormal protein [
• Fibronectin is secreted by the liver; levels in the plasma of affected individuals is reduced [
## Chapter Notes
Philippe Campeau laboratory:
Dr Campeau focuses on studying new skeletal dysplasias, new forms of epilepsy, and chromatin-remodeling disorders. His lab identifies disease-causing genes, studies the pathologic basis of disease in cells and mice, and strives to improve the management of children affected by these conditions, notably through clinical trials.
Philippe M Campeau, MD (2020-present)Jade England, MD, MSc (2020-present)Ashley McFarquhar, BSc; McGill University (2020-2025)
22 May 2025 (sw) Comprehensive update posted live
19 March 2020 (sw) Review posted live
3 July 2019 (pmc) Original submission
• 22 May 2025 (sw) Comprehensive update posted live
• 19 March 2020 (sw) Review posted live
• 3 July 2019 (pmc) Original submission
## Author Notes
Philippe Campeau laboratory:
Dr Campeau focuses on studying new skeletal dysplasias, new forms of epilepsy, and chromatin-remodeling disorders. His lab identifies disease-causing genes, studies the pathologic basis of disease in cells and mice, and strives to improve the management of children affected by these conditions, notably through clinical trials.
## Author History
Philippe M Campeau, MD (2020-present)Jade England, MD, MSc (2020-present)Ashley McFarquhar, BSc; McGill University (2020-2025)
## Revision History
22 May 2025 (sw) Comprehensive update posted live
19 March 2020 (sw) Review posted live
3 July 2019 (pmc) Original submission
• 22 May 2025 (sw) Comprehensive update posted live
• 19 March 2020 (sw) Review posted live
• 3 July 2019 (pmc) Original submission
## References
## Literature Cited
|
[] |
19/3/2020
|
22/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sms
|
sms
|
[
"del(17)(p11.2)",
"del(17)(p11.2)",
"Retinoic acid-induced protein 1",
"RAI1",
"Smith-Magenis Syndrome"
] |
Smith-Magenis Syndrome
|
Ann CM Smith, John Berens, Kerry E Boyd, Christine Brennan, Andrea Gropman, Barbara Haas-Givler, Christopher Vlangos, Rebecca Foster, Rachel Franciskovich, Santhosh Girirajan, Nancy Raitano Lee, Cora Taylor, Sinan Omer Turnacioglu, Sarah H Elsea
|
Summary Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbances, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. Most individuals function in the mild-to-moderate range of intellectual disability. Behavioral manifestations, including significant sleep disturbances, stereotypies, and maladaptive and self-injurious behaviors, are generally not recognized until age 18 months or older and continue to change until adulthood. Sensory issues are frequently noted, including avoidant behavior and repetitive seeking of specific textures, sounds, and experiences. Significant anxiety is common as are problems with executive function, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS. The diagnosis of SMS is established in a SMS is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for Smith-Magenis syndrome (SMS) have been published.
A subtly distinctive facial appearance that becomes more evident with age (See
Developmental delay and/or intellectual disability, including early speech delays (expressive delays greater than receptive speech) with or without associated hearing loss
A distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors, as well as self-injurious behaviors
Mild-to-moderate infantile-onset hypotonia
Feeding difficulties and poor growth
Sleep disturbances
Short stature (prepubertal)
Childhood-onset obesity
Scoliosis
Minor skeletal anomalies, including brachydactyly
Signs of peripheral neuropathy including infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor of upper extremity. In later childhood, a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap) may be apparent.
Ophthalmologic abnormalities including strabismus, progressive myopia, iris anomalies, microcornea, refractive errors, and retinal detachment. In adults, keratoconus and glaucoma are seen.
Otolaryngologic abnormalities including middle ear dysfunction (frequent otitis media, fluctuating hearing loss leading to tympanostomy tube placement), hyperacusis, laryngeal anomalies (polyps, nodules, edema, or partial vocal cord paralysis), velopharyngeal insufficiency and/or structural vocal fold abnormalities, and hoarse/deep voice
Inverted diurnal circadian melatonin rhythm (diurnal secretion profile)
Hyperlipidemia (during childhood) including increased total cholesterol and/or low-density lipoprotein cholesterol
Immune function abnormalities (especially low immunoglobulin A)
Cortical atrophy
Ventriculomegaly
The diagnosis of SMS
A heterozygous deletion of 17p11.2 that includes
A heterozygous pathogenic (or likely pathogenic) variant 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 [
Molecular genetic testing approaches can include a combination of
Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded karyotype analysis, provided the resolution is adequate (≥550 band), it is not uncommon for the deletion to be overlooked, particularly when the indication for the cytogenetic study is other than SMS. Therefore, CMA has replaced G-banded cytogenetic analysis and FISH analysis as a first-line test in the diagnosis of SMS.
If CMA does not detect a deletion of 17p11.2 and the diagnosis of SMS is still suspected, single-gene testing of
For an introduction to multigene panels click
When the diagnosis of SMS has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Smith-Magenis Syndrome
See
See
A chromosomal microarray (CMA) that includes probe coverage of
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
Sequence analysis (particularly of exon 3, in which >99% of all pathogenic and likely pathogenic variants have been found to date) detects
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. Breakpoints of large deletions and/or deletion of adjacent genes may not be determined. 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 subtly distinctive facial appearance that becomes more evident with age (See
• Developmental delay and/or intellectual disability, including early speech delays (expressive delays greater than receptive speech) with or without associated hearing loss
• A distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors, as well as self-injurious behaviors
• Mild-to-moderate infantile-onset hypotonia
• Feeding difficulties and poor growth
• Sleep disturbances
• Short stature (prepubertal)
• Childhood-onset obesity
• Scoliosis
• Minor skeletal anomalies, including brachydactyly
• Signs of peripheral neuropathy including infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor of upper extremity. In later childhood, a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap) may be apparent.
• Ophthalmologic abnormalities including strabismus, progressive myopia, iris anomalies, microcornea, refractive errors, and retinal detachment. In adults, keratoconus and glaucoma are seen.
• Otolaryngologic abnormalities including middle ear dysfunction (frequent otitis media, fluctuating hearing loss leading to tympanostomy tube placement), hyperacusis, laryngeal anomalies (polyps, nodules, edema, or partial vocal cord paralysis), velopharyngeal insufficiency and/or structural vocal fold abnormalities, and hoarse/deep voice
• Inverted diurnal circadian melatonin rhythm (diurnal secretion profile)
• Hyperlipidemia (during childhood) including increased total cholesterol and/or low-density lipoprotein cholesterol
• Immune function abnormalities (especially low immunoglobulin A)
• Cortical atrophy
• Ventriculomegaly
• A heterozygous deletion of 17p11.2 that includes
• A heterozygous pathogenic (or likely pathogenic) variant involving
## Suggestive Findings
A subtly distinctive facial appearance that becomes more evident with age (See
Developmental delay and/or intellectual disability, including early speech delays (expressive delays greater than receptive speech) with or without associated hearing loss
A distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors, as well as self-injurious behaviors
Mild-to-moderate infantile-onset hypotonia
Feeding difficulties and poor growth
Sleep disturbances
Short stature (prepubertal)
Childhood-onset obesity
Scoliosis
Minor skeletal anomalies, including brachydactyly
Signs of peripheral neuropathy including infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor of upper extremity. In later childhood, a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap) may be apparent.
Ophthalmologic abnormalities including strabismus, progressive myopia, iris anomalies, microcornea, refractive errors, and retinal detachment. In adults, keratoconus and glaucoma are seen.
Otolaryngologic abnormalities including middle ear dysfunction (frequent otitis media, fluctuating hearing loss leading to tympanostomy tube placement), hyperacusis, laryngeal anomalies (polyps, nodules, edema, or partial vocal cord paralysis), velopharyngeal insufficiency and/or structural vocal fold abnormalities, and hoarse/deep voice
Inverted diurnal circadian melatonin rhythm (diurnal secretion profile)
Hyperlipidemia (during childhood) including increased total cholesterol and/or low-density lipoprotein cholesterol
Immune function abnormalities (especially low immunoglobulin A)
Cortical atrophy
Ventriculomegaly
• A subtly distinctive facial appearance that becomes more evident with age (See
• Developmental delay and/or intellectual disability, including early speech delays (expressive delays greater than receptive speech) with or without associated hearing loss
• A distinct neurobehavioral phenotype that includes stereotypic and maladaptive behaviors, as well as self-injurious behaviors
• Mild-to-moderate infantile-onset hypotonia
• Feeding difficulties and poor growth
• Sleep disturbances
• Short stature (prepubertal)
• Childhood-onset obesity
• Scoliosis
• Minor skeletal anomalies, including brachydactyly
• Signs of peripheral neuropathy including infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor of upper extremity. In later childhood, a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap) may be apparent.
• Ophthalmologic abnormalities including strabismus, progressive myopia, iris anomalies, microcornea, refractive errors, and retinal detachment. In adults, keratoconus and glaucoma are seen.
• Otolaryngologic abnormalities including middle ear dysfunction (frequent otitis media, fluctuating hearing loss leading to tympanostomy tube placement), hyperacusis, laryngeal anomalies (polyps, nodules, edema, or partial vocal cord paralysis), velopharyngeal insufficiency and/or structural vocal fold abnormalities, and hoarse/deep voice
• Inverted diurnal circadian melatonin rhythm (diurnal secretion profile)
• Hyperlipidemia (during childhood) including increased total cholesterol and/or low-density lipoprotein cholesterol
• Immune function abnormalities (especially low immunoglobulin A)
• Cortical atrophy
• Ventriculomegaly
## Establishing the Diagnosis
The diagnosis of SMS
A heterozygous deletion of 17p11.2 that includes
A heterozygous pathogenic (or likely pathogenic) variant 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 [
Molecular genetic testing approaches can include a combination of
Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded karyotype analysis, provided the resolution is adequate (≥550 band), it is not uncommon for the deletion to be overlooked, particularly when the indication for the cytogenetic study is other than SMS. Therefore, CMA has replaced G-banded cytogenetic analysis and FISH analysis as a first-line test in the diagnosis of SMS.
If CMA does not detect a deletion of 17p11.2 and the diagnosis of SMS is still suspected, single-gene testing of
For an introduction to multigene panels click
When the diagnosis of SMS has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Smith-Magenis Syndrome
See
See
A chromosomal microarray (CMA) that includes probe coverage of
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
Sequence analysis (particularly of exon 3, in which >99% of all pathogenic and likely pathogenic variants have been found to date) detects
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. Breakpoints of large deletions and/or deletion of adjacent genes may not be determined. 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 heterozygous deletion of 17p11.2 that includes
• A heterozygous pathogenic (or likely pathogenic) variant involving
## Option 1
Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded karyotype analysis, provided the resolution is adequate (≥550 band), it is not uncommon for the deletion to be overlooked, particularly when the indication for the cytogenetic study is other than SMS. Therefore, CMA has replaced G-banded cytogenetic analysis and FISH analysis as a first-line test in the diagnosis of SMS.
If CMA does not detect a deletion of 17p11.2 and the diagnosis of SMS is still suspected, single-gene testing of
For an introduction to multigene panels click
## Option 2
When the diagnosis of SMS has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Smith-Magenis Syndrome
See
See
A chromosomal microarray (CMA) that includes probe coverage of
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
Sequence analysis (particularly of exon 3, in which >99% of all pathogenic and likely pathogenic variants have been found to date) detects
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. Breakpoints of large deletions and/or deletion of adjacent genes may not be determined. 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
To date, more than 400 individuals with a deletion or pathogenic variant involving
SMS has a clinically recognizable phenotype that includes physical, developmental, and behavioral features (see
Clinical Features of Smith-Magenis Syndrome
Brachycephaly
Midface retrusion
Relative prognathism w/age
Broad, square-shaped face
Everted, "tented" vermilion of the upper lip
Deep-set, close-spaced eyes
Short broad hands
Dental anomalies (missing premolars, taurodontism)
Obesity (>90th centile for weight), w/abdominal fat deposition (esp after age 10 yrs)
Infantile hypotonia
Generalized lethargy (infancy)
Oral sensorimotor dysfunction (early childhood)
Sensory processing issues
Developmental delay / cognitive impairment
Speech-language impairment
Sleep disturbances & inverted circadian rhythm
Attention-seeking behaviors
Inattention ± hyperactivity
Tantrums, behavioral dysregulation
Impulsivity
Stereotypic behaviors
Self-injurious behaviors
Hyporeflexia
Signs of peripheral neuropathy
Middle ear & laryngeal anomalies
Hearing loss (79%)
Hyperacusis (74%)
Hoarse/deep voice
Short stature
Scoliosis
Mild ventriculomegaly on brain imaging
Hyperacusis
Tracheobronchial problems
Velopharyngeal insufficiency
Ocular abnormalities (strabismus, myopia, iris anomalies, &/or microcornea)
REM sleep abnormalities
Hypercholesterolemia/hypertriglyceridemia
Chronic constipation
Features of autism spectrum disorder
Immune function abnormalities (esp low IgA)
Cardiac defects
Thyroid function abnormalities
Seizures (11%-30%); pubertal onset of catamenial seizures in females
Renal / urinary tract abnormalities
EEG abnormalities (slowing, spikes) in absence of clinical seizures
Forearm abnormalities
Cleft lip/palate
Retinal detachment; keratoconus (adulthood)
Dystonia
Ig = immunoglobulin; PV = pathogenic variant
Based on
Frequency varies by study.
The facial appearance in SMS is characterized by a broad, square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanted palpebral fissures, deep-set eyes, broad nasal bridge, midfacial retrusion (formerly known as midfacial hypoplasia), short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted vermilion of the upper lip (see
The facial appearance in SMS becomes more recognizable in early childhood (see
Clinical signs of
In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [
In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
Some individuals with a large deletion extending into
One adult was reported to have a history of psychogenic seizures consisting of hyperventilation with tremors and a rapid pulse [
A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [
A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [
A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [
Developmental delays are evident in early childhood, with most individuals with SMS functioning in the mild-to-moderate range of intellectual disability. When reported, measured developmental or intelligence quotients range from 20 to 78, with a majority falling in the moderate range. Individuals with heterozygous deletions of 17p11.2 are more cognitively impaired than those with intragenic
Note: Due to the maladaptive behaviors and sleep deficits, cognitive functioning may not be accurately assessed in many individuals and test scores may be an underestimation of an individual's true cognitive capacity.
In infancy, crying is infrequent and often hoarse.
Most infants show markedly decreased babbling and vocalization for age.
By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [
Analysis of data from the
With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [
Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g.,
A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an
Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [
While socialization and social interest may be relative strengths [
Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [
Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [
The behavioral manifestations of SMS, which includes sleep, maladaptive and self-injurious behaviors (SIB), and stereotypies, is generally not recognized until age 18 months or older and escalates with age, often coinciding with expected life cycle stages: 18-24 months, school age, and onset of puberty [
With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [
One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [
A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [
The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [
A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see
Nail yanking generally does not become a major problem until late childhood.
Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [
Note: Given the high rates of SIB, including self-insertion of objects or digits into body orifices, caution must be taken when evaluating individuals with SMS for maltreatment or abuse. Although individuals with intellectual disability are at high risk for maltreatment, abuse may also be incorrectly suspected due to SIB or self-insertion behaviors.
Head banging, which may begin as early as age 18 months
Frequent outbursts / temper tantrums
Attention-seeking behaviors (especially from adults)
Impulsivity, which may increase over time, particularly in females [
Inattention with or without hyperactivity
Oppositional behaviors
Aggression
Rapid mood shifts
Anxiety, which can become a significant issue in adolescence and adulthood
Toileting difficulties
The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [
Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
Teeth grinding
Vocal stereotypies, "crickets" sound (comforting, self-regulating)
Body rocking
Spinning or twirling objects
Finger lick and repetitive page turning ("lick and flip") behavior [
Sleep disturbances are characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings and excessive daytime sleepiness [
Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [
Diminished REM sleep was documented in more than half of those who underwent polysomnography [
Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [
Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [
At birth, weight, length, and head circumference are generally in the normal range.
Feeding difficulties in infancy leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow and textural aversion.
In early infancy, length and weight gradually decelerate; short stature (height <5th centile) is frequently observed (67%), especially at young ages, but may not persist into adulthood.
Dietary preferences, hyperphagia, and food foraging at night (especially at older ages), coupled with a general sedentary lifestyle and psychotropic medication side effects (affecting appetite / weight gain), contribute to obesity (increased BMI), typically beginning in school-age children (age 6-9 years) [
Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [
Gastroesophageal reflux and constipation are frequently reported.
Oral sensorimotor dysfunction is a significant issue, including the following:
Lingual weakness, asymmetry, and/or limited mobility
Weak bilabial seal (64%)
Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
Open-mouth posture with tongue protrusion and frequent drooling
A high prevalence (~90%) of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism, has been reported. This is accompanied by an age-related increase in dental caries and poor gingival health due to decreased oral hygiene, supporting the need for increased dental care in adolescent years [
Mild-to-moderate scoliosis, most commonly of the mid-thoracic region, is seen in approximately 60% of affected individuals age four years and older, although vertebral anomalies are seen in only a few to date.
A tethered cord has been reported in three individuals with
Hands and feet are usually small for age.
Markedly flat or highly arched feet and unusual gait are generally observed.
Ocular abnormalities are present in approximately 85% of affected individuals and include strabismus, progressive myopia, iris anomalies, and/or microcornea. About 20% of affected individuals older than age ten years experience retinal detachment, which may be due to a combination of aggressive/self-injurious behaviors and high myopia. Adults may experience keratoconus and glaucoma.
Otitis media occurs frequently (≥3 episodes/year) and often leads to tympanostomy tube placement (85%).
Hearing loss is documented in more than 79% of affected individuals [
A pattern of fluctuating and progressive hearing decline occurs with age, including sensorineural hearing loss (48%) after age 11 years [
Hyperacusis, or oversensitivity to certain frequencies/sounds tolerable to listeners with normal hearing, is reported in approximately 74% [
Laryngeal anomalies, including polyps, nodules, edema, or partial vocal cord paralysis, are common.
Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.
Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Congenital heart defects remain rare among individuals with SMS due to heterozygous pathogenic
Genitourinary anomalies are found in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those who have a heterozygous pathogenic variant in
Duplicated collecting renal system
Unilateral renal agenesis and ectopic kidney
Ureterovesical obstruction
Malposition of the ureterovesical junction
Additionally, the majority of affected individuals have nocturnal enuresis in childhood. Genital anomalies reported include cryptorchidism, shawl, or undeveloped scrotum in males, and infantile cervix and/or hypoplastic uterus in females [
More than 50% of affected individuals have low serum immunoglobulin (Ig) profiles, which may increase susceptibility to sinopulmonary infections. A systematic study of serum Ig profiles (IgA, IgG, IgM) in a large cohort (age 4-27 years) documented diminished immunologic function in most affected individuals (60%). Recurrent otitis media (88%), upper respiratory infections (61%), pneumonia (47%), and/or sinusitis (42%) requiring antibiotics are frequently reported [
The specific incidence of endocrine abnormalities in individuals with SMS remains undefined.
About 25% of affected individuals have mild hypothyroidism.
Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [
Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [
In addition to skin problems due to self-injurious behaviors, a minority of affected individuals have rosy cheeks (which may be related to drooling and/or eczema) and/or hyperkeratosis (~20%) over the hands, feet, or knees.
Complaints of dry skin remain common, especially among those with an
Hair and skin color often appears fairer compared to other family members.
Fibrofolliculomas associated with deletion of
The risk of cancer appears to be no greater than in the general population for most individuals with SMS. However, SMS due to a heterozygous 17p11.2 deletion often results in haploinsufficiency of
Individuals with SMS due to a deletion that contains
Features of BHDS have been described in several individuals with SMS [
Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [
To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [
A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
A female with renal oncocytoma and confirmed second
A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or
A male with SMS due to a confirmed
A female with SMS and a confirmed
The most common structural brain abnormalities identified on imaging are non-specific and include ventriculomegaly and cortical atrophy. Also reported are enlarged posterior fossa, periventricular gray matter heterotopia, and decreased grey matter in the insula and lenticular nucleus [
Co-occurrence of moyamoya disease and SMS has been reported in an individual with a large deletion of 17p11.2 [
Foreshortened frontal lobes with a choroid plexus hemangioma have been reported on neuropathologic examination [
Insufficient longitudinal data are available to accurately determine life expectancy. One would expect that in the absence of major organ involvement the life expectancy of individuals with SMS would not differ from that of individuals with intellectual disability at large. Anecdotally, the oldest known individual with SMS lived to age 88 years [A Smith & E Magenis, unpublished data]. In the month prior to her death, she was reportedly her usual alert, happy, "SMS" self with ongoing sleep issues and was being treated for chronic recurrent sinusitis. Four days prior to death, she suffered an apparent right-sided stroke with left-sided weakness. No autopsy was performed.
Recurrence of SMS in two sibs, a 37-year-old male and his older 54-year-old sister, with deletion of 17p11.2 due to gonadal mosaicism and transmission from their 79-year-old mosaic mother (62% mosaicism in lymphocytes), has been reported [
Several genotype-phenotype correlations have been proposed for individuals with SMS depending on the molecular mechanism.
Individuals with a heterozygous deletion of 17p11.2 including
Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Only a single individual with a heterozygous pathogenic variant in
Genitourinary anomalies are reported in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those with a heterozygous pathogenic variant in
Parental origin of the 17p deletion has not been documented to affect the phenotype, suggesting that imprinting does not play a role in the expression of the typical SMS phenotype.
Note: See
Higher rates of onychotillomania and polyembolokoilamania (90%) have been reported in individuals with a heterozygous pathogenic variant in
The risk of obesity and obesity-related health issues is higher in individuals with a heterozygous pathogenic variant in
Individuals with a heterozygous pathogenic variant in
The birth incidence of SMS is estimated to be 1:25,000 births [
• Brachycephaly
• Midface retrusion
• Relative prognathism w/age
• Broad, square-shaped face
• Everted, "tented" vermilion of the upper lip
• Deep-set, close-spaced eyes
• Short broad hands
• Dental anomalies (missing premolars, taurodontism)
• Obesity (>90th centile for weight), w/abdominal fat deposition (esp after age 10 yrs)
• Infantile hypotonia
• Generalized lethargy (infancy)
• Oral sensorimotor dysfunction (early childhood)
• Sensory processing issues
• Developmental delay / cognitive impairment
• Speech-language impairment
• Sleep disturbances & inverted circadian rhythm
• Attention-seeking behaviors
• Inattention ± hyperactivity
• Tantrums, behavioral dysregulation
• Impulsivity
• Stereotypic behaviors
• Self-injurious behaviors
• Hyporeflexia
• Signs of peripheral neuropathy
• Middle ear & laryngeal anomalies
• Hearing loss (79%)
• Hyperacusis (74%)
• Hoarse/deep voice
• Short stature
• Scoliosis
• Mild ventriculomegaly on brain imaging
• Hyperacusis
• Tracheobronchial problems
• Velopharyngeal insufficiency
• Ocular abnormalities (strabismus, myopia, iris anomalies, &/or microcornea)
• REM sleep abnormalities
• Hypercholesterolemia/hypertriglyceridemia
• Chronic constipation
• Features of autism spectrum disorder
• Immune function abnormalities (esp low IgA)
• Cardiac defects
• Thyroid function abnormalities
• Seizures (11%-30%); pubertal onset of catamenial seizures in females
• Renal / urinary tract abnormalities
• EEG abnormalities (slowing, spikes) in absence of clinical seizures
• Forearm abnormalities
• Cleft lip/palate
• Retinal detachment; keratoconus (adulthood)
• Dystonia
• In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [
• In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
• Some individuals with a large deletion extending into
• A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [
• A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [
• A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [
• In infancy, crying is infrequent and often hoarse.
• Most infants show markedly decreased babbling and vocalization for age.
• By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [
• Analysis of data from the
• With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
• A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [
• Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g.,
• A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an
• Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [
• While socialization and social interest may be relative strengths [
• Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [
• Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [
• With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [
• One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [
• A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [
• The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [
• A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
• Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• Head banging, which may begin as early as age 18 months
• Frequent outbursts / temper tantrums
• Attention-seeking behaviors (especially from adults)
• Impulsivity, which may increase over time, particularly in females [
• Inattention with or without hyperactivity
• Oppositional behaviors
• Aggression
• Rapid mood shifts
• Anxiety, which can become a significant issue in adolescence and adulthood
• Toileting difficulties
• The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [
• Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
• Teeth grinding
• Vocal stereotypies, "crickets" sound (comforting, self-regulating)
• Body rocking
• Spinning or twirling objects
• Finger lick and repetitive page turning ("lick and flip") behavior [
• Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [
• Diminished REM sleep was documented in more than half of those who underwent polysomnography [
• Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
• Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
• Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [
• Lingual weakness, asymmetry, and/or limited mobility
• Weak bilabial seal (64%)
• Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
• Open-mouth posture with tongue protrusion and frequent drooling
• Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
• Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.
• Duplicated collecting renal system
• Unilateral renal agenesis and ectopic kidney
• Ureterovesical obstruction
• Malposition of the ureterovesical junction
• About 25% of affected individuals have mild hypothyroidism.
• Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
• While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [
• Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [
• Complaints of dry skin remain common, especially among those with an
• Hair and skin color often appears fairer compared to other family members.
• Fibrofolliculomas associated with deletion of
• Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [
• To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
• A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
• An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
## Clinical Description
To date, more than 400 individuals with a deletion or pathogenic variant involving
SMS has a clinically recognizable phenotype that includes physical, developmental, and behavioral features (see
Clinical Features of Smith-Magenis Syndrome
Brachycephaly
Midface retrusion
Relative prognathism w/age
Broad, square-shaped face
Everted, "tented" vermilion of the upper lip
Deep-set, close-spaced eyes
Short broad hands
Dental anomalies (missing premolars, taurodontism)
Obesity (>90th centile for weight), w/abdominal fat deposition (esp after age 10 yrs)
Infantile hypotonia
Generalized lethargy (infancy)
Oral sensorimotor dysfunction (early childhood)
Sensory processing issues
Developmental delay / cognitive impairment
Speech-language impairment
Sleep disturbances & inverted circadian rhythm
Attention-seeking behaviors
Inattention ± hyperactivity
Tantrums, behavioral dysregulation
Impulsivity
Stereotypic behaviors
Self-injurious behaviors
Hyporeflexia
Signs of peripheral neuropathy
Middle ear & laryngeal anomalies
Hearing loss (79%)
Hyperacusis (74%)
Hoarse/deep voice
Short stature
Scoliosis
Mild ventriculomegaly on brain imaging
Hyperacusis
Tracheobronchial problems
Velopharyngeal insufficiency
Ocular abnormalities (strabismus, myopia, iris anomalies, &/or microcornea)
REM sleep abnormalities
Hypercholesterolemia/hypertriglyceridemia
Chronic constipation
Features of autism spectrum disorder
Immune function abnormalities (esp low IgA)
Cardiac defects
Thyroid function abnormalities
Seizures (11%-30%); pubertal onset of catamenial seizures in females
Renal / urinary tract abnormalities
EEG abnormalities (slowing, spikes) in absence of clinical seizures
Forearm abnormalities
Cleft lip/palate
Retinal detachment; keratoconus (adulthood)
Dystonia
Ig = immunoglobulin; PV = pathogenic variant
Based on
Frequency varies by study.
The facial appearance in SMS is characterized by a broad, square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanted palpebral fissures, deep-set eyes, broad nasal bridge, midfacial retrusion (formerly known as midfacial hypoplasia), short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted vermilion of the upper lip (see
The facial appearance in SMS becomes more recognizable in early childhood (see
Clinical signs of
In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [
In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
Some individuals with a large deletion extending into
One adult was reported to have a history of psychogenic seizures consisting of hyperventilation with tremors and a rapid pulse [
A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [
A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [
A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [
Developmental delays are evident in early childhood, with most individuals with SMS functioning in the mild-to-moderate range of intellectual disability. When reported, measured developmental or intelligence quotients range from 20 to 78, with a majority falling in the moderate range. Individuals with heterozygous deletions of 17p11.2 are more cognitively impaired than those with intragenic
Note: Due to the maladaptive behaviors and sleep deficits, cognitive functioning may not be accurately assessed in many individuals and test scores may be an underestimation of an individual's true cognitive capacity.
In infancy, crying is infrequent and often hoarse.
Most infants show markedly decreased babbling and vocalization for age.
By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [
Analysis of data from the
With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [
Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g.,
A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an
Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [
While socialization and social interest may be relative strengths [
Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [
Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [
The behavioral manifestations of SMS, which includes sleep, maladaptive and self-injurious behaviors (SIB), and stereotypies, is generally not recognized until age 18 months or older and escalates with age, often coinciding with expected life cycle stages: 18-24 months, school age, and onset of puberty [
With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [
One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [
A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [
The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [
A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see
Nail yanking generally does not become a major problem until late childhood.
Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [
Note: Given the high rates of SIB, including self-insertion of objects or digits into body orifices, caution must be taken when evaluating individuals with SMS for maltreatment or abuse. Although individuals with intellectual disability are at high risk for maltreatment, abuse may also be incorrectly suspected due to SIB or self-insertion behaviors.
Head banging, which may begin as early as age 18 months
Frequent outbursts / temper tantrums
Attention-seeking behaviors (especially from adults)
Impulsivity, which may increase over time, particularly in females [
Inattention with or without hyperactivity
Oppositional behaviors
Aggression
Rapid mood shifts
Anxiety, which can become a significant issue in adolescence and adulthood
Toileting difficulties
The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [
Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
Teeth grinding
Vocal stereotypies, "crickets" sound (comforting, self-regulating)
Body rocking
Spinning or twirling objects
Finger lick and repetitive page turning ("lick and flip") behavior [
Sleep disturbances are characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings and excessive daytime sleepiness [
Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [
Diminished REM sleep was documented in more than half of those who underwent polysomnography [
Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [
Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [
At birth, weight, length, and head circumference are generally in the normal range.
Feeding difficulties in infancy leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow and textural aversion.
In early infancy, length and weight gradually decelerate; short stature (height <5th centile) is frequently observed (67%), especially at young ages, but may not persist into adulthood.
Dietary preferences, hyperphagia, and food foraging at night (especially at older ages), coupled with a general sedentary lifestyle and psychotropic medication side effects (affecting appetite / weight gain), contribute to obesity (increased BMI), typically beginning in school-age children (age 6-9 years) [
Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [
Gastroesophageal reflux and constipation are frequently reported.
Oral sensorimotor dysfunction is a significant issue, including the following:
Lingual weakness, asymmetry, and/or limited mobility
Weak bilabial seal (64%)
Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
Open-mouth posture with tongue protrusion and frequent drooling
A high prevalence (~90%) of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism, has been reported. This is accompanied by an age-related increase in dental caries and poor gingival health due to decreased oral hygiene, supporting the need for increased dental care in adolescent years [
Mild-to-moderate scoliosis, most commonly of the mid-thoracic region, is seen in approximately 60% of affected individuals age four years and older, although vertebral anomalies are seen in only a few to date.
A tethered cord has been reported in three individuals with
Hands and feet are usually small for age.
Markedly flat or highly arched feet and unusual gait are generally observed.
Ocular abnormalities are present in approximately 85% of affected individuals and include strabismus, progressive myopia, iris anomalies, and/or microcornea. About 20% of affected individuals older than age ten years experience retinal detachment, which may be due to a combination of aggressive/self-injurious behaviors and high myopia. Adults may experience keratoconus and glaucoma.
Otitis media occurs frequently (≥3 episodes/year) and often leads to tympanostomy tube placement (85%).
Hearing loss is documented in more than 79% of affected individuals [
A pattern of fluctuating and progressive hearing decline occurs with age, including sensorineural hearing loss (48%) after age 11 years [
Hyperacusis, or oversensitivity to certain frequencies/sounds tolerable to listeners with normal hearing, is reported in approximately 74% [
Laryngeal anomalies, including polyps, nodules, edema, or partial vocal cord paralysis, are common.
Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.
Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Congenital heart defects remain rare among individuals with SMS due to heterozygous pathogenic
Genitourinary anomalies are found in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those who have a heterozygous pathogenic variant in
Duplicated collecting renal system
Unilateral renal agenesis and ectopic kidney
Ureterovesical obstruction
Malposition of the ureterovesical junction
Additionally, the majority of affected individuals have nocturnal enuresis in childhood. Genital anomalies reported include cryptorchidism, shawl, or undeveloped scrotum in males, and infantile cervix and/or hypoplastic uterus in females [
More than 50% of affected individuals have low serum immunoglobulin (Ig) profiles, which may increase susceptibility to sinopulmonary infections. A systematic study of serum Ig profiles (IgA, IgG, IgM) in a large cohort (age 4-27 years) documented diminished immunologic function in most affected individuals (60%). Recurrent otitis media (88%), upper respiratory infections (61%), pneumonia (47%), and/or sinusitis (42%) requiring antibiotics are frequently reported [
The specific incidence of endocrine abnormalities in individuals with SMS remains undefined.
About 25% of affected individuals have mild hypothyroidism.
Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [
Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [
In addition to skin problems due to self-injurious behaviors, a minority of affected individuals have rosy cheeks (which may be related to drooling and/or eczema) and/or hyperkeratosis (~20%) over the hands, feet, or knees.
Complaints of dry skin remain common, especially among those with an
Hair and skin color often appears fairer compared to other family members.
Fibrofolliculomas associated with deletion of
The risk of cancer appears to be no greater than in the general population for most individuals with SMS. However, SMS due to a heterozygous 17p11.2 deletion often results in haploinsufficiency of
Individuals with SMS due to a deletion that contains
Features of BHDS have been described in several individuals with SMS [
Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [
To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [
A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
A female with renal oncocytoma and confirmed second
A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or
A male with SMS due to a confirmed
A female with SMS and a confirmed
The most common structural brain abnormalities identified on imaging are non-specific and include ventriculomegaly and cortical atrophy. Also reported are enlarged posterior fossa, periventricular gray matter heterotopia, and decreased grey matter in the insula and lenticular nucleus [
Co-occurrence of moyamoya disease and SMS has been reported in an individual with a large deletion of 17p11.2 [
Foreshortened frontal lobes with a choroid plexus hemangioma have been reported on neuropathologic examination [
Insufficient longitudinal data are available to accurately determine life expectancy. One would expect that in the absence of major organ involvement the life expectancy of individuals with SMS would not differ from that of individuals with intellectual disability at large. Anecdotally, the oldest known individual with SMS lived to age 88 years [A Smith & E Magenis, unpublished data]. In the month prior to her death, she was reportedly her usual alert, happy, "SMS" self with ongoing sleep issues and was being treated for chronic recurrent sinusitis. Four days prior to death, she suffered an apparent right-sided stroke with left-sided weakness. No autopsy was performed.
Recurrence of SMS in two sibs, a 37-year-old male and his older 54-year-old sister, with deletion of 17p11.2 due to gonadal mosaicism and transmission from their 79-year-old mosaic mother (62% mosaicism in lymphocytes), has been reported [
• Brachycephaly
• Midface retrusion
• Relative prognathism w/age
• Broad, square-shaped face
• Everted, "tented" vermilion of the upper lip
• Deep-set, close-spaced eyes
• Short broad hands
• Dental anomalies (missing premolars, taurodontism)
• Obesity (>90th centile for weight), w/abdominal fat deposition (esp after age 10 yrs)
• Infantile hypotonia
• Generalized lethargy (infancy)
• Oral sensorimotor dysfunction (early childhood)
• Sensory processing issues
• Developmental delay / cognitive impairment
• Speech-language impairment
• Sleep disturbances & inverted circadian rhythm
• Attention-seeking behaviors
• Inattention ± hyperactivity
• Tantrums, behavioral dysregulation
• Impulsivity
• Stereotypic behaviors
• Self-injurious behaviors
• Hyporeflexia
• Signs of peripheral neuropathy
• Middle ear & laryngeal anomalies
• Hearing loss (79%)
• Hyperacusis (74%)
• Hoarse/deep voice
• Short stature
• Scoliosis
• Mild ventriculomegaly on brain imaging
• Hyperacusis
• Tracheobronchial problems
• Velopharyngeal insufficiency
• Ocular abnormalities (strabismus, myopia, iris anomalies, &/or microcornea)
• REM sleep abnormalities
• Hypercholesterolemia/hypertriglyceridemia
• Chronic constipation
• Features of autism spectrum disorder
• Immune function abnormalities (esp low IgA)
• Cardiac defects
• Thyroid function abnormalities
• Seizures (11%-30%); pubertal onset of catamenial seizures in females
• Renal / urinary tract abnormalities
• EEG abnormalities (slowing, spikes) in absence of clinical seizures
• Forearm abnormalities
• Cleft lip/palate
• Retinal detachment; keratoconus (adulthood)
• Dystonia
• In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [
• In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
• Some individuals with a large deletion extending into
• A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [
• A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [
• A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [
• In infancy, crying is infrequent and often hoarse.
• Most infants show markedly decreased babbling and vocalization for age.
• By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [
• Analysis of data from the
• With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
• A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [
• Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g.,
• A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an
• Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [
• While socialization and social interest may be relative strengths [
• Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [
• Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [
• With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [
• One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [
• A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [
• The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [
• A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
• Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• Head banging, which may begin as early as age 18 months
• Frequent outbursts / temper tantrums
• Attention-seeking behaviors (especially from adults)
• Impulsivity, which may increase over time, particularly in females [
• Inattention with or without hyperactivity
• Oppositional behaviors
• Aggression
• Rapid mood shifts
• Anxiety, which can become a significant issue in adolescence and adulthood
• Toileting difficulties
• The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [
• Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
• Teeth grinding
• Vocal stereotypies, "crickets" sound (comforting, self-regulating)
• Body rocking
• Spinning or twirling objects
• Finger lick and repetitive page turning ("lick and flip") behavior [
• Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [
• Diminished REM sleep was documented in more than half of those who underwent polysomnography [
• Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
• Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
• Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [
• Lingual weakness, asymmetry, and/or limited mobility
• Weak bilabial seal (64%)
• Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
• Open-mouth posture with tongue protrusion and frequent drooling
• Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
• Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.
• Duplicated collecting renal system
• Unilateral renal agenesis and ectopic kidney
• Ureterovesical obstruction
• Malposition of the ureterovesical junction
• About 25% of affected individuals have mild hypothyroidism.
• Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
• While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [
• Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [
• Complaints of dry skin remain common, especially among those with an
• Hair and skin color often appears fairer compared to other family members.
• Fibrofolliculomas associated with deletion of
• Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [
• To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
• A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
• An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
## Facial Appearance
The facial appearance in SMS is characterized by a broad, square-shaped face, brachycephaly, prominent forehead, synophrys, mildly upslanted palpebral fissures, deep-set eyes, broad nasal bridge, midfacial retrusion (formerly known as midfacial hypoplasia), short, full-tipped nose with reduced nasal height, micrognathia in infancy changing to relative prognathia with age, and a distinct appearance of the mouth, with fleshy everted vermilion of the upper lip (see
The facial appearance in SMS becomes more recognizable in early childhood (see
## Neurologic Manifestations
Clinical signs of
In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [
In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
Some individuals with a large deletion extending into
One adult was reported to have a history of psychogenic seizures consisting of hyperventilation with tremors and a rapid pulse [
A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [
A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [
A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [
• In infancy and early childhood, these include infantile hypotonia, hyporeflexia, relative insensitivity to pain, and mild intention tremor (6-8 Hz) of the upper extremities [
• In later childhood, affected children often exhibit a characteristic appearance of the legs and feet observed in peripheral nerve syndromes or neuropathies (i.e., "inverted champagne bottle appearance") with pes cavus or pes planus deformity and unusual broad-based gait (foot flap). This can cause pain and discomfort.
• Some individuals with a large deletion extending into
• A male born with bilateral cleft lip/palate and congenital heart defect who developed left hemiparesis at age 4.5 years [
• A 10-year-old female with a ventricular septal defect who was also diagnosed with moyamoya disease and had evidence of ischemic changes at age five years [
• A 32-year-old female with evidence of severe atherosclerotic disease of the intracranial vessels documented after she experienced an ischemic infarct postoperatively following repeat cardiac surgery [
## Neurodevelopmental Features
Developmental delays are evident in early childhood, with most individuals with SMS functioning in the mild-to-moderate range of intellectual disability. When reported, measured developmental or intelligence quotients range from 20 to 78, with a majority falling in the moderate range. Individuals with heterozygous deletions of 17p11.2 are more cognitively impaired than those with intragenic
Note: Due to the maladaptive behaviors and sleep deficits, cognitive functioning may not be accurately assessed in many individuals and test scores may be an underestimation of an individual's true cognitive capacity.
In infancy, crying is infrequent and often hoarse.
Most infants show markedly decreased babbling and vocalization for age.
By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [
Analysis of data from the
With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [
Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g.,
A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an
Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [
While socialization and social interest may be relative strengths [
Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [
Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [
• In infancy, crying is infrequent and often hoarse.
• Most infants show markedly decreased babbling and vocalization for age.
• By age two to three years, significant expressive language deficits relative to receptive language skills are recognized [
• Analysis of data from the
• With appropriate intervention and a total communication program that includes sign/gesture language and other augmentative communication approaches, verbal speech generally develops by school age; however, articulation problems usually persist. Speech intensity may be mildly elevated with a rapid rate and moderate explosiveness, accompanied by hypernasality and hoarse vocal quality.
• A high percentage of children and adults (50%-80%) present with a hoarse vocal quality [
• Deficits in verbal comprehension, vocabulary, and word reasoning are common [e.g.,
• A comparison of individuals with SMS with a 17p11.2 deletion had similar profiles related to speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy ability. Slight differences were found when communication profiles of individuals with SMS due to an
• Communication strengths noted in more than 40% of individuals with SMS included social interest, humor, and memory for people, past events, and/or facts [
• While socialization and social interest may be relative strengths [
• Affected individuals typically have relative weaknesses observed in sequential processing and short-term memory [
• Relative strengths include long-term memory and perceptual closure (i.e., a process whereby an incomplete visual stimulus is perceived to be complete: "parts of a whole") [
## Behavioral Manifestations
The behavioral manifestations of SMS, which includes sleep, maladaptive and self-injurious behaviors (SIB), and stereotypies, is generally not recognized until age 18 months or older and escalates with age, often coinciding with expected life cycle stages: 18-24 months, school age, and onset of puberty [
With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [
One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [
A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [
The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [
A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see
Nail yanking generally does not become a major problem until late childhood.
Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [
Note: Given the high rates of SIB, including self-insertion of objects or digits into body orifices, caution must be taken when evaluating individuals with SMS for maltreatment or abuse. Although individuals with intellectual disability are at high risk for maltreatment, abuse may also be incorrectly suspected due to SIB or self-insertion behaviors.
Head banging, which may begin as early as age 18 months
Frequent outbursts / temper tantrums
Attention-seeking behaviors (especially from adults)
Impulsivity, which may increase over time, particularly in females [
Inattention with or without hyperactivity
Oppositional behaviors
Aggression
Rapid mood shifts
Anxiety, which can become a significant issue in adolescence and adulthood
Toileting difficulties
The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [
Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
Teeth grinding
Vocal stereotypies, "crickets" sound (comforting, self-regulating)
Body rocking
Spinning or twirling objects
Finger lick and repetitive page turning ("lick and flip") behavior [
Sleep disturbances are characterized by fragmented and shortened sleep cycles with frequent nocturnal and early morning awakenings and excessive daytime sleepiness [
Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [
Diminished REM sleep was documented in more than half of those who underwent polysomnography [
Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [
Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [
• With age, the gap between intellectual attainment and emotional development appears to widen for many people with SMS, and this disparity poses significant behavioral and programmatic challenges in older children and adults [
• One study found that 90% of individuals with SMS (ages 4 and 18 years) demonstrated significant social impairment (35% in the mild-to-moderate range and 55% in the severe range per the Social Responsiveness Scale) per parent report, with manifestations that overlapped those of children with ASD or other developmental disorders [
• A large-scale investigation of children and adults with SMS (ages 4 to 30 years) and six other genetic syndromes associated with intellectual or learning disabilities reported high levels of autistic features on the Social Responsiveness Scale, 2nd edition (SRS-2), a parent report measure [
• The degree of sleep disturbance remains one of the strongest predictors of maladaptive behavior [
• A direct correlation exists between the number of different types, intensity, and frequency of SIB and the level of intellectual impairment.
• Three behaviors distinctive to SMS include nail yanking (onychotillomania), skin picking, and insertion of foreign objects into body orifices (polyembolokoilamania); prevalence rates for these behaviors range from 25% to 90% of affected individuals depending on the age and group studied (see
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• The overall prevalence of SIB increases with age, as does the number of different types of SIB exhibited [
• Nail yanking generally does not become a major problem until late childhood.
• Object insertion in ears is most relevant in both children and adults; other body orifices (nose, vagina, and rectum) are generally not reported until late teens / adulthood [
• Head banging, which may begin as early as age 18 months
• Frequent outbursts / temper tantrums
• Attention-seeking behaviors (especially from adults)
• Impulsivity, which may increase over time, particularly in females [
• Inattention with or without hyperactivity
• Oppositional behaviors
• Aggression
• Rapid mood shifts
• Anxiety, which can become a significant issue in adolescence and adulthood
• Toileting difficulties
• The spasmodic upper body squeeze or "self-hug" behavior, which may provide an effective clinical diagnostic marker for the syndrome [
• Mouthing of hands or objects, which persists from early childhood to ages where this is not socially acceptable
• Teeth grinding
• Vocal stereotypies, "crickets" sound (comforting, self-regulating)
• Body rocking
• Spinning or twirling objects
• Finger lick and repetitive page turning ("lick and flip") behavior [
• Parents usually do not recognize significant sleep problems before age 12-18 months, although fragmented sleep with reduced total sleep time has been documented as early as age six months [
• Diminished REM sleep was documented in more than half of those who underwent polysomnography [
• Actigraphy-based sleep estimates document developmental differences in nocturnal arousal patterns by age and time of night [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
• Due to the propensity of weight gain as affected individuals age, obstructive sleep apnea may also develop and can contribute to the overall sleep disturbance.
• Disrupted sleep becomes a significant problem in early childhood and is a major issue for caregivers, who themselves may become sleep deprived [
• Affected individuals have a reduction in 24-hour and night sleep compared to healthy pediatric controls, with estimated sleep about one hour less than expected across all ages. This is evidenced by decreased total night sleep, lower sleep efficiency, earlier sleep onset and final sleep offset, increased waking after sleep onset (WASO), and increased duration of daytime naps (beyond typical age) [
• Developmental sleep changes from childhood through adolescence/adulthood are evidenced by an age-related variation in the timing of wake onset (but not sleep onset) and WASO [
• Age differences are also associated with different patterns of sleep for SMS compared to healthy controls [
## Growth and Feeding
At birth, weight, length, and head circumference are generally in the normal range.
Feeding difficulties in infancy leading to failure to thrive are common, including marked oral motor dysfunction with poor suck and swallow and textural aversion.
In early infancy, length and weight gradually decelerate; short stature (height <5th centile) is frequently observed (67%), especially at young ages, but may not persist into adulthood.
Dietary preferences, hyperphagia, and food foraging at night (especially at older ages), coupled with a general sedentary lifestyle and psychotropic medication side effects (affecting appetite / weight gain), contribute to obesity (increased BMI), typically beginning in school-age children (age 6-9 years) [
Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [
• Obesity may lead to increased risk for related health issues (e.g., diabetes mellitus type 2) in adulthood.
• Individuals with SMS display unique food-related behaviors manifested by a constant obsession with and hyperfixation on food that is not entirely driven by hunger alone [
## Gastrointestinal
Gastroesophageal reflux and constipation are frequently reported.
## Oral and Dental Anomalies
Oral sensorimotor dysfunction is a significant issue, including the following:
Lingual weakness, asymmetry, and/or limited mobility
Weak bilabial seal (64%)
Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
Open-mouth posture with tongue protrusion and frequent drooling
A high prevalence (~90%) of dental anomalies, specifically tooth agenesis (especially premolars) and taurodontism, has been reported. This is accompanied by an age-related increase in dental caries and poor gingival health due to decreased oral hygiene, supporting the need for increased dental care in adolescent years [
• Lingual weakness, asymmetry, and/or limited mobility
• Weak bilabial seal (64%)
• Palate abnormalities (64%), although cleft lip and/or palate occur in fewer than 25% of affected individuals
• Open-mouth posture with tongue protrusion and frequent drooling
## Musculoskeletal Manifestations
Mild-to-moderate scoliosis, most commonly of the mid-thoracic region, is seen in approximately 60% of affected individuals age four years and older, although vertebral anomalies are seen in only a few to date.
A tethered cord has been reported in three individuals with
Hands and feet are usually small for age.
Markedly flat or highly arched feet and unusual gait are generally observed.
## Ocular Abnormalities
Ocular abnormalities are present in approximately 85% of affected individuals and include strabismus, progressive myopia, iris anomalies, and/or microcornea. About 20% of affected individuals older than age ten years experience retinal detachment, which may be due to a combination of aggressive/self-injurious behaviors and high myopia. Adults may experience keratoconus and glaucoma.
## Ears and Hearing
Otitis media occurs frequently (≥3 episodes/year) and often leads to tympanostomy tube placement (85%).
Hearing loss is documented in more than 79% of affected individuals [
A pattern of fluctuating and progressive hearing decline occurs with age, including sensorineural hearing loss (48%) after age 11 years [
Hyperacusis, or oversensitivity to certain frequencies/sounds tolerable to listeners with normal hearing, is reported in approximately 74% [
## Laryngeal Anomalies
Laryngeal anomalies, including polyps, nodules, edema, or partial vocal cord paralysis, are common.
Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.
• Velopharyngeal insufficiency and/or structural vocal fold abnormalities without reported vocal hyperfunction are seen in most individuals with SMS.
• Functional impairments in voice (hoarseness) may contribute to the marked delays in expressive speech.
## Cardiovascular Defects
Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Congenital heart defects remain rare among individuals with SMS due to heterozygous pathogenic
## Genitourinary Anomalies
Genitourinary anomalies are found in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those who have a heterozygous pathogenic variant in
Duplicated collecting renal system
Unilateral renal agenesis and ectopic kidney
Ureterovesical obstruction
Malposition of the ureterovesical junction
Additionally, the majority of affected individuals have nocturnal enuresis in childhood. Genital anomalies reported include cryptorchidism, shawl, or undeveloped scrotum in males, and infantile cervix and/or hypoplastic uterus in females [
• Duplicated collecting renal system
• Unilateral renal agenesis and ectopic kidney
• Ureterovesical obstruction
• Malposition of the ureterovesical junction
## Immunologic Manifestations
More than 50% of affected individuals have low serum immunoglobulin (Ig) profiles, which may increase susceptibility to sinopulmonary infections. A systematic study of serum Ig profiles (IgA, IgG, IgM) in a large cohort (age 4-27 years) documented diminished immunologic function in most affected individuals (60%). Recurrent otitis media (88%), upper respiratory infections (61%), pneumonia (47%), and/or sinusitis (42%) requiring antibiotics are frequently reported [
## Endocrine
The specific incidence of endocrine abnormalities in individuals with SMS remains undefined.
About 25% of affected individuals have mild hypothyroidism.
Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [
Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [
• About 25% of affected individuals have mild hypothyroidism.
• Puberty typically occurs within the normal time frame; however, precocious puberty (premature adrenarche), premature ovarian failure [A Smith, personal observation], and delayed sexual maturation have been observed.
• While short stature occurs in SMS, only one published case of isolated growth hormone deficiency has been reported to date [
• Adrenal aplasia/hypoplasia was described in one affected male infant who died unexpectedly after palatoplasty [
## Dermatologic Manifestations
In addition to skin problems due to self-injurious behaviors, a minority of affected individuals have rosy cheeks (which may be related to drooling and/or eczema) and/or hyperkeratosis (~20%) over the hands, feet, or knees.
Complaints of dry skin remain common, especially among those with an
Hair and skin color often appears fairer compared to other family members.
Fibrofolliculomas associated with deletion of
• Complaints of dry skin remain common, especially among those with an
• Hair and skin color often appears fairer compared to other family members.
• Fibrofolliculomas associated with deletion of
## Malignancy and Other Features of Birt-Hogg-Dubé Syndrome (BHDS)
The risk of cancer appears to be no greater than in the general population for most individuals with SMS. However, SMS due to a heterozygous 17p11.2 deletion often results in haploinsufficiency of
Individuals with SMS due to a deletion that contains
Features of BHDS have been described in several individuals with SMS [
Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [
To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [
A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
A female with renal oncocytoma and confirmed second
A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or
• Typically, BHDS-related spontaneous pneumothorax occurs in adults younger than age 40 years [
• To date, renal tumors have been reported in four adults with heterozygous deletions of 17p11.2 [
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
• A female with biopsy-documented fibrofolliculoma and a 4-mm lung cyst showed no evidence of renal tumors at age 25 years based on an MRI surveillance study.
• An online survey of parents of individuals with SMS (due to either heterozygous deletions of 17p11.2 or
• A male with bilateral renal tumors on imaging (histopathology not available) and no skin or lung findings at age 57 years [
• A female with bilateral pathologically confirmed hybrid oncocytic tumors without evidence of skin lesions or lung findings at age 50 years [
• A male who died of unrelated causes at age 45 years was found on autopsy to have an oncocytic neoplasm with features of chromophobe renal cell carcinoma; tumor tissue contained a second
• A female with renal oncocytoma and confirmed second
## Other Manifestations
A male with SMS due to a confirmed
A female with SMS and a confirmed
## Neuroimaging Abnormalities
The most common structural brain abnormalities identified on imaging are non-specific and include ventriculomegaly and cortical atrophy. Also reported are enlarged posterior fossa, periventricular gray matter heterotopia, and decreased grey matter in the insula and lenticular nucleus [
Co-occurrence of moyamoya disease and SMS has been reported in an individual with a large deletion of 17p11.2 [
## Neuropathologic Abnormalities
Foreshortened frontal lobes with a choroid plexus hemangioma have been reported on neuropathologic examination [
## Prognosis
Insufficient longitudinal data are available to accurately determine life expectancy. One would expect that in the absence of major organ involvement the life expectancy of individuals with SMS would not differ from that of individuals with intellectual disability at large. Anecdotally, the oldest known individual with SMS lived to age 88 years [A Smith & E Magenis, unpublished data]. In the month prior to her death, she was reportedly her usual alert, happy, "SMS" self with ongoing sleep issues and was being treated for chronic recurrent sinusitis. Four days prior to death, she suffered an apparent right-sided stroke with left-sided weakness. No autopsy was performed.
Recurrence of SMS in two sibs, a 37-year-old male and his older 54-year-old sister, with deletion of 17p11.2 due to gonadal mosaicism and transmission from their 79-year-old mosaic mother (62% mosaicism in lymphocytes), has been reported [
## Genotype-Phenotype Correlations
Several genotype-phenotype correlations have been proposed for individuals with SMS depending on the molecular mechanism.
Individuals with a heterozygous deletion of 17p11.2 including
Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Only a single individual with a heterozygous pathogenic variant in
Genitourinary anomalies are reported in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those with a heterozygous pathogenic variant in
Parental origin of the 17p deletion has not been documented to affect the phenotype, suggesting that imprinting does not play a role in the expression of the typical SMS phenotype.
Note: See
Higher rates of onychotillomania and polyembolokoilamania (90%) have been reported in individuals with a heterozygous pathogenic variant in
The risk of obesity and obesity-related health issues is higher in individuals with a heterozygous pathogenic variant in
Individuals with a heterozygous pathogenic variant in
## Deletions of 17p11.2 Including
Individuals with a heterozygous deletion of 17p11.2 including
Cardiovascular defects are identified in fewer than 50% of affected individuals with SMS who have a deletion of 17p11.2. Only a single individual with a heterozygous pathogenic variant in
Genitourinary anomalies are reported in 15%-35% of affected individuals who have a deletion of 17p11.2 but have not been reported in those with a heterozygous pathogenic variant in
Parental origin of the 17p deletion has not been documented to affect the phenotype, suggesting that imprinting does not play a role in the expression of the typical SMS phenotype.
Note: See
## Pathogenic Variants in
Higher rates of onychotillomania and polyembolokoilamania (90%) have been reported in individuals with a heterozygous pathogenic variant in
The risk of obesity and obesity-related health issues is higher in individuals with a heterozygous pathogenic variant in
Individuals with a heterozygous pathogenic variant in
## Prevalence
The birth incidence of SMS is estimated to be 1:25,000 births [
## Genetically Related (Allelic) Disorders
Individuals with larger deletions extending distally to include
Individuals with 17p11.2 duplication syndrome (
Yuan-Harel-Lupski (YUHAL) syndrome (OMIM
• Individuals with larger deletions extending distally to include
• Individuals with 17p11.2 duplication syndrome (
• Yuan-Harel-Lupski (YUHAL) syndrome (OMIM
## Differential Diagnosis
Smith-Magenis syndrome (SMS) should be distinguished from other syndromes that include developmental delay, infantile hypotonia, short stature, distinctive facies, and behavioral manifestations. The pervasive behavioral aspects and circadian sleep disorder associated with inverted melatonin secretion can help distinguish SMS from other neurodevelopmental disorders. However, because the phenotype of SMS is broad and changes with time, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series for genes associated with:
The most common of the neurodevelopmental disorders of interest in the differential diagnosis of SMS include Down syndrome (trisomy 21) and those listed in
Disorders with Developmental Delay / Intellectual Disability of Interest in the Differential Diagnosis of Smith-Magenis Syndrome
Hypotonia
Early feeding issues & speech delay
CHD (<25% in SMS)
Velopharyngeal insufficiency
Cleft palate
Low Igs
Strabismus
Hearing loss
Psychiatric comorbidities (e.g., ASD, ADHD, anxiety)
Skeletal anomalies (scoliosis, vertebral anomalies)
Infantile hypotonia
Lethargy
Early growth abnormalities
Childhood obesity (hyperphagia)
Strabismus
Behavior issues (tantrums, autistic features, ADHD, anxiety)
Sleep disturbances
Early-onset seizure disorder (photic stimulation triggers)
Language impairment
ASD, ADHD
Challenging behaviors, aggression
Speech delays
Hypotonia, gait issues
Seizures
High pain threshold
Autistic features
Sleep issues
Speech-language delay
Strabismus
Scoliosis
Behavioral features (autistic features, aggression, anxiety)
Sleep disturbances w/multiple awakenings
Hypotonia
Lethargy
Broad forehead, hypertelorism, synophrys, & midface retrusion
Significant speech-language delay
Sleep disturbance
Challenging behaviors, stereotypies, self-injury, mood disorder
Hypotonia
Autistic-like behaviors
Hypotonia
Facial features (broad, upslanting palpebral fissures, midface hypoplasia, synophrys)
Seizures
Brachydactyly, hypermobile joints, scoliosis
Short stature & obesity
Visceral malformations (20%-30%), e.g., CHD, GU
Decreased pain sensitivity
Sleep disorder
Behavioral issues (self-injury, ASD)
Hypotonia
Speech-language delay
Strabismus
Feeding issues / GERD
Seizures
Scoliosis
Sleep disturbance
Self-injurious, stereotypic, autistic-like behaviors
Facial dysmorphism
Short stature
Seizures
Urogenital anomalies
Disruptive behavior / ADHD
Sleep disturbance
Speech impairment
Ocular abnormalities
Hypotonia
Seizures
Sleep disturbances (circadian rhythm disruption, i.e., downregulation of clock genes)
Abnormal behaviors (e.g., autistic-like features, self-injury, aggression)
Hyperphagia
Hypotonia
Autistic features, ADHD, anxiety
Vision abnormalities (strabismus, myopia, keratoconus)
Dysmorphic facial features (short philtrum, downturned mouth, exaggerated Cupid's bow, relative prognathia, coarsening w/age)
Hypotonia
Severe myopia
Scoliosis
Obesity
Sleep issues
Stereotypies & behavioral issues (ADHD, anxiety, aggression)
Dysmorphic facial features (brachycephaly, brachydactyly)
ID (learning disabilities to ASD)
Obesity
Sleep disturbance
Stereotypies & behavioral issues (ADHD, anxiety, aggression)
AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder;
CHD = congenital heart defect; DD = developmental delay; GERD = gastroesophageal reflux disease; GU = genitourinary; ID = intellectual disability; Ig = immunoglobulin; MOI = mode of inheritance; NDD = neurodevelopmental disorder; PV = pathogenic variant; PWCR = Prader-Willi critical region
Recurrence risk depends on the underlying genetic mechanism in the proband.
Typically
Transcriptionally regulates
Possible
Paralog to
• Hypotonia
• Early feeding issues & speech delay
• CHD (<25% in SMS)
• Velopharyngeal insufficiency
• Cleft palate
• Low Igs
• Strabismus
• Hearing loss
• Psychiatric comorbidities (e.g., ASD, ADHD, anxiety)
• Skeletal anomalies (scoliosis, vertebral anomalies)
• Infantile hypotonia
• Lethargy
• Early growth abnormalities
• Childhood obesity (hyperphagia)
• Strabismus
• Behavior issues (tantrums, autistic features, ADHD, anxiety)
• Sleep disturbances
• Early-onset seizure disorder (photic stimulation triggers)
• Language impairment
• ASD, ADHD
• Challenging behaviors, aggression
• Speech delays
• Hypotonia, gait issues
• Seizures
• High pain threshold
• Autistic features
• Sleep issues
• Speech-language delay
• Strabismus
• Scoliosis
• Behavioral features (autistic features, aggression, anxiety)
• Sleep disturbances w/multiple awakenings
• Hypotonia
• Lethargy
• Broad forehead, hypertelorism, synophrys, & midface retrusion
• Significant speech-language delay
• Sleep disturbance
• Challenging behaviors, stereotypies, self-injury, mood disorder
• Hypotonia
• Autistic-like behaviors
• Hypotonia
• Facial features (broad, upslanting palpebral fissures, midface hypoplasia, synophrys)
• Seizures
• Brachydactyly, hypermobile joints, scoliosis
• Short stature & obesity
• Visceral malformations (20%-30%), e.g., CHD, GU
• Decreased pain sensitivity
• Sleep disorder
• Behavioral issues (self-injury, ASD)
• Hypotonia
• Speech-language delay
• Strabismus
• Feeding issues / GERD
• Seizures
• Scoliosis
• Sleep disturbance
• Self-injurious, stereotypic, autistic-like behaviors
• Facial dysmorphism
• Short stature
• Seizures
• Urogenital anomalies
• Disruptive behavior / ADHD
• Sleep disturbance
• Speech impairment
• Ocular abnormalities
• Hypotonia
• Seizures
• Sleep disturbances (circadian rhythm disruption, i.e., downregulation of clock genes)
• Abnormal behaviors (e.g., autistic-like features, self-injury, aggression)
• Hyperphagia
• Hypotonia
• Autistic features, ADHD, anxiety
• Vision abnormalities (strabismus, myopia, keratoconus)
• Dysmorphic facial features (short philtrum, downturned mouth, exaggerated Cupid's bow, relative prognathia, coarsening w/age)
• Hypotonia
• Severe myopia
• Scoliosis
• Obesity
• Sleep issues
• Stereotypies & behavioral issues (ADHD, anxiety, aggression)
• Dysmorphic facial features (brachycephaly, brachydactyly)
• ID (learning disabilities to ASD)
• Obesity
• Sleep disturbance
• Stereotypies & behavioral issues (ADHD, anxiety, aggression)
## Management
Management guidelines for Smith-Magenis syndrome (SMS) have been published by
To establish the extent of disease and needs in an individual diagnosed with SMS, the evaluations summarized in
Smith-Magenis Syndrome: Recommended Evaluations Following Initial Diagnosis
EEG in those w/clinical seizures or suspected seizures
Neuroimaging (MRI or CT scan) in accordance w/findings such as seizures &/or motor asymmetry
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Sleep history w/particular attention to sleep/wake schedules & signs/symptoms of obstructive sleep apnea
Polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea in those w/evidence of sleep-disordered breathing
Signs/symptoms of GERD
Constipation
Caloric intake
Attention to evidence of strabismus, microcornea, iris anomalies, & refractive error
In adults: keratoconus & glaucoma
Audiologic assessment for CHL &/or SNHL
Consider eval for velopharyngeal insufficiency in those w/functional impairments.
Qualitative Igs
Susceptibility to sinopulmonary infections, aspiration pneumonia
Detailed dermatologic exam
Biopsy of suspicious lesion(s)
Chest radiograph
Chest CT
Assess safety concerns /need to monitor overnight to prevent/avert wandering, food foraging, &/or self-injury.
Assess for aggressive behaviors.
Range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets)
Safety eval for person w/SMS & caregivers
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BHDS =
To include quantitative serum Igs (IgG, IgA, IgM)
Screening for adrenal function should be considered in individuals with larger deletions extending into 17p12.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for SMS. 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
Smith-Magenis Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for SMS.
Importantly, several ASMs may cause sleepiness, so this & timing of dosing should be kept in mind & adjusted as needed given the circadian disturbance in SMS & possible exacerbation.
Avoid ASMs assoc w/weight gain (i.e., valproic acid)
Education of parents/caregivers
Identify & treat swallowing/feeding problems & optimize oral sensorimotor development.
Develop skills related to swallowing & speech production by ↑ sensory input, fostering movement of articulators, ↑ oral motor endurance, & ↓ hypersensitivity.
Develop a comprehensive behavioral support plan for home & school at onset of maladaptive behaviors (typically starting in early elementary school).
Develop structured school program w/one-on-one support & curricula matched to known cognitive & behavior profile of SMS.
Behavioral therapies include special education techniques emphasizing individualized instruction, structure, & routine to minimize behavioral outbursts in school.
Assess for underlying reasons for changes in behavior (
Insight about vulnerabilities & relative strengths in sensory processing patterns (i.e., visual processing & oral sensory processing) may aid caregivers in adapting activity demands, modifying environments, & facilitating appropriate & supportive social interactions.
Atypical patterns of sensory processing & more problematic/atypical behaviors may become more prominent w/age.
Specialized developmental psychiatric & psychological services for assessment & treatment for psychiatric or mental health concerns
Psychotropic medication & psychological services to ↓ maladaptive behaviors, ↑ attention &/or ↓ hyperactivity, ↓ anxiety, & stabilize mood
Melatonin receptor agonist: 1st FDA-approved treatment of nighttime sleep disturbance in SMS.
A randomized crossover study using tasimelteon showed effective improvement of sleep quality & total sleep time.
Mgmt strategies to limit access to food due to biologically based intense food-related behaviors in SMS (i.e., hyperphagia, obsessions/fixations on food, impaired satiety) require a multicomponent individualized approach to ↓ obesity health risks.
A trial using an MC4R agonist, setmelanotide, for obesity in persons w/SMS failed to significantly ↓ body weight but did impact self-reported "hunger."
There are published cases of renal cancer in adults w/SMS w/deletion of 17p11.2.
Recommendations include kidney cancer surveillance starting at 20 yrs & eval for both skin & lung manifestations of BHDS.
Combination of ID, severe behavioral abnormalities, & sleep disturbance takes significant toll on caretakers/parents & sibs.
Incl family support services & resources as essential components of a holistic mgmt plan.
ASM = anti-seizure medication; BHDS =
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 2024 PRISMS Clinical and Research Consortium treatment recommendation:
The potential for more problematic or atypical behaviors with increased age underscores the need for early and ongoing intervention and caregiver education [
Based on an extensive review of psychotropic medication use in a large cohort of individuals with SMS (n=62), use of polypharmacy and/or serial trials with minimal effectiveness was observed. Benzodiazepines obtained the lowest mean efficacy score in the "slightly worse" range, suggesting that use of these drugs may be detrimental to individuals with SMS [
Sleep management is a challenge for physicians and parents. Prior to beginning any trial, a child's medical status and baseline sleep pattern must be considered.
Dosages should be kept low (≤3 mg). However, melatonin dispensed over the counter is not regulated by the FDA; thus, dosages may not be exact. No early and controlled melatonin treatment trials have been conducted. A monitored trial of four to six weeks on melatonin may be worth considering in affected individuals with sleep disturbance.
Nine individuals with SMS were treated with oral beta-1-adrenergic antagonists (acebutolol, 10 mg/kg) [
Parents also reported subjective improvement in daytime behaviors with increased concentration. Contraindications to the use of beta-1-adrenergic antagonists include asthma, pulmonary problems, some cardiovascular disease, and diabetes mellitus.
Dietary changes with portion management in addition to increased movement and physical activity, limiting sedentary activity, and discouraging nighttime eating
See
See Got Transition,
Parents report high rates of depression and anxiety, and family stress is significantly higher in families of individuals with SMS than in those of children with non-specific developmental disabilities [
The following information represents typical management recommendations for individuals with developmental delay and/or 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
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
Consultation with specialized services (developmental pediatric, psychiatric, psychological) for concerns about emotions and behavior may be helpful in guiding parents through management strategies and options. A specialized physician (developmental pediatrician or psychiatrist) may discuss prescription medication trials when necessary (e.g., for attention-deficit/hyperactivity disorder).
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Individuals may qualify and benefit from interventions used in treatment of neurodevelopmental disorders and autism spectrum disorder, including applied behavior analysis (ABA). ABA interventions are science based and targeted to the individual's behavioral, social, and adaptive strengths and weaknesses. Strategies for supports and interventions are typically developed with the team led by a board-certified behavior analyst (BCBA).
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Smith-Magenis Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Annually in adolescents & adults
Presurgical eval for possible premature cerebrovascular disease is recommended for persons w/SMS who require open-heart surgery in adolescence or adulthood.
Otolaryngologic follow up for assessment & mgmt of otitis media & other sinus abnormalities
Audiologic eval to monitor for CHL or SNHL annually or as clinically indicated
Routine urinalysis to evaluate for occult urinary tract infections
Gynecologic eval per gynecologist
Age ≥20 yrs
Since BHDS is an adult-onset disorder, additional screening for symptoms related to BHDS in children w/SMS is not indicated.
BHDS =
Assess for new manifestations such as seizures or changes in behavior.
Particularly in school-age children
Periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultation can be an important adjunct to the team evaluation.
Symptoms include onset of neurologic deficits of lower extremities, gait disturbance, loss of bowel/bladder control, progressive deformities of feet, and/or spinal stenosis.
Use of psychoactive medications in SMS often begins in childhood with use of sleep aids and trials of different psychoactive medications to reduce/manage maladaptive behavior, with mixed response; no single regimen has shown consistent efficacy, and adverse reactions to some medications have been reported [
Lacking well-controlled trials, when starting a new medication, care should be taken to track sleep and behavior changes over several days/weeks to monitor for potential side effects (e.g., increased appetite, weight gain) and adverse reactions and/or to determine potential efficacy.
Pharmacologic intervention should be considered on an individual basis with recognition that some medications may exacerbate sleep or behavioral issues and may cause weight gain. Pharmacogenetic testing panels to identify potential gene-drug interactions may aid in tailoring therapeutic strategies for the individual.
See
Search
• EEG in those w/clinical seizures or suspected seizures
• Neuroimaging (MRI or CT scan) in accordance w/findings such as seizures &/or motor asymmetry
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Sleep history w/particular attention to sleep/wake schedules & signs/symptoms of obstructive sleep apnea
• Polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea in those w/evidence of sleep-disordered breathing
• Signs/symptoms of GERD
• Constipation
• Caloric intake
• Attention to evidence of strabismus, microcornea, iris anomalies, & refractive error
• In adults: keratoconus & glaucoma
• Audiologic assessment for CHL &/or SNHL
• Consider eval for velopharyngeal insufficiency in those w/functional impairments.
• Qualitative Igs
• Susceptibility to sinopulmonary infections, aspiration pneumonia
• Detailed dermatologic exam
• Biopsy of suspicious lesion(s)
• Chest radiograph
• Chest CT
• Assess safety concerns /need to monitor overnight to prevent/avert wandering, food foraging, &/or self-injury.
• Assess for aggressive behaviors.
• Range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets)
• Safety eval for person w/SMS & caregivers
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none has been demonstrated effective specifically for SMS.
• Importantly, several ASMs may cause sleepiness, so this & timing of dosing should be kept in mind & adjusted as needed given the circadian disturbance in SMS & possible exacerbation.
• Avoid ASMs assoc w/weight gain (i.e., valproic acid)
• Education of parents/caregivers
• Identify & treat swallowing/feeding problems & optimize oral sensorimotor development.
• Develop skills related to swallowing & speech production by ↑ sensory input, fostering movement of articulators, ↑ oral motor endurance, & ↓ hypersensitivity.
• Develop a comprehensive behavioral support plan for home & school at onset of maladaptive behaviors (typically starting in early elementary school).
• Develop structured school program w/one-on-one support & curricula matched to known cognitive & behavior profile of SMS.
• Behavioral therapies include special education techniques emphasizing individualized instruction, structure, & routine to minimize behavioral outbursts in school.
• Assess for underlying reasons for changes in behavior (
• Insight about vulnerabilities & relative strengths in sensory processing patterns (i.e., visual processing & oral sensory processing) may aid caregivers in adapting activity demands, modifying environments, & facilitating appropriate & supportive social interactions.
• Atypical patterns of sensory processing & more problematic/atypical behaviors may become more prominent w/age.
• Specialized developmental psychiatric & psychological services for assessment & treatment for psychiatric or mental health concerns
• Psychotropic medication & psychological services to ↓ maladaptive behaviors, ↑ attention &/or ↓ hyperactivity, ↓ anxiety, & stabilize mood
• Melatonin receptor agonist: 1st FDA-approved treatment of nighttime sleep disturbance in SMS.
• A randomized crossover study using tasimelteon showed effective improvement of sleep quality & total sleep time.
• Mgmt strategies to limit access to food due to biologically based intense food-related behaviors in SMS (i.e., hyperphagia, obsessions/fixations on food, impaired satiety) require a multicomponent individualized approach to ↓ obesity health risks.
• A trial using an MC4R agonist, setmelanotide, for obesity in persons w/SMS failed to significantly ↓ body weight but did impact self-reported "hunger."
• There are published cases of renal cancer in adults w/SMS w/deletion of 17p11.2.
• Recommendations include kidney cancer surveillance starting at 20 yrs & eval for both skin & lung manifestations of BHDS.
• Combination of ID, severe behavioral abnormalities, & sleep disturbance takes significant toll on caretakers/parents & sibs.
• Incl family support services & resources as essential components of a holistic mgmt 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.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Annually in adolescents & adults
• Presurgical eval for possible premature cerebrovascular disease is recommended for persons w/SMS who require open-heart surgery in adolescence or adulthood.
• Otolaryngologic follow up for assessment & mgmt of otitis media & other sinus abnormalities
• Audiologic eval to monitor for CHL or SNHL annually or as clinically indicated
• Routine urinalysis to evaluate for occult urinary tract infections
• Gynecologic eval per gynecologist
• Age ≥20 yrs
• Since BHDS is an adult-onset disorder, additional screening for symptoms related to BHDS in children w/SMS is not indicated.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SMS, the evaluations summarized in
Smith-Magenis Syndrome: Recommended Evaluations Following Initial Diagnosis
EEG in those w/clinical seizures or suspected seizures
Neuroimaging (MRI or CT scan) in accordance w/findings such as seizures &/or motor asymmetry
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Sleep history w/particular attention to sleep/wake schedules & signs/symptoms of obstructive sleep apnea
Polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea in those w/evidence of sleep-disordered breathing
Signs/symptoms of GERD
Constipation
Caloric intake
Attention to evidence of strabismus, microcornea, iris anomalies, & refractive error
In adults: keratoconus & glaucoma
Audiologic assessment for CHL &/or SNHL
Consider eval for velopharyngeal insufficiency in those w/functional impairments.
Qualitative Igs
Susceptibility to sinopulmonary infections, aspiration pneumonia
Detailed dermatologic exam
Biopsy of suspicious lesion(s)
Chest radiograph
Chest CT
Assess safety concerns /need to monitor overnight to prevent/avert wandering, food foraging, &/or self-injury.
Assess for aggressive behaviors.
Range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets)
Safety eval for person w/SMS & caregivers
Community or
Social work involvement for parental support
Home nursing referral
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BHDS =
To include quantitative serum Igs (IgG, IgA, IgM)
Screening for adrenal function should be considered in individuals with larger deletions extending into 17p12.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• EEG in those w/clinical seizures or suspected seizures
• Neuroimaging (MRI or CT scan) in accordance w/findings such as seizures &/or motor asymmetry
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Sleep history w/particular attention to sleep/wake schedules & signs/symptoms of obstructive sleep apnea
• Polysomnogram (overnight sleep study) to evaluate for obstructive sleep apnea in those w/evidence of sleep-disordered breathing
• Signs/symptoms of GERD
• Constipation
• Caloric intake
• Attention to evidence of strabismus, microcornea, iris anomalies, & refractive error
• In adults: keratoconus & glaucoma
• Audiologic assessment for CHL &/or SNHL
• Consider eval for velopharyngeal insufficiency in those w/functional impairments.
• Qualitative Igs
• Susceptibility to sinopulmonary infections, aspiration pneumonia
• Detailed dermatologic exam
• Biopsy of suspicious lesion(s)
• Chest radiograph
• Chest CT
• Assess safety concerns /need to monitor overnight to prevent/avert wandering, food foraging, &/or self-injury.
• Assess for aggressive behaviors.
• Range of mitigating strategies (e.g., enclosed bed system / "safe space" for containment during sleep, bedroom adaptations, locked kitchen cabinets)
• Safety eval for person w/SMS & caregivers
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for SMS. 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
Smith-Magenis Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for SMS.
Importantly, several ASMs may cause sleepiness, so this & timing of dosing should be kept in mind & adjusted as needed given the circadian disturbance in SMS & possible exacerbation.
Avoid ASMs assoc w/weight gain (i.e., valproic acid)
Education of parents/caregivers
Identify & treat swallowing/feeding problems & optimize oral sensorimotor development.
Develop skills related to swallowing & speech production by ↑ sensory input, fostering movement of articulators, ↑ oral motor endurance, & ↓ hypersensitivity.
Develop a comprehensive behavioral support plan for home & school at onset of maladaptive behaviors (typically starting in early elementary school).
Develop structured school program w/one-on-one support & curricula matched to known cognitive & behavior profile of SMS.
Behavioral therapies include special education techniques emphasizing individualized instruction, structure, & routine to minimize behavioral outbursts in school.
Assess for underlying reasons for changes in behavior (
Insight about vulnerabilities & relative strengths in sensory processing patterns (i.e., visual processing & oral sensory processing) may aid caregivers in adapting activity demands, modifying environments, & facilitating appropriate & supportive social interactions.
Atypical patterns of sensory processing & more problematic/atypical behaviors may become more prominent w/age.
Specialized developmental psychiatric & psychological services for assessment & treatment for psychiatric or mental health concerns
Psychotropic medication & psychological services to ↓ maladaptive behaviors, ↑ attention &/or ↓ hyperactivity, ↓ anxiety, & stabilize mood
Melatonin receptor agonist: 1st FDA-approved treatment of nighttime sleep disturbance in SMS.
A randomized crossover study using tasimelteon showed effective improvement of sleep quality & total sleep time.
Mgmt strategies to limit access to food due to biologically based intense food-related behaviors in SMS (i.e., hyperphagia, obsessions/fixations on food, impaired satiety) require a multicomponent individualized approach to ↓ obesity health risks.
A trial using an MC4R agonist, setmelanotide, for obesity in persons w/SMS failed to significantly ↓ body weight but did impact self-reported "hunger."
There are published cases of renal cancer in adults w/SMS w/deletion of 17p11.2.
Recommendations include kidney cancer surveillance starting at 20 yrs & eval for both skin & lung manifestations of BHDS.
Combination of ID, severe behavioral abnormalities, & sleep disturbance takes significant toll on caretakers/parents & sibs.
Incl family support services & resources as essential components of a holistic mgmt plan.
ASM = anti-seizure medication; BHDS =
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 2024 PRISMS Clinical and Research Consortium treatment recommendation:
The potential for more problematic or atypical behaviors with increased age underscores the need for early and ongoing intervention and caregiver education [
Based on an extensive review of psychotropic medication use in a large cohort of individuals with SMS (n=62), use of polypharmacy and/or serial trials with minimal effectiveness was observed. Benzodiazepines obtained the lowest mean efficacy score in the "slightly worse" range, suggesting that use of these drugs may be detrimental to individuals with SMS [
Sleep management is a challenge for physicians and parents. Prior to beginning any trial, a child's medical status and baseline sleep pattern must be considered.
Dosages should be kept low (≤3 mg). However, melatonin dispensed over the counter is not regulated by the FDA; thus, dosages may not be exact. No early and controlled melatonin treatment trials have been conducted. A monitored trial of four to six weeks on melatonin may be worth considering in affected individuals with sleep disturbance.
Nine individuals with SMS were treated with oral beta-1-adrenergic antagonists (acebutolol, 10 mg/kg) [
Parents also reported subjective improvement in daytime behaviors with increased concentration. Contraindications to the use of beta-1-adrenergic antagonists include asthma, pulmonary problems, some cardiovascular disease, and diabetes mellitus.
Dietary changes with portion management in addition to increased movement and physical activity, limiting sedentary activity, and discouraging nighttime eating
See
See Got Transition,
Parents report high rates of depression and anxiety, and family stress is significantly higher in families of individuals with SMS than in those of children with non-specific developmental disabilities [
The following information represents typical management recommendations for individuals with developmental delay and/or 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
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
Consultation with specialized services (developmental pediatric, psychiatric, psychological) for concerns about emotions and behavior may be helpful in guiding parents through management strategies and options. A specialized physician (developmental pediatrician or psychiatrist) may discuss prescription medication trials when necessary (e.g., for attention-deficit/hyperactivity disorder).
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Individuals may qualify and benefit from interventions used in treatment of neurodevelopmental disorders and autism spectrum disorder, including applied behavior analysis (ABA). ABA interventions are science based and targeted to the individual's behavioral, social, and adaptive strengths and weaknesses. Strategies for supports and interventions are typically developed with the team led by a board-certified behavior analyst (BCBA).
• Many ASMs may be effective; none has been demonstrated effective specifically for SMS.
• Importantly, several ASMs may cause sleepiness, so this & timing of dosing should be kept in mind & adjusted as needed given the circadian disturbance in SMS & possible exacerbation.
• Avoid ASMs assoc w/weight gain (i.e., valproic acid)
• Education of parents/caregivers
• Identify & treat swallowing/feeding problems & optimize oral sensorimotor development.
• Develop skills related to swallowing & speech production by ↑ sensory input, fostering movement of articulators, ↑ oral motor endurance, & ↓ hypersensitivity.
• Develop a comprehensive behavioral support plan for home & school at onset of maladaptive behaviors (typically starting in early elementary school).
• Develop structured school program w/one-on-one support & curricula matched to known cognitive & behavior profile of SMS.
• Behavioral therapies include special education techniques emphasizing individualized instruction, structure, & routine to minimize behavioral outbursts in school.
• Assess for underlying reasons for changes in behavior (
• Insight about vulnerabilities & relative strengths in sensory processing patterns (i.e., visual processing & oral sensory processing) may aid caregivers in adapting activity demands, modifying environments, & facilitating appropriate & supportive social interactions.
• Atypical patterns of sensory processing & more problematic/atypical behaviors may become more prominent w/age.
• Specialized developmental psychiatric & psychological services for assessment & treatment for psychiatric or mental health concerns
• Psychotropic medication & psychological services to ↓ maladaptive behaviors, ↑ attention &/or ↓ hyperactivity, ↓ anxiety, & stabilize mood
• Melatonin receptor agonist: 1st FDA-approved treatment of nighttime sleep disturbance in SMS.
• A randomized crossover study using tasimelteon showed effective improvement of sleep quality & total sleep time.
• Mgmt strategies to limit access to food due to biologically based intense food-related behaviors in SMS (i.e., hyperphagia, obsessions/fixations on food, impaired satiety) require a multicomponent individualized approach to ↓ obesity health risks.
• A trial using an MC4R agonist, setmelanotide, for obesity in persons w/SMS failed to significantly ↓ body weight but did impact self-reported "hunger."
• There are published cases of renal cancer in adults w/SMS w/deletion of 17p11.2.
• Recommendations include kidney cancer surveillance starting at 20 yrs & eval for both skin & lung manifestations of BHDS.
• Combination of ID, severe behavioral abnormalities, & sleep disturbance takes significant toll on caretakers/parents & sibs.
• Incl family support services & resources as essential components of a holistic mgmt 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.
• Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
• PT, OT, and speech-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
The following information represents typical management recommendations for individuals with developmental delay and/or 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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-language services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
## Neurobehavioral/Psychiatric Concerns
Consultation with specialized services (developmental pediatric, psychiatric, psychological) for concerns about emotions and behavior may be helpful in guiding parents through management strategies and options. A specialized physician (developmental pediatrician or psychiatrist) may discuss prescription medication trials when necessary (e.g., for attention-deficit/hyperactivity disorder).
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Individuals may qualify and benefit from interventions used in treatment of neurodevelopmental disorders and autism spectrum disorder, including applied behavior analysis (ABA). ABA interventions are science based and targeted to the individual's behavioral, social, and adaptive strengths and weaknesses. Strategies for supports and interventions are typically developed with the team led by a board-certified behavior analyst (BCBA).
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Smith-Magenis Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Annually in adolescents & adults
Presurgical eval for possible premature cerebrovascular disease is recommended for persons w/SMS who require open-heart surgery in adolescence or adulthood.
Otolaryngologic follow up for assessment & mgmt of otitis media & other sinus abnormalities
Audiologic eval to monitor for CHL or SNHL annually or as clinically indicated
Routine urinalysis to evaluate for occult urinary tract infections
Gynecologic eval per gynecologist
Age ≥20 yrs
Since BHDS is an adult-onset disorder, additional screening for symptoms related to BHDS in children w/SMS is not indicated.
BHDS =
Assess for new manifestations such as seizures or changes in behavior.
Particularly in school-age children
Periodic neurodevelopmental assessments and/or developmental/behavioral pediatric consultation can be an important adjunct to the team evaluation.
Symptoms include onset of neurologic deficits of lower extremities, gait disturbance, loss of bowel/bladder control, progressive deformities of feet, and/or spinal stenosis.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Annually in adolescents & adults
• Presurgical eval for possible premature cerebrovascular disease is recommended for persons w/SMS who require open-heart surgery in adolescence or adulthood.
• Otolaryngologic follow up for assessment & mgmt of otitis media & other sinus abnormalities
• Audiologic eval to monitor for CHL or SNHL annually or as clinically indicated
• Routine urinalysis to evaluate for occult urinary tract infections
• Gynecologic eval per gynecologist
• Age ≥20 yrs
• Since BHDS is an adult-onset disorder, additional screening for symptoms related to BHDS in children w/SMS is not indicated.
## Agents/Circumstances to Avoid
Use of psychoactive medications in SMS often begins in childhood with use of sleep aids and trials of different psychoactive medications to reduce/manage maladaptive behavior, with mixed response; no single regimen has shown consistent efficacy, and adverse reactions to some medications have been reported [
Lacking well-controlled trials, when starting a new medication, care should be taken to track sleep and behavior changes over several days/weeks to monitor for potential side effects (e.g., increased appetite, weight gain) and adverse reactions and/or to determine potential efficacy.
Pharmacologic intervention should be considered on an individual basis with recognition that some medications may exacerbate sleep or behavioral issues and may cause weight gain. Pharmacogenetic testing panels to identify potential gene-drug interactions may aid in tailoring therapeutic strategies for the individual.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Smith-Magenis syndrome (SMS) is an autosomal dominant disorder typically caused by a heterozygous
Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as the result of a
Rarely, individuals diagnosed with SMS have the disorder as the result of:
A 17p11.2 deletion [
A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
An intragenic
Genomic or molecular genetic testing that will detect the genetic alteration present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. In addition, chromosome analysis of the parents should be performed for all newly diagnosed individuals found to have a 17p11.2 deletion; complex familial chromosome rearrangements leading to 17p11.2 deletion and SMS are rare but have been reported [
If the 17p11.2 deletion or intragenic
The proband has a
The proband inherited a genetic alteration 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 genetic alteration that is present in the germ (gonadal) cells only.
Note: Parents found to have an
If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1% (recurrence risk attributable to the possibility of gonadal mosaicism in a parent) [
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%.
The offspring of an individual with SMS are at a 50% risk of having SMS, assuming the other biological parent does not also have SMS.
Individuals (females) with SMS are known to have given birth to a child with SMS [
Fertility issues in SMS remain unstudied.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults from families in which a chromosome rearrangement has been identified.
Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells.
Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded analysis provided the resolution is adequate (≥550 band), this approach is not recommended for prenatal testing because it is not uncommon for the deletion to be overlooked.
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 concerns may be helpful.
• Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as the result of a
• Rarely, individuals diagnosed with SMS have the disorder as the result of:
• A 17p11.2 deletion [
• A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
• An intragenic
• A 17p11.2 deletion [
• A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
• An intragenic
• Genomic or molecular genetic testing that will detect the genetic alteration present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. In addition, chromosome analysis of the parents should be performed for all newly diagnosed individuals found to have a 17p11.2 deletion; complex familial chromosome rearrangements leading to 17p11.2 deletion and SMS are rare but have been reported [
• If the 17p11.2 deletion or intragenic
• The proband has a
• The proband inherited a genetic alteration 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 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 [
• Note: 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.
• A 17p11.2 deletion [
• A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
• An intragenic
• The proband has a
• The proband inherited a genetic alteration 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 genetic alteration that is present in the germ (gonadal) cells only.
• If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1% (recurrence risk attributable to the possibility of gonadal mosaicism in a parent) [
• If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%.
• The offspring of an individual with SMS are at a 50% risk of having SMS, assuming the other biological parent does not also have SMS.
• Individuals (females) with SMS are known to have given birth to a child with SMS [
• Fertility issues in SMS remain unstudied.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults from families in which a chromosome rearrangement has been identified.
• Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
• In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells.
• Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded analysis provided the resolution is adequate (≥550 band), this approach is not recommended for prenatal testing because it is not uncommon for the deletion to be overlooked.
## Mode of Inheritance
Smith-Magenis syndrome (SMS) is an autosomal dominant disorder typically caused by a heterozygous
## Risk to Family Members
Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as the result of a
Rarely, individuals diagnosed with SMS have the disorder as the result of:
A 17p11.2 deletion [
A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
An intragenic
Genomic or molecular genetic testing that will detect the genetic alteration present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. In addition, chromosome analysis of the parents should be performed for all newly diagnosed individuals found to have a 17p11.2 deletion; complex familial chromosome rearrangements leading to 17p11.2 deletion and SMS are rare but have been reported [
If the 17p11.2 deletion or intragenic
The proband has a
The proband inherited a genetic alteration 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 genetic alteration that is present in the germ (gonadal) cells only.
Note: Parents found to have an
If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1% (recurrence risk attributable to the possibility of gonadal mosaicism in a parent) [
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%.
The offspring of an individual with SMS are at a 50% risk of having SMS, assuming the other biological parent does not also have SMS.
Individuals (females) with SMS are known to have given birth to a child with SMS [
Fertility issues in SMS remain unstudied.
• Almost all individuals reported to date with SMS whose biological parents have undergone genetic testing have the disorder as the result of a
• Rarely, individuals diagnosed with SMS have the disorder as the result of:
• A 17p11.2 deletion [
• A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
• An intragenic
• A 17p11.2 deletion [
• A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
• An intragenic
• Genomic or molecular genetic testing that will detect the genetic alteration present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. In addition, chromosome analysis of the parents should be performed for all newly diagnosed individuals found to have a 17p11.2 deletion; complex familial chromosome rearrangements leading to 17p11.2 deletion and SMS are rare but have been reported [
• If the 17p11.2 deletion or intragenic
• The proband has a
• The proband inherited a genetic alteration 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 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 [
• Note: 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.
• A 17p11.2 deletion [
• A 17p11.2 deletion resulting from a structural chromosome rearrangement in a parent [
• An intragenic
• The proband has a
• The proband inherited a genetic alteration 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 genetic alteration that is present in the germ (gonadal) cells only.
• If neither parent is found to have the genetic alteration identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is likely less than 1% (recurrence risk attributable to the possibility of gonadal mosaicism in a parent) [
• If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%.
• The offspring of an individual with SMS are at a 50% risk of having SMS, assuming the other biological parent does not also have SMS.
• Individuals (females) with SMS are known to have given birth to a child with SMS [
• Fertility issues in SMS remain unstudied.
## 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 from families in which a chromosome rearrangement has been identified.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults from families in which a chromosome rearrangement has been identified.
## Prenatal Testing and Preimplantation Genetic Testing
Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells.
Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded analysis provided the resolution is adequate (≥550 band), this approach is not recommended for prenatal testing because it is not uncommon for the deletion to be overlooked.
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 concerns may be helpful.
• Once the SMS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
• In the rare instance of a complex familial chromosome rearrangement, prenatal testing is possible for a pregnancy at increased risk using prenatal chromosomal microarray analysis (CMA) and sequencing on fetal cells.
• Note: Although a visible interstitial deletion of chromosome 17p11.2 can be detected in all individuals with the common approximately 3.7-Mb deletion by a routine G-banded analysis provided the resolution is adequate (≥550 band), this approach is not recommended for prenatal testing because it is not uncommon for the deletion to be overlooked.
## Resources
France
Germany
Member of PRISMS International Partnership Program
Australia
United Kingdom
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• France
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• Germany
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• Member of PRISMS International Partnership Program
• Australia
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• United Kingdom
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## Molecular Genetics
Smith-Magenis Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Smith-Magenis Syndrome (
Smith-Magenis syndrome is caused by either a microdeletion of 17p11.2 including
## Molecular Pathogenesis
Smith-Magenis syndrome is caused by either a microdeletion of 17p11.2 including
## Chapter Notes
The authors of the
Inquiries/questions received by PRISMS at
Judith E Allanson, MD; Children's Hospital of Eastern Ottawa (2001-2009)Albert J Allen, MD, PhD; Eli Lilly Laboratories, Inc (2001-2005)John Berens, MD, FAAP, FACP (2025-present)Kerry E Boyd, MD, FRCP(C) (2009-present)Christine Brennan, PhD, CCC-SLP (2019-present)Jane Charles, MD; Medical University of South Carolina (2019-2025)Elisabeth Dykens, PhD; University of California, Los Angeles (2001-2005)Sarah H Elsea, PhD, FACMG (2001-present)Brenda M Finucane, MS, CGC; Autism & Developmental Medicine Institute (2001-2025)Rebecca Foster, PhD (2019-present)Rachel Franciskovich, MS, CGC (2025-present)Santhosh Girirajan, MBBS, PhD (2019-present)Andrea Gropman, MD, FAAP, FACMG (2005-present)Barbara Haas-Givler, MEd, BCBA (2005-present)Kyle P Johnson, MD; Oregon Health and Science University (2004-2012)Gonzalo Laje, MD; National Institute of Mental Health (2012-2019)James R Lupski, MD, PhD, FAAP, FACMG, FAAAS; Baylor College of Medicine (2001-2012)Ellen Magenis, MD, FAAP, FACMG; Oregon Health and Science University (2001-2019)Lorraine Potocki, MD, FACMG; Baylor College of Medicine (2001-2019)Nancy Raitano Lee, PhD (2025-present)Ann CM Smith, MA, DSc (hon), CGC (2001-present)Beth Solomon, MS; National Institutes of Health (2001-2012)Cora Taylor, PhD (2025-present)Sinan Omer Turnacioglu, MD (2025-present)Christopher Vlangos, PhD, FACMG (2025-present)
29 May 2025 (gm) Comprehensive update posted live
20 June 2019 (ma) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
7 January 2010 (me) Comprehensive update posted live
11 August 2006 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
22 October 2001 (me) Review posted live
23 May 2001 (as) Original submission
• 29 May 2025 (gm) Comprehensive update posted live
• 20 June 2019 (ma) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 7 January 2010 (me) Comprehensive update posted live
• 11 August 2006 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 22 October 2001 (me) Review posted live
• 23 May 2001 (as) Original submission
## Author Notes
The authors of the
Inquiries/questions received by PRISMS at
## Author History
Judith E Allanson, MD; Children's Hospital of Eastern Ottawa (2001-2009)Albert J Allen, MD, PhD; Eli Lilly Laboratories, Inc (2001-2005)John Berens, MD, FAAP, FACP (2025-present)Kerry E Boyd, MD, FRCP(C) (2009-present)Christine Brennan, PhD, CCC-SLP (2019-present)Jane Charles, MD; Medical University of South Carolina (2019-2025)Elisabeth Dykens, PhD; University of California, Los Angeles (2001-2005)Sarah H Elsea, PhD, FACMG (2001-present)Brenda M Finucane, MS, CGC; Autism & Developmental Medicine Institute (2001-2025)Rebecca Foster, PhD (2019-present)Rachel Franciskovich, MS, CGC (2025-present)Santhosh Girirajan, MBBS, PhD (2019-present)Andrea Gropman, MD, FAAP, FACMG (2005-present)Barbara Haas-Givler, MEd, BCBA (2005-present)Kyle P Johnson, MD; Oregon Health and Science University (2004-2012)Gonzalo Laje, MD; National Institute of Mental Health (2012-2019)James R Lupski, MD, PhD, FAAP, FACMG, FAAAS; Baylor College of Medicine (2001-2012)Ellen Magenis, MD, FAAP, FACMG; Oregon Health and Science University (2001-2019)Lorraine Potocki, MD, FACMG; Baylor College of Medicine (2001-2019)Nancy Raitano Lee, PhD (2025-present)Ann CM Smith, MA, DSc (hon), CGC (2001-present)Beth Solomon, MS; National Institutes of Health (2001-2012)Cora Taylor, PhD (2025-present)Sinan Omer Turnacioglu, MD (2025-present)Christopher Vlangos, PhD, FACMG (2025-present)
## Revision History
29 May 2025 (gm) Comprehensive update posted live
20 June 2019 (ma) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
7 January 2010 (me) Comprehensive update posted live
11 August 2006 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
22 October 2001 (me) Review posted live
23 May 2001 (as) Original submission
• 29 May 2025 (gm) Comprehensive update posted live
• 20 June 2019 (ma) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 7 January 2010 (me) Comprehensive update posted live
• 11 August 2006 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 22 October 2001 (me) Review posted live
• 23 May 2001 (as) Original submission
## References
## Literature Cited
Infants with Smith-Magenis syndrome (SMS). Female age nine months (left) and male age 30 months (right). Note brachycephaly, broad forehead, upslanting palpebral fissures, short, upturned nose, and characteristic downturned "tent"-shaped vermilion of the upper lip with mild micrognathia. Fair (hypopigmented) complexion with rosy "pudgy" cheeks is also seen.
Images courtesy of Ann CM Smith, MA, DSc (Hon), SMS Research Team, National Human Genome Research Institute, National Institutes of Health, HHS, Bethesda, MD.
Early school-age children with Smith-Magenis syndrome (SMS). Male age four years (left) and female age five years (right); the female is also pictured at age 15 years in
Images courtesy of Ann CM Smith, MA, DSc (Hon), SMS Research Team, National Human Genome Research Institute, National Institutes of Health, HHS, Bethesda, MD.
Adolescent females with Smith-Magenis syndrome (SMS) caused by
Images courtesy of Ann C.M. Smith, M.A., D.Sc. (Hon), SMS Research Team, National Human Genome Research Institute, National Institutes of Health, HHS, Bethesda, MD.
|
[] |
22/10/2001
|
29/5/2025
|
10/3/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
snyder-robinson
|
snyder-robinson
|
[
"Spermine Synthase Deficiency",
"Spermine Synthase Deficiency",
"Spermine synthase",
"SMS",
"Snyder-Robinson Syndrome"
] |
Snyder-Robinson Syndrome
|
Charles E Schwartz, Caleb Bupp, Mary Jo Kutler, Angela Peron
|
Summary Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by facial dysmorphism, asthenic build, progressive kyphoscoliosis, early-onset osteoporosis, and seizures. To date, only affected males have been reported. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to mild-to-profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year. Seizure onset varies but typically occurs in early childhood. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma. Rare findings may include nonspecific kidney manifestations. The diagnosis of SRS is established in a male proband with a hemizygous loss-of-function SRS is inherited in an X-linked manner. If the mother of the proband has an
|
## Diagnosis
Formal diagnostic criteria have not been established for Snyder-Robinson syndrome (SRS).
SRS
The diagnosis of SRS
Note: (1) Per ACMG/AMG 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 findings suggest the diagnosis of SRS, molecular genetic testing approaches can include the use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Snyder-Robinson 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.
Although several intragenic deletions and deletions and duplications that span
•
## Suggestive Findings
SRS
•
## Establishing the Diagnosis
The diagnosis of SRS
Note: (1) Per ACMG/AMG 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 findings suggest the diagnosis of SRS, molecular genetic testing approaches can include the use of a
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Snyder-Robinson 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.
Although several intragenic deletions and deletions and duplications that span
## Option 1
When the phenotypic findings suggest the diagnosis of SRS, molecular genetic testing approaches can include the use of a
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Snyder-Robinson 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.
Although several intragenic deletions and deletions and duplications that span
## Other Testing
## Clinical Characteristics
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability (ID) syndrome belonging to the group of polyaminopathies (disorders related to the polyamine pathway). SRS has a specific clinical phenotype consisting of facial dysmorphism, asthenic build, progressive kyphoscoliosis, early-onset osteoporosis, ID, and seizures. To date, the authors are aware of around 100 individuals with a pathogenic variant in
Snyder-Robinson Syndrome: Frequency of Select Features
No clear genotype-phenotype correlations have been established for SRS. Even within a family, the phenotype varies; for example, in one family IQ values ranged from 46 to 77.
Based on the limited data available, the
A male infant with an
All individuals with SRS have deficient spermine synthase enzyme activity. However, as its prevalence in the general population has not been determined, penetrance of deficient spermine synthase activity as SRS cannot be estimated.
The prevalence of SRS is unknown. To date, the authors are aware of at least 100 individuals with SRS [A Peron, unpublished data], and 31 individuals have been evaluated and reported in the literature (see
## Clinical Description
Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability (ID) syndrome belonging to the group of polyaminopathies (disorders related to the polyamine pathway). SRS has a specific clinical phenotype consisting of facial dysmorphism, asthenic build, progressive kyphoscoliosis, early-onset osteoporosis, ID, and seizures. To date, the authors are aware of around 100 individuals with a pathogenic variant in
Snyder-Robinson Syndrome: Frequency of Select Features
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlations have been established for SRS. Even within a family, the phenotype varies; for example, in one family IQ values ranged from 46 to 77.
Based on the limited data available, the
A male infant with an
## Penetrance
All individuals with SRS have deficient spermine synthase enzyme activity. However, as its prevalence in the general population has not been determined, penetrance of deficient spermine synthase activity as SRS cannot be estimated.
## Prevalence
The prevalence of SRS is unknown. To date, the authors are aware of at least 100 individuals with SRS [A Peron, unpublished data], and 31 individuals have been evaluated and reported in the literature (see
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
X-linked ID syndromes with overlapping findings of SRS and osteoporosis are summarized in
X-Linked Intellectual Disability Syndromes with Overlapping Findings of Snyder-Robinson Syndrome and Osteoporosis
DD
Growth restriction
Muscle weakness
Osteoporosis
ID
Asthenic habitus
Seizures
ID
Hypotonia
↓ muscle mass
Unsteady gait / ataxia
Moderate-to-severe ID
Osteoporosis
Scoliosis
Seizures
Speech abnormalities
Excessively friendly demeanor
Normal facial features
Normal stature
ID
Thin habitus
Hypernasal voice
DD = developmental delay; ID = intellectual disability; SRS = Snyder-Robinson syndrome
Xp21 deletion includes deletion of
• DD
• Growth restriction
• Muscle weakness
• Osteoporosis
• ID
• Asthenic habitus
• Seizures
• ID
• Hypotonia
• ↓ muscle mass
• Unsteady gait / ataxia
• Moderate-to-severe ID
• Osteoporosis
• Scoliosis
• Seizures
• Speech abnormalities
• Excessively friendly demeanor
• Normal facial features
• Normal stature
• ID
• Thin habitus
• Hypernasal voice
## Management
To establish the extent of disease and needs in an individual diagnosed with SRS, the evaluations summarized in
Snyder-Robinson Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment for hypotonia
To incl brain MRI to assess abnormal calcification &/or brain abnormalities
Consider EEG if seizures are a concern.
Assessment for hypospadias & cryptorchism
Renal ultrasound
DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; SRS = Snyder-Robinson syndrome
Bisphosphonates have been used for osteoporosis in general; their efficacy in SRS has not been demonstrated, and initial evidence of efficacy is controversial.
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
Snyder-Robinson Syndrome: Treatment of Manifestations
Carbamazepine, phenobarbital, clobazam, levetiracetam & valproic acid have successfully controlled seizures in some persons.
Avoid medications known to affect bone (e.g., some ASMs), as they can potentially worsen osteoporosis & ↑ risk of spontaneous fractures.
Calcium supplementation has slightly improved bone mineral density in a few persons.
The use of bisphosphonates is controversial & no studies currently demonstrate their effectiveness.
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 (but contact sports should be avoided because of the risk of fractures).
ASM = anti-seizure medication; OT = occupational therapy; 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
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.
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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Snyder-Robinson Syndrome: Recommended Surveillance
Clinical exam & DXA scans to monitor progression of osteoporosis
Radiographs to investigate for factures
Referral to endocrinologist to manage calcium supplementation due to risk of ectopic calcification secondary to calcium supplementation
Monitor for kyphoscoliosis.
Orthopedic eval as indicated
Monitor for nephrocalcinosis & renal cysts.
Monitor kidney function, considering creatine levels in the context of low muscle mass.
DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
Avoid medications known to affect bone (e.g., some ASMs), as they can potentially worsen osteoporosis and increase the risk of spontaneous fractures.
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment for hypotonia
• To incl brain MRI to assess abnormal calcification &/or brain abnormalities
• Consider EEG if seizures are a concern.
• Assessment for hypospadias & cryptorchism
• Renal ultrasound
• Carbamazepine, phenobarbital, clobazam, levetiracetam & valproic acid have successfully controlled seizures in some persons.
• Avoid medications known to affect bone (e.g., some ASMs), as they can potentially worsen osteoporosis & ↑ risk of spontaneous fractures.
• Calcium supplementation has slightly improved bone mineral density in a few persons.
• The use of bisphosphonates is controversial & no studies currently demonstrate their effectiveness.
• 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 (but contact sports should be avoided because of the risk of fractures).
• 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.
• 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
• Clinical exam & DXA scans to monitor progression of osteoporosis
• Radiographs to investigate for factures
• Referral to endocrinologist to manage calcium supplementation due to risk of ectopic calcification secondary to calcium supplementation
• Monitor for kyphoscoliosis.
• Orthopedic eval as indicated
• Monitor for nephrocalcinosis & renal cysts.
• Monitor kidney function, considering creatine levels in the context of low muscle mass.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SRS, the evaluations summarized in
Snyder-Robinson Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment for hypotonia
To incl brain MRI to assess abnormal calcification &/or brain abnormalities
Consider EEG if seizures are a concern.
Assessment for hypospadias & cryptorchism
Renal ultrasound
DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; SRS = Snyder-Robinson syndrome
Bisphosphonates have been used for osteoporosis in general; their efficacy in SRS has not been demonstrated, and initial evidence of efficacy is controversial.
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
• Assessment for hypotonia
• To incl brain MRI to assess abnormal calcification &/or brain abnormalities
• Consider EEG if seizures are a concern.
• Assessment for hypospadias & cryptorchism
• Renal ultrasound
## 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
Snyder-Robinson Syndrome: Treatment of Manifestations
Carbamazepine, phenobarbital, clobazam, levetiracetam & valproic acid have successfully controlled seizures in some persons.
Avoid medications known to affect bone (e.g., some ASMs), as they can potentially worsen osteoporosis & ↑ risk of spontaneous fractures.
Calcium supplementation has slightly improved bone mineral density in a few persons.
The use of bisphosphonates is controversial & no studies currently demonstrate their effectiveness.
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 (but contact sports should be avoided because of the risk of fractures).
ASM = anti-seizure medication; OT = occupational therapy; 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
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.
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
• Carbamazepine, phenobarbital, clobazam, levetiracetam & valproic acid have successfully controlled seizures in some persons.
• Avoid medications known to affect bone (e.g., some ASMs), as they can potentially worsen osteoporosis & ↑ risk of spontaneous fractures.
• Calcium supplementation has slightly improved bone mineral density in a few persons.
• The use of bisphosphonates is controversial & no studies currently demonstrate their effectiveness.
• 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 (but contact sports should be avoided because of the risk of fractures).
• 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.
• 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
## 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
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Snyder-Robinson Syndrome: Recommended Surveillance
Clinical exam & DXA scans to monitor progression of osteoporosis
Radiographs to investigate for factures
Referral to endocrinologist to manage calcium supplementation due to risk of ectopic calcification secondary to calcium supplementation
Monitor for kyphoscoliosis.
Orthopedic eval as indicated
Monitor for nephrocalcinosis & renal cysts.
Monitor kidney function, considering creatine levels in the context of low muscle mass.
DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
• Clinical exam & DXA scans to monitor progression of osteoporosis
• Radiographs to investigate for factures
• Referral to endocrinologist to manage calcium supplementation due to risk of ectopic calcification secondary to calcium supplementation
• Monitor for kyphoscoliosis.
• Orthopedic eval as indicated
• Monitor for nephrocalcinosis & renal cysts.
• Monitor kidney function, considering creatine levels in the context of low muscle mass.
## Agents/Circumstances to Avoid
Avoid medications known to affect bone (e.g., some ASMs), as they can potentially worsen osteoporosis and increase the risk of spontaneous fractures.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Snyder-Robinson syndrome (SRS) 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 (carrier). 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 gonadal mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
Of the 31 individuals reported to date with a pathogenic variant in
Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
If the
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected;
Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
If the proband represents a simplex case (i.e., a single occurrence in a family) 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 somatic/gonadal mosaicism [
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 pathogenic variant in the family.
Note: Females are heterozygotes for this X-linked disorder; hypothetically, they could develop clinical findings related to the disorder secondary to partial loss of spermine synthase function or skewing of X-chromosome inactivation. To date, no identified heterozygotes have had signs or symptoms attributable to their
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 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 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 (carrier). 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 gonadal mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
• Of the 31 individuals reported to date with a pathogenic variant in
• Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
• Of the 31 individuals reported to date with a pathogenic variant in
• Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
• If the
• Of the 31 individuals reported to date with a pathogenic variant in
• Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
• If the proband represents a simplex case (i.e., a single occurrence in a family) 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 somatic/gonadal mosaicism [
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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
Snyder-Robinson syndrome (SRS) 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 (carrier). 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 gonadal mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
Of the 31 individuals reported to date with a pathogenic variant in
Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
If the
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected;
Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
If the proband represents a simplex case (i.e., a single occurrence in a family) 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 somatic/gonadal mosaicism [
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 (carrier). 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 gonadal mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), the affected male may have a
• Of the 31 individuals reported to date with a pathogenic variant in
• Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
• Of the 31 individuals reported to date with a pathogenic variant in
• Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
• If the
• Of the 31 individuals reported to date with a pathogenic variant in
• Maternal somatic mosaicism (variant allele frequency: 3% in blood) has been reported in one family to date [
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
• If the proband represents a simplex case (i.e., a single occurrence in a family) 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 somatic/gonadal mosaicism [
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes. In the families reported to date, features of SRS have not been observed in heterozygous females.
## Carrier Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the pathogenic variant in the family.
Note: Females are heterozygotes for this X-linked disorder; hypothetically, they could develop clinical findings related to the disorder secondary to partial loss of spermine synthase function or skewing of X-chromosome inactivation. To date, no identified heterozygotes have had signs or symptoms attributable to their
## 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 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
Snyder-Robinson Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Snyder-Robinson Syndrome (
Polyamines are small organic molecules containing at least two amino groups. They play a wide range of regulatory functions in the cell, ensuring normal cell growth, differentiation, and survival [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Polyamines are small organic molecules containing at least two amino groups. They play a wide range of regulatory functions in the cell, ensuring normal cell growth, differentiation, and survival [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Dr Angela Peron (
Dr Peron, Dr Bupp, and Dr Charles Schwartz (
The
Contact Dr Schwartz and Dr Peron to inquire about review of
The authors would like to thank all individuals with SRS and their families.
Jessica Albert, PhD; National Human Genome Research Institute (2013-2020)Cornelius F Boerkoel, MD, PhD; National Human Genome Research Institute (2013-2020)Caleb Bupp, MD (2025-present)Mary Jo Kutler, DO (2020-present)Angela Peron, MD, PhD (2020-present)Roger E Stevenson, MD; Greenwood Genetic Center (2013-2020)Charles E Schwartz, PhD (2013-present)
7 August 2025 (sw) Comprehensive update posted live
13 February 2020 (sw) Comprehensive update posted live
27 June 2013 (me) Review posted live
28 January 2013 (ja) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 13 February 2020 (sw) Comprehensive update posted live
• 27 June 2013 (me) Review posted live
• 28 January 2013 (ja) Original submission
## Author Notes
Dr Angela Peron (
Dr Peron, Dr Bupp, and Dr Charles Schwartz (
The
Contact Dr Schwartz and Dr Peron to inquire about review of
## Acknowledgments
The authors would like to thank all individuals with SRS and their families.
## Author History
Jessica Albert, PhD; National Human Genome Research Institute (2013-2020)Cornelius F Boerkoel, MD, PhD; National Human Genome Research Institute (2013-2020)Caleb Bupp, MD (2025-present)Mary Jo Kutler, DO (2020-present)Angela Peron, MD, PhD (2020-present)Roger E Stevenson, MD; Greenwood Genetic Center (2013-2020)Charles E Schwartz, PhD (2013-present)
## Revision History
7 August 2025 (sw) Comprehensive update posted live
13 February 2020 (sw) Comprehensive update posted live
27 June 2013 (me) Review posted live
28 January 2013 (ja) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 13 February 2020 (sw) Comprehensive update posted live
• 27 June 2013 (me) Review posted live
• 28 January 2013 (ja) Original submission
## References
## Literature Cited
|
[] |
27/6/2013
|
7/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sost
|
sost
|
[
"SOST-Related Endosteal Hyperostosis, van Buchem type (van Buchem Disease)",
"SOST-Related Sclerosteosis",
"Sclerostin",
"SOST",
"SOST-Related Sclerosing Bone Dysplasias"
] |
Natasha Appelman-Dijkstra, Antoon Van Lierop, Socrates Papapoulos
|
Summary The major clinical features of The manifestations of van Buchem disease are generally milder than The diagnosis of a
|
For synonyms and outdated names see
For other genetic causes of this phenotype see
## Diagnosis
Generalized progressive skeletal overgrowth, most pronounced in the skull and mandible, leading to:
Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
Tall stature with accelerated bone growth beginning in childhood.
Variable cutaneous or bony syndactyly of fingers two (index) and three (middle), and occasionally fingers three and other fingers. The syndactyly is usually bilateral but not necessarily symmetric. (Note: Syndactyly is not present in individuals with van Buchem disease.)
Radial deviation of the terminal phalanges
Dysplastic or absent nails
Widening (hyperostosis) and increased density (sclerosis) of the calvarium, the base of the skull, and the shafts of the tubular bones
Undermodeling of the shafts of the tubular bones of the metacarpals and phalanges
Broad and dense clavicles and ribs
Sclerosis of the scapulae and pelvis without an increase in size
High bone mineral density (z score >5 standard deviations above the mean) measured by dual-energy x-ray absorptiometry [
Note: The majority of persons affected with
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
When the clinical and radiographic findings suggest the diagnosis of
For an introduction to multigene panels click
In individuals from the Netherlands with suspected
When the diagnosis of a
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
Targeted deletion analysis 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 the 52-kb deletion downstream of
A homozygous 52-kb deletion downstream of
• Generalized progressive skeletal overgrowth, most pronounced in the skull and mandible, leading to:
• Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
• Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
• Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
• Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
• Tall stature with accelerated bone growth beginning in childhood.
• Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
• Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
• Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
• Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
• Tall stature with accelerated bone growth beginning in childhood.
• Variable cutaneous or bony syndactyly of fingers two (index) and three (middle), and occasionally fingers three and other fingers. The syndactyly is usually bilateral but not necessarily symmetric. (Note: Syndactyly is not present in individuals with van Buchem disease.)
• Radial deviation of the terminal phalanges
• Dysplastic or absent nails
• Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
• Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
• Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
• Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
• Tall stature with accelerated bone growth beginning in childhood.
• Widening (hyperostosis) and increased density (sclerosis) of the calvarium, the base of the skull, and the shafts of the tubular bones
• Undermodeling of the shafts of the tubular bones of the metacarpals and phalanges
• Broad and dense clavicles and ribs
• Sclerosis of the scapulae and pelvis without an increase in size
• High bone mineral density (z score >5 standard deviations above the mean) measured by dual-energy x-ray absorptiometry [
• For an introduction to multigene panels click
## Suggestive Findings
Generalized progressive skeletal overgrowth, most pronounced in the skull and mandible, leading to:
Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
Tall stature with accelerated bone growth beginning in childhood.
Variable cutaneous or bony syndactyly of fingers two (index) and three (middle), and occasionally fingers three and other fingers. The syndactyly is usually bilateral but not necessarily symmetric. (Note: Syndactyly is not present in individuals with van Buchem disease.)
Radial deviation of the terminal phalanges
Dysplastic or absent nails
Widening (hyperostosis) and increased density (sclerosis) of the calvarium, the base of the skull, and the shafts of the tubular bones
Undermodeling of the shafts of the tubular bones of the metacarpals and phalanges
Broad and dense clavicles and ribs
Sclerosis of the scapulae and pelvis without an increase in size
High bone mineral density (z score >5 standard deviations above the mean) measured by dual-energy x-ray absorptiometry [
Note: The majority of persons affected with
• Generalized progressive skeletal overgrowth, most pronounced in the skull and mandible, leading to:
• Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
• Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
• Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
• Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
• Tall stature with accelerated bone growth beginning in childhood.
• Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
• Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
• Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
• Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
• Tall stature with accelerated bone growth beginning in childhood.
• Variable cutaneous or bony syndactyly of fingers two (index) and three (middle), and occasionally fingers three and other fingers. The syndactyly is usually bilateral but not necessarily symmetric. (Note: Syndactyly is not present in individuals with van Buchem disease.)
• Radial deviation of the terminal phalanges
• Dysplastic or absent nails
• Potentially lethal elevation of intracranial pressure in childhood or early adulthood as a result of calvarial overgrowth;
• Entrapment of the seventh cranial nerve leading to recurrent facial palsy that is initially intermittent and eventually constant, resulting in impaired facial movements in adulthood;
• Conductive hearing loss in childhood followed by additional entrapment of the eighth cranial nerve and closure of the oval and round windows, leading to sensorineural hearing loss in adulthood;
• Distortion of the face with asymmetric mandibular hypertrophy, frontal bossing, midface hypoplasia, or proptosis;
• Tall stature with accelerated bone growth beginning in childhood.
• Widening (hyperostosis) and increased density (sclerosis) of the calvarium, the base of the skull, and the shafts of the tubular bones
• Undermodeling of the shafts of the tubular bones of the metacarpals and phalanges
• Broad and dense clavicles and ribs
• Sclerosis of the scapulae and pelvis without an increase in size
• High bone mineral density (z score >5 standard deviations above the mean) measured by dual-energy x-ray absorptiometry [
## 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
When the clinical and radiographic findings suggest the diagnosis of
For an introduction to multigene panels click
In individuals from the Netherlands with suspected
When the diagnosis of a
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
Targeted deletion analysis 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 the 52-kb deletion downstream of
A homozygous 52-kb deletion downstream of
• For an introduction to multigene panels click
## Option 1
When the clinical and radiographic findings suggest the diagnosis of
For an introduction to multigene panels click
In individuals from the Netherlands with suspected
• For an introduction to multigene panels click
## Option 2
When the diagnosis of a
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
Targeted deletion analysis 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 the 52-kb deletion downstream of
A homozygous 52-kb deletion downstream of
## Clinical Characteristics
Modified from
Other, less common nerve entrapment syndromes in
Bone mineral density measured by dual-energy x-ray absorptiometry (DXA) is greatly increased, with z scores ranging from 7.7 to 14.4 standard deviations (SD) above the mean at the spine and 7.8 to 11.5 SD above the mean at the hip in individuals with
Histologic examination of bone reveals increased bone volume and thickness of cortex and trabeculae, increased osteoblastic bone formation with normal or decreased osteoclastic bone resorption, and no abnormal mineralization of bone tissue [
The high bone density in
The risk for fractures, osteomyelitis, or bone marrow failure is not increased.
There is no apparent difference in phenotype associated with any of the known
The phenotype of van Buchem disease, which is caused by a
In the 2023 revision of the Nosology of Genetic Skeletal Disorders, the
In the past, sclerosteosis and van Buchem disease have been grouped with other dense bone disorders under nonspecific general terms including "marble bones," "osteopetrosis," and "Albers-Schönberg disease." Diagnostic precision and syndromic delineation followed, and the term "sclerosteosis" became established. Similarly, van Buchem and his colleagues employed the designation "hyperostosis corticalis generalisata familiaris" for the condition that is now known as van Buchem disease.
There have been only 31 reported individuals with van Buchem disease, of which 29 were from the Netherlands and two were from Germany [
## Clinical Description
Modified from
Other, less common nerve entrapment syndromes in
Bone mineral density measured by dual-energy x-ray absorptiometry (DXA) is greatly increased, with z scores ranging from 7.7 to 14.4 standard deviations (SD) above the mean at the spine and 7.8 to 11.5 SD above the mean at the hip in individuals with
Histologic examination of bone reveals increased bone volume and thickness of cortex and trabeculae, increased osteoblastic bone formation with normal or decreased osteoclastic bone resorption, and no abnormal mineralization of bone tissue [
The high bone density in
The risk for fractures, osteomyelitis, or bone marrow failure is not increased.
## Clinical Features of
Other, less common nerve entrapment syndromes in
## Clinical Features of Van Buchem Disease
## Laboratory Tests
## Bone Findings
Bone mineral density measured by dual-energy x-ray absorptiometry (DXA) is greatly increased, with z scores ranging from 7.7 to 14.4 standard deviations (SD) above the mean at the spine and 7.8 to 11.5 SD above the mean at the hip in individuals with
Histologic examination of bone reveals increased bone volume and thickness of cortex and trabeculae, increased osteoblastic bone formation with normal or decreased osteoclastic bone resorption, and no abnormal mineralization of bone tissue [
The high bone density in
The risk for fractures, osteomyelitis, or bone marrow failure is not increased.
## Genotype-Phenotype Correlations
There is no apparent difference in phenotype associated with any of the known
The phenotype of van Buchem disease, which is caused by a
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders, the
In the past, sclerosteosis and van Buchem disease have been grouped with other dense bone disorders under nonspecific general terms including "marble bones," "osteopetrosis," and "Albers-Schönberg disease." Diagnostic precision and syndromic delineation followed, and the term "sclerosteosis" became established. Similarly, van Buchem and his colleagues employed the designation "hyperostosis corticalis generalisata familiaris" for the condition that is now known as van Buchem disease.
## Prevalence
There have been only 31 reported individuals with van Buchem disease, of which 29 were from the Netherlands and two were from Germany [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The osteoscleroses, notably osteopetrosis, characterized by increased bone density with no bone overgrowth and little or no disturbance of the contours of the bones;
The craniotubular dysplasias, characterized by abnormal modeling of the skeleton and moderate sclerosis of the calvarium and base of the skull.
The predominant feature of the craniotubular hyperostoses is overgrowth of bone, which leads to alterations of contours and increase in radiologic density of the skeleton. The bones are often very resistant to trauma. In addition to
Other Craniotubular Hyperostoses to Consider in the Differential Diagnosis of
Hyperostosis of long bones & skull
Facial deformity
Cranial nerve impingement & hearing loss
Tall stature
Hyperostosis of long bones & skull
Cranial nerve impingement & hearing loss
Enlargement of mandible
Smooth or bony swellings of palate (taurus palatinum)
Milder phenotype
Normal height
No syndactyly
Hyperostosis of skull
Facial deformity w/hypertelorism
Cranial nerve impingement & hearing loss
Severe progressive sclerosing bone dysplasia w/maximal involvement of craniofacial skeleton
Long bones, ribs, & pelvis less affected
Short stature
No syndactyly
Facial dysmorphism
Severe hyperostosis of calvarium, skull base, & mandible
Short stature & lean body habitus
Broad clavicles & ribs, scoliosis, & diaphyseal expansion of long bones
1 of 2 persons reported had recurrent fractures.
Hyperostosis of long bones
Frontal bossing, enlargement of mandible, proptosis, & cranial nerve impingement later in life in those w/severe disease
Proximal muscle weakness
Severe limb pain
Joint contractures
No syndactyly
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Craniodiaphyseal dysplasia is possibly heterogeneous. Heterozygous pathogenic variants in
Diagnosis of Camurati-Engelmann disease (CED) is established in a proband with the characteristic radiographic findings or (if radiographic findings are inconclusive) a heterozygous pathogenic variant in
• The osteoscleroses, notably osteopetrosis, characterized by increased bone density with no bone overgrowth and little or no disturbance of the contours of the bones;
• The craniotubular dysplasias, characterized by abnormal modeling of the skeleton and moderate sclerosis of the calvarium and base of the skull.
• Hyperostosis of long bones & skull
• Facial deformity
• Cranial nerve impingement & hearing loss
• Tall stature
• Hyperostosis of long bones & skull
• Cranial nerve impingement & hearing loss
• Enlargement of mandible
• Smooth or bony swellings of palate (taurus palatinum)
• Milder phenotype
• Normal height
• No syndactyly
• Hyperostosis of skull
• Facial deformity w/hypertelorism
• Cranial nerve impingement & hearing loss
• Severe progressive sclerosing bone dysplasia w/maximal involvement of craniofacial skeleton
• Long bones, ribs, & pelvis less affected
• Short stature
• No syndactyly
• Facial dysmorphism
• Severe hyperostosis of calvarium, skull base, & mandible
• Short stature & lean body habitus
• Broad clavicles & ribs, scoliosis, & diaphyseal expansion of long bones
• 1 of 2 persons reported had recurrent fractures.
• Hyperostosis of long bones
• Frontal bossing, enlargement of mandible, proptosis, & cranial nerve impingement later in life in those w/severe disease
• Proximal muscle weakness
• Severe limb pain
• Joint contractures
• No syndactyly
## Management
No clinical practice guidelines for
To establish the extent of disease in an individual diagnosed with a
Radiographs of affected areas
DXA scan
Assessment of necessity for surgical correction of syndactyly when present
Neurologic eval for consequences of cranial nerve entrapment
Assessment for manifestations of ↑ intracranial pressure
DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
No specific treatment for
In one adult with severe van Buchem disease, treatment with glucocorticoids was successful in suppressing bone formation and disease progression [
Note: The bones in individuals with
Hearing aids
Middle ear surgery for conductive loss
Cochlear implant if obliteration of internal auricular canal & damage to auditory nerve is present
May be performed for cosmetic reasons or if mouth closure is impaired due to mandible overgrowth
Tooth extraction may be difficult.
Mgmt by an orthodontic or craniofacial team is recommended.
Craniectomy
Ventriculoperitoneal drain
From age 5 yrs onward, but usually in young adulthood
In South Africa this procedure is undertaken at an increasingly young age.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Intermittently until age 18 yrs
Every 5 yrs in adults
Serum P1NP, alkaline phosphatase, & osteocalcin
Urine NTX & serum CTX
Annually in childhood
As needed in adults
Every 6 mos until age 18 yrs
Annually in adults
CTX = type I collagen cross-linked C-terminal telopeptide; NTX = type I collagen cross-linked N-terminal telopeptide; P1NP = procollagen type 1 amino terminal propeptide
As no published guidelines are available, all suggested intervals are at the discretion of the treating physician.
Frequent measurement of bone mineral density has little clinical consequence in individuals with
Measurement of bone markers can be helpful to evaluate effect of treatment with glucocorticoids. During childhood bone markers are difficult to interpret in individuals with
Avoid agents known to suppress bone resorption:
Bisphosphonates
Denosumab
Selective estrogen receptor modulators
Avoid agents known to stimulate bone formation:
Teriparatide
Abaloparatide
Romozosumab
See
Search
• Radiographs of affected areas
• DXA scan
• Assessment of necessity for surgical correction of syndactyly when present
• Neurologic eval for consequences of cranial nerve entrapment
• Assessment for manifestations of ↑ intracranial pressure
• Hearing aids
• Middle ear surgery for conductive loss
• Cochlear implant if obliteration of internal auricular canal & damage to auditory nerve is present
• May be performed for cosmetic reasons or if mouth closure is impaired due to mandible overgrowth
• Tooth extraction may be difficult.
• Mgmt by an orthodontic or craniofacial team is recommended.
• Craniectomy
• Ventriculoperitoneal drain
• From age 5 yrs onward, but usually in young adulthood
• In South Africa this procedure is undertaken at an increasingly young age.
• Intermittently until age 18 yrs
• Every 5 yrs in adults
• Serum P1NP, alkaline phosphatase, & osteocalcin
• Urine NTX & serum CTX
• Annually in childhood
• As needed in adults
• Every 6 mos until age 18 yrs
• Annually in adults
• Bisphosphonates
• Denosumab
• Selective estrogen receptor modulators
• Teriparatide
• Abaloparatide
• Romozosumab
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with a
Radiographs of affected areas
DXA scan
Assessment of necessity for surgical correction of syndactyly when present
Neurologic eval for consequences of cranial nerve entrapment
Assessment for manifestations of ↑ intracranial pressure
DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Radiographs of affected areas
• DXA scan
• Assessment of necessity for surgical correction of syndactyly when present
• Neurologic eval for consequences of cranial nerve entrapment
• Assessment for manifestations of ↑ intracranial pressure
## Treatment of Manifestations
No specific treatment for
In one adult with severe van Buchem disease, treatment with glucocorticoids was successful in suppressing bone formation and disease progression [
Note: The bones in individuals with
Hearing aids
Middle ear surgery for conductive loss
Cochlear implant if obliteration of internal auricular canal & damage to auditory nerve is present
May be performed for cosmetic reasons or if mouth closure is impaired due to mandible overgrowth
Tooth extraction may be difficult.
Mgmt by an orthodontic or craniofacial team is recommended.
Craniectomy
Ventriculoperitoneal drain
From age 5 yrs onward, but usually in young adulthood
In South Africa this procedure is undertaken at an increasingly young age.
• Hearing aids
• Middle ear surgery for conductive loss
• Cochlear implant if obliteration of internal auricular canal & damage to auditory nerve is present
• May be performed for cosmetic reasons or if mouth closure is impaired due to mandible overgrowth
• Tooth extraction may be difficult.
• Mgmt by an orthodontic or craniofacial team is recommended.
• Craniectomy
• Ventriculoperitoneal drain
• From age 5 yrs onward, but usually in young adulthood
• In South Africa this procedure is undertaken at an increasingly young age.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Intermittently until age 18 yrs
Every 5 yrs in adults
Serum P1NP, alkaline phosphatase, & osteocalcin
Urine NTX & serum CTX
Annually in childhood
As needed in adults
Every 6 mos until age 18 yrs
Annually in adults
CTX = type I collagen cross-linked C-terminal telopeptide; NTX = type I collagen cross-linked N-terminal telopeptide; P1NP = procollagen type 1 amino terminal propeptide
As no published guidelines are available, all suggested intervals are at the discretion of the treating physician.
Frequent measurement of bone mineral density has little clinical consequence in individuals with
Measurement of bone markers can be helpful to evaluate effect of treatment with glucocorticoids. During childhood bone markers are difficult to interpret in individuals with
• Intermittently until age 18 yrs
• Every 5 yrs in adults
• Serum P1NP, alkaline phosphatase, & osteocalcin
• Urine NTX & serum CTX
• Annually in childhood
• As needed in adults
• Every 6 mos until age 18 yrs
• Annually in adults
## Agents/Circumstances to Avoid
Avoid agents known to suppress bone resorption:
Bisphosphonates
Denosumab
Selective estrogen receptor modulators
Avoid agents known to stimulate bone formation:
Teriparatide
Abaloparatide
Romozosumab
• Bisphosphonates
• Denosumab
• Selective estrogen receptor modulators
• Teriparatide
• Abaloparatide
• Romozosumab
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for the genetic alteration identified in the proband 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 genetic alterations 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 genetic alteration in the proband.
Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of a
If both parents are known to be heterozygous for a genetic alteration associated with a
Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of a
Unless an affected individual's reproductive partner also has an
If the reproductive partner of the proband is heterozygous for a genetic alteration associated with a
Carrier testing for at-risk family members requires prior identification of the genetic alterations associated 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, are carriers, or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with a
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 individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for the genetic alteration identified in the proband 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 genetic alterations 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 genetic alteration 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 genetic alteration in the proband.
• Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of 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 genetic alteration in the proband.
• If both parents are known to be heterozygous for a genetic alteration associated with a
• Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of a
• Unless an affected individual's reproductive partner also has an
• If the reproductive partner of the proband is heterozygous for a genetic alteration associated with 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 carriers and for the reproductive partners of individuals affected with a
## Mode of Inheritance
## Risk to Family Members
The parents of an individual with
Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for the genetic alteration identified in the proband 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 genetic alterations 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 genetic alteration in the proband.
Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of a
If both parents are known to be heterozygous for a genetic alteration associated with a
Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of a
Unless an affected individual's reproductive partner also has an
If the reproductive partner of the proband is heterozygous for a genetic alteration associated with a
• The parents of an individual with
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for the genetic alteration identified in the proband 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 genetic alterations 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 genetic alteration 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 genetic alteration in the proband.
• Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of 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 genetic alteration in the proband.
• If both parents are known to be heterozygous for a genetic alteration associated with a
• Heterozygotes have increased bone mass and calvarial widening, but signs and symptoms of a
• Unless an affected individual's reproductive partner also has an
• If the reproductive partner of the proband is heterozygous for a genetic alteration associated with a
## Carrier Detection
Carrier testing for at-risk family members requires prior identification of the genetic alterations associated with 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 and for the reproductive partners of individuals affected with 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 carriers and for the reproductive partners of individuals affected with a
## 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
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
SOST-Related Sclerosing Bone Dysplasias: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SOST-Related Sclerosing Bone Dysplasias (
Individuals with
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Individuals with
## Molecular Pathogenesis
Individuals with
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Individuals with
## Chapter Notes
Dr Natasha Appelman-Dijkstra would be happy to communicate with persons who have any questions regarding
Natasha Appelman-Dijkstra, MD, PhD (2019-present)Peter H Beighton, MD, PhD, FRCP, FRCPCH, FRSSA; University of Cape Town (2002-2019)Mary E Brunkow, PhD; Institute for Systems Biology, Seattle (2002-2019)Herman Hamersma, MD; Flora Clinic, Roodepoort (2002-2019)Socrates Papapoulos, MD, PhD (2019-present)Antoon Van Lierop, MD, PhD (2019-present)
1 August 2024 (sw) Comprehensive update posted live
21 March 2019 (ha) Comprehensive update posted live
12 January 2012 (me) Comprehensive update posted live
2 February 2007 (me) Comprehensive update posted live
23 September 2004 (me) Comprehensive update posted live
4 June 2002 (tk/me) Review posted live
5 February 2002 (phb) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 21 March 2019 (ha) Comprehensive update posted live
• 12 January 2012 (me) Comprehensive update posted live
• 2 February 2007 (me) Comprehensive update posted live
• 23 September 2004 (me) Comprehensive update posted live
• 4 June 2002 (tk/me) Review posted live
• 5 February 2002 (phb) Original submission
## Author Notes
Dr Natasha Appelman-Dijkstra would be happy to communicate with persons who have any questions regarding
## Author History
Natasha Appelman-Dijkstra, MD, PhD (2019-present)Peter H Beighton, MD, PhD, FRCP, FRCPCH, FRSSA; University of Cape Town (2002-2019)Mary E Brunkow, PhD; Institute for Systems Biology, Seattle (2002-2019)Herman Hamersma, MD; Flora Clinic, Roodepoort (2002-2019)Socrates Papapoulos, MD, PhD (2019-present)Antoon Van Lierop, MD, PhD (2019-present)
## Revision History
1 August 2024 (sw) Comprehensive update posted live
21 March 2019 (ha) Comprehensive update posted live
12 January 2012 (me) Comprehensive update posted live
2 February 2007 (me) Comprehensive update posted live
23 September 2004 (me) Comprehensive update posted live
4 June 2002 (tk/me) Review posted live
5 February 2002 (phb) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 21 March 2019 (ha) Comprehensive update posted live
• 12 January 2012 (me) Comprehensive update posted live
• 2 February 2007 (me) Comprehensive update posted live
• 23 September 2004 (me) Comprehensive update posted live
• 4 June 2002 (tk/me) Review posted live
• 5 February 2002 (phb) Original submission
## References
## Literature Cited
|
[] |
4/6/2002
|
1/8/2024
|
10/1/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sotos
|
sotos
|
[
"Histone-lysine N-methyltransferase, H3 lysine-36 specific",
"NSD1",
"Sotos Syndrome"
] |
Sotos Syndrome
|
Sharon Ocansey, Trevor RP Cole, Nazneen Rahman, Katrina Tatton-Brown
|
Summary Sotos syndrome is characterized by a distinctive facial appearance (broad, prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, tall chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference ≥2 SD above the mean). These three clinical features (distinctive facial features, learning disability, and overgrowth) are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral findings (most notably autism spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures. The diagnosis of Sotos syndrome is established in a proband with a heterozygous Sotos syndrome is inherited in an autosomal dominant manner. About 5% of individuals diagnosed with Sotos syndrome have an affected parent; approximately 95% of individuals have the disorder as the result of a
|
## Diagnosis
No consensus clinical diagnostic criteria Sotos syndrome have been published.
Sotos syndrome
Broad, prominent forehead with a dolichocephalic head shape
Sparse frontotemporal hair
Downslanting palpebral fissures
Malar flushing
Long narrow face (particularly bitemporal narrowing)
Tall chin
Note: Facial shape is retained into adulthood. However, with time the chin becomes broader (squarer in shape).
Early developmental delay
Mild-to-severe intellectual impairment
Tall stature. Height ≥2 standard deviations (SD) above the mean (i.e., ~98th centile). Note: Height may normalize in adulthood.
Macrocephaly. Head circumference ≥2 SD above the mean (i.e., ~98th centile), usually present at all ages. Congenital macrocephaly is observed in most individuals. Head growth velocity tends to increase during the first year of life, and macrocephaly persists into adulthood [
The diagnosis of Sotos syndrome
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 Sotos syndrome, molecular genetic testing approaches can include
For an introduction to CMA click
For an introduction to multigene panels click
When the diagnosis of Sotos syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sotos 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
A recurrent 1.9-Mb 5q35 microdeletion encompassing
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., the 1.9-Mb deletion) 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.
Gene-targeted deletion/duplication analysis may detect an additional 1%-5% of partial-gene deletions.
• Broad, prominent forehead with a dolichocephalic head shape
• Sparse frontotemporal hair
• Downslanting palpebral fissures
• Malar flushing
• Long narrow face (particularly bitemporal narrowing)
• Tall chin
• Early developmental delay
• Mild-to-severe intellectual impairment
• Tall stature. Height ≥2 standard deviations (SD) above the mean (i.e., ~98th centile). Note: Height may normalize in adulthood.
• Macrocephaly. Head circumference ≥2 SD above the mean (i.e., ~98th centile), usually present at all ages. Congenital macrocephaly is observed in most individuals. Head growth velocity tends to increase during the first year of life, and macrocephaly persists into adulthood [
• For an introduction to CMA click
• For an introduction to multigene panels click
## Suggestive Findings
Sotos syndrome
Broad, prominent forehead with a dolichocephalic head shape
Sparse frontotemporal hair
Downslanting palpebral fissures
Malar flushing
Long narrow face (particularly bitemporal narrowing)
Tall chin
Note: Facial shape is retained into adulthood. However, with time the chin becomes broader (squarer in shape).
Early developmental delay
Mild-to-severe intellectual impairment
Tall stature. Height ≥2 standard deviations (SD) above the mean (i.e., ~98th centile). Note: Height may normalize in adulthood.
Macrocephaly. Head circumference ≥2 SD above the mean (i.e., ~98th centile), usually present at all ages. Congenital macrocephaly is observed in most individuals. Head growth velocity tends to increase during the first year of life, and macrocephaly persists into adulthood [
• Broad, prominent forehead with a dolichocephalic head shape
• Sparse frontotemporal hair
• Downslanting palpebral fissures
• Malar flushing
• Long narrow face (particularly bitemporal narrowing)
• Tall chin
• Early developmental delay
• Mild-to-severe intellectual impairment
• Tall stature. Height ≥2 standard deviations (SD) above the mean (i.e., ~98th centile). Note: Height may normalize in adulthood.
• Macrocephaly. Head circumference ≥2 SD above the mean (i.e., ~98th centile), usually present at all ages. Congenital macrocephaly is observed in most individuals. Head growth velocity tends to increase during the first year of life, and macrocephaly persists into adulthood [
## Establishing the Diagnosis
The diagnosis of Sotos syndrome
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 Sotos syndrome, molecular genetic testing approaches can include
For an introduction to CMA click
For an introduction to multigene panels click
When the diagnosis of Sotos syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sotos 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
A recurrent 1.9-Mb 5q35 microdeletion encompassing
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., the 1.9-Mb deletion) 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.
Gene-targeted deletion/duplication analysis may detect an additional 1%-5% of partial-gene deletions.
• For an introduction to CMA click
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Sotos syndrome, molecular genetic testing approaches can include
For an introduction to CMA click
For an introduction to multigene panels click
• For an introduction to CMA click
• For an introduction to multigene panels click
## Option 2
When the diagnosis of Sotos syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sotos 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
A recurrent 1.9-Mb 5q35 microdeletion encompassing
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., the 1.9-Mb deletion) 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.
Gene-targeted deletion/duplication analysis may detect an additional 1%-5% of partial-gene deletions.
## Clinical Characteristics
To date, more than 900 individuals have been identified with a pathogenic variant in
Sotos Syndrome: Frequency of Select Features
Based on
ASD = autism spectrum disorder; PDA = patent ductus arteriosus; SD = standard deviations; VUR = vesicoureteral reflux
Before age ten years, affected children often demonstrate rapid linear growth. They are often described as being considerably taller than their peers. Approximately 90% of children have a height and/or head circumference at least two standard deviations (SD) above the mean [
Height may normalize in adulthood, but macrocephaly is usually present at all ages [
Auxologic data shows that individuals with an
De Boer and colleagues have characterized and reviewed these problems and compared persons with Sotos syndrome who have
Ocular. Astigmatism, cataracts, myopia, strabismus, nystagmus, hypermetropia
Auricular. Cholesteatoma, sensorineural and conductive hearing loss
Gastrointestinal. Constipation, gastroesophageal reflux, Hirschsprung disease
Genitourinary. Cryptorchidism, hypospadias, hydrocele, phimosis
Musculoskeletal. Pectus excavatum, talipes equinovarus, vertebral anomalies, contractures, 2-3 toe syndactyly
Skin. Hemangiomas, hyper- or hypopigmentation
Craniofacial. Craniosynostosis
Endocrine. Hypothyroidism, neonatal hypoglycemia
Renal. Nephrocalcinosis
Lungs. Subpleural blebs
Hemihypertrophy
Umbilical and/or inguinal hernias
Nail and tooth anomalies. Hypoplastic nails, hypodontia
Through the evaluation of 234 individuals with Sotos syndrome with an
Genotype-phenotype correlations for intragenic pathogenic variants and 5q35 microdeletions are not evident for other clinical features associated with Sotos syndrome (i.e., cardiac abnormalities, renal anomalies, seizures, scoliosis), nor were correlations observed between the type of intragenic pathogenic variant (missense vs truncating) and phenotype or between position of pathogenic variant (5' vs 3' UTR) and phenotype [
To date, no unaffected parent or sib with an
Of note, expressivity is highly variable. Individuals with the same genetic alteration, even within the same family, can be affected differently [
Sotos syndrome has previously been referred to as cerebral gigantism. This term is now outdated and should no longer be used. Sotos syndrome is included under the umbrella term of overgrowth-intellectual disability (OGID) syndromes [
Sotos syndrome is estimated to occur in 1:14,000 live births [K Tatton-Brown, TRP Cole, N Rahman, unpublished data].
• Ocular. Astigmatism, cataracts, myopia, strabismus, nystagmus, hypermetropia
• Auricular. Cholesteatoma, sensorineural and conductive hearing loss
• Gastrointestinal. Constipation, gastroesophageal reflux, Hirschsprung disease
• Genitourinary. Cryptorchidism, hypospadias, hydrocele, phimosis
• Musculoskeletal. Pectus excavatum, talipes equinovarus, vertebral anomalies, contractures, 2-3 toe syndactyly
• Skin. Hemangiomas, hyper- or hypopigmentation
• Craniofacial. Craniosynostosis
• Endocrine. Hypothyroidism, neonatal hypoglycemia
• Renal. Nephrocalcinosis
• Lungs. Subpleural blebs
• Hemihypertrophy
• Umbilical and/or inguinal hernias
• Nail and tooth anomalies. Hypoplastic nails, hypodontia
## Clinical Description
To date, more than 900 individuals have been identified with a pathogenic variant in
Sotos Syndrome: Frequency of Select Features
Based on
ASD = autism spectrum disorder; PDA = patent ductus arteriosus; SD = standard deviations; VUR = vesicoureteral reflux
Before age ten years, affected children often demonstrate rapid linear growth. They are often described as being considerably taller than their peers. Approximately 90% of children have a height and/or head circumference at least two standard deviations (SD) above the mean [
Height may normalize in adulthood, but macrocephaly is usually present at all ages [
Auxologic data shows that individuals with an
De Boer and colleagues have characterized and reviewed these problems and compared persons with Sotos syndrome who have
Ocular. Astigmatism, cataracts, myopia, strabismus, nystagmus, hypermetropia
Auricular. Cholesteatoma, sensorineural and conductive hearing loss
Gastrointestinal. Constipation, gastroesophageal reflux, Hirschsprung disease
Genitourinary. Cryptorchidism, hypospadias, hydrocele, phimosis
Musculoskeletal. Pectus excavatum, talipes equinovarus, vertebral anomalies, contractures, 2-3 toe syndactyly
Skin. Hemangiomas, hyper- or hypopigmentation
Craniofacial. Craniosynostosis
Endocrine. Hypothyroidism, neonatal hypoglycemia
Renal. Nephrocalcinosis
Lungs. Subpleural blebs
Hemihypertrophy
Umbilical and/or inguinal hernias
Nail and tooth anomalies. Hypoplastic nails, hypodontia
• Ocular. Astigmatism, cataracts, myopia, strabismus, nystagmus, hypermetropia
• Auricular. Cholesteatoma, sensorineural and conductive hearing loss
• Gastrointestinal. Constipation, gastroesophageal reflux, Hirschsprung disease
• Genitourinary. Cryptorchidism, hypospadias, hydrocele, phimosis
• Musculoskeletal. Pectus excavatum, talipes equinovarus, vertebral anomalies, contractures, 2-3 toe syndactyly
• Skin. Hemangiomas, hyper- or hypopigmentation
• Craniofacial. Craniosynostosis
• Endocrine. Hypothyroidism, neonatal hypoglycemia
• Renal. Nephrocalcinosis
• Lungs. Subpleural blebs
• Hemihypertrophy
• Umbilical and/or inguinal hernias
• Nail and tooth anomalies. Hypoplastic nails, hypodontia
## Cardinal Features
Before age ten years, affected children often demonstrate rapid linear growth. They are often described as being considerably taller than their peers. Approximately 90% of children have a height and/or head circumference at least two standard deviations (SD) above the mean [
Height may normalize in adulthood, but macrocephaly is usually present at all ages [
Auxologic data shows that individuals with an
## Major Features
## Associated Features
De Boer and colleagues have characterized and reviewed these problems and compared persons with Sotos syndrome who have
Ocular. Astigmatism, cataracts, myopia, strabismus, nystagmus, hypermetropia
Auricular. Cholesteatoma, sensorineural and conductive hearing loss
Gastrointestinal. Constipation, gastroesophageal reflux, Hirschsprung disease
Genitourinary. Cryptorchidism, hypospadias, hydrocele, phimosis
Musculoskeletal. Pectus excavatum, talipes equinovarus, vertebral anomalies, contractures, 2-3 toe syndactyly
Skin. Hemangiomas, hyper- or hypopigmentation
Craniofacial. Craniosynostosis
Endocrine. Hypothyroidism, neonatal hypoglycemia
Renal. Nephrocalcinosis
Lungs. Subpleural blebs
Hemihypertrophy
Umbilical and/or inguinal hernias
Nail and tooth anomalies. Hypoplastic nails, hypodontia
• Ocular. Astigmatism, cataracts, myopia, strabismus, nystagmus, hypermetropia
• Auricular. Cholesteatoma, sensorineural and conductive hearing loss
• Gastrointestinal. Constipation, gastroesophageal reflux, Hirschsprung disease
• Genitourinary. Cryptorchidism, hypospadias, hydrocele, phimosis
• Musculoskeletal. Pectus excavatum, talipes equinovarus, vertebral anomalies, contractures, 2-3 toe syndactyly
• Skin. Hemangiomas, hyper- or hypopigmentation
• Craniofacial. Craniosynostosis
• Endocrine. Hypothyroidism, neonatal hypoglycemia
• Renal. Nephrocalcinosis
• Lungs. Subpleural blebs
• Hemihypertrophy
• Umbilical and/or inguinal hernias
• Nail and tooth anomalies. Hypoplastic nails, hypodontia
## Genotype-Phenotype Correlations
Through the evaluation of 234 individuals with Sotos syndrome with an
Genotype-phenotype correlations for intragenic pathogenic variants and 5q35 microdeletions are not evident for other clinical features associated with Sotos syndrome (i.e., cardiac abnormalities, renal anomalies, seizures, scoliosis), nor were correlations observed between the type of intragenic pathogenic variant (missense vs truncating) and phenotype or between position of pathogenic variant (5' vs 3' UTR) and phenotype [
## Penetrance
To date, no unaffected parent or sib with an
Of note, expressivity is highly variable. Individuals with the same genetic alteration, even within the same family, can be affected differently [
## Nomenclature
Sotos syndrome has previously been referred to as cerebral gigantism. This term is now outdated and should no longer be used. Sotos syndrome is included under the umbrella term of overgrowth-intellectual disability (OGID) syndromes [
## Prevalence
Sotos syndrome is estimated to occur in 1:14,000 live births [K Tatton-Brown, TRP Cole, N Rahman, unpublished data].
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Overgrowth conditions that may be confused with Sotos syndrome are summarized in
Overgrowth Conditions to Consider in the Differential Diagnosis of Sotos Syndrome
Typical but subtle facial appearance, esp in early childhood
↑ height, macrocephaly, scoliosis, ligamentous laxity
Frequently hypotonic at birth (may present w/mixed central hypotonia / peripheral hypertonia)
The face is subtly different, w/hypertelorism, round face, & "stuck-on" chin.
Other features that do not overlap w/Sotos syndrome are most similar to
Pre- & postnatal overgrowth
Variable ID
Similar (but distinctive) facial appearance
Advanced bone age
Scoliosis
Joint hypermobility
Sotos syndrome &
Round face shape w/ocular hypertelorism
Prognathism is not observed, but chin appears "stuck on," frequently w/horizontal crease between chin & lower lip.
Assoc joint problems (e.g., camptodactyly & contractures)
Infants often have hoarse, low-pitched cry.
Typical but subtle facial appearance, esp in early childhood
↑ height, macrocephaly, scoliosis, ligamentous laxity
Frequently hypotonic at birth (may present w/mixed central hypotonia / peripheral hypertonia)
BWS should be clinically distinguishable from Sotos syndrome (molecular testing is indicated in persons w/clinical overlap).
Macroglossia
Anterior earlobe creases / helical pits
Omphalocele
Visceromegaly
↑ risk of embryonal tumors, esp Wilms tumor
Overgrowth
Variable ID
Joint hypermobility
Scoliosis
Round face w/coarse features
Prominent central incisors, narrow palpebral fissures, thick, low-set eyebrows
Tendency toward overweight & obesity
Macrocephaly
ID
Typical but subtle facial appearance may overlap w/Sotos syndrome: dolichocephalic head shape, prominent jaw & forehead.
Predominantly affects males
Affected males often have large ears, which is not common in Sotos syndrome.
Macro-orchidism after puberty
Pre- & postnatal overgrowth
Variable ID
Predominantly affects males
Polydactyly
Supernumerary nipples
Diastasis recti
Pectus excavatum
Facial gestalt differs
Characteristic facial appearance w/dolichocephaly, prominent forehead, & downslanting palpebral fissures
Scoliosis, ↑ height (>2 SD) in childhood
Assoc w/variable ID
Ophthalmic abnormalities are common in Malan syndrome & less common in Sotos syndrome.
↑ height is less common in older children & adults.
Recognizable appearance w/macrocephaly, bossing of forehead, & coarse facial features (in ~60%)
Head circumference ↑ to >98th centile until age 10-18 mos
Development of multiple jaw keratocysts, frequently beginning in 2nd decade
Basal cell carcinomas usually from 3rd decade onward
Skeletal anomalies (e.g., bifid ribs or wedge-shaped vertebrae)
Absence, usually, of DD
Macrocephaly
Somewhat similar facial gestalt
May be assoc w/ASD
Vascular malformations
Hamartomatous polyps of distal ileum & colon
Pigmented macules on shaft of penis
Lipomas
↑ risk of thyroid & breast cancer
AD = autosomal dominant; AR = autosomal recessive; ASD = autistic spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PV = pathogenic variant; XL = X-linked
Given the overlap in findings between Sotos syndrome,
In some individuals thought to have
Beckwith-Wiedemann syndrome (BWS) without multilocus imprinting disturbances is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by an epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous maternally inherited
Other conditions to consider in the differential diagnosis of Sotos syndrome include the following:
• Typical but subtle facial appearance, esp in early childhood
• ↑ height, macrocephaly, scoliosis, ligamentous laxity
• Frequently hypotonic at birth (may present w/mixed central hypotonia / peripheral hypertonia)
• The face is subtly different, w/hypertelorism, round face, & "stuck-on" chin.
• Other features that do not overlap w/Sotos syndrome are most similar to
• Pre- & postnatal overgrowth
• Variable ID
• Similar (but distinctive) facial appearance
• Advanced bone age
• Scoliosis
• Joint hypermobility
• Sotos syndrome &
• Round face shape w/ocular hypertelorism
• Prognathism is not observed, but chin appears "stuck on," frequently w/horizontal crease between chin & lower lip.
• Assoc joint problems (e.g., camptodactyly & contractures)
• Infants often have hoarse, low-pitched cry.
• Typical but subtle facial appearance, esp in early childhood
• ↑ height, macrocephaly, scoliosis, ligamentous laxity
• Frequently hypotonic at birth (may present w/mixed central hypotonia / peripheral hypertonia)
• BWS should be clinically distinguishable from Sotos syndrome (molecular testing is indicated in persons w/clinical overlap).
• Macroglossia
• Anterior earlobe creases / helical pits
• Omphalocele
• Visceromegaly
• ↑ risk of embryonal tumors, esp Wilms tumor
• Overgrowth
• Variable ID
• Joint hypermobility
• Scoliosis
• Round face w/coarse features
• Prominent central incisors, narrow palpebral fissures, thick, low-set eyebrows
• Tendency toward overweight & obesity
• Macrocephaly
• ID
• Typical but subtle facial appearance may overlap w/Sotos syndrome: dolichocephalic head shape, prominent jaw & forehead.
• Predominantly affects males
• Affected males often have large ears, which is not common in Sotos syndrome.
• Macro-orchidism after puberty
• Pre- & postnatal overgrowth
• Variable ID
• Predominantly affects males
• Polydactyly
• Supernumerary nipples
• Diastasis recti
• Pectus excavatum
• Facial gestalt differs
• Characteristic facial appearance w/dolichocephaly, prominent forehead, & downslanting palpebral fissures
• Scoliosis, ↑ height (>2 SD) in childhood
• Assoc w/variable ID
• Ophthalmic abnormalities are common in Malan syndrome & less common in Sotos syndrome.
• ↑ height is less common in older children & adults.
• Recognizable appearance w/macrocephaly, bossing of forehead, & coarse facial features (in ~60%)
• Head circumference ↑ to >98th centile until age 10-18 mos
• Development of multiple jaw keratocysts, frequently beginning in 2nd decade
• Basal cell carcinomas usually from 3rd decade onward
• Skeletal anomalies (e.g., bifid ribs or wedge-shaped vertebrae)
• Absence, usually, of DD
• Macrocephaly
• Somewhat similar facial gestalt
• May be assoc w/ASD
• Vascular malformations
• Hamartomatous polyps of distal ileum & colon
• Pigmented macules on shaft of penis
• Lipomas
• ↑ risk of thyroid & breast cancer
## Management
No clinical practice guidelines for Sotos 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 Sotos syndrome, the evaluations summarized in
Sotos Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl baseline echocardiogram
Blood pressure measurement
To include baseline renal US
In adults in whom diagnosis has just been established, renal US to evaluate for renal damage from quiescent chronic VUR
Assessment for cryptorchidism, hydrocele, hypospadias
To incl brain MRI if progressive macrocephaly or unexplained neurologic features are present
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Contractures & scoliosis
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; ASD = autism spectrum disorder; GER = gastroesophageal reflux; MOI = mode of inheritance; OFC = orbitofrontal cortex; US = ultrasound; VUR = vesicoureteral reflux
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for Sotos syndrome. 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
Sotos Syndrome: Treatment of Manifestations
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.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GER = gastroesophageal reflux; OT = occupational therapy; PT = physical therapy; VUR = vesicoureteral reflux
If brain MRI has been performed and ventricular dilatation demonstrated, shunting should not usually be necessary as the "arrested hydrocephalus" associated with Sotos syndrome is typically not obstructive and not associated with raised intracranial pressure. If raised intracranial pressure is suspected, investigation and management in consultation with neurologists and neurosurgeons would be appropriate.
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
Sotos Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Monitor those w/eye abnormalities as clinically indicated.
Assess for changes in visual acuity.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
The absolute risk of sacrococcygeal teratoma and neuroblastoma is low (~1%) [
Wilms tumor risk is not significantly increased and routine renal ultrasound examination is not indicated [
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl baseline echocardiogram
• Blood pressure measurement
• To include baseline renal US
• In adults in whom diagnosis has just been established, renal US to evaluate for renal damage from quiescent chronic VUR
• Assessment for cryptorchidism, hydrocele, hypospadias
• To incl brain MRI if progressive macrocephaly or unexplained neurologic features are present
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Contractures & scoliosis
• 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
• 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
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor those w/eye abnormalities as clinically indicated.
• Assess for changes in visual acuity.
• The absolute risk of sacrococcygeal teratoma and neuroblastoma is low (~1%) [
• Wilms tumor risk is not significantly increased and routine renal ultrasound examination is not indicated [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Sotos syndrome, the evaluations summarized in
Sotos Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl baseline echocardiogram
Blood pressure measurement
To include baseline renal US
In adults in whom diagnosis has just been established, renal US to evaluate for renal damage from quiescent chronic VUR
Assessment for cryptorchidism, hydrocele, hypospadias
To incl brain MRI if progressive macrocephaly or unexplained neurologic features are present
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Contractures & scoliosis
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; ASD = autism spectrum disorder; GER = gastroesophageal reflux; MOI = mode of inheritance; OFC = orbitofrontal cortex; US = ultrasound; VUR = vesicoureteral reflux
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
• To incl baseline echocardiogram
• Blood pressure measurement
• To include baseline renal US
• In adults in whom diagnosis has just been established, renal US to evaluate for renal damage from quiescent chronic VUR
• Assessment for cryptorchidism, hydrocele, hypospadias
• To incl brain MRI if progressive macrocephaly or unexplained neurologic features are present
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Contractures & scoliosis
• 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 Sotos syndrome. 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
Sotos Syndrome: Treatment of Manifestations
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.
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; GER = gastroesophageal reflux; OT = occupational therapy; PT = physical therapy; VUR = vesicoureteral reflux
If brain MRI has been performed and ventricular dilatation demonstrated, shunting should not usually be necessary as the "arrested hydrocephalus" associated with Sotos syndrome is typically not obstructive and not associated with raised intracranial pressure. If raised intracranial pressure is suspected, investigation and management in consultation with neurologists and neurosurgeons would be appropriate.
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 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.
• 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
Sotos Syndrome: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Monitor those w/eye abnormalities as clinically indicated.
Assess for changes in visual acuity.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
The absolute risk of sacrococcygeal teratoma and neuroblastoma is low (~1%) [
Wilms tumor risk is not significantly increased and routine renal ultrasound examination is not indicated [
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Monitor those w/eye abnormalities as clinically indicated.
• Assess for changes in visual acuity.
• The absolute risk of sacrococcygeal teratoma and neuroblastoma is low (~1%) [
• Wilms tumor risk is not significantly increased and routine renal ultrasound examination is not indicated [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Sotos syndrome is inherited in an autosomal dominant manner.
About 5% of individuals diagnosed with Sotos syndrome have an affected parent.
Approximately 95% of individuals diagnosed with Sotos syndrome have the disorder as the result of a
If neither parent of an individual with a molecular diagnosis of Sotos syndrome has clinical features of Sotos syndrome, it is very unlikely a parent is heterozygous for a Sotos syndrome-related genetic alteration. Molecular genetic testing of the parent for the genetic alteration identified in the proband can be used to confirm the genetic status of the parents and inform recurrence risk assessment.
If the Sotos syndrome-related 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 pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
If a parent of the proband is affected and/or has an
Intrafamilial clinical variability has been reported; sibs with the same Sotos syndrome-related genetic alteration can be affected differently [
If the genetic status of the parents is unknown and both parents 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 Sotos syndrome because of the possibility of parental gonadal mosaicism. Parental somatic/gonadal mosaicism has been reported in the unaffected father of an affected individual [
Each child of an individual with Sotos syndrome has a 50% chance of inheriting the
Phenotypic expression can vary from one generation to the next; thus, it is not possible to accurately predict how heterozygous offspring may be 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.
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.
• About 5% of individuals diagnosed with Sotos syndrome have an affected parent.
• Approximately 95% of individuals diagnosed with Sotos syndrome have the disorder as the result of a
• If neither parent of an individual with a molecular diagnosis of Sotos syndrome has clinical features of Sotos syndrome, it is very unlikely a parent is heterozygous for a Sotos syndrome-related genetic alteration. Molecular genetic testing of the parent for the genetic alteration identified in the proband can be used to confirm the genetic status of the parents and inform recurrence risk assessment.
• If the Sotos syndrome-related 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 pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• If a parent of the proband is affected and/or has an
• Intrafamilial clinical variability has been reported; sibs with the same Sotos syndrome-related genetic alteration can be affected differently [
• If the genetic status of the parents is unknown and both parents 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 Sotos syndrome because of the possibility of parental gonadal mosaicism. Parental somatic/gonadal mosaicism has been reported in the unaffected father of an affected individual [
• Each child of an individual with Sotos syndrome has a 50% chance of inheriting the
• Phenotypic expression can vary from one generation to the next; thus, it is not possible to accurately predict how heterozygous offspring may be 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.
## Mode of Inheritance
Sotos syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
About 5% of individuals diagnosed with Sotos syndrome have an affected parent.
Approximately 95% of individuals diagnosed with Sotos syndrome have the disorder as the result of a
If neither parent of an individual with a molecular diagnosis of Sotos syndrome has clinical features of Sotos syndrome, it is very unlikely a parent is heterozygous for a Sotos syndrome-related genetic alteration. Molecular genetic testing of the parent for the genetic alteration identified in the proband can be used to confirm the genetic status of the parents and inform recurrence risk assessment.
If the Sotos syndrome-related 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 pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
If a parent of the proband is affected and/or has an
Intrafamilial clinical variability has been reported; sibs with the same Sotos syndrome-related genetic alteration can be affected differently [
If the genetic status of the parents is unknown and both parents 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 Sotos syndrome because of the possibility of parental gonadal mosaicism. Parental somatic/gonadal mosaicism has been reported in the unaffected father of an affected individual [
Each child of an individual with Sotos syndrome has a 50% chance of inheriting the
Phenotypic expression can vary from one generation to the next; thus, it is not possible to accurately predict how heterozygous offspring may be affected.
• About 5% of individuals diagnosed with Sotos syndrome have an affected parent.
• Approximately 95% of individuals diagnosed with Sotos syndrome have the disorder as the result of a
• If neither parent of an individual with a molecular diagnosis of Sotos syndrome has clinical features of Sotos syndrome, it is very unlikely a parent is heterozygous for a Sotos syndrome-related genetic alteration. Molecular genetic testing of the parent for the genetic alteration identified in the proband can be used to confirm the genetic status of the parents and inform recurrence risk assessment.
• If the Sotos syndrome-related 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 pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism [
• If a parent of the proband is affected and/or has an
• Intrafamilial clinical variability has been reported; sibs with the same Sotos syndrome-related genetic alteration can be affected differently [
• If the genetic status of the parents is unknown and both parents 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 Sotos syndrome because of the possibility of parental gonadal mosaicism. Parental somatic/gonadal mosaicism has been reported in the unaffected father of an affected individual [
• Each child of an individual with Sotos syndrome has a 50% chance of inheriting the
• Phenotypic expression can vary from one generation to the next; thus, it is not possible to accurately predict how heterozygous offspring may be affected.
## 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
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
Sotos Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sotos Syndrome (
Two nuclear receptor interaction domains (NID
Two proline-tryptophan-tryptophan-proline (PWWP) domains
Five plant homeo domains (PHD)
A SET (su(var)3-9, enhancer of zeste, trithorax) domain
The most distinctive of these domains are the SET and associated SAC (SET-associated Cys-rich) domains, which are found in histone methyltransferases that regulate chromatin states. The SET domain of NSD1 has unique histone specificity, methylating lysine residue 36 on histone H3, and lysine residue 20 on histone H4 (K36H3 and K20H4) [
• Two nuclear receptor interaction domains (NID
• Two proline-tryptophan-tryptophan-proline (PWWP) domains
• Five plant homeo domains (PHD)
• A SET (su(var)3-9, enhancer of zeste, trithorax) domain
## Chapter Notes
5 June 2025 (gm) Comprehensive update posted live
1 August 2019 (ha) Comprehensive update posted live
19 November 2015 (me) Comprehensive update posted live
8 March 2012 (me) Comprehensive update posted live
10 December 2009 (me) Comprehensive update posted live
23 March 2007 (me) Comprehensive update posted live
17 December 2004 (me) Review posted live
26 May 2004 (tc) Original submission
• 5 June 2025 (gm) Comprehensive update posted live
• 1 August 2019 (ha) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 8 March 2012 (me) Comprehensive update posted live
• 10 December 2009 (me) Comprehensive update posted live
• 23 March 2007 (me) Comprehensive update posted live
• 17 December 2004 (me) Review posted live
• 26 May 2004 (tc) Original submission
## Revision History
5 June 2025 (gm) Comprehensive update posted live
1 August 2019 (ha) Comprehensive update posted live
19 November 2015 (me) Comprehensive update posted live
8 March 2012 (me) Comprehensive update posted live
10 December 2009 (me) Comprehensive update posted live
23 March 2007 (me) Comprehensive update posted live
17 December 2004 (me) Review posted live
26 May 2004 (tc) Original submission
• 5 June 2025 (gm) Comprehensive update posted live
• 1 August 2019 (ha) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 8 March 2012 (me) Comprehensive update posted live
• 10 December 2009 (me) Comprehensive update posted live
• 23 March 2007 (me) Comprehensive update posted live
• 17 December 2004 (me) Review posted live
• 26 May 2004 (tc) Original submission
## References
## Literature Cited
|
[] |
17/12/2004
|
5/6/2025
|
1/12/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sox2
|
sox2
|
[
"Anophthalmia-Esophageal Atresia-Genital Abnormalities (AEG) Syndrome",
"Transcription factor SOX-2",
"SOX2",
"SOX2 Disorder"
] |
Kathleen A Williamson, T Michael Yates, David R FitzPatrick
|
Summary The phenotypic spectrum of The diagnosis of
|
With the current widespread use of advanced molecular genetic testing, it is apparent that the clinical spectrum associated with
## Diagnosis
Bilateral anophthalmia and/or microphthalmia
Unilateral anophthalmia or microphthalmia
Genital abnormalities. Frequently cryptorchidism and/or micropenis in males (commonly a manifestation of hypogonadotropic hypogonadism); infrequently uterus hypoplasia and ovary or vaginal agenesis in females
Tracheoesophageal fistula and/or esophageal atresia
Delayed motor development / learning disability
Postnatal growth failure
Seizures with gray matter heterotopia
Spasticity, dystonia, or status dystonicus
The diagnosis of
For details about heterozygous deletions of 3q26.33 involving
Note: 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 a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of
Note: Most deletions involving
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, whole-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 a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Bilateral anophthalmia and/or microphthalmia
• Unilateral anophthalmia or microphthalmia
• Genital abnormalities. Frequently cryptorchidism and/or micropenis in males (commonly a manifestation of hypogonadotropic hypogonadism); infrequently uterus hypoplasia and ovary or vaginal agenesis in females
• Tracheoesophageal fistula and/or esophageal atresia
• Delayed motor development / learning disability
• Postnatal growth failure
• Seizures with gray matter heterotopia
• Spasticity, dystonia, or status dystonicus
• Note: Most deletions involving
• For an introduction to multigene panels click
## Suggestive Findings
Bilateral anophthalmia and/or microphthalmia
Unilateral anophthalmia or microphthalmia
Genital abnormalities. Frequently cryptorchidism and/or micropenis in males (commonly a manifestation of hypogonadotropic hypogonadism); infrequently uterus hypoplasia and ovary or vaginal agenesis in females
Tracheoesophageal fistula and/or esophageal atresia
Delayed motor development / learning disability
Postnatal growth failure
Seizures with gray matter heterotopia
Spasticity, dystonia, or status dystonicus
• Bilateral anophthalmia and/or microphthalmia
• Unilateral anophthalmia or microphthalmia
• Genital abnormalities. Frequently cryptorchidism and/or micropenis in males (commonly a manifestation of hypogonadotropic hypogonadism); infrequently uterus hypoplasia and ovary or vaginal agenesis in females
• Tracheoesophageal fistula and/or esophageal atresia
• Delayed motor development / learning disability
• Postnatal growth failure
• Seizures with gray matter heterotopia
• Spasticity, dystonia, or status dystonicus
## Establishing the Diagnosis
The diagnosis of
For details about heterozygous deletions of 3q26.33 involving
Note: 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 a combination of
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas comprehensive genomic testing does not. Individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of
Note: Most deletions involving
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, whole-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 a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Note: Most deletions involving
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of
Note: Most deletions involving
For an introduction to multigene panels click
• Note: Most deletions involving
• 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, whole-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 a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
## Clinical Characteristics
To date, 174 individuals from 157 families have been identified with
Select Features of
Data were extracted from full text case reports exclusively describing
Frequency refers to the number of times the term was used in all included case reports.
In the 174 individuals reported (114 individuals reviewed by
Unilateral anophthalmia or microphthalmia and a normal eye
Unilateral anophthalmia with cataract in the contralateral eye
Unilateral microphthalmia with coloboma or iris defect in the contralateral eye
Bilateral or unilateral coloboma
Optic nerve hypoplasia or aplasia
Bilateral or unilateral congenital aphakia
Cataract
Retinal dysplasia
Anterior segment dysgenesis (including sclerocornea or microcornea)
Refractive error
Thirteen individuals with loss-of-function
A monozygotic twin with tracheoesophageal fistula and unilateral reduced palpebral fissure whose twin had unilateral anophthalmia as part of anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome [
A sibling fetus in a family with AEG syndrome, with brain anomalies and 11 rib pairs [
A woman with intellectual disability, corpus callosum agenesis, hypogonadotropic hypogonadism, vaginal agenesis, and spastic paraparesis [
A mother (with either heterozygosity or a high level of mosaicism of the
Two individuals identified in an intellectual disability cohort with mild microcornea, delayed speech and walking, esophageal stenosis, hearing deficits and mild facial hypoplasia in one; and strabismus, delayed speech, dystonic movements and spastic diplegia, hypogonadotropic hypogonadism, and corpus callosum and hippocampus malformation in the other individual [
Three individuals with mild ocular defects (esotropia, macro excavated optic disc, or thin retinal layer) and a combination of developmental delay, seizures, hypotonia or dystonia, tracheoesophageal fistula, suprasellar teratoma, and gonadal dysgenesis [
Four individuals, one of whom had a
In females, malformations are less frequent and can include hypoplastic or hemi-uterus, ovary or vaginal agenesis, and vaginal adhesions [
A minority of affected individuals develop early continual dystonic posturing that is similar to that seen in dystonic cerebral palsy but without evidence of basal ganglia injury on neuroimaging. These children should be considered at risk for status dystonicus, which can be triggered by any major physiologic stress and can lead to protracted periods of hospitalization and critical care.
Spasticity, including diplegia, paraparesis, or quadriparesis was reported in 13 individuals. One of these individuals, who also had a dystonic movement disorder and unilateral strabismus as the only eye defect, had a 1.6- to 2-megabase (Mb) deletion encompassing
Additionally, feeding difficulty or gastroesophageal reflux was observed in multiple individuals.
Almost all
Variable expressivity is observed with some recurrent pathogenic variants (
The most common variant,
The
The extraocular features of
Large deletions encompassing
Duplications encompassing
Penetrance appears to be complete for nonmosaic loss-of-function pathogenic variants. Although normal eye development is possible in
Each of the hypothetic explanations for the embryonic origin of the small or missing eyes associated with
If the primary defect is in the mechanism of optic fissure closure, the predicted order of severity would be iris coloboma, choroidal/retinal coloboma, microphthalmia with coloboma or orbital cyst, and anophthalmia.
If lens induction is impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
If the main effects of
It is also possible that complete failure of optic vesicle formation results in anophthalmia without optic nerve formation.
It is not yet clear which of these spectra are associated with
Prevalence is approximately 1:250,000 (UK estimate) [Author, personal data], extrapolated from
• Unilateral anophthalmia or microphthalmia and a normal eye
• Unilateral anophthalmia with cataract in the contralateral eye
• Unilateral microphthalmia with coloboma or iris defect in the contralateral eye
• Bilateral or unilateral coloboma
• Optic nerve hypoplasia or aplasia
• Bilateral or unilateral congenital aphakia
• Cataract
• Retinal dysplasia
• Anterior segment dysgenesis (including sclerocornea or microcornea)
• Refractive error
• A monozygotic twin with tracheoesophageal fistula and unilateral reduced palpebral fissure whose twin had unilateral anophthalmia as part of anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome [
• A sibling fetus in a family with AEG syndrome, with brain anomalies and 11 rib pairs [
• A woman with intellectual disability, corpus callosum agenesis, hypogonadotropic hypogonadism, vaginal agenesis, and spastic paraparesis [
• A mother (with either heterozygosity or a high level of mosaicism of the
• Two individuals identified in an intellectual disability cohort with mild microcornea, delayed speech and walking, esophageal stenosis, hearing deficits and mild facial hypoplasia in one; and strabismus, delayed speech, dystonic movements and spastic diplegia, hypogonadotropic hypogonadism, and corpus callosum and hippocampus malformation in the other individual [
• Three individuals with mild ocular defects (esotropia, macro excavated optic disc, or thin retinal layer) and a combination of developmental delay, seizures, hypotonia or dystonia, tracheoesophageal fistula, suprasellar teratoma, and gonadal dysgenesis [
• Four individuals, one of whom had a
• The most common variant,
• The
• The extraocular features of
• Large deletions encompassing
• If the primary defect is in the mechanism of optic fissure closure, the predicted order of severity would be iris coloboma, choroidal/retinal coloboma, microphthalmia with coloboma or orbital cyst, and anophthalmia.
• If lens induction is impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
• If the main effects of
• It is also possible that complete failure of optic vesicle formation results in anophthalmia without optic nerve formation.
## Clinical Description
To date, 174 individuals from 157 families have been identified with
Select Features of
Data were extracted from full text case reports exclusively describing
Frequency refers to the number of times the term was used in all included case reports.
In the 174 individuals reported (114 individuals reviewed by
Unilateral anophthalmia or microphthalmia and a normal eye
Unilateral anophthalmia with cataract in the contralateral eye
Unilateral microphthalmia with coloboma or iris defect in the contralateral eye
Bilateral or unilateral coloboma
Optic nerve hypoplasia or aplasia
Bilateral or unilateral congenital aphakia
Cataract
Retinal dysplasia
Anterior segment dysgenesis (including sclerocornea or microcornea)
Refractive error
Thirteen individuals with loss-of-function
A monozygotic twin with tracheoesophageal fistula and unilateral reduced palpebral fissure whose twin had unilateral anophthalmia as part of anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome [
A sibling fetus in a family with AEG syndrome, with brain anomalies and 11 rib pairs [
A woman with intellectual disability, corpus callosum agenesis, hypogonadotropic hypogonadism, vaginal agenesis, and spastic paraparesis [
A mother (with either heterozygosity or a high level of mosaicism of the
Two individuals identified in an intellectual disability cohort with mild microcornea, delayed speech and walking, esophageal stenosis, hearing deficits and mild facial hypoplasia in one; and strabismus, delayed speech, dystonic movements and spastic diplegia, hypogonadotropic hypogonadism, and corpus callosum and hippocampus malformation in the other individual [
Three individuals with mild ocular defects (esotropia, macro excavated optic disc, or thin retinal layer) and a combination of developmental delay, seizures, hypotonia or dystonia, tracheoesophageal fistula, suprasellar teratoma, and gonadal dysgenesis [
Four individuals, one of whom had a
In females, malformations are less frequent and can include hypoplastic or hemi-uterus, ovary or vaginal agenesis, and vaginal adhesions [
A minority of affected individuals develop early continual dystonic posturing that is similar to that seen in dystonic cerebral palsy but without evidence of basal ganglia injury on neuroimaging. These children should be considered at risk for status dystonicus, which can be triggered by any major physiologic stress and can lead to protracted periods of hospitalization and critical care.
Spasticity, including diplegia, paraparesis, or quadriparesis was reported in 13 individuals. One of these individuals, who also had a dystonic movement disorder and unilateral strabismus as the only eye defect, had a 1.6- to 2-megabase (Mb) deletion encompassing
Additionally, feeding difficulty or gastroesophageal reflux was observed in multiple individuals.
• Unilateral anophthalmia or microphthalmia and a normal eye
• Unilateral anophthalmia with cataract in the contralateral eye
• Unilateral microphthalmia with coloboma or iris defect in the contralateral eye
• Bilateral or unilateral coloboma
• Optic nerve hypoplasia or aplasia
• Bilateral or unilateral congenital aphakia
• Cataract
• Retinal dysplasia
• Anterior segment dysgenesis (including sclerocornea or microcornea)
• Refractive error
• A monozygotic twin with tracheoesophageal fistula and unilateral reduced palpebral fissure whose twin had unilateral anophthalmia as part of anophthalmia-esophageal atresia-genital abnormalities (AEG) syndrome [
• A sibling fetus in a family with AEG syndrome, with brain anomalies and 11 rib pairs [
• A woman with intellectual disability, corpus callosum agenesis, hypogonadotropic hypogonadism, vaginal agenesis, and spastic paraparesis [
• A mother (with either heterozygosity or a high level of mosaicism of the
• Two individuals identified in an intellectual disability cohort with mild microcornea, delayed speech and walking, esophageal stenosis, hearing deficits and mild facial hypoplasia in one; and strabismus, delayed speech, dystonic movements and spastic diplegia, hypogonadotropic hypogonadism, and corpus callosum and hippocampus malformation in the other individual [
• Three individuals with mild ocular defects (esotropia, macro excavated optic disc, or thin retinal layer) and a combination of developmental delay, seizures, hypotonia or dystonia, tracheoesophageal fistula, suprasellar teratoma, and gonadal dysgenesis [
• Four individuals, one of whom had a
## Genotype-Phenotype Correlations
Almost all
Variable expressivity is observed with some recurrent pathogenic variants (
The most common variant,
The
The extraocular features of
Large deletions encompassing
Duplications encompassing
• The most common variant,
• The
• The extraocular features of
• Large deletions encompassing
## Penetrance
Penetrance appears to be complete for nonmosaic loss-of-function pathogenic variants. Although normal eye development is possible in
## Nomenclature
Each of the hypothetic explanations for the embryonic origin of the small or missing eyes associated with
If the primary defect is in the mechanism of optic fissure closure, the predicted order of severity would be iris coloboma, choroidal/retinal coloboma, microphthalmia with coloboma or orbital cyst, and anophthalmia.
If lens induction is impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
If the main effects of
It is also possible that complete failure of optic vesicle formation results in anophthalmia without optic nerve formation.
It is not yet clear which of these spectra are associated with
• If the primary defect is in the mechanism of optic fissure closure, the predicted order of severity would be iris coloboma, choroidal/retinal coloboma, microphthalmia with coloboma or orbital cyst, and anophthalmia.
• If lens induction is impaired, the predicted clinical spectrum would be congenital cataract > microphthalmia > anophthalmia.
• If the main effects of
• It is also possible that complete failure of optic vesicle formation results in anophthalmia without optic nerve formation.
## Prevalence
Prevalence is approximately 1:250,000 (UK estimate) [Author, personal data], extrapolated from
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes associated with ocular manifestations frequently observed in
Genes of Interest in the Differential Diagnosis of
Malformations of the ears, teeth, fingers, skeleton, or genitourinary system
Mild-to-severe ID or DD in ~60% of affected males
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MCOPS5 = microphthalmia, syndromic 5; MOI = mode of inheritance; XL = X-linked
• Malformations of the ears, teeth, fingers, skeleton, or genitourinary system
• Mild-to-severe ID or DD in ~60% of affected males
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl best corrected visual acuity, assessment of refractive error, fundus exam
Consider referral to ophthalmo-plastic surgeon for children w/anophthalmia & extreme microphthalmia.
W/attention to brain/pituitary malformations, optic nerve/chiasm/tract
Mesial temporal heterotopia is highly assoc w/future epilepsy.
Growth hormone & thyroid function;
Gonadotropins (when age appropriate).
Consider referral to urologist for cryptorchidism or other genital malformations.
For those w/micropenis, refer to endocrinologist for consideration of eval for hypogonadotropic hypogonadism.
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 ongoing PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Use of community or online
Need for social work involvement for parental support.
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy/therapist; PT = physical therapy/therapist
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Prostheses: Consider optically clear expanders to stimulate growth of the orbit & periorbital tissues.
Community vision services through early intervention or school district
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical 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.
Consider 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 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
OT = occupational therapist; PT = physical therapist
See
Search
• Incl best corrected visual acuity, assessment of refractive error, fundus exam
• Consider referral to ophthalmo-plastic surgeon for children w/anophthalmia & extreme microphthalmia.
• W/attention to brain/pituitary malformations, optic nerve/chiasm/tract
• Mesial temporal heterotopia is highly assoc w/future epilepsy.
• Growth hormone & thyroid function;
• Gonadotropins (when age appropriate).
• Consider referral to urologist for cryptorchidism or other genital malformations.
• For those w/micropenis, refer to endocrinologist for consideration of eval for hypogonadotropic hypogonadism.
• 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 ongoing PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Use of community or online
• Need for social work involvement for parental support.
• Prostheses: Consider optically clear expanders to stimulate growth of the orbit & periorbital tissues.
• Community vision services through early intervention or school district
• 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.
## 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
Incl best corrected visual acuity, assessment of refractive error, fundus exam
Consider referral to ophthalmo-plastic surgeon for children w/anophthalmia & extreme microphthalmia.
W/attention to brain/pituitary malformations, optic nerve/chiasm/tract
Mesial temporal heterotopia is highly assoc w/future epilepsy.
Growth hormone & thyroid function;
Gonadotropins (when age appropriate).
Consider referral to urologist for cryptorchidism or other genital malformations.
For those w/micropenis, refer to endocrinologist for consideration of eval for hypogonadotropic hypogonadism.
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 ongoing PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Use of community or online
Need for social work involvement for parental support.
ADL = activities of daily living; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy/therapist; PT = physical therapy/therapist
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Incl best corrected visual acuity, assessment of refractive error, fundus exam
• Consider referral to ophthalmo-plastic surgeon for children w/anophthalmia & extreme microphthalmia.
• W/attention to brain/pituitary malformations, optic nerve/chiasm/tract
• Mesial temporal heterotopia is highly assoc w/future epilepsy.
• Growth hormone & thyroid function;
• Gonadotropins (when age appropriate).
• Consider referral to urologist for cryptorchidism or other genital malformations.
• For those w/micropenis, refer to endocrinologist for consideration of eval for hypogonadotropic hypogonadism.
• 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 ongoing PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Use of community or online
• Need for social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Prostheses: Consider optically clear expanders to stimulate growth of the orbit & periorbital tissues.
Community vision services through early intervention or school district
ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical 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.
Consider 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 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.
• Prostheses: Consider optically clear expanders to stimulate growth of the orbit & periorbital tissues.
• Community vision services through early intervention or school district
• 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.
## Communication Issues
Consider 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 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
OT = occupational therapist; PT = physical therapist
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Approximately 60% of individuals diagnosed with
Some individuals diagnosed with
One individual with unilateral anophthalmia had a similarly affected mother [
Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
Some individuals diagnosed with
Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
Paternal transmission of a
Recommendations for the evaluation of the parents of a proband with an apparent
Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
If the genetic alteration 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 mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
The incidence of parental germline mosaicism in
The family history of some individuals diagnosed with
If a parent is affected and/or has the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial clinical variability is observed in
If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. The incidence of parental germline mosaicism in
If a parent has a balanced structural chromosome rearrangement involving the 3q26.33 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
Each child of a female proband with a constitutional
Transmission of a constitutional loss-of-function pathogenic variant from a male proband to offspring has not been reported.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 causative genetic alteration has been identified in an affected family member (or a parent is known to have a structural chromosome rearrangement involving the 3q26.33 region), prenatal testing for a pregnancy at increased risk is possible and preimplantation genetic testing for
Note: The severity of disease and specific clinical findings vary and cannot be accurately predicted by the family history or results of molecular 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.
• Approximately 60% of individuals diagnosed with
• Some individuals diagnosed with
• One individual with unilateral anophthalmia had a similarly affected mother [
• Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
• A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
• One individual with unilateral anophthalmia had a similarly affected mother [
• Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
• A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
• Some individuals diagnosed with
• Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
• Paternal transmission of a
• Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
• Paternal transmission of a
• Recommendations for the evaluation of the parents of a proband with an apparent
• Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
• Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
• Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• If the genetic alteration 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 mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
• The incidence of parental germline mosaicism in
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
• The incidence of parental germline mosaicism in
• The family history of some individuals diagnosed with
• One individual with unilateral anophthalmia had a similarly affected mother [
• Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
• A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
• Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
• Paternal transmission of a
• Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
• Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
• The incidence of parental germline mosaicism in
• If a parent is affected and/or has the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial clinical variability is observed in
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. The incidence of parental germline mosaicism in
• If a parent has a balanced structural chromosome rearrangement involving the 3q26.33 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• Each child of a female proband with a constitutional
• Transmission of a constitutional loss-of-function pathogenic variant from a male proband to offspring has not been reported.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 60% of individuals diagnosed with
Some individuals diagnosed with
One individual with unilateral anophthalmia had a similarly affected mother [
Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
Some individuals diagnosed with
Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
Paternal transmission of a
Recommendations for the evaluation of the parents of a proband with an apparent
Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
If the genetic alteration 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 mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
The incidence of parental germline mosaicism in
The family history of some individuals diagnosed with
If a parent is affected and/or has the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial clinical variability is observed in
If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. The incidence of parental germline mosaicism in
If a parent has a balanced structural chromosome rearrangement involving the 3q26.33 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
Each child of a female proband with a constitutional
Transmission of a constitutional loss-of-function pathogenic variant from a male proband to offspring has not been reported.
• Approximately 60% of individuals diagnosed with
• Some individuals diagnosed with
• One individual with unilateral anophthalmia had a similarly affected mother [
• Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
• A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
• One individual with unilateral anophthalmia had a similarly affected mother [
• Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
• A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
• Some individuals diagnosed with
• Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
• Paternal transmission of a
• Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
• Paternal transmission of a
• Recommendations for the evaluation of the parents of a proband with an apparent
• Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
• Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
• Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• If the genetic alteration 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 mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
• The incidence of parental germline mosaicism in
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
• The incidence of parental germline mosaicism in
• The family history of some individuals diagnosed with
• One individual with unilateral anophthalmia had a similarly affected mother [
• Maternal transmission of an identical and recurrent pathogenic variant has been observed in two families: a four-generation family with eye defects ranging from microcornea or retinal tuft with refractive error to bilateral anophthalmia [
• A mother with a pathogenic variant (heterozygous or high-level mosaicism) who was minimally affected with isolated hypogonadotropic hypogonadism had two affected children: one with bilateral anophthalmia and subtle endocrine abnormalities and the other with unilateral microphthalmia with coloboma [
• Maternal somatic/germline mosaicism was reported in four families with sib recurrence of
• Paternal transmission of a
• Molecular genetic testing (ideally of parental DNA extracted from more than one tissue source, e.g., leukocytes and buccal cells) if the proband has an intragenic
• Routine karyotyping with additional FISH analysis if the proband has a deletion of 3q26.33 or other chromosome rearrangement involving 3q26.33, to determine if either parent has a balanced chromosome rearrangement involving the 3q26.33 region.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism. Note: Testing of parental DNA may not detect all instances of somatic and germline mosaicism.
• The incidence of parental germline mosaicism in
• If a parent is affected and/or has the genetic alteration identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%. Intrafamilial clinical variability is observed in
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. The incidence of parental germline mosaicism in
• If a parent has a balanced structural chromosome rearrangement involving the 3q26.33 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• Each child of a female proband with a constitutional
• Transmission of a constitutional loss-of-function pathogenic variant from a male proband to offspring has not been reported.
## 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 causative genetic alteration has been identified in an affected family member (or a parent is known to have a structural chromosome rearrangement involving the 3q26.33 region), prenatal testing for a pregnancy at increased risk is possible and preimplantation genetic testing for
Note: The severity of disease and specific clinical findings vary and cannot be accurately predicted by the family history or results of molecular 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
Note on Table A,
SOX2 Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SOX2 Disorder (
Reported heterozygous deletions of 3q26.33 involving
A
A cytogenetically visible deletion of 3q26.33 that either encompasses
A
Notable
Recurrent variant specifically assoc w/status dystonicus [
Less frequent variants, esp those that alter residues adjacent to Tyr160, are also assoc w/severe phenotype.
Variants listed in the table have been provided by the authors.
• A
• A cytogenetically visible deletion of 3q26.33 that either encompasses
• A
• Recurrent variant specifically assoc w/status dystonicus [
• Less frequent variants, esp those that alter residues adjacent to Tyr160, are also assoc w/severe phenotype.
## Molecular Pathogenesis
Reported heterozygous deletions of 3q26.33 involving
A
A cytogenetically visible deletion of 3q26.33 that either encompasses
A
Notable
Recurrent variant specifically assoc w/status dystonicus [
Less frequent variants, esp those that alter residues adjacent to Tyr160, are also assoc w/severe phenotype.
Variants listed in the table have been provided by the authors.
• A
• A cytogenetically visible deletion of 3q26.33 that either encompasses
• A
• Recurrent variant specifically assoc w/status dystonicus [
• Less frequent variants, esp those that alter residues adjacent to Tyr160, are also assoc w/severe phenotype.
## Chapter Notes
Professor Veronica van Heyningen for continued helpful collaboration
MACS family support organization for their interest and support
30 July 2020 (bp) Comprehensive update posted live
31 July 2014 (me) Comprehensive update posted live
25 August 2009 (me) Comprehensive update posted live
7 March 2008 (cd) Revision: FISH analysis available clinically
5 December 2007 (cd) Revision: deletion/duplication analysis available clinically
23 February 2006 (me) Review posted live
14 April 2005 (drf) Original submission
• Professor Veronica van Heyningen for continued helpful collaboration
• MACS family support organization for their interest and support
• 30 July 2020 (bp) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 25 August 2009 (me) Comprehensive update posted live
• 7 March 2008 (cd) Revision: FISH analysis available clinically
• 5 December 2007 (cd) Revision: deletion/duplication analysis available clinically
• 23 February 2006 (me) Review posted live
• 14 April 2005 (drf) Original submission
## Acknowledgments
Professor Veronica van Heyningen for continued helpful collaboration
MACS family support organization for their interest and support
• Professor Veronica van Heyningen for continued helpful collaboration
• MACS family support organization for their interest and support
## Revision History
30 July 2020 (bp) Comprehensive update posted live
31 July 2014 (me) Comprehensive update posted live
25 August 2009 (me) Comprehensive update posted live
7 March 2008 (cd) Revision: FISH analysis available clinically
5 December 2007 (cd) Revision: deletion/duplication analysis available clinically
23 February 2006 (me) Review posted live
14 April 2005 (drf) Original submission
• 30 July 2020 (bp) Comprehensive update posted live
• 31 July 2014 (me) Comprehensive update posted live
• 25 August 2009 (me) Comprehensive update posted live
• 7 March 2008 (cd) Revision: FISH analysis available clinically
• 5 December 2007 (cd) Revision: deletion/duplication analysis available clinically
• 23 February 2006 (me) Review posted live
• 14 April 2005 (drf) Original submission
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"V Tziaferi, D Kelberman, MT Dattani. The role of SOX2 in hypogonadotropic hypogonadism.. Sex Dev. 2008;2:194-9",
"KA Williamson, DR FitzPatrick. The genetic architecture of microphthalmia, anophthalmia and coloboma.. Eur J Med Genet. 2014;57:369-80",
"KA Williamson, HN Hall, LJ Owen, BJ Livesey, IM Hanson, GGW Adams, S Bodek, P Calvas, B Castle, M Clarke, AT Deng, P Edery, R Fisher, G Gillessen-Kaesbach, E Heon, J Hurst, D Josifova, B Lorenz, S McKee, F Meire, AT Moore, M Parker, CM Reiff, J Self, ES Tobias, JBGM Verheij, M Willems, D Williams, V van Heyningen, JA Marsh, DR FitzPatrick. Recurrent heterozygous PAX6 missense variants cause severe bilateral microphthalmia via predictable effects on DNA-protein interaction.. Genet Med. 2020;22:598-609",
"KA Williamson, AM Hever, J Rainger, RC Rogers, A Magee, Z Fiedler, WT Keng, FH Sharkey, N McGill, CJ Hill, A Schneider, M Messina, PD Turnpenny, JA Fantes, V van Heyningen, DR FitzPatrick. Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome.. Hum Mol Genet. 2006;15:1413-22",
"M Zanolli, JI Oporto, JI Verdaguer, JP López, S Zacharías, P Romero, D Ossandón, O Denk, O Acuña, JM López, R Stevenson, B Álamos, H Iturriaga. Genetic testing for inherited ocular conditions in a developing country.. Ophthalmic Genet. 2020;41:36-40",
"JC Zenteno, G Gascon-Guzman, JL Tovilla-Canales. Bilateral anophthalmia and brain malformations caused by a 20-bp deletion in the SOX2 gene.. Clin Genet. 2005;68:564-6",
"JC Zenteno, HJ Perez-Cano, M Aguinaga. Anophthalmia-esophageal atresia syndrome caused by an SOX2 gene deletion in monozygotic twin brothers with markedly discordant phenotypes.. Am J Med Genet A. 2006;140:1899-903",
"J Zhou, F Kherani, TM Bardakjian, J Katowitz, N Hughes, LA Schimmenti, A Schneider, TL Young. Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia.. Mol Vis. 2008;14:583-92"
] |
23/2/2006
|
30/7/2020
|
7/3/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
spg11
|
spg11
|
[
"SPG11",
"Spatacsin",
"SPG11",
"Spastic Paraplegia 11"
] |
Spastic Paraplegia 11
|
Giovanni Stevanin
|
Summary Spastic paraplegia 11 (SPG11) is characterized by progressive spasticity and weakness of the lower limbs frequently associated with the following: mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs. Less frequent findings include: cerebellar signs (ataxia, nystagmus, saccadic pursuit); retinal degeneration; The diagnosis of SPG11 is established in a proband with characteristic clinical and MRI findings and biallelic pathogenic variants in SPG11 is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for an
|
## Diagnosis
Spastic paraplegia 11 (SPG11)
Progressive spasticity and weakness of the lower limbs
Mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline with onset in the first to third decade
Axonal, motor, or sensorimotor peripheral neuropathy (>80% of individuals) [
Pseudobulbar involvement with dysarthria and/or dysphagia
Increased reflexes in the upper limbs
Cerebellar signs (ataxia or ocular signs including nystagmus and/or saccadic pursuit)
Retinal degeneration (Kjellin syndrome) * [
Scoliosis
Extrapyramidal signs such as parkinsonism [
* Kjellin syndrome is characterized by retinal degeneration, autosomal recessive hereditary spastic paraplegia, and thin corpus callosum initially associated with spastic paraplegia 15 (SPG15) but more often occurring in individuals with SPG11. See
Thinning of the corpus callosum (TCC) (>90% of individuals) [
Cortical atrophy is frequently observed.
White matter hyperintensities [
Only frontal and occipital periventricular hyperintensities may be seen initially.
Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
Atrophy of both the brain stem and the cerebellum can be observed [
The basal ganglia may also be affected [
Note: 60% of individuals with TCC, cognitive impairment, and spastic paraparesis were found to have biallelic
The diagnosis of spastic paraplegia 11 (SPG11)
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. Because the phenotype of SPG11 is broad, individuals with the distinctive findings described in
When the phenotypic, imaging, and electrophysiology findings suggest the diagnosis of SPG11, 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 spastic paraplegia,
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 11
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.
• Progressive spasticity and weakness of the lower limbs
• Mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline with onset in the first to third decade
• Axonal, motor, or sensorimotor peripheral neuropathy (>80% of individuals) [
• Pseudobulbar involvement with dysarthria and/or dysphagia
• Increased reflexes in the upper limbs
• Cerebellar signs (ataxia or ocular signs including nystagmus and/or saccadic pursuit)
• Retinal degeneration (Kjellin syndrome) * [
•
• Scoliosis
• Extrapyramidal signs such as parkinsonism [
• Thinning of the corpus callosum (TCC) (>90% of individuals) [
• Cortical atrophy is frequently observed.
• White matter hyperintensities [
• Only frontal and occipital periventricular hyperintensities may be seen initially.
• Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
• Only frontal and occipital periventricular hyperintensities may be seen initially.
• Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
• Atrophy of both the brain stem and the cerebellum can be observed [
• The basal ganglia may also be affected [
• Only frontal and occipital periventricular hyperintensities may be seen initially.
• Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
• For an introduction to multigene panels click
## Suggestive Findings
Spastic paraplegia 11 (SPG11)
Progressive spasticity and weakness of the lower limbs
Mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline with onset in the first to third decade
Axonal, motor, or sensorimotor peripheral neuropathy (>80% of individuals) [
Pseudobulbar involvement with dysarthria and/or dysphagia
Increased reflexes in the upper limbs
Cerebellar signs (ataxia or ocular signs including nystagmus and/or saccadic pursuit)
Retinal degeneration (Kjellin syndrome) * [
Scoliosis
Extrapyramidal signs such as parkinsonism [
* Kjellin syndrome is characterized by retinal degeneration, autosomal recessive hereditary spastic paraplegia, and thin corpus callosum initially associated with spastic paraplegia 15 (SPG15) but more often occurring in individuals with SPG11. See
Thinning of the corpus callosum (TCC) (>90% of individuals) [
Cortical atrophy is frequently observed.
White matter hyperintensities [
Only frontal and occipital periventricular hyperintensities may be seen initially.
Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
Atrophy of both the brain stem and the cerebellum can be observed [
The basal ganglia may also be affected [
Note: 60% of individuals with TCC, cognitive impairment, and spastic paraparesis were found to have biallelic
• Progressive spasticity and weakness of the lower limbs
• Mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline with onset in the first to third decade
• Axonal, motor, or sensorimotor peripheral neuropathy (>80% of individuals) [
• Pseudobulbar involvement with dysarthria and/or dysphagia
• Increased reflexes in the upper limbs
• Cerebellar signs (ataxia or ocular signs including nystagmus and/or saccadic pursuit)
• Retinal degeneration (Kjellin syndrome) * [
•
• Scoliosis
• Extrapyramidal signs such as parkinsonism [
• Thinning of the corpus callosum (TCC) (>90% of individuals) [
• Cortical atrophy is frequently observed.
• White matter hyperintensities [
• Only frontal and occipital periventricular hyperintensities may be seen initially.
• Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
• Only frontal and occipital periventricular hyperintensities may be seen initially.
• Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
• Atrophy of both the brain stem and the cerebellum can be observed [
• The basal ganglia may also be affected [
• Only frontal and occipital periventricular hyperintensities may be seen initially.
• Periventricular, confluent leukoencephalopathy often increases in severity with disease duration [
## Establishing the Diagnosis
The diagnosis of spastic paraplegia 11 (SPG11)
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. Because the phenotype of SPG11 is broad, individuals with the distinctive findings described in
When the phenotypic, imaging, and electrophysiology findings suggest the diagnosis of SPG11, 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 spastic paraplegia,
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 11
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.
• For an introduction to multigene panels click
## Option 1
When the phenotypic, imaging, and electrophysiology findings suggest the diagnosis of SPG11, 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 spastic paraplegia,
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 11
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
Onset of spastic paraplegia 11 (SPG11) occurs mainly during infancy or adolescence (age 1-31 years) and is characterized by gait disorders or less frequently by intellectual disability [
Approximately ten years after onset, most affected individuals have the complete clinical picture of SPG11, including progressive lower-limb spasticity, atrophy of the corpus callosum with intellectual disability, and/or progressive cognitive decline. Thinning of the corpus callosum appears to correlate with disease severity [
Cognitive decline with low Mini Mental State Evaluation (MMSE) scores, found in the majority of affected individuals, worsens with time and includes severe short-term memory impairment, emotional lability, childish behavior, reduced verbal fluency, and attention deficit indicative of executive dysfunction [
Intellectual disability, found in most individuals with early onset, is characterized by learning difficulties in childhood and low IQ.
Eye findings can include the following:
Macular excavation or degeneration as reported in the Kjellin syndrome [
Strabismus
Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus in individuals with the longest disease duration
Visual evoked potentials with increased latencies and decreased amplitudes [
Additional features are severe weakness, dysarthria, distal or generalized muscle wasting, and less frequently,
Missense and splice site variants are more often associated with later onset [
SPG11 is one of several autosomal recessive disorders in which hereditary spastic paraplegia is associated with thin corpus callosum (HSP-TCC).
Based on the EMG and NCV patterns and on anterior horn cell abnormalities seen in some affected individuals, several authors have characterized SPG11 as upper and lower motor neuron disease [
The estimated prevalence for HSP of all types ranges from 1:100,000 to 10:100,000 depending on the country. Since SPG11 was found to account for 19%-31% of autosomal recessive HSP [
As expected in autosomal recessive disorders, most families with SPG11 originate from countries in which consanguinity is common, particularly the Mediterranean basin or the Middle East [
• Macular excavation or degeneration as reported in the Kjellin syndrome [
• Strabismus
• Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus in individuals with the longest disease duration
• Visual evoked potentials with increased latencies and decreased amplitudes [
## Clinical Description
Onset of spastic paraplegia 11 (SPG11) occurs mainly during infancy or adolescence (age 1-31 years) and is characterized by gait disorders or less frequently by intellectual disability [
Approximately ten years after onset, most affected individuals have the complete clinical picture of SPG11, including progressive lower-limb spasticity, atrophy of the corpus callosum with intellectual disability, and/or progressive cognitive decline. Thinning of the corpus callosum appears to correlate with disease severity [
Cognitive decline with low Mini Mental State Evaluation (MMSE) scores, found in the majority of affected individuals, worsens with time and includes severe short-term memory impairment, emotional lability, childish behavior, reduced verbal fluency, and attention deficit indicative of executive dysfunction [
Intellectual disability, found in most individuals with early onset, is characterized by learning difficulties in childhood and low IQ.
Eye findings can include the following:
Macular excavation or degeneration as reported in the Kjellin syndrome [
Strabismus
Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus in individuals with the longest disease duration
Visual evoked potentials with increased latencies and decreased amplitudes [
Additional features are severe weakness, dysarthria, distal or generalized muscle wasting, and less frequently,
• Macular excavation or degeneration as reported in the Kjellin syndrome [
• Strabismus
• Cerebellar ocular signs such as abnormal saccadic pursuit and nystagmus in individuals with the longest disease duration
• Visual evoked potentials with increased latencies and decreased amplitudes [
## Genotype-Phenotype Correlations
Missense and splice site variants are more often associated with later onset [
## Nomenclature
SPG11 is one of several autosomal recessive disorders in which hereditary spastic paraplegia is associated with thin corpus callosum (HSP-TCC).
Based on the EMG and NCV patterns and on anterior horn cell abnormalities seen in some affected individuals, several authors have characterized SPG11 as upper and lower motor neuron disease [
## Prevalence
The estimated prevalence for HSP of all types ranges from 1:100,000 to 10:100,000 depending on the country. Since SPG11 was found to account for 19%-31% of autosomal recessive HSP [
As expected in autosomal recessive disorders, most families with SPG11 originate from countries in which consanguinity is common, particularly the Mediterranean basin or the Middle East [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
See
There are other forms of spastic paraplegia associated with thinning of the corpus callosum and mental impairment and it is often difficult to distinguish them from SPG11 on clinical grounds (
Other Hereditary Spastic Paraplegias Associated with Thin Corpus Callosum (HSP-TCC) and Mental Impairment of Interest in the Differential Diagnosis of Spastic Paraplegia 11 (SPG11)
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HSP = hereditary spastic paraplegia; ID = intellectual disability; MOI = mode of inheritance; TCC = thin corpus callosum
See
Lower motor neuron degeneration may mimic
## Management
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 11 (SPG11), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neuropsychological testing to assess the cognitive impairment and decline
Neuro-urologic examination for those with sphincter disturbance
Electrophysiologic investigations (e.g., ENMG, VEP, SEP)
Ocular investigations (e.g., funduscopic examination, OCT)
Consultation with a clinical geneticist and/or genetic counselor
No specific drug treatment or cure exists for SPG11.
Care by a multidisciplinary team that may include a general practitioner, neurologist, clinical geneticist, physiotherapist, physical therapist, social worker, and psychologist should be considered.
Symptomatic treatment to reduce pyramidal hyperactivity in the lower limbs includes the following:
Physiotherapy for stretching of the spastic muscles to prevent contractures. Adapted dance or movements are also helpful to maintain strength (see
Antispastic drugs such as baclofen and tizanidine
Botulin toxin and intrathecal baclofen, which can be considered when oral drugs are ineffective and spasticity is severe and disabling
When sphincter disturbances become a problem, urodynamic evaluation should be performed in order to adapt treatment and monitor follow up. Anticholinergic drugs are indicated for urinary urgency.
Psychiatric manifestations should be treated in accordance with standard practice.
Follow up of sphincter disturbances is important to prevent bladder dysfunction and infection.
Early regular physiotherapy helps to prevent contractures.
Specialized outpatient clinic evaluations are suggested every six months to adjust medication and physical rehabilitation that will depend on disease severity.
Annual brain MRI can be used to follow the atrophy of the corpus callosum, cerebellum, and brain stem, and to monitor increases in the size and intensity of white matter hyperintensities.
Annual electrophysiologic investigations (e.g., ENMG, VEP, SEP) are recommended to follow the extent of the disease.
Visual acuity should be assessed annually.
See
Search
• Neuropsychological testing to assess the cognitive impairment and decline
• Neuro-urologic examination for those with sphincter disturbance
• Electrophysiologic investigations (e.g., ENMG, VEP, SEP)
• Ocular investigations (e.g., funduscopic examination, OCT)
• Consultation with a clinical geneticist and/or genetic counselor
• Physiotherapy for stretching of the spastic muscles to prevent contractures. Adapted dance or movements are also helpful to maintain strength (see
• Antispastic drugs such as baclofen and tizanidine
• Botulin toxin and intrathecal baclofen, which can be considered when oral drugs are ineffective and spasticity is severe and disabling
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 11 (SPG11), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neuropsychological testing to assess the cognitive impairment and decline
Neuro-urologic examination for those with sphincter disturbance
Electrophysiologic investigations (e.g., ENMG, VEP, SEP)
Ocular investigations (e.g., funduscopic examination, OCT)
Consultation with a clinical geneticist and/or genetic counselor
• Neuropsychological testing to assess the cognitive impairment and decline
• Neuro-urologic examination for those with sphincter disturbance
• Electrophysiologic investigations (e.g., ENMG, VEP, SEP)
• Ocular investigations (e.g., funduscopic examination, OCT)
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No specific drug treatment or cure exists for SPG11.
Care by a multidisciplinary team that may include a general practitioner, neurologist, clinical geneticist, physiotherapist, physical therapist, social worker, and psychologist should be considered.
Symptomatic treatment to reduce pyramidal hyperactivity in the lower limbs includes the following:
Physiotherapy for stretching of the spastic muscles to prevent contractures. Adapted dance or movements are also helpful to maintain strength (see
Antispastic drugs such as baclofen and tizanidine
Botulin toxin and intrathecal baclofen, which can be considered when oral drugs are ineffective and spasticity is severe and disabling
When sphincter disturbances become a problem, urodynamic evaluation should be performed in order to adapt treatment and monitor follow up. Anticholinergic drugs are indicated for urinary urgency.
Psychiatric manifestations should be treated in accordance with standard practice.
• Physiotherapy for stretching of the spastic muscles to prevent contractures. Adapted dance or movements are also helpful to maintain strength (see
• Antispastic drugs such as baclofen and tizanidine
• Botulin toxin and intrathecal baclofen, which can be considered when oral drugs are ineffective and spasticity is severe and disabling
## Prevention of Secondary Complications
Follow up of sphincter disturbances is important to prevent bladder dysfunction and infection.
Early regular physiotherapy helps to prevent contractures.
## Surveillance
Specialized outpatient clinic evaluations are suggested every six months to adjust medication and physical rehabilitation that will depend on disease severity.
Annual brain MRI can be used to follow the atrophy of the corpus callosum, cerebellum, and brain stem, and to monitor increases in the size and intensity of white matter hyperintensities.
Annual electrophysiologic investigations (e.g., ENMG, VEP, SEP) are recommended to follow the extent of the disease.
Visual acuity should be assessed annually.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spastic paraplegia 11 (SPG11) is inherited in an autosomal recessive manner.
In almost all cases, the parents of an affected child are heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a
In one rare case, a proband inherited one
Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
If each parent is known to be heterozygous for an
Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
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 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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.
• In almost all cases, the parents of an affected child are heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a
• In one rare case, a proband inherited one
• Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
• If each parent is known to be heterozygous for an
• Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
• 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
Spastic paraplegia 11 (SPG11) is inherited in an autosomal recessive manner.
## Risk to Family Members
In almost all cases, the parents of an affected child are heterozygotes (i.e., carriers of one
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a
In one rare case, a proband inherited one
Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
If each parent is known to be heterozygous for an
Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
• In almost all cases, the parents of an affected child are heterozygotes (i.e., carriers of one
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a
• In one rare case, a proband inherited one
• Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
• If each parent is known to be heterozygous for an
• Heterozygotes (carriers) are typically asymptomatic but abnormal ocular fundus may occasionally be observed [
## 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 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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
Tom Wahlig Stiftung
Germany
Associazione Italiana Vivere la Paraparesi Spastica
Italy
•
•
•
• Australia
•
•
•
•
•
•
• Tom Wahlig Stiftung
• Germany
•
•
• Associazione Italiana Vivere la Paraparesi Spastica
• Italy
•
•
•
## Molecular Genetics
Spastic Paraplegia 11: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spastic Paraplegia 11 (
The loss of spatacsin function is associated with reduced clearance of lipids from lysosomes with accumulation of gangliosides and cholesterol [
## Molecular Pathogenesis
The loss of spatacsin function is associated with reduced clearance of lipids from lysosomes with accumulation of gangliosides and cholesterol [
## Chapter Notes
Giovanni Stevanin, PhD is a molecular biologist with expertise in spinocerebellar degeneration. He is Director of Research at INSERM and Professor at the Ecole Pratique des Hautes Etudes / Paris Sciences Lettres University. He co-leads a research team at the Institut du Cerveau et de la Moelle Epinière (Paris, France) and the international network on spastic paraplegias and ataxias (SPATAX; see below).
The author suggests the following organization for patient registries and information on ataxia and spastic paraparesis:
SPATAX NetworkInstitut du Cerveau et de la Moelle EpinièrePitié-Salpêtrière Hospital47 Bd de l’Hôpital75013 Paris, FranceEmail: [email protected]:
The author's work is financially supported by the French Agency for Research (ANR), the Spastic Paraplegia Foundation (US), the European Union through the H2020 program, the Erare program, and the French Strümpell Lorrain Association (ASL).
Alexis Brice, MD; Hôpital Pitié-Salpêtrière (2008-2019)Alexandra Durr, MD, PhD; Hôpital Pitié-Salpêtrière (2008-2019)Giovanni Stevanin, PhD (2008-present)
19 December 2019 (sw) Comprehensive update posted live
31 January 2013 (me) Comprehensive update posted live
3 September 2009 (cd) Revision: deletion/duplication analysis available clinically
27 March 2008 (me) Review posted live
26 November 2007 (gs) Original submission
• 19 December 2019 (sw) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 3 September 2009 (cd) Revision: deletion/duplication analysis available clinically
• 27 March 2008 (me) Review posted live
• 26 November 2007 (gs) Original submission
## Author Notes
Giovanni Stevanin, PhD is a molecular biologist with expertise in spinocerebellar degeneration. He is Director of Research at INSERM and Professor at the Ecole Pratique des Hautes Etudes / Paris Sciences Lettres University. He co-leads a research team at the Institut du Cerveau et de la Moelle Epinière (Paris, France) and the international network on spastic paraplegias and ataxias (SPATAX; see below).
The author suggests the following organization for patient registries and information on ataxia and spastic paraparesis:
SPATAX NetworkInstitut du Cerveau et de la Moelle EpinièrePitié-Salpêtrière Hospital47 Bd de l’Hôpital75013 Paris, FranceEmail: [email protected]:
## Acknowledgments
The author's work is financially supported by the French Agency for Research (ANR), the Spastic Paraplegia Foundation (US), the European Union through the H2020 program, the Erare program, and the French Strümpell Lorrain Association (ASL).
## Author History
Alexis Brice, MD; Hôpital Pitié-Salpêtrière (2008-2019)Alexandra Durr, MD, PhD; Hôpital Pitié-Salpêtrière (2008-2019)Giovanni Stevanin, PhD (2008-present)
## Revision History
19 December 2019 (sw) Comprehensive update posted live
31 January 2013 (me) Comprehensive update posted live
3 September 2009 (cd) Revision: deletion/duplication analysis available clinically
27 March 2008 (me) Review posted live
26 November 2007 (gs) Original submission
• 19 December 2019 (sw) Comprehensive update posted live
• 31 January 2013 (me) Comprehensive update posted live
• 3 September 2009 (cd) Revision: deletion/duplication analysis available clinically
• 27 March 2008 (me) Review posted live
• 26 November 2007 (gs) Original submission
## References
## Literature Cited
|
[
"M Anheim, C Lagier-Tourenne, G Stevanin, M Fleury, A Durr, IJ Namer, P Denora, A Brice, JL Mandel, M Koenig, C Tranchant. SPG11 spastic paraplegia. A new cause of juvenile parkinsonism.. J Neurol. 2009;256:104-8",
"A Boukhris, G Stevanin, I Feki, P Denora, N Elleuch, MI Miladi, C Goizet, J Truchetto, S Belal, A Brice, C Mhiri. Tunisian hereditary spastic paraplegias: clinical variability supported by genetic heterogeneity.. Clin Genet. 2009;75:527-36",
"M Boutry, A Pierga, R Matusiak, J Branchu, M Houllegatte, Y Ibrahim, E Balse, KH El Hachimi, A Brice, G Stevanin, F Darios. Loss of spatacsin impairs cholesterol trafficking and calcium homeostasis.. Commun Biol. 2019;2:380",
"M Boutry, J Branchu, C Lustremant, C Pujol, J Pernelle, R Matusiak, A Seyer, M Poirel, E Chu-Van, A Pierga, K Dobrenis, JP Puech, C Caillaud, A Durr, A Brice, B Colsch, F Mochel, KH El Hachimi, G Stevanin, F Darios. Inhibition of lysosome membrane recycling causes accumulation of gangliosides that contribute to neurodegeneration.. Cell Rep. 2018;23:3813-26",
"J Chang, S Lee, C Blackstone. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.. J Clin Invest. 2014;124:5249-62",
"H Daoud, S Zhou, A Noreau, M Sabbagh, V Belzil, A Dionne-Laporte, C Tranchant, P Dion, GA Rouleau. Exome sequencing reveals SPG11 mutations causing juvenile ALS.. Neurobiol Aging. 2012;33:839.e5-9",
"PS Denora, K Smets, F Zolfanelli, C Ceuterick-de Groote, C Casali, T Deconinck, A Sieben, M Gonzales, S Zuchner, F Darios, D Peeters, A Brice, A Malandrini, P De Jonghe, FM Santorelli, G Stevanin, JJ Martin, KH El Hachimi. Motor neuron degeneration in spastic paraplegia 11 mimics amyotrophic lateral sclerosis lesions.. Brain. 2016;139:1723-34",
"PS Denora, K Brockmann, M Ciccolella, J Truchetto, G Stevanin, FM Santorelli. Identification of a de novo mutation in SPG11.. Mov Disord. 2010;25:501-3",
"PS Denora, D Schlesinger, C Casali, F Kok, A Tessa, A Boukhris, H Azzedine, MT Dotti, C Bruno, J Truchetto, R Biancheri, E Fedirko, M Di Rocco, C Bueno, A Malandrini, R Battini, E Sickl, MF de Leva, O Boespflug-Tanguy, G Silvestri, A Simonati, E Said, A Ferbert, C Criscuolo, K Heinimann, A Modoni, P Weber, S Palmeri, M Plasilova, F Pauri, D Cassandrini, C Battisti, A Pini, M Tosetti, E Hauser, M Masciullo, R Di Fabio, F Piccolo, E Denis, G Cioni, R Massa, E Della Giustina, O Calabrese, MA Melone, G De Michele, A Federico, E Bertini, A Durr, K Brockmann, MS van der Knaap, M Zatz, A Filla, A Brice, G Stevanin, FM Santorelli. Screening of ARHSP-TCC patients expands the spectrum of SPG11 mutations and includes a large scale gene deletion.. Hum Mutat. 2009;30:E500-19",
"I Faber, ARM Martinez, CR Martins, ML Maia, JP Souza, CM Lourenço, W Marques, C Montecchiani, A Orlacchio, JL Pedroso, OGP Barsottini, CD Ramos, Í Lopes-Cendes, JH Friedman, BJ Amorim, MC França. SPG11-related parkinsonism: Clinical profile, molecular imaging and l-dopa response.. Mov Disord. 2018a;33:1650-6",
"I Faber, ARM Martinez, TJR de Rezende, CR Martins, MP Martins, CM Lourenço, W Marques, C Montecchiani, A Orlacchio, JL Pedroso, OGP Barsottini, Í Lopes-Cendes, MC França. SPG11 mutations cause widespread white matter and basal ganglia abnormalities, but restricted cortical damage.. Neuroimage Clin. 2018b;19:848-57",
"MC França, CL Yasuda, FR Pereira, A D'Abreu, CM Lopes-Ramos, MV Rosa, F Cendes, I Lopes-Cendes. White and grey matter abnormalities in patients with SPG11 mutations.. J Neurol Neurosurg Psychiatry. 2012;83:828-33",
"S Günther, E Elert-Dobkowska, AS Soehn, S Hinreiner, G Yoon, R Heller, Y Hellenbroich, CA Hübner, PN Ray, U Hehr, P Bauer, A Sulek, C Beetz. High Frequency of Pathogenic Rearrangements in SPG11 and Extensive Contribution of Mutational Hotspots and Founder Alleles.. Hum Mutat. 2016;37:703-9",
"U Hehr, P Bauer, B Winner, R Schule, A Olmez, W Koehler, G Uyanik, A Engel, D Lenz, A Seibel, A Hehr, S Ploetz, J Gamez, A Rolfs, J Weis, TM Ringer, M Bonin, G Schuierer, J Marienhagen, U Bogdahn, BH Weber, H Topaloglu, L Schols, O Riess, J Winkler. Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.. Ann Neurol. 2007;62:656-65",
"J Hirst, LD Barlow, GC Francisco, DA Sahlender, MN Seaman, JB Dacks, MS Robinson. The fifth adaptor protein complex.. PLoS Biol. 2011;9",
"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",
"E Kara, A Tucci, C Manzoni, DS Lynch, M Elpidorou, C Bettencourt, V Chelban, A Manole, SA Hamed, NA Haridy, M Federoff, E Preza, D Hughes, A Pittman, Z Jaunmuktane, S Brandner, G Xiromerisiou, S Wiethoff, L Schottlaender, C Proukakis, H Morris, T Warner, KP Bhatia, LV Korlipara, AB Singleton, J Hardy, NW Wood, PA Lewis, H Houlden. Genetic and phenotypic characterization of complex hereditary spastic paraplegia.. Brain. 2016;139:1904-18",
"T Kawarai, R Miyamoto, A Mori, R Oki, A Tsukamoto-Miyashiro, N Matsui, Y Miyazaki, A Orlacchio, Y Izumi, Y Nishida, R. Kaji. Late-onset spastic paraplegia: Aberrant SPG11 transcripts generated by a novel splice site donor mutation.. J Neurol Sci. 2015;359:250-5",
"A Manole, V Chelban, NA Haridy, SA Hamed, A Berardo, MM Reilly, H Houlden. Severe axonal neuropathy is a late manifestation of SPG11.. J Neurol. 2016;263:2278-86",
"E Martin, C Yanicostas, A Rastetter, SM Naini, A Maouedj, E Kabashi, S Rivaud-Péchoux, A Brice, G Stevanin, N Soussi-Yanicostas. Spatacsin and spastizin act in the same pathway required for proper spinal motor neuron axon outgrowth in zebrafish.. Neurobiol Dis. 2012;48:299-308",
"C Montecchiani, L Pedace, T Lo Giudice, A Casella, M Mearini, F Gaudiello, JL Pedroso, C Terracciano, C Caltagirone, R Massa, PH St George-Hyslop, OG Barsottini, T Kawarai, A Orlacchio. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.. Brain. 2016;139:73-85",
"S Morais, L Raymond, M Mairey, P Coutinho, E Brandão, P Ribeiro, JL Loureiro, J Sequeiros, A Brice, I Alonso, G Stevanin. Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias.. Eur J Hum Genet. 2017;25:1217-28",
"M Mukai, K Koh, Y Ohnuki, E Nagata, Y Takiyama, S. Takizawa. Novel SPG11 mutations in a patient with symptoms mimicking multiple sclerosis.. Intern Med. 2018;57:3183-6",
"A Orlacchio, C Babalini, A Borreca, C Patrono, R Massa, S Basaran, RP Munhoz, EA Rogaeva, PH St George-Hyslop, G Bernardi, T Kawarai. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.. Brain. 2010;133:591-8",
"H Orlén, A Melberg, R Raininko, E Kumlien, M Entesarian, P Söderberg, M Påhlman, N Darin, M Kyllerman, E Holmberg, H Engler, U Eriksson, N. Dahl. SPG11 mutations cause Kjellin syndrome, a hereditary spastic paraplegia with thin corpus callosum and central retinal degeneration.. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:984-92",
"A Özoğuz, Ö Uyan, G Birdal, C Iskender, E Kartal, S Lahut, Ö Ömür, ZS Agim, AG Eken, NE Sen, P Kavak, C Saygı, PC Sapp, P Keagle, Y Parman, E Tan, F Koç, F Deymeer, P Oflazer, H Hanağası, H Gürvit, B Bilgiç, H Durmuş, M Ertaş, D Kotan, MA Akalın, H Güllüoğlu, M Zarifoğlu, F Aysal, N Döşoğlu, K Bilguvar, M Günel, Ö Keskin, T Akgün, H Özçelik, JE Landers, RH Brown, AN Başak. The distinct genetic pattern of ALS in Turkey and novel mutations.. Neurobiol Aging. 2015;36:1764.e9-1764.e18",
"B Pascual, ST de Bot, MR Daniels, MC França, C Toro, M Riverol, P Hedera, MT Bassi, N Bresolin, BP van de Warrenburg, B Kremer, J Nicolai, P Charles, J Xu, S Singh, NJ Patronas, SH Fung, MD Gregory, JC Masdeu. \"Ears of the lynx\" MRI sign is associated with SPG11 and SPG15 hereditary spastic paraplegia.. Am J Neuroradiol. 2019;40:199-203",
"T Pozner, A Schray, M Regensburger, DC Lie, U Schlötzer-Schrehardt, J Winkler, S Turan, B Winner. Tideglusib rescues neurite pathology of SPG11 iPSC derived cortical neurons.. Front Neurosci. 2018;12:914",
"B Puech, A Lacour, G Stevanin, BG Sautiere, D Devos, C Depienne, E Denis, E Mundwiller, D Ferriby, P Vermersch, S Defoort-Dhellemmes. Kjellin syndrome: long-term neuro-ophthalmologic follow-up and novel mutations in the SPG11 gene.. Ophthalmology. 2011;118:564-73",
"S Rajakulendran, C Paisán-Ruiz, H Houlden. Thinning of the corpus callosum and cerebellar atrophy is correlated with phenotypic severity in a family with spastic paraplegia type 11.. J Clin Neurol. 2011;7:102-4",
"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 Romagnolo, S Masera, A Mattioda, G Superti, FM Santorelli, T Mongini, L Pinessi, P Cavalla. Atypical hereditary spastic paraplegia mimicking multiple sclerosis associated with a novel SPG11 mutation.. Eur J Neurol. 2014;21:e14-5",
"A Rubegni, E Storti, A Tessa, A Federico, FM Santorelli. Hereditary spastic paraplegia type 11 with a very late onset.. J Neurol. 2015;262:1987-9",
"L Southgate, D Dafou, J Hoyle, N Li, E Kinning, P Critchley, AH Németh, K Talbot, PS Bindu, S Sinha, AB Taly, S Raghavendra, F Müller, ER Maher, RC Trembath. Novel SPG11 mutations in Asian kindreds and disruption of spatacsin function in the zebrafish.. Neurogenetics. 2010;11:379-89",
"M Słabicki, M Theis, DB Krastev, S Samsonov, E Mundwiller, M Junqueira, M Paszkowski-Rogacz, J Teyra, AK Heninger, I Poser, F Prieur, J Truchetto, C Confavreux, C Marelli, A Durr, JP Camdessanche, A Brice, A Shevchenko, MT Pisabarro, G Stevanin, F Buchholz. A genome-scale DNA repair RNAi screen identifies SPG48 as a novel gene associated with hereditary spastic paraplegia.. PLoS Biol. 2010;8",
"G Stevanin, H Azzedine, P Denora, A Boukhris, M Tazir, A Lossos, AL Rosa, I Lerer, A Hamri, P Alegria, J Loureiro, M Tada, D Hannequin, M Anheim, C Goizet, V Gonzalez-Martinez, I Le Ber, S Forlani, K Iwabuchi, V Meiner, G Uyanik, AK Erichsen, I Feki, F Pasquier, S Belarbi, VT Cruz, C Depienne, J Truchetto, G Garrigues, C Tallaksen, C Tranchant, M Nishizawa, J Vale, P Coutinho, FM Santorelli, C Mhiri, A Brice, A Durr. Mutations in SPG11 are frequent in autosomal recessive spastic paraplegia with thin corpus callosum, cognitive decline and lower motor neuron degeneration.. Brain. 2008;131:772-84",
"G Stevanin, FM Santorelli, H Azzedine, P Coutinho, J Chomilier, PS Denora, E Martin, AM Ouvrard-Hernandez, A Tessa, N Bouslam, A Lossos, P Charles, JL Loureiro, N Elleuch, C Confavreux, VT Cruz, M Ruberg, E Leguern, D Grid, M Tazir, B Fontaine, A Filla, E Bertini, A Durr, A Brice. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum.. Nat Genet. 2007;39:366-72"
] |
27/3/2008
|
19/12/2019
|
30/10/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
spg15
|
spg15
|
[
"Hereditary Spastic Paraplegia Type 15",
"HSP-ZFYVE26",
"SPG15",
"ZFYVE26-Related Hereditary Spastic Paraplegia",
"SPG15",
"Hereditary Spastic Paraplegia Type 15",
"HSP-ZFYVE26",
"ZFYVE26-Related Hereditary Spastic Paraplegia",
"Zinc finger FYVE domain-containing protein 26",
"ZFYVE26",
"Spastic Paraplegia 15"
] |
Spastic Paraplegia 15
|
Darius Ebrahimi-Fakhari, Julian E Alecu, Craig Blackstone
|
Summary Spastic paraplegia 15 (SPG15), typically an early-onset complex hereditary spastic paraplegia, is characterized by progressive spasticity that begins in the lower extremities and is associated with several manifestations resulting from central and peripheral nervous system dysfunction. While onset of spasticity is typically in mid- to late childhood or adolescence (i.e., between ages 5 and 18 years), other manifestations, such as developmental delay or learning disability, may be present earlier, often preceding motor involvement. Individuals with adult onset have also been reported. The diagnosis of SPG15 is established in a proband with suggestive findings and biallelic pathogenic variants in SPG15 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for spastic paraplegia 15 (SPG15) have been published.
Spastic paraplegia 15 (SPG15)
Spasticity and weakness with progression from a spastic diplegia to a spastic tetraplegia with associated pyramidal signs (Babinski sign, hyperreflexia, ankle clonus)
Learning disability or intellectual disability, progressive cognitive impairment
Dysarthria and cerebellar signs
Peripheral neuropathy (axonal sensorimotor neuropathy)
Distal amyotrophy / loss of muscle bulk
Less common:
Extrapyramidal movement disorders including focal dystonia and parkinsonism
Retinopathy
Sensorineural hearing impairment
Epilepsy
Cataracts
Nerve conduction studies show an axonal sensorimotor neuropathy in a subset of affected individuals.
Electroretinography may show changes consistent with retinopathy in a subset of affected individuals.
Thinning of the corpus callosum (most commonly the anterior parts) (70%)
Periventricular white matter signal changes (>50%). The periventricular white matter signal changes in SPG15 can have a characteristic appearance involving the forceps minor. This is known as the “ears of the lynx” sign, as hypointense signal on T
Cerebral and cerebellar atrophy (~25%)
The diagnosis of SPG15
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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 15
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.
Gene-targeted deletion/duplication analysis has not identified any deletions or duplications.
• Spasticity and weakness with progression from a spastic diplegia to a spastic tetraplegia with associated pyramidal signs (Babinski sign, hyperreflexia, ankle clonus)
• Learning disability or intellectual disability, progressive cognitive impairment
• Dysarthria and cerebellar signs
• Peripheral neuropathy (axonal sensorimotor neuropathy)
• Distal amyotrophy / loss of muscle bulk
• Less common:
• Extrapyramidal movement disorders including focal dystonia and parkinsonism
• Retinopathy
• Sensorineural hearing impairment
• Epilepsy
• Cataracts
• Extrapyramidal movement disorders including focal dystonia and parkinsonism
• Retinopathy
• Sensorineural hearing impairment
• Epilepsy
• Cataracts
• Extrapyramidal movement disorders including focal dystonia and parkinsonism
• Retinopathy
• Sensorineural hearing impairment
• Epilepsy
• Cataracts
• Nerve conduction studies show an axonal sensorimotor neuropathy in a subset of affected individuals.
• Electroretinography may show changes consistent with retinopathy in a subset of affected individuals.
• Thinning of the corpus callosum (most commonly the anterior parts) (70%)
• Periventricular white matter signal changes (>50%). The periventricular white matter signal changes in SPG15 can have a characteristic appearance involving the forceps minor. This is known as the “ears of the lynx” sign, as hypointense signal on T
• Cerebral and cerebellar atrophy (~25%)
## Suggestive Findings
Spastic paraplegia 15 (SPG15)
Spasticity and weakness with progression from a spastic diplegia to a spastic tetraplegia with associated pyramidal signs (Babinski sign, hyperreflexia, ankle clonus)
Learning disability or intellectual disability, progressive cognitive impairment
Dysarthria and cerebellar signs
Peripheral neuropathy (axonal sensorimotor neuropathy)
Distal amyotrophy / loss of muscle bulk
Less common:
Extrapyramidal movement disorders including focal dystonia and parkinsonism
Retinopathy
Sensorineural hearing impairment
Epilepsy
Cataracts
Nerve conduction studies show an axonal sensorimotor neuropathy in a subset of affected individuals.
Electroretinography may show changes consistent with retinopathy in a subset of affected individuals.
Thinning of the corpus callosum (most commonly the anterior parts) (70%)
Periventricular white matter signal changes (>50%). The periventricular white matter signal changes in SPG15 can have a characteristic appearance involving the forceps minor. This is known as the “ears of the lynx” sign, as hypointense signal on T
Cerebral and cerebellar atrophy (~25%)
• Spasticity and weakness with progression from a spastic diplegia to a spastic tetraplegia with associated pyramidal signs (Babinski sign, hyperreflexia, ankle clonus)
• Learning disability or intellectual disability, progressive cognitive impairment
• Dysarthria and cerebellar signs
• Peripheral neuropathy (axonal sensorimotor neuropathy)
• Distal amyotrophy / loss of muscle bulk
• Less common:
• Extrapyramidal movement disorders including focal dystonia and parkinsonism
• Retinopathy
• Sensorineural hearing impairment
• Epilepsy
• Cataracts
• Extrapyramidal movement disorders including focal dystonia and parkinsonism
• Retinopathy
• Sensorineural hearing impairment
• Epilepsy
• Cataracts
• Extrapyramidal movement disorders including focal dystonia and parkinsonism
• Retinopathy
• Sensorineural hearing impairment
• Epilepsy
• Cataracts
• Nerve conduction studies show an axonal sensorimotor neuropathy in a subset of affected individuals.
• Electroretinography may show changes consistent with retinopathy in a subset of affected individuals.
• Thinning of the corpus callosum (most commonly the anterior parts) (70%)
• Periventricular white matter signal changes (>50%). The periventricular white matter signal changes in SPG15 can have a characteristic appearance involving the forceps minor. This is known as the “ears of the lynx” sign, as hypointense signal on T
• Cerebral and cerebellar atrophy (~25%)
## Establishing the Diagnosis
The diagnosis of SPG15
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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 15
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.
Gene-targeted deletion/duplication analysis has not identified any 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 Spastic Paraplegia 15
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.
Gene-targeted deletion/duplication analysis has not identified any deletions or duplications.
## Clinical Characteristics
Spastic paraplegia 15 (SPG15), a form of early-onset complex hereditary spastic paraplegia, is characterized by progressive spasticity that begins in the lower extremities and is associated with several manifestations resulting from central and peripheral nervous system dysfunction (
The following clinical description of SPG15 is based on a review of more than 70 individuals with biallelic pathogenic variants in
Of note, some clinical features may present or progress in an age-dependent manner.
Spastic Paraplegia 15: Frequency of Select Features
Many individuals, over the course of years, become nonambulatory and ultimately require mobility aids or a wheelchair.
Spasticity progresses to involve the upper extremities in some cases, resulting in a spastic tetraplegia, but continues to be more severe in the legs.
Associated complications may include dysphagia, contractures secondary to progressive spasticity, scoliosis, foot deformities, and dysregulation of bladder and bowel function.
Thinning of the corpus callosum
Signal abnormalities of the periventricular white matter
Cerebral and/or cerebellar atrophy
Seizures are uncommon.
Sensorineural hearing impairment is found in a subset of individuals.
No genotype-phenotype correlations for
Hereditary spastic paraplegia (HSP) is classified clinically as "uncomplicated" (nonsyndromic) or "complicated" (syndromic).
Uncomplicated (or "pure") HSP is characterized by progressive lower-extremity spasticity and weakness, bladder dysfunction, and diminution of lower-extremity vibration sensation [
Complicated HSP, such as SPG15, is characterized by the impairments present in uncomplicated HSP plus other neurologic findings (intellectual disability, extrapyramidal movement disorders, cerebellar dysfunction, peripheral neuropathy, muscle atrophy, seizures, and others).
Kjellin syndrome refers to a syndrome consisting of retinal degeneration and spastic paraplegia accompanied by cognitive impairment. The clinical description preceded the discovery of the genes now known to be associated with SPG11 and SPG15. Both SPG11 and SPG15 can present with Kjellin syndrome.
SPG15 is rare. To date about 75 individuals have been reported.
Families with SPG15 have been reported from North America, Europe, the Middle East, Indian subcontinent, East Asia, and South America. Many affected individuals have a history of consanguinity; however, this could be the result of ascertainment bias, as initial reports have mainly focused on families from countries with high rates of consanguinity. More recently, SPG15 has been reported in populations with low rates of consanguinity, often associated with compound heterozygous variants.
• Thinning of the corpus callosum
• Signal abnormalities of the periventricular white matter
• Cerebral and/or cerebellar atrophy
• Seizures are uncommon.
• Sensorineural hearing impairment is found in a subset of individuals.
• Uncomplicated (or "pure") HSP is characterized by progressive lower-extremity spasticity and weakness, bladder dysfunction, and diminution of lower-extremity vibration sensation [
• Complicated HSP, such as SPG15, is characterized by the impairments present in uncomplicated HSP plus other neurologic findings (intellectual disability, extrapyramidal movement disorders, cerebellar dysfunction, peripheral neuropathy, muscle atrophy, seizures, and others).
• Kjellin syndrome refers to a syndrome consisting of retinal degeneration and spastic paraplegia accompanied by cognitive impairment. The clinical description preceded the discovery of the genes now known to be associated with SPG11 and SPG15. Both SPG11 and SPG15 can present with Kjellin syndrome.
## Clinical Description
Spastic paraplegia 15 (SPG15), a form of early-onset complex hereditary spastic paraplegia, is characterized by progressive spasticity that begins in the lower extremities and is associated with several manifestations resulting from central and peripheral nervous system dysfunction (
The following clinical description of SPG15 is based on a review of more than 70 individuals with biallelic pathogenic variants in
Of note, some clinical features may present or progress in an age-dependent manner.
Spastic Paraplegia 15: Frequency of Select Features
Many individuals, over the course of years, become nonambulatory and ultimately require mobility aids or a wheelchair.
Spasticity progresses to involve the upper extremities in some cases, resulting in a spastic tetraplegia, but continues to be more severe in the legs.
Associated complications may include dysphagia, contractures secondary to progressive spasticity, scoliosis, foot deformities, and dysregulation of bladder and bowel function.
Thinning of the corpus callosum
Signal abnormalities of the periventricular white matter
Cerebral and/or cerebellar atrophy
Seizures are uncommon.
Sensorineural hearing impairment is found in a subset of individuals.
• Thinning of the corpus callosum
• Signal abnormalities of the periventricular white matter
• Cerebral and/or cerebellar atrophy
• Seizures are uncommon.
• Sensorineural hearing impairment is found in a subset of individuals.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Nomenclature
Hereditary spastic paraplegia (HSP) is classified clinically as "uncomplicated" (nonsyndromic) or "complicated" (syndromic).
Uncomplicated (or "pure") HSP is characterized by progressive lower-extremity spasticity and weakness, bladder dysfunction, and diminution of lower-extremity vibration sensation [
Complicated HSP, such as SPG15, is characterized by the impairments present in uncomplicated HSP plus other neurologic findings (intellectual disability, extrapyramidal movement disorders, cerebellar dysfunction, peripheral neuropathy, muscle atrophy, seizures, and others).
Kjellin syndrome refers to a syndrome consisting of retinal degeneration and spastic paraplegia accompanied by cognitive impairment. The clinical description preceded the discovery of the genes now known to be associated with SPG11 and SPG15. Both SPG11 and SPG15 can present with Kjellin syndrome.
• Uncomplicated (or "pure") HSP is characterized by progressive lower-extremity spasticity and weakness, bladder dysfunction, and diminution of lower-extremity vibration sensation [
• Complicated HSP, such as SPG15, is characterized by the impairments present in uncomplicated HSP plus other neurologic findings (intellectual disability, extrapyramidal movement disorders, cerebellar dysfunction, peripheral neuropathy, muscle atrophy, seizures, and others).
• Kjellin syndrome refers to a syndrome consisting of retinal degeneration and spastic paraplegia accompanied by cognitive impairment. The clinical description preceded the discovery of the genes now known to be associated with SPG11 and SPG15. Both SPG11 and SPG15 can present with Kjellin syndrome.
## Prevalence
SPG15 is rare. To date about 75 individuals have been reported.
Families with SPG15 have been reported from North America, Europe, the Middle East, Indian subcontinent, East Asia, and South America. Many affected individuals have a history of consanguinity; however, this could be the result of ascertainment bias, as initial reports have mainly focused on families from countries with high rates of consanguinity. More recently, SPG15 has been reported in populations with low rates of consanguinity, often associated with compound heterozygous variants.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
SPG15 is one of the more common forms of complex hereditary spastic paraplegia with onset typically during childhood or adolescence. The initial clinical presentation of SPG15 is often nonspecific.
A clinical differential diagnosis, after exclusion of acquired causes of spasticity, is best built on the combination of spasticity and neuroimaging findings. The most common neuroimaging findings:
Thinning of the corpus callosum
Signal abnormalities of the periventricular white matter
Cerebral and/or cerebellar atrophy
While these findings are not specific, they can help guide a differential diagnosis. A thin corpus callosum is found in a number of hereditary spastic paraplegias. In SPG15, thinning of the corpus callosum tends to be identified in the anterior parts, in contrast to the
Similar to
In addition to SPG11, overlapping clinical features exist with other forms of complex hereditary spastic paraplegia associated with thinning of the corpus callosum (see
Autosomal Recessive Hereditary Spastic Paraplegias Associated with Thin Corpus Callosum (HSP-TCC) in the Differential Diagnosis of Spastic Paraplegia 15
DD/ID = developmental delay / intellectual disability; SPG = spastic paraplegia
See
See also
• Thinning of the corpus callosum
• Signal abnormalities of the periventricular white matter
• Cerebral and/or cerebellar atrophy
## Management
No clinical practice guidelines for spastic paraplegia 15 (SPG15) have been published.
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 15 (SPG15), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 15
Clinical assessment may incl the Spastic Paraplegia Rating Scale
Brain MRI (if not performed at diagnosis)
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Formal assessment of intellectual abilities
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
DD/ID = developmental delay / intellectual disability; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Dystonia and/or parkinsonism
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
At present, no treatment prevents, halts, or reverses neuronal degeneration in SPG15. Treatment is directed at reducing symptoms and preventing secondary complications. Multidisciplinary care involving a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, speech and language pathologist, and feeding team is recommended.
Treatment of Manifestations in Individuals with Spastic Paraplegia 15
PT
Antispasticity medications (oral or intrathecal baclofen & others)
Botulinum toxin injections
Surgical treatment
Progression of contractures, scoliosis, foot deformities, & loss of ambulation may be delayed w/PT & antispasticity treatment.
Consider need for positioning & mobility devices.
Monitor skin integrity.
PT
Referral to orthopedic surgery
Variable response; evidence is limited.
Assess treatment response w/Unified Parkinson's Disease Rating Scale.
Botulinum toxin injections for focal dystonia
Anti-dystonia medications
PT, OT
Consultation w/social worker
Therapy by speech & language therapist
Anticholinergic agents for sialorrhea
G-tube feeds
Anticholinergic drugs for urinary urgency
Referral to urologist
Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Proton pump inhibitors, histamine receptor antagonists, or antacids as needed
Consideration of fundoplication in refractory cases
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing.
Referral to palliative care when deemed appropriate by family & health care providers
DD/ID = developmental delay / intellectual disability; GER = gastroesophageal reflux; OT = occupational therapy; PT = physical therapy
Affected individuals should be evaluated periodically (i.e., every 6-12 months) by an interdisciplinary team that may include a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech and language pathologist, and feeding team to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations.
Recommended Surveillance for Individuals with Spastic Paraplegia 15
PT/OT eval
Monitor for musculoskeletal complications of spasticity.
Hip/spine x-rays as needed
Eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia or aspiration risk.
Monitor bladder function.
Monitor for urinary tract infections.
Urodynamic testing
OT = occupational therapy; PT = physical therapy
See
Search
• Clinical assessment may incl the Spastic Paraplegia Rating Scale
• Brain MRI (if not performed at diagnosis)
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Formal assessment of intellectual abilities
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• PT
• Antispasticity medications (oral or intrathecal baclofen & others)
• Botulinum toxin injections
• Surgical treatment
• Progression of contractures, scoliosis, foot deformities, & loss of ambulation may be delayed w/PT & antispasticity treatment.
• Consider need for positioning & mobility devices.
• Monitor skin integrity.
• PT
• Referral to orthopedic surgery
• Variable response; evidence is limited.
• Assess treatment response w/Unified Parkinson's Disease Rating Scale.
• Botulinum toxin injections for focal dystonia
• Anti-dystonia medications
• PT, OT
• Consultation w/social worker
• Therapy by speech & language therapist
• Anticholinergic agents for sialorrhea
• G-tube feeds
• Anticholinergic drugs for urinary urgency
• Referral to urologist
• Stool softeners, prokinetics, osmotic agents, or laxatives as needed
• Proton pump inhibitors, histamine receptor antagonists, or antacids as needed
• Consideration of fundoplication in refractory cases
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing.
• Referral to palliative care when deemed appropriate by family & health care providers
• PT/OT eval
• Monitor for musculoskeletal complications of spasticity.
• Hip/spine x-rays as needed
• Eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia or aspiration risk.
• Monitor bladder function.
• Monitor for urinary tract infections.
• Urodynamic testing
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 15 (SPG15), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 15
Clinical assessment may incl the Spastic Paraplegia Rating Scale
Brain MRI (if not performed at diagnosis)
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Formal assessment of intellectual abilities
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
DD/ID = developmental delay / intellectual disability; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Dystonia and/or parkinsonism
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Clinical assessment may incl the Spastic Paraplegia Rating Scale
• Brain MRI (if not performed at diagnosis)
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Formal assessment of intellectual abilities
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
At present, no treatment prevents, halts, or reverses neuronal degeneration in SPG15. Treatment is directed at reducing symptoms and preventing secondary complications. Multidisciplinary care involving a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, speech and language pathologist, and feeding team is recommended.
Treatment of Manifestations in Individuals with Spastic Paraplegia 15
PT
Antispasticity medications (oral or intrathecal baclofen & others)
Botulinum toxin injections
Surgical treatment
Progression of contractures, scoliosis, foot deformities, & loss of ambulation may be delayed w/PT & antispasticity treatment.
Consider need for positioning & mobility devices.
Monitor skin integrity.
PT
Referral to orthopedic surgery
Variable response; evidence is limited.
Assess treatment response w/Unified Parkinson's Disease Rating Scale.
Botulinum toxin injections for focal dystonia
Anti-dystonia medications
PT, OT
Consultation w/social worker
Therapy by speech & language therapist
Anticholinergic agents for sialorrhea
G-tube feeds
Anticholinergic drugs for urinary urgency
Referral to urologist
Stool softeners, prokinetics, osmotic agents, or laxatives as needed
Proton pump inhibitors, histamine receptor antagonists, or antacids as needed
Consideration of fundoplication in refractory cases
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement &/or home nursing.
Referral to palliative care when deemed appropriate by family & health care providers
DD/ID = developmental delay / intellectual disability; GER = gastroesophageal reflux; OT = occupational therapy; PT = physical therapy
• PT
• Antispasticity medications (oral or intrathecal baclofen & others)
• Botulinum toxin injections
• Surgical treatment
• Progression of contractures, scoliosis, foot deformities, & loss of ambulation may be delayed w/PT & antispasticity treatment.
• Consider need for positioning & mobility devices.
• Monitor skin integrity.
• PT
• Referral to orthopedic surgery
• Variable response; evidence is limited.
• Assess treatment response w/Unified Parkinson's Disease Rating Scale.
• Botulinum toxin injections for focal dystonia
• Anti-dystonia medications
• PT, OT
• Consultation w/social worker
• Therapy by speech & language therapist
• Anticholinergic agents for sialorrhea
• G-tube feeds
• Anticholinergic drugs for urinary urgency
• Referral to urologist
• Stool softeners, prokinetics, osmotic agents, or laxatives as needed
• Proton pump inhibitors, histamine receptor antagonists, or antacids as needed
• Consideration of fundoplication in refractory cases
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement &/or home nursing.
• Referral to palliative care when deemed appropriate by family & health care providers
## Surveillance
Affected individuals should be evaluated periodically (i.e., every 6-12 months) by an interdisciplinary team that may include a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech and language pathologist, and feeding team to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations.
Recommended Surveillance for Individuals with Spastic Paraplegia 15
PT/OT eval
Monitor for musculoskeletal complications of spasticity.
Hip/spine x-rays as needed
Eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in those w/dysphagia or aspiration risk.
Monitor bladder function.
Monitor for urinary tract infections.
Urodynamic testing
OT = occupational therapy; PT = physical therapy
• PT/OT eval
• Monitor for musculoskeletal complications of spasticity.
• Hip/spine x-rays as needed
• Eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in those w/dysphagia or aspiration risk.
• Monitor bladder function.
• Monitor for urinary tract infections.
• Urodynamic testing
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spastic paraplegia 15 (SPG15) 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 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 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 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 affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Spastic paraplegia 15 (SPG15) 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 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 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
• 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 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
Cambridge House
27 Cambridge Park
London E11 2PU
United Kingdom
Associazione Italiana Vivere la Paraparesi Spastica
Italy
Australia
Tom Wahlig Stiftung
Germany
•
• Cambridge House
• 27 Cambridge Park
• London E11 2PU
• United Kingdom
•
•
• Associazione Italiana Vivere la Paraparesi Spastica
• Italy
•
•
• Australia
•
•
•
•
•
•
• Tom Wahlig Stiftung
• Germany
•
## Molecular Genetics
Spastic Paraplegia 15: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spastic Paraplegia 15 (
The ZFYVE26 protein, also known as spastizin, associates with the SPG11 protein and the adaptor protein complex 5 (AP-5) [
ZFYVE26 is required for generating mature autophagosomes, a process that is impaired when the protein is defective or absent [
## Molecular Pathogenesis
The ZFYVE26 protein, also known as spastizin, associates with the SPG11 protein and the adaptor protein complex 5 (AP-5) [
ZFYVE26 is required for generating mature autophagosomes, a process that is impaired when the protein is defective or absent [
## Chapter Notes
For inquiries about research on SPG15, the authors suggest the foundations/organizations in
The authors are grateful to their patients and their families who participate in research. Research on hereditary spastic paraplegia by DE-F is supported by grants from the Spastic Paraplegia Foundation Inc, Cure AP-4 Foundation Inc, CureSPG50 Foundation, and a joint research agreement with Astellas Pharmaceuticals.
27 May 2021 (bp) Review posted live
22 February 2021 (def) Original submission
• 27 May 2021 (bp) Review posted live
• 22 February 2021 (def) Original submission
## Author Notes
For inquiries about research on SPG15, the authors suggest the foundations/organizations in
## Acknowledgments
The authors are grateful to their patients and their families who participate in research. Research on hereditary spastic paraplegia by DE-F is supported by grants from the Spastic Paraplegia Foundation Inc, Cure AP-4 Foundation Inc, CureSPG50 Foundation, and a joint research agreement with Astellas Pharmaceuticals.
## Revision History
27 May 2021 (bp) Review posted live
22 February 2021 (def) Original submission
• 27 May 2021 (bp) Review posted live
• 22 February 2021 (def) Original submission
## References
## Literature Cited
Ears of the lynx sign in SPG15
Axial T
|
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"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 Schicks, M Synofzik, H Petursson, J Huttenlocher, M Reimold, L Schöls, P Bauer. Atypical juvenile parkinsonism in a consanguineous SPG15 family.. Mov Disord. 2011;26:564-6",
"R Schüle, T Holland-Letz, S Klimpe, J Kassubek, T Klopstock, V Mall, S Otto, B Winner, L. Schöls. The Spastic Paraplegia Rating Scale (SPRS): a reliable and valid measure of disease severity.. Neurology. 2006;67:430-4",
"R Schüle, N Schlipf, M Synofzik, S Klebe, S Klimpe, U Hehr, B Winner, T Lindig, A Dotzer, O Riess, J Winkler, L Schöls, P Bauer. Frequency and phenotype of SPG11 and SPG15 in complicated hereditary spastic paraplegia.. J Neurol Neurosurg Psychiatry. 2009;80:1402-4",
"S Srivastava, A D'Amore, JS Cohen, LC Swanson, I Ricca, A Pini, A Fatemi, D Ebrahimi-Fakhari, FM Santorelli. Expansion of the genetic landscape of ERLIN2-related disorders.. Ann Clin Transl Neurol. 2020;7:573-8",
"C Vantaggiato, C Crimella, G Airoldi, R Polishchuk, S Bonato, E Brighina, M Scarlato, O Musumeci, A Toscano, A Martinuzzi, FM Santorelli, A Ballabio, N Bresolin, E Clementi, MT Bassi. Defective autophagy in spastizin mutated patients with hereditary spastic paraparesis type 15.. Brain. 2013;136:3119-39",
"M Vinci, M Fchera, S Antonino Musumeci, F Cali, G. Aurelio Vitello. Novel c.C2254T (p.Q752*) mutation in ZFYVE26 (SPG15) gene in a patient with hereditary spastic paraparesis.. J Genet. 2018;97:1469-72",
"G Yoon, B Baskin, M Tarnopolsky, KM Boycott, MT Geraghty, E Sell, S Goobie, W Meschino, B Banwell, PN Ray. Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort.. Neurogenetics. 2013;14:181-8"
] |
27/5/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
spg17
|
spg17
|
[
"Spastic Paraplegia 17",
"Silver Syndrome",
"Distal Hereditary Motor Neuropathy Type V (dHMN-V)",
"Variants of Charcot-Marie-Tooth Disease Type 2",
"Seipin",
"BSCL2",
"BSCL2-Related Neurologic Disorders/Seipinopathy"
] |
Daisuke Ito
|
Summary The spectrum of The diagnosis of a
|
Distal hereditary motor neuropathy type V (dHMN-V)
Silver syndrome
Variants of Charcot-Marie-Tooth disease type 2
Spastic paraplegia 17
For other genetic causes of these phenotypes see
• Distal hereditary motor neuropathy type V (dHMN-V)
• Silver syndrome
• Variants of Charcot-Marie-Tooth disease type 2
• Spastic paraplegia 17
## Diagnosis
The phenotypic spectrum of
Onset of symptoms from the first to seventh decade (range: age 6-66 years; mean: age 19 years)
Slow disease progression
Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and 1st dorsal interosseus muscles) that is frequently unilateral
Paresthesia, sensory loss, and sphincter disturbances usually absent
Note: In the upper limbs, changes of the MNCV and CMAP are more frequently seen in the median nerve than in the ulnar nerve.
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 [
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
When the phenotypic and laboratory findings suggest the diagnosis of
Note: All reported pathogenic variants (
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 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
Because this disorder is defined by the presence of a causative pathogenic variant 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.
• Onset of symptoms from the first to seventh decade (range: age 6-66 years; mean: age 19 years)
• Slow disease progression
• Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
• Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and 1st dorsal interosseus muscles) that is frequently unilateral
• Paresthesia, sensory loss, and sphincter disturbances usually absent
• Note: In the upper limbs, changes of the MNCV and CMAP are more frequently seen in the median nerve than in the ulnar nerve.
• Note: All reported pathogenic variants (
• For an introduction to multigene panels click
## Suggestive Findings
Onset of symptoms from the first to seventh decade (range: age 6-66 years; mean: age 19 years)
Slow disease progression
Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and 1st dorsal interosseus muscles) that is frequently unilateral
Paresthesia, sensory loss, and sphincter disturbances usually absent
Note: In the upper limbs, changes of the MNCV and CMAP are more frequently seen in the median nerve than in the ulnar nerve.
• Onset of symptoms from the first to seventh decade (range: age 6-66 years; mean: age 19 years)
• Slow disease progression
• Upper motor neuron involvement: gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses
• Lower motor neuron involvement: amyotrophy (wasting) of the peroneal muscles and the small muscles of the hand (particularly the thenar and 1st dorsal interosseus muscles) that is frequently unilateral
• Paresthesia, sensory loss, and sphincter disturbances usually absent
• Note: In the upper limbs, changes of the MNCV and CMAP are more frequently seen in the median nerve than in the ulnar nerve.
## 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 [
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
When the phenotypic and laboratory findings suggest the diagnosis of
Note: All reported pathogenic variants (
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 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
Because this disorder is defined by the presence of a causative pathogenic variant 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.
• Note: All reported pathogenic variants (
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
Note: All reported pathogenic variants (
For an introduction to multigene panels click
• Note: All reported pathogenic variants (
• 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 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
Because this disorder is defined by the presence of a causative pathogenic variant 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
Pure hereditary spastic paraparesis (pHSP) when no additional clinical or electrophysiologic features (except foot deformity) are present
Complicated hereditary spastic paraparesis (cHSP) when spasticity is accompanied by amyotrophy of the distal muscles of the legs and/or pathologic nerve conduction velocities. This latter group may also be diagnosed as hereditary motor and sensory neuropathy (HMSN) type V.
Affected individuals often present with other signs of pyramidal tract involvement such as extensor plantar responses. Individuals with spasticity in the lower limbs often complain of leg stiffness and muscle cramps.
Wasting and weakness of the distal muscles of the lower limbs leading to a steppage gait
Stiffness and spasticity
Individuals with the
Individuals with the
Pathogenic variant
A variant of unknown significance (
Note: (1) Pathogenic null variants in
Reduced penetrance for
Silver syndrome was first described in 1966 in two British families [
The prevalence of
• Pure hereditary spastic paraparesis (pHSP) when no additional clinical or electrophysiologic features (except foot deformity) are present
• Complicated hereditary spastic paraparesis (cHSP) when spasticity is accompanied by amyotrophy of the distal muscles of the legs and/or pathologic nerve conduction velocities. This latter group may also be diagnosed as hereditary motor and sensory neuropathy (HMSN) type V.
• Wasting and weakness of the distal muscles of the lower limbs leading to a steppage gait
• Stiffness and spasticity
## Clinical Description
Pure hereditary spastic paraparesis (pHSP) when no additional clinical or electrophysiologic features (except foot deformity) are present
Complicated hereditary spastic paraparesis (cHSP) when spasticity is accompanied by amyotrophy of the distal muscles of the legs and/or pathologic nerve conduction velocities. This latter group may also be diagnosed as hereditary motor and sensory neuropathy (HMSN) type V.
Affected individuals often present with other signs of pyramidal tract involvement such as extensor plantar responses. Individuals with spasticity in the lower limbs often complain of leg stiffness and muscle cramps.
Wasting and weakness of the distal muscles of the lower limbs leading to a steppage gait
Stiffness and spasticity
• Pure hereditary spastic paraparesis (pHSP) when no additional clinical or electrophysiologic features (except foot deformity) are present
• Complicated hereditary spastic paraparesis (cHSP) when spasticity is accompanied by amyotrophy of the distal muscles of the legs and/or pathologic nerve conduction velocities. This latter group may also be diagnosed as hereditary motor and sensory neuropathy (HMSN) type V.
• Wasting and weakness of the distal muscles of the lower limbs leading to a steppage gait
• Stiffness and spasticity
## Genotype-Phenotype Correlations
Individuals with the
Individuals with the
Pathogenic variant
A variant of unknown significance (
Note: (1) Pathogenic null variants in
## Penetrance
Reduced penetrance for
## Nomenclature
Silver syndrome was first described in 1966 in two British families [
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
In addition to
Exon 7 skipping in
## Differential Diagnosis
ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
SPG3A, caused by pathogenic variants in
Charcot-Marie-Tooth neuropathy type 2 (See
Spinal CMT (dHMN II) caused by pathogenic variants in
ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
Acquired motor neuron disorders (e.g., multifocal motor neuropathy, amyotrophic lateral sclerosis)
Entrapment syndromes of the upper extremities (e.g., carpal tunnel syndrome, compression of ulnar nerve)
•
• ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
• SPG3A, caused by pathogenic variants in
• ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
• SPG3A, caused by pathogenic variants in
•
• Charcot-Marie-Tooth neuropathy type 2 (See
• Spinal CMT (dHMN II) caused by pathogenic variants in
• ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
• Charcot-Marie-Tooth neuropathy type 2 (See
• Spinal CMT (dHMN II) caused by pathogenic variants in
• ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
• ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
• SPG3A, caused by pathogenic variants in
• Charcot-Marie-Tooth neuropathy type 2 (See
• Spinal CMT (dHMN II) caused by pathogenic variants in
• ALS4 (juvenile-onset motor neuron disease) caused by pathogenic variants in
• Acquired motor neuron disorders (e.g., multifocal motor neuropathy, amyotrophic lateral sclerosis)
• Entrapment syndromes of the upper extremities (e.g., carpal tunnel syndrome, compression of ulnar nerve)
## Management
To establish the extent of disease and needs in an individual diagnosed with
Physical examination to determine extent of weakness and atrophy,
EMG with NCV
Complete family history
Consultation with a clinical geneticist and/or genetic counselor
Treatment remains symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, clinical geneticists, and physical and occupational therapists.
Physiotherapy is appropriate.
Orthopedic treatment includes orthopedic shoes and calipers (polypropylene devices that fit between the thighs and hold the legs and hips in a balanced position for standing, used in conjunction with crutches or a walker) to stabilize gait. Foot deformities are corrected surgically.
Early regular physiotherapy can prevent contractures to a certain extent.
Annual neurologic evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist is appropriate.
See
Search
• Physical examination to determine extent of weakness and atrophy,
• EMG with NCV
• Complete family history
• 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
Physical examination to determine extent of weakness and atrophy,
EMG with NCV
Complete family history
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination to determine extent of weakness and atrophy,
• EMG with NCV
• Complete family history
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment remains symptomatic and affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, clinical geneticists, and physical and occupational therapists.
Physiotherapy is appropriate.
Orthopedic treatment includes orthopedic shoes and calipers (polypropylene devices that fit between the thighs and hold the legs and hips in a balanced position for standing, used in conjunction with crutches or a walker) to stabilize gait. Foot deformities are corrected surgically.
## Prevention of Secondary Complications
Early regular physiotherapy can prevent contractures to a certain extent.
## Surveillance
Annual neurologic evaluation of gait, strength, muscular atrophy, and deep tendon reflexes by a neurologist is appropriate.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with a
A proband with a
Molecular genetic testing is recommended for the parents of a proband with an apparent
The family history of some individuals diagnosed with a
If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
If a parent is affected/known to have 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.
Once the 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 in North America would consider use of prenatal testing to be personal decision, discussion of these issues may be helpful. In Europe and other parts of the world, prenatal testing may be discouraged if treatment is not available.
• Most individuals diagnosed with a
• A proband with a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• The family history of some individuals diagnosed with a
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• If a parent is affected/known to have 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
## Risk to Family Members
Most individuals diagnosed with a
A proband with a
Molecular genetic testing is recommended for the parents of a proband with an apparent
The family history of some individuals diagnosed with a
If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
If a parent is affected/known to have the
If the
If the parents have not been tested for the
• Most individuals diagnosed with a
• A proband with a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• The family history of some individuals diagnosed with a
• If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.
• If a parent is affected/known to have the
• 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 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.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers in North America would consider use of prenatal testing to be personal decision, discussion of these issues may be helpful. In Europe and other parts of the world, prenatal testing may be discouraged if treatment is not available.
## Resources
•
•
•
•
•
•
## Molecular Genetics
BSCL2-Related Neurologic Disorders / Seipinopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for BSCL2-Related Neurologic Disorders / Seipinopathy (
Note: Exon 7 skipping due to pathogenic variant c.985C>T results in an autosomal recessive early-onset progressive encephalopathy (OMIM
Variants listed in the table have been provided by the author.
## Chapter Notes
Michaela Auer-Grumbach, MD; Medical University Graz (2005-2009)Daisuke Ito, MD, PhD (2009-present)Klaus Wagner, MD, PhD; Medical University Graz (2005-2009)
24 May 2018 (sw) Comprehensive update posted live
7 June 2012 (cd) Revision: targeted mutation analysis no longer offered clinically
15 September 2011 (me) Comprehensive update posted live
3 September 2009 (me) Comprehensive update posted live
6 December 2005 (me) Review posted live
2 February 2005 (kw) Original submission
• 24 May 2018 (sw) Comprehensive update posted live
• 7 June 2012 (cd) Revision: targeted mutation analysis no longer offered clinically
• 15 September 2011 (me) Comprehensive update posted live
• 3 September 2009 (me) Comprehensive update posted live
• 6 December 2005 (me) Review posted live
• 2 February 2005 (kw) Original submission
## Author History
Michaela Auer-Grumbach, MD; Medical University Graz (2005-2009)Daisuke Ito, MD, PhD (2009-present)Klaus Wagner, MD, PhD; Medical University Graz (2005-2009)
## Revision History
24 May 2018 (sw) Comprehensive update posted live
7 June 2012 (cd) Revision: targeted mutation analysis no longer offered clinically
15 September 2011 (me) Comprehensive update posted live
3 September 2009 (me) Comprehensive update posted live
6 December 2005 (me) Review posted live
2 February 2005 (kw) Original submission
• 24 May 2018 (sw) Comprehensive update posted live
• 7 June 2012 (cd) Revision: targeted mutation analysis no longer offered clinically
• 15 September 2011 (me) Comprehensive update posted live
• 3 September 2009 (me) Comprehensive update posted live
• 6 December 2005 (me) Review posted live
• 2 February 2005 (kw) Original submission
## References
## Literature Cited
|
[
"M Auer-Grumbach, WN Loscher, K Wagner, E Petek, E Korner, H Offenbacher, HP Hartung. Phenotypic and genotypic heterogeneity in hereditary motor neuronopathy type V: a clinical, electrophysiological and genetic study.. Brain 2000;123:1612-23",
"M Auer-Grumbach, B Schlotter-Weigel, H Lochmuller, G Strobl-Wildemann, P Auer-Grumbach, R Fischer, H Offenbacher, EB Zwick, T Robl, G Hartl, HP Hartung, K Wagner, C Windpassinger. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation.. Ann Neurol 2005;57:415-24",
"B Chen, R Zheng, X Luan, W Zhang, Z Wang, Y Yuan. Clinical and pathological study of distal motor neuropathy with N88S mutation in BSCL2.. Neuropathology. 2009;29:543-7",
"BO Choi, MH Park, KW Chung, HM Woo, H Koo, HK Chung, KG Choi, KD Park, HJ Lee, YS Hyun, SK Koo. Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.. Neurogenetics. 2013;14:35-42",
"I Dierick, J Baets, J Irobi, A Jacobs, E De Vriendt, T Deconinck, L Merlini, P Van den Bergh, VM Rasic, W Robberecht, D Fischer, RJ Morales, Z Mitrovic, P Seeman, R Mazanec, A Kochanski, A Jordanova, M Auer-Grumbach, AT Helderman-van den Enden, JH Wokke, E Nelis, P De Jonghe, V Timmerman. Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study.. Brain 2008;131:1217-27",
"W Fei, X Du, H Yang. Seipin, adipogenesis and lipid droplets.. Trends Endocrinol Metab. 2011;22:204-10",
"CT Hsiao, PC Tsai, CC Lin, YT Liu, YH Huang, YC Liao, HW Huang, KP Lin, BW Soong, YC Lee. Clinical and molecular characterization of BSCL2 mutations in a Taiwanese cohort with hereditary neuropathy.. PLoS One. 2016;11",
"J Irobi, P Van den Bergh, L Merlini, C Verellen, L Van Maldergem, I Dierick, N Verpoorten, A Jordanova, C Windpassinger, E De Vriendt, V Van Gerwen, M Auer-Grumbach, K Wagner, V Timmerman, P De Jonghe. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V.. Brain. 2004;127:2124-30",
"D Ito, N Suzuki. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.. Ann Neurol. 2007;61:237-50",
"D Ito, N Suzuki. Seipinopathy: a novel endoplasmic reticulum stress-associated disease.. Brain. 2009;132:8-15",
"M Luigetti, GM Fabrizi, F Madia, M Ferrarini, A Conte, A Delgrande, PA Tonali, M Sabatelli. Seipin S90L mutation in an Italian family with CMT2/dHMN and pyramidal signs.. Muscle Nerve. 2010;42:448-51",
"H Patel, PE Hart, TT Warner, RS Houlston, MA Patton, S Jeffery, AH Crosby. The Silver syndrome variant of hereditary spastic paraplegia maps to chromosome 11q12-q14, with evidence for genetic heterogeneity within this subtype.. Am J Hum Genet. 2001;69:209-15",
"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",
"JR Silver. Familial spastic paraplegia with amyotrophy of the hands.. Ann Hum Genet. 1966;30:69-75",
"C Windpassinger, K Wagner, E Petek, R Fischer, M Auer-Grumbach. Refinement of the Silver syndrome locus on chromosome 11q12-q14 in four families and exclusion of eight candidate genes.. Hum Genet. 2003;114:99-109",
"T Yagi, D Ito, Y Nihei, T Ishihara, N Suzuki. N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress.. Hum Mol Genet. 2011;20:3831-40"
] |
6/12/2005
|
24/5/2018
|
7/6/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
spg20
|
spg20
|
[
"SPART-Related Hereditary Spastic Paraplegia (SPART-HSP)",
"SPG20",
"SPG20",
"SPART-Related Hereditary Spastic Paraplegia (SPART-HSP)",
"Spartin",
"SPART",
"Troyer Syndrome"
] |
Troyer Syndrome
|
Emma Baple, Jacob Day, Allison Newman, Andrew Crosby
|
Summary Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, short stature, and subtle skeletal abnormalities. Most affected children exhibit delays in walking and speech and difficulty in managing oral secretions, followed by increased lower-limb spasticity and slow deterioration in both gait and speech. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. Emotional lability / difficulty in controlling emotions and affective disorders such as inappropriate euphoria and/or crying are frequently described. Life expectancy is normal. The diagnosis of Troyer syndrome is established in a proband with characteristic clinical findings and/or biallelic pathogenic variants in Troyer syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for Troyer syndrome have been published.
Troyer syndrome
Developmental delay in early infancy / childhood: poor feeding, swallowing difficulties, delayed speech, delayed walking
Childhood-onset spastic paraplegia
Symmetric amyotrophy of the small muscles of hands and feet
Progressive dysarthria and persistent drooling
Learning difficulties
Emotional lability
Short stature
At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape
Pyramidal signs: hyperreflexia, extensor plantar responses
Extrapyramidal signs: mild choreoathetoid movements
Cerebellar signs: dysdiadochokinesia, mild intention tremor, ataxia
Skeletal abnormalities: pes cavus, pes planus, mild talipes equinovarus, kyphoscoliosis, pectus carinatum
The diagnosis of Troyer syndrome
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 a combination of
When the phenotypic and imaging findings suggest the diagnosis of Troyer syndrome, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variant
For an introduction to multigene panels click
When the diagnosis of Troyer syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Troyer 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
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 large intragenic deletions/duplications have been reported in individuals with Troyer syndrome.
• Developmental delay in early infancy / childhood: poor feeding, swallowing difficulties, delayed speech, delayed walking
• Childhood-onset spastic paraplegia
• Symmetric amyotrophy of the small muscles of hands and feet
• Progressive dysarthria and persistent drooling
• Learning difficulties
• Emotional lability
• Short stature
• At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape
• Pyramidal signs: hyperreflexia, extensor plantar responses
• Extrapyramidal signs: mild choreoathetoid movements
• Cerebellar signs: dysdiadochokinesia, mild intention tremor, ataxia
• Skeletal abnormalities: pes cavus, pes planus, mild talipes equinovarus, kyphoscoliosis, pectus carinatum
• Note: Targeted analysis for pathogenic variant
• For an introduction to multigene panels click
## Suggestive Findings
Troyer syndrome
Developmental delay in early infancy / childhood: poor feeding, swallowing difficulties, delayed speech, delayed walking
Childhood-onset spastic paraplegia
Symmetric amyotrophy of the small muscles of hands and feet
Progressive dysarthria and persistent drooling
Learning difficulties
Emotional lability
Short stature
At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape
Pyramidal signs: hyperreflexia, extensor plantar responses
Extrapyramidal signs: mild choreoathetoid movements
Cerebellar signs: dysdiadochokinesia, mild intention tremor, ataxia
Skeletal abnormalities: pes cavus, pes planus, mild talipes equinovarus, kyphoscoliosis, pectus carinatum
• Developmental delay in early infancy / childhood: poor feeding, swallowing difficulties, delayed speech, delayed walking
• Childhood-onset spastic paraplegia
• Symmetric amyotrophy of the small muscles of hands and feet
• Progressive dysarthria and persistent drooling
• Learning difficulties
• Emotional lability
• Short stature
• At birth: low/low-normal birth weight, relative macrocephaly, triangular face shape
• Pyramidal signs: hyperreflexia, extensor plantar responses
• Extrapyramidal signs: mild choreoathetoid movements
• Cerebellar signs: dysdiadochokinesia, mild intention tremor, ataxia
• Skeletal abnormalities: pes cavus, pes planus, mild talipes equinovarus, kyphoscoliosis, pectus carinatum
## Establishing the Diagnosis
The diagnosis of Troyer syndrome
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 a combination of
When the phenotypic and imaging findings suggest the diagnosis of Troyer syndrome, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variant
For an introduction to multigene panels click
When the diagnosis of Troyer syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Troyer 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
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 large intragenic deletions/duplications have been reported in individuals with Troyer syndrome.
• Note: Targeted analysis for pathogenic variant
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of Troyer syndrome, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variant
For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variant
• For an introduction to multigene panels click
## Option 2
When the diagnosis of Troyer syndrome is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Troyer 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
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 large intragenic deletions/duplications have been reported in individuals with Troyer syndrome.
## Clinical Characteristics
Troyer syndrome is characterized by both developmental and neurodegenerative processes. Symptoms are usually apparent in early childhood and progress slowly. The cardinal features of Troyer syndrome include global developmental delay, spastic paraparesis, distal amyotrophy, dysarthria, persistent drooling, learning difficulties, emotional lability, and skeletal manifestations including short stature [
Progressive spastic dysarthria has been reported with brisk jaw jerk, often accompanied by slow, spastic tongue movements. Excessive drooling is commonly observed in childhood and persists into adulthood in the most severely affected individuals [
Microcephaly and macrocephaly have both been reported [
Short stature when compared to parents and/or sibs [
Overgrowth of the maxilla leading to overbite (5/6 individuals) [
Small feet with pes cavus (17/21 individuals) [
"Hammer toes" in the most severely affected individuals [
Hyperextensible proximal interphalangeal joints of the fingers (8/21) [
Brachydactyly (5/6 individuals), clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges [
Mild knee valgus (4/21) [
Mild kyphoscoliosis has been reported but radiographic correlation was not available [
Pectus carinatum [
Delayed bone age [
No clinically relevant genotype-phenotype correlations have been observed.
A previous study documented 21 individuals with Troyer syndrome in a population of approximately 50,000 Old Order Amish in Ohio [
Troyer syndrome has now been reported in several additional individuals worldwide. A recurrent variant was identified in affected individuals from Omani, Turkish, and Filipino families (see
The estimated worldwide prevalence is less than one in 10,000,000 [
• Short stature when compared to parents and/or sibs [
• Overgrowth of the maxilla leading to overbite (5/6 individuals) [
• Small feet with pes cavus (17/21 individuals) [
• "Hammer toes" in the most severely affected individuals [
• Hyperextensible proximal interphalangeal joints of the fingers (8/21) [
• Brachydactyly (5/6 individuals), clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges [
• Mild knee valgus (4/21) [
• Mild kyphoscoliosis has been reported but radiographic correlation was not available [
• Pectus carinatum [
• Delayed bone age [
## Clinical Description
Troyer syndrome is characterized by both developmental and neurodegenerative processes. Symptoms are usually apparent in early childhood and progress slowly. The cardinal features of Troyer syndrome include global developmental delay, spastic paraparesis, distal amyotrophy, dysarthria, persistent drooling, learning difficulties, emotional lability, and skeletal manifestations including short stature [
Progressive spastic dysarthria has been reported with brisk jaw jerk, often accompanied by slow, spastic tongue movements. Excessive drooling is commonly observed in childhood and persists into adulthood in the most severely affected individuals [
Microcephaly and macrocephaly have both been reported [
Short stature when compared to parents and/or sibs [
Overgrowth of the maxilla leading to overbite (5/6 individuals) [
Small feet with pes cavus (17/21 individuals) [
"Hammer toes" in the most severely affected individuals [
Hyperextensible proximal interphalangeal joints of the fingers (8/21) [
Brachydactyly (5/6 individuals), clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges [
Mild knee valgus (4/21) [
Mild kyphoscoliosis has been reported but radiographic correlation was not available [
Pectus carinatum [
Delayed bone age [
• Short stature when compared to parents and/or sibs [
• Overgrowth of the maxilla leading to overbite (5/6 individuals) [
• Small feet with pes cavus (17/21 individuals) [
• "Hammer toes" in the most severely affected individuals [
• Hyperextensible proximal interphalangeal joints of the fingers (8/21) [
• Brachydactyly (5/6 individuals), clinodactyly, camptodactyly, and hypoplastic fifth middle phalanges [
• Mild knee valgus (4/21) [
• Mild kyphoscoliosis has been reported but radiographic correlation was not available [
• Pectus carinatum [
• Delayed bone age [
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been observed.
## Prevalence
A previous study documented 21 individuals with Troyer syndrome in a population of approximately 50,000 Old Order Amish in Ohio [
Troyer syndrome has now been reported in several additional individuals worldwide. A recurrent variant was identified in affected individuals from Omani, Turkish, and Filipino families (see
The estimated worldwide prevalence is less than one in 10,000,000 [
## Genetically Related Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Troyer syndrome shares some features with Silver syndrome,
Genetic Disorders of Interest in the Differential Diagnosis of Troyer Syndrome
AR = autosomal recessive; MOI = mode of inheritance
Silver-Russell syndrome is caused by abnormal methylation of chromosome 11p15.5, maternal uniparental disomy of chromosome 7, pathogenic gain-of-function variants in
See
## Management
No clinical practice guidelines for Troyer 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 of an individual diagnosed with Troyer syndrome, the evaluations summarized in
Troyer Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech-language eval; incl assessment for dysarthria & tongue dyspraxia
Eval for early intervention / special education
Physical exam for skeletal abnormalities
Radiographs for kyphoscoliosis as needed
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
No specific treatment to prevent or reverse the neurologic degeneration in Troyer syndrome currently exists. Treatments are directed at reducing symptoms, maintaining mobility, and improving balance, strength, and agility. Individuals should be evaluated periodically (annually or as needed) by a neurologist, physiatrist, occupational therapist, and speech-language therapist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms. See also
Troyer Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
Daily PT regimen directed toward maintaining & improving cardiovascular health, muscle strength, & gait & reducing spasticity. These recommendations are based on the experience of ~200 persons w/HSP, who nearly unanimously reported benefit from daily physical exercise.
OT, assistive walking devices, & ankle-foot orthoses as required
Speech-language therapy to improve/maintain speech & swallowing
Communication devices as required
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
HSP = hereditary spastic paraplegia; 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.
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.
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.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Troyer Syndrome: Recommended Surveillance
Measurement of growth parameters
Assess for dysphagia, nutritional status, & safety of oral intake.
Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.
See
Search
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech-language eval; incl assessment for dysarthria & tongue dyspraxia
• Eval for early intervention / special education
• Physical exam for skeletal abnormalities
• Radiographs for kyphoscoliosis as needed
• Community or
• Social work involvement for parental support
• Home nursing referral
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
• Daily PT regimen directed toward maintaining & improving cardiovascular health, muscle strength, & gait & reducing spasticity. These recommendations are based on the experience of ~200 persons w/HSP, who nearly unanimously reported benefit from daily physical exercise.
• OT, assistive walking devices, & ankle-foot orthoses as required
• Speech-language therapy to improve/maintain speech & swallowing
• Communication devices as required
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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
• Assess for dysphagia, nutritional status, & safety of oral intake.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with Troyer syndrome, the evaluations summarized in
Troyer Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech-language eval; incl assessment for dysarthria & tongue dyspraxia
Eval for early intervention / special education
Physical exam for skeletal abnormalities
Radiographs for kyphoscoliosis as needed
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance
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.
• To incl motor, adaptive, cognitive, & speech-language eval; incl assessment for dysarthria & tongue dyspraxia
• Eval for early intervention / special education
• Physical exam for skeletal abnormalities
• Radiographs for kyphoscoliosis as needed
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
No specific treatment to prevent or reverse the neurologic degeneration in Troyer syndrome currently exists. Treatments are directed at reducing symptoms, maintaining mobility, and improving balance, strength, and agility. Individuals should be evaluated periodically (annually or as needed) by a neurologist, physiatrist, occupational therapist, and speech-language therapist to assess progression and develop treatment strategies to maximize walking ability and reduce symptoms. See also
Troyer Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
Daily PT regimen directed toward maintaining & improving cardiovascular health, muscle strength, & gait & reducing spasticity. These recommendations are based on the experience of ~200 persons w/HSP, who nearly unanimously reported benefit from daily physical exercise.
OT, assistive walking devices, & ankle-foot orthoses as required
Speech-language therapy to improve/maintain speech & swallowing
Communication devices as required
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
HSP = hereditary spastic paraplegia; 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.
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.
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.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
• Daily PT regimen directed toward maintaining & improving cardiovascular health, muscle strength, & gait & reducing spasticity. These recommendations are based on the experience of ~200 persons w/HSP, who nearly unanimously reported benefit from daily physical exercise.
• OT, assistive walking devices, & ankle-foot orthoses as required
• Speech-language therapy to improve/maintain speech & swallowing
• Communication devices as required
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
## 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.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Troyer Syndrome: Recommended Surveillance
Measurement of growth parameters
Assess for dysphagia, nutritional status, & safety of oral intake.
• Measurement of growth parameters
• Assess for dysphagia, nutritional status, & safety of oral intake.
## Agents/Circumstances to Avoid
Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely interfere with overall mobility.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Troyer syndrome is inherited in an autosomal recessive manner.
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.
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.
Carrier testing should be considered for the reproductive partners of affected individuals and established carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in the Amish and Mennonite population with Ohio ancestry; a recurrent variant has been identified in Omani, Turkish, and Filipino families (see
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 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 optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
• Carrier testing should be considered for the reproductive partners of affected individuals and established carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in the Amish and Mennonite population with Ohio ancestry; a recurrent variant has been identified in Omani, Turkish, and Filipino families (see
## Mode of Inheritance
Troyer syndrome is inherited in an autosomal recessive manner.
## 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.
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
• 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.
## 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.
Carrier testing should be considered for the reproductive partners of affected individuals and established carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in the Amish and Mennonite population with Ohio ancestry; a recurrent variant has been identified in Omani, Turkish, and Filipino families (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 carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of affected individuals and established carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in the Amish and Mennonite population with Ohio ancestry; a recurrent variant has been identified in Omani, Turkish, and Filipino families (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 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
Troyer Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Troyer Syndrome (
Spartin has been shown to localize to endosomes and lipid droplets, with recent studies confirming it has a critical role in the turnover of both lipid droplets (lipophagy) and damaged lysosomes (lisophagy) [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Spartin has been shown to localize to endosomes and lipid droplets, with recent studies confirming it has a critical role in the turnover of both lipid droplets (lipophagy) and damaged lysosomes (lisophagy) [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Further information on our work with the Amish and Mennonite communities can be found at
Prof Andrew Crosby, Prof Emma Baple, and Dr Jacob Day are actively involved in clinical research regarding individuals with hereditary spastic paraplegia (HSP). They would be happy to communicate with persons who have any questions regarding diagnosis of HSP, Troyer syndrome, or other considerations.
Prof Andrew Crosby, Prof Emma Baple, and Dr Jacob Day are also interested in hearing from clinicians treating families affected by HSP in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
The authors would like to thank the patients and their families as well as the collaborators who have been involved in describing Troyer syndrome. We would also like to thank Dr Olivia Wenger, Dr Ethan Scott, staff at the
Emma Baple, MBBS, MRCPCH, PhD (2019-present)Andrew Crosby, PhD (2004-present)Jacob Day, MRCP, BM BCh, BA (2025-present)Gaurav Harlalka, MRes; University of London (2011-2019)Allison Newman, MSci (2025-present)Heema Patel, PhD; University of London (2004-2019)
14 August 2025 (sw) Comprehensive update posted live
6 June 2019 (sw) Comprehensive update posted live
4 August 2011 (me) Comprehensive update posted live
16 November 2004 (me) Review posted live
11 August 2004 (ac) Original submission
• 14 August 2025 (sw) Comprehensive update posted live
• 6 June 2019 (sw) Comprehensive update posted live
• 4 August 2011 (me) Comprehensive update posted live
• 16 November 2004 (me) Review posted live
• 11 August 2004 (ac) Original submission
## Author Notes
Further information on our work with the Amish and Mennonite communities can be found at
Prof Andrew Crosby, Prof Emma Baple, and Dr Jacob Day are actively involved in clinical research regarding individuals with hereditary spastic paraplegia (HSP). They would be happy to communicate with persons who have any questions regarding diagnosis of HSP, Troyer syndrome, or other considerations.
Prof Andrew Crosby, Prof Emma Baple, and Dr Jacob Day are also interested in hearing from clinicians treating families affected by HSP 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
The authors would like to thank the patients and their families as well as the collaborators who have been involved in describing Troyer syndrome. We would also like to thank Dr Olivia Wenger, Dr Ethan Scott, staff at the
## Author History
Emma Baple, MBBS, MRCPCH, PhD (2019-present)Andrew Crosby, PhD (2004-present)Jacob Day, MRCP, BM BCh, BA (2025-present)Gaurav Harlalka, MRes; University of London (2011-2019)Allison Newman, MSci (2025-present)Heema Patel, PhD; University of London (2004-2019)
## Revision History
14 August 2025 (sw) Comprehensive update posted live
6 June 2019 (sw) Comprehensive update posted live
4 August 2011 (me) Comprehensive update posted live
16 November 2004 (me) Review posted live
11 August 2004 (ac) Original submission
• 14 August 2025 (sw) Comprehensive update posted live
• 6 June 2019 (sw) Comprehensive update posted live
• 4 August 2011 (me) Comprehensive update posted live
• 16 November 2004 (me) Review posted live
• 11 August 2004 (ac) Original submission
## References
## Literature Cited
|
[] |
16/11/2004
|
14/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
spg3a
|
spg3a
|
[
"ATL1-HSP",
"SPG3A",
"SPG3A",
"ATL1-HSP",
"Atlastin-1",
"ATL1",
"Spastic Paraplegia 3A"
] |
Spastic Paraplegia 3A
|
Peter Hedera
|
Summary Spastic paraplegia 3A (SPG3A; also known as The diagnosis of
|
## Diagnosis
Spastic paraplegia 3A (SPG3A; also known as
Early age of onset, from infancy to ten years (average age: 4 years)
Progressive bilateral and mostly symmetric lower-extremity weakness and spasticity resulting from axonal degeneration of the corticospinal tracts
Diminished vibration sense caused by impairment of dorsal columns
Urinary bladder hyperactivity
The diagnosis of
Note: Identification of a heterozygous
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 Spastic Paraplegia 3A
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.
• Early age of onset, from infancy to ten years (average age: 4 years)
• Progressive bilateral and mostly symmetric lower-extremity weakness and spasticity resulting from axonal degeneration of the corticospinal tracts
• Diminished vibration sense caused by impairment of dorsal columns
• Urinary bladder hyperactivity
## Suggestive Findings
Spastic paraplegia 3A (SPG3A; also known as
Early age of onset, from infancy to ten years (average age: 4 years)
Progressive bilateral and mostly symmetric lower-extremity weakness and spasticity resulting from axonal degeneration of the corticospinal tracts
Diminished vibration sense caused by impairment of dorsal columns
Urinary bladder hyperactivity
• Early age of onset, from infancy to ten years (average age: 4 years)
• Progressive bilateral and mostly symmetric lower-extremity weakness and spasticity resulting from axonal degeneration of the corticospinal tracts
• Diminished vibration sense caused by impairment of dorsal columns
• Urinary bladder hyperactivity
## Establishing the Diagnosis
The diagnosis of
Note: Identification of a heterozygous
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 Spastic Paraplegia 3A
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
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 3A
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
Spastic paraplegia 3A (SPG3A; also known as
Most persons with early-onset
Findings also seen in
Other phenotypes observed in the spectrum of
Adult-onset
Hereditary sensory neuropathy type ID (HSN1D), an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. A pathogenic
Clinical presentation with a pure autonomic failure followed by the development of spastic paraplegia was reported in one individual with a novel pathogenic
Clinical presentation mimicking a severe neonatal-onset cerebral palsy with quadriparesis was reported in an individual with a
Findings not universally seen in
Hyperreflexia of the upper extremities
Impairment of vibration sensation at the ankles
Urinary bladder hyperactivity
No specific genotype-phenotype correlations have been reported; however:
Early-onset disease has been associated with missense variants around the GTPase binding domain.
Late-onset disease has been associated with frameshift variants in the C terminus that result in premature truncation of the protein, as well as some missense variants in the GTPase binding domain [
Overall, penetrance of pathogenic variants is high (~80%-90%) [
The lowest penetrance, 30%, was reported for the
Prevalence of autosomal dominant (AD) HSP has been estimated at 0.5-5:100,000 [
SPG3A is the third most common cause of AD HSP in all age groups. Metanalysis of epidemiologic studies suggested that SPG3A accounts for about 5% of all AD HSP, with an estimated prevalence of 0.025-0.25:100,000 [
SPG3A, the most common cause of early onset of AD HSP before age ten years, accounts for 40% of AD HSP in this age group [
• Adult-onset
• Hereditary sensory neuropathy type ID (HSN1D), an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. A pathogenic
• Clinical presentation with a pure autonomic failure followed by the development of spastic paraplegia was reported in one individual with a novel pathogenic
• Clinical presentation mimicking a severe neonatal-onset cerebral palsy with quadriparesis was reported in an individual with a
• Hyperreflexia of the upper extremities
• Impairment of vibration sensation at the ankles
• Urinary bladder hyperactivity
• Early-onset disease has been associated with missense variants around the GTPase binding domain.
• Late-onset disease has been associated with frameshift variants in the C terminus that result in premature truncation of the protein, as well as some missense variants in the GTPase binding domain [
## Clinical Description
Spastic paraplegia 3A (SPG3A; also known as
Most persons with early-onset
Findings also seen in
Other phenotypes observed in the spectrum of
Adult-onset
Hereditary sensory neuropathy type ID (HSN1D), an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. A pathogenic
Clinical presentation with a pure autonomic failure followed by the development of spastic paraplegia was reported in one individual with a novel pathogenic
Clinical presentation mimicking a severe neonatal-onset cerebral palsy with quadriparesis was reported in an individual with a
Findings not universally seen in
Hyperreflexia of the upper extremities
Impairment of vibration sensation at the ankles
Urinary bladder hyperactivity
• Adult-onset
• Hereditary sensory neuropathy type ID (HSN1D), an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. A pathogenic
• Clinical presentation with a pure autonomic failure followed by the development of spastic paraplegia was reported in one individual with a novel pathogenic
• Clinical presentation mimicking a severe neonatal-onset cerebral palsy with quadriparesis was reported in an individual with a
• Hyperreflexia of the upper extremities
• Impairment of vibration sensation at the ankles
• Urinary bladder hyperactivity
## Genotype-Phenotype Correlations
No specific genotype-phenotype correlations have been reported; however:
Early-onset disease has been associated with missense variants around the GTPase binding domain.
Late-onset disease has been associated with frameshift variants in the C terminus that result in premature truncation of the protein, as well as some missense variants in the GTPase binding domain [
• Early-onset disease has been associated with missense variants around the GTPase binding domain.
• Late-onset disease has been associated with frameshift variants in the C terminus that result in premature truncation of the protein, as well as some missense variants in the GTPase binding domain [
## Penetrance
Overall, penetrance of pathogenic variants is high (~80%-90%) [
The lowest penetrance, 30%, was reported for the
## Prevalence
Prevalence of autosomal dominant (AD) HSP has been estimated at 0.5-5:100,000 [
SPG3A is the third most common cause of AD HSP in all age groups. Metanalysis of epidemiologic studies suggested that SPG3A accounts for about 5% of all AD HSP, with an estimated prevalence of 0.025-0.25:100,000 [
SPG3A, the most common cause of early onset of AD HSP before age ten years, accounts for 40% of AD HSP in this age group [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Hereditary spastic paraplegia (HSP) is a progressive condition with a gradual worsening of spasticity and weakness of the lower extremities. Overall, the age of onset, disease severity, and rate of progression differ among different types of autosomal dominant (AD) HSP; there is also considerable variability within the same genetic forms of HSP. For a general discussion of the differential diagnosis of spastic paraplegia/paraparesis syndrome, see
Spastic paraplegia 3A (SPG3A; also known as
Autosomal Dominant Hereditary Spastic Paraplegias of Interest in the Differential Diagnosis of Spastic Paraplegia 3A
Axonal motor neuropathy common
Probably 2nd most common cause of early-onset AD HSP
Occasionally manifests in infancy
Probably most aggressive form of AD HSP
→ wheelchair dependency in a relatively short period of time
Early age of onset (age <4 yrs)
Mild postural tremor common
May have onset in 1st decade
Mild, minimally progressive clinical course
Pes cavus & distal amyotrophy common
Reported in a single family
Occasionally presents in infancy
Tends to have more progressive course
Most common type of AD HSP
Usual onset age <10 yrs
Uncomplicated phenotype
AD HSP = autosomal dominant hereditary spastic paraplegia
See
• Axonal motor neuropathy common
• Probably 2nd most common cause of early-onset AD HSP
• Occasionally manifests in infancy
• Probably most aggressive form of AD HSP
• → wheelchair dependency in a relatively short period of time
• Early age of onset (age <4 yrs)
• Mild postural tremor common
• May have onset in 1st decade
• Mild, minimally progressive clinical course
• Pes cavus & distal amyotrophy common
• Reported in a single family
• Occasionally presents in infancy
• Tends to have more progressive course
• Most common type of AD HSP
• Usual onset age <10 yrs
• Uncomplicated phenotype
## Management
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 3A (SPG3A; also known as
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 3A
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
Physical therapy needs
To assess small motor function, e.g., hands, feet, face, fingers, & toes
To assess ADL
Speech disorder (dysarthria)
Swallowing disorder (dysphagia)
Use of community or
Need for social work involvement for caregiver support.
Based on information provided by
ADL = activities of daily living; EMG = electromyography; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy
Spastic Paraplegia Rating Scale (SPRS) [
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Treatment for spasticity, distal weakness, and urinary bladder dysfunction (the primary manifestations of
Management by multidisciplinary specialists including a physiatrist, physical therapist, and speech therapist is recommended.
Treatment of Manifestations in Individuals with Spastic Paraplegia 3A
Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures
Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance
Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL
Massage, ultrasound, electrical stimulation, whirlpool
Anodal spinal direct current stimulation
Determine exact cause of swallowing malfunction.
Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
Feet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Training how to fall to minimize risk of injury
To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
To assist w/household modifications to meet special needs
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
The role of surgical hamstring and heel cord lengthening and release of the adductor longus remains unknown, but should be considered if contractures appear.
Demonstrated by
Baclofen can be tried first, and can be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.
There is no consensus regarding the frequency of clinical follow-up visits, but routine reevaluations are warranted (see
Recommended Surveillance for Individuals with Spastic Paraplegia 3A
ADL = activities of daily living; OT = occupational therapist; PT = physical therapist
Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely affect overall mobility.
See
The use of regional anesthesia, such as spinal or epidural anesthesia, during delivery in women with
Search
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• Physical therapy needs
• To assess small motor function, e.g., hands, feet, face, fingers, & toes
• To assess ADL
• Speech disorder (dysarthria)
• Swallowing disorder (dysphagia)
• Use of community or
• Need for social work involvement for caregiver support.
• Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures
• Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance
• Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL
• Massage, ultrasound, electrical stimulation, whirlpool
• Anodal spinal direct current stimulation
• Determine exact cause of swallowing malfunction.
• Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
• Feet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
• Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Training how to fall to minimize risk of injury
• To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
• To assist w/household modifications to meet special needs
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 3A (SPG3A; also known as
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 3A
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
Physical therapy needs
To assess small motor function, e.g., hands, feet, face, fingers, & toes
To assess ADL
Speech disorder (dysarthria)
Swallowing disorder (dysphagia)
Use of community or
Need for social work involvement for caregiver support.
Based on information provided by
ADL = activities of daily living; EMG = electromyography; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy
Spastic Paraplegia Rating Scale (SPRS) [
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• Physical therapy needs
• To assess small motor function, e.g., hands, feet, face, fingers, & toes
• To assess ADL
• Speech disorder (dysarthria)
• Swallowing disorder (dysphagia)
• Use of community or
• Need for social work involvement for caregiver support.
## Treatment of Manifestations
Treatment for spasticity, distal weakness, and urinary bladder dysfunction (the primary manifestations of
Management by multidisciplinary specialists including a physiatrist, physical therapist, and speech therapist is recommended.
Treatment of Manifestations in Individuals with Spastic Paraplegia 3A
Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures
Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance
Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL
Massage, ultrasound, electrical stimulation, whirlpool
Anodal spinal direct current stimulation
Determine exact cause of swallowing malfunction.
Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
Feet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Training how to fall to minimize risk of injury
To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
To assist w/household modifications to meet special needs
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
The role of surgical hamstring and heel cord lengthening and release of the adductor longus remains unknown, but should be considered if contractures appear.
Demonstrated by
Baclofen can be tried first, and can be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.
• Stretching exercises to improve flexibility, ↓ spasticity, & maintain or improve joint range of motion & prevent joint contractures
• Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination, & balance
• Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL
• Massage, ultrasound, electrical stimulation, whirlpool
• Anodal spinal direct current stimulation
• Determine exact cause of swallowing malfunction.
• Modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
• Feet: appropriate footwear; orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
• Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Training how to fall to minimize risk of injury
• To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
• To assist w/household modifications to meet special needs
## Surveillance
There is no consensus regarding the frequency of clinical follow-up visits, but routine reevaluations are warranted (see
Recommended Surveillance for Individuals with Spastic Paraplegia 3A
ADL = activities of daily living; OT = occupational therapist; PT = physical therapist
## Agents/Circumstances to Avoid
Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely affect overall mobility.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
The use of regional anesthesia, such as spinal or epidural anesthesia, during delivery in women with
## Therapies Under Investigation
Search
## Genetic Counseling
Spastic paraplegia 3A (SPG3A; also known as
Autosomal recessive inheritance of
Most individuals (>95%) diagnosed with
A proband with
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
* Misattributed parentage can also be explored as an alternative explanation for an apparent
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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 use of prenatal testing is a personal decision, discussion of these issues may be helpful.
• Most individuals (>95%) diagnosed with
• A proband with
• 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
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• 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
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Spastic paraplegia 3A (SPG3A; also known as
Autosomal recessive inheritance of
## Risk to Family Members (Autosomal Dominant Inheritance)
Most individuals (>95%) diagnosed with
A proband with
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
* Misattributed parentage can also be explored as an alternative explanation for an apparent
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 (>95%) diagnosed with
• A proband with
• 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
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• 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
## 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 use of prenatal testing is a personal decision, discussion of these issues may be helpful.
## Resources
Australia
•
• Australia
•
•
•
•
•
## Molecular Genetics
Spastic Paraplegia 3A: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spastic Paraplegia 3A (
Atlastin-1 interacts with spastin, encoded by
Most disease-causing missense variants cluster around the GTPase domain, resulting in reduction of catalytic activity.
Atlastin-1 forms tetrameric complexes; therefore, heterocomplexes of normal and abnormal atlastin-1 may interfere with tetramer activity [
Expression of pathogenic variants of atlastin-1 results in abnormal connectivity of ER complex. These ER-shaping defects may represent a novel neuropathogenic mechanism [
Atlastin-1 is expressed in neuronal growth cones. Knockdown of atlastin-1 expression was found to impair axonal elongation [
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
• Most disease-causing missense variants cluster around the GTPase domain, resulting in reduction of catalytic activity.
• Atlastin-1 forms tetrameric complexes; therefore, heterocomplexes of normal and abnormal atlastin-1 may interfere with tetramer activity [
• Expression of pathogenic variants of atlastin-1 results in abnormal connectivity of ER complex. These ER-shaping defects may represent a novel neuropathogenic mechanism [
• Atlastin-1 is expressed in neuronal growth cones. Knockdown of atlastin-1 expression was found to impair axonal elongation [
## Molecular Pathogenesis
Atlastin-1 interacts with spastin, encoded by
Most disease-causing missense variants cluster around the GTPase domain, resulting in reduction of catalytic activity.
Atlastin-1 forms tetrameric complexes; therefore, heterocomplexes of normal and abnormal atlastin-1 may interfere with tetramer activity [
Expression of pathogenic variants of atlastin-1 results in abnormal connectivity of ER complex. These ER-shaping defects may represent a novel neuropathogenic mechanism [
Atlastin-1 is expressed in neuronal growth cones. Knockdown of atlastin-1 expression was found to impair axonal elongation [
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
• Most disease-causing missense variants cluster around the GTPase domain, resulting in reduction of catalytic activity.
• Atlastin-1 forms tetrameric complexes; therefore, heterocomplexes of normal and abnormal atlastin-1 may interfere with tetramer activity [
• Expression of pathogenic variants of atlastin-1 results in abnormal connectivity of ER complex. These ER-shaping defects may represent a novel neuropathogenic mechanism [
• Atlastin-1 is expressed in neuronal growth cones. Knockdown of atlastin-1 expression was found to impair axonal elongation [
## Chapter Notes
P Hedera is supported by NIH (NINDS) grant K02NS057666
18 June 2020 (bp) Comprehensive update posted live
11 December 2014 (me) Comprehensive update posted live
9 February 2012 (cd) Revision: single-exon deletion in
21 September 2010 (me) Review posted live
26 April 2010 (ph) Original submission
• 18 June 2020 (bp) Comprehensive update posted live
• 11 December 2014 (me) Comprehensive update posted live
• 9 February 2012 (cd) Revision: single-exon deletion in
• 21 September 2010 (me) Review posted live
• 26 April 2010 (ph) Original submission
## Acknowledgments
P Hedera is supported by NIH (NINDS) grant K02NS057666
## Revision History
18 June 2020 (bp) Comprehensive update posted live
11 December 2014 (me) Comprehensive update posted live
9 February 2012 (cd) Revision: single-exon deletion in
21 September 2010 (me) Review posted live
26 April 2010 (ph) Original submission
• 18 June 2020 (bp) Comprehensive update posted live
• 11 December 2014 (me) Comprehensive update posted live
• 9 February 2012 (cd) Revision: single-exon deletion in
• 21 September 2010 (me) Review posted live
• 26 April 2010 (ph) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
21/9/2010
|
18/6/2020
|
9/2/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
spg4
|
spg4
|
[
"SPAST-HSP",
"SPG4",
"SPG4",
"SPAST-HSP",
"Spastin",
"SPAST",
"Spastic Paraplegia 4"
] |
Spastic Paraplegia 4
|
Livia Parodi, Siri Lynne Rydning, Chantal Tallaksen, Alexandra Durr
|
Summary Spastic paraplegia 4 (SPG4; also known as The diagnosis of
|
## Diagnosis
Spastic paraplegia 4 (SPG4; also known as
Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait with or without spasticity at rest and mild proximal weakness, often accompanied by urinary urgency
Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses). Mildly impaired vibration sensation in the ankles is present in the majority of individuals.
Family history consistent with autosomal dominant inheritance, or exclusion of other causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)
Note: The presence of other signs/symptoms suggestive of complicated hereditary spastic paraplegia does not exclude
Often normal in individuals with
Spinal cord atrophy can occur in
Mild vermis atrophy, a thin corpus callosum, subtle white matter changes, and/or cerebellar atrophy have been reported [
Note: The MRI is useful in identifying anomalies of the brain, cerebro-medullary junction, and medulla that are characteristic of disorders discussed in
The diagnosis of
Note: (1) Failure to detect a pathogenic variant/deletion does not absolutely exclude the diagnosis. (2) Once non-genetic causes have been excluded, testing for
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
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 spastic paraplegia,
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 Spastic Paraplegia 4
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
Benign variants can affect the phenotype (see
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.
Exon and multiexon deletions and duplications account for approximately 20%-25% of
• Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait with or without spasticity at rest and mild proximal weakness, often accompanied by urinary urgency
• Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses). Mildly impaired vibration sensation in the ankles is present in the majority of individuals.
• Family history consistent with autosomal dominant inheritance, or exclusion of other causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)
• Often normal in individuals with
• Spinal cord atrophy can occur in
• Mild vermis atrophy, a thin corpus callosum, subtle white matter changes, and/or cerebellar atrophy have been reported [
• For an introduction to multigene panels click
## Suggestive Findings
Spastic paraplegia 4 (SPG4; also known as
Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait with or without spasticity at rest and mild proximal weakness, often accompanied by urinary urgency
Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses). Mildly impaired vibration sensation in the ankles is present in the majority of individuals.
Family history consistent with autosomal dominant inheritance, or exclusion of other causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)
Note: The presence of other signs/symptoms suggestive of complicated hereditary spastic paraplegia does not exclude
Often normal in individuals with
Spinal cord atrophy can occur in
Mild vermis atrophy, a thin corpus callosum, subtle white matter changes, and/or cerebellar atrophy have been reported [
Note: The MRI is useful in identifying anomalies of the brain, cerebro-medullary junction, and medulla that are characteristic of disorders discussed in
• Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait with or without spasticity at rest and mild proximal weakness, often accompanied by urinary urgency
• Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses). Mildly impaired vibration sensation in the ankles is present in the majority of individuals.
• Family history consistent with autosomal dominant inheritance, or exclusion of other causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)
• Often normal in individuals with
• Spinal cord atrophy can occur in
• Mild vermis atrophy, a thin corpus callosum, subtle white matter changes, and/or cerebellar atrophy have been reported [
## Establishing the Diagnosis
The diagnosis of
Note: (1) Failure to detect a pathogenic variant/deletion does not absolutely exclude the diagnosis. (2) Once non-genetic causes have been excluded, testing for
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
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 spastic paraplegia,
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 Spastic Paraplegia 4
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
Benign variants can affect the phenotype (see
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.
Exon and multiexon deletions and duplications account for approximately 20%-25% 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 spastic paraplegia,
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 Spastic Paraplegia 4
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
Benign variants can affect the phenotype (see
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.
Exon and multiexon deletions and duplications account for approximately 20%-25% of
## Clinical Characteristics
The cardinal clinical feature of spastic paraplegia 4 (
Age at onset of symptoms ranges from infancy to the eighth decade. Age at onset is variable even among family members with the same pathogenic variant. A recent study including more than 500 individuals with
Disease severity generally worsens with the duration of the disease, although some individuals remain mildly affected all their lives. Disease severity is variable even among family members with the same pathogenic variant. After long disease duration (20 years), approximately 50% of individuals need assistance for walking, and approximately 10% require a wheelchair. Disease progression is more rapid in individuals with late onset (age >35 years) than in those with early onset [
Comparing men and women,
Leg spasms are frequent and may also develop before the onset of spasticity. Spasms are more frequent after physical activity, and tend to disappear when spasticity becomes more severe.
Bladder dysfunction remains one of the most frequent problems for affected individuals and may be more frequent in individuals with
Subtle cognitive impairment has been documented [
Extensive neuropsychological assessment of nine adults with
Neuropathy has been reported in individuals with
Non-motor symptoms are more frequent than previously acknowledged.
Restless legs syndrome has been associated with
Hand tremor was reported in 10% of a large cohort of Dutch individuals with
Seizures, intellectual disability, and cerebellar ataxia are rare. A few individuals with severe dementia have been reported [
Recently, after analyzing a cohort of more than 500 individuals with
It is important to note that age at onset and clinical severity are highly variable for a given variant, even in the same family. The observed difference in age of onset between related individuals ranged from 27 years to 69 years [
The most plausible explanation for intra and interfamilial variability is the presence of genetic modifiers.
Penetrance is age dependent and mostly complete in individuals with
Penetrance may be sex dependent.
The gene in which mutation is responsible for spastic paraplegia at the SPG4 locus,
The most recent epidemiologic study estimates a global prevalence of autosomal dominant-HSP (AD-HSP) of 1-5:100,000 [
Among AD-HSPs,
Geographic prevalence may vary;
## Clinical Description
The cardinal clinical feature of spastic paraplegia 4 (
Age at onset of symptoms ranges from infancy to the eighth decade. Age at onset is variable even among family members with the same pathogenic variant. A recent study including more than 500 individuals with
Disease severity generally worsens with the duration of the disease, although some individuals remain mildly affected all their lives. Disease severity is variable even among family members with the same pathogenic variant. After long disease duration (20 years), approximately 50% of individuals need assistance for walking, and approximately 10% require a wheelchair. Disease progression is more rapid in individuals with late onset (age >35 years) than in those with early onset [
Comparing men and women,
Leg spasms are frequent and may also develop before the onset of spasticity. Spasms are more frequent after physical activity, and tend to disappear when spasticity becomes more severe.
Bladder dysfunction remains one of the most frequent problems for affected individuals and may be more frequent in individuals with
Subtle cognitive impairment has been documented [
Extensive neuropsychological assessment of nine adults with
Neuropathy has been reported in individuals with
Non-motor symptoms are more frequent than previously acknowledged.
Restless legs syndrome has been associated with
Hand tremor was reported in 10% of a large cohort of Dutch individuals with
Seizures, intellectual disability, and cerebellar ataxia are rare. A few individuals with severe dementia have been reported [
## Genotype-Phenotype Correlations
Recently, after analyzing a cohort of more than 500 individuals with
It is important to note that age at onset and clinical severity are highly variable for a given variant, even in the same family. The observed difference in age of onset between related individuals ranged from 27 years to 69 years [
The most plausible explanation for intra and interfamilial variability is the presence of genetic modifiers.
## Penetrance
Penetrance is age dependent and mostly complete in individuals with
Penetrance may be sex dependent.
## Nomenclature
The gene in which mutation is responsible for spastic paraplegia at the SPG4 locus,
## Prevalence
The most recent epidemiologic study estimates a global prevalence of autosomal dominant-HSP (AD-HSP) of 1-5:100,000 [
Among AD-HSPs,
Geographic prevalence may vary;
## Genetically Related (Allelic) Disorders
Some individuals with a
## Differential Diagnosis
See
With the exceptions of
Other Types of Autosomal Dominant Pure Spastic Paraplegia (AD-HSP) to Consider in the Differential Diagnosis of
Earlier onset (often age <10 yrs)
More muscle wasting in lower limbs & scoliosis
Fewer sphincter disturbances
Less frequent impairment of vibration sense at the ankles & ↑ reflexes in upper limbs
2nd most common type of AD-HSP
More frequent peripheral neuropathy or amyotrophy
3rd most common type of AD-HSP
In simplex cases (i.e., spasticity in one individual in a family), all possible causes of spasticity in the legs must be considered because several non-genetic causes of spasticity are more common than
• Earlier onset (often age <10 yrs)
• More muscle wasting in lower limbs & scoliosis
• Fewer sphincter disturbances
• Less frequent impairment of vibration sense at the ankles & ↑ reflexes in upper limbs
• 2nd most common type of AD-HSP
• More frequent peripheral neuropathy or amyotrophy
• 3rd most common type of AD-HSP
## Management
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 4 (
Neuro-urologic examination is advised for individuals who have sphincter disturbances.
Whether neuropsychological testing should be performed to assess the cognitive impairment frequently reported in individuals with
Electrophysiologic investigations may be advisable in case of pain and/or edema in the lower limbs to evaluate for associated neuropathy. Neuropathy, while not a feature of
Spinal MRI examination to exclude any additional degenerative disorder can be considered if unusual symptoms or pain are present.
Consultation with a clinical geneticist and/or genetic counselor is appropriate.
Treatment is symptomatic as there is still no curative or disease-modifying treatment for
Symptomatic treatment includes use of the following:
Antispastic drugs for leg spasticity
Anticholinergic antispasmodic drugs for urinary urgency
Regular physiotherapy for stretching of spastic muscles. Stretching should be done manually at all levels (hips, knees, ankles) and preceded by heat conditioning. Early regular physiotherapy can prevent contractures to a certain extent. Intensive and early physiotherapy delays the development of symptoms related to spasticity and prolongs the ability to walk [Author, personal observation]. To date, the effectiveness of physical therapy in individuals with HSP is only documented in a small number of case reports and uncontrolled studies.
Botulinum toxin and intrathecal baclofen can be proposed when oral drugs are ineffective and spasticity is severe and disabling. In children, orthopedic treatment and botulinum toxin injections may also contribute to better ambulatory function. A recent study of a mixed cohort of 33 individuals with HSP suggested that botulinum toxin-A injections provide some benefits, not only for spasticity, but also for fatigue [
Urodynamic evaluation should be performed early in all affected individuals complaining of urgency or other problems, such as voiding difficulties, urine retention, and/or frequent urinary infections. Such symptoms should be monitored and treated according to individual needs and disease evolution. Follow up of the sphincter disturbances is important to prevent bladder dysfunction. Treatment options include anticholinergic drugs and intravesical botulinum-toxin injections [
Specialized outpatient evaluations are suggested every six to 12 months to update medications and physical rehabilitation.
See
Search
A double-blind crossover trial with gabapentin did not show improvement of spasticity in persons with
• Neuro-urologic examination is advised for individuals who have sphincter disturbances.
• Whether neuropsychological testing should be performed to assess the cognitive impairment frequently reported in individuals with
• Electrophysiologic investigations may be advisable in case of pain and/or edema in the lower limbs to evaluate for associated neuropathy. Neuropathy, while not a feature of
• Spinal MRI examination to exclude any additional degenerative disorder can be considered if unusual symptoms or pain are present.
• Consultation with a clinical geneticist and/or genetic counselor is appropriate.
• Antispastic drugs for leg spasticity
• Anticholinergic antispasmodic drugs for urinary urgency
• Regular physiotherapy for stretching of spastic muscles. Stretching should be done manually at all levels (hips, knees, ankles) and preceded by heat conditioning. Early regular physiotherapy can prevent contractures to a certain extent. Intensive and early physiotherapy delays the development of symptoms related to spasticity and prolongs the ability to walk [Author, personal observation]. To date, the effectiveness of physical therapy in individuals with HSP is only documented in a small number of case reports and uncontrolled studies.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 4 (
Neuro-urologic examination is advised for individuals who have sphincter disturbances.
Whether neuropsychological testing should be performed to assess the cognitive impairment frequently reported in individuals with
Electrophysiologic investigations may be advisable in case of pain and/or edema in the lower limbs to evaluate for associated neuropathy. Neuropathy, while not a feature of
Spinal MRI examination to exclude any additional degenerative disorder can be considered if unusual symptoms or pain are present.
Consultation with a clinical geneticist and/or genetic counselor is appropriate.
• Neuro-urologic examination is advised for individuals who have sphincter disturbances.
• Whether neuropsychological testing should be performed to assess the cognitive impairment frequently reported in individuals with
• Electrophysiologic investigations may be advisable in case of pain and/or edema in the lower limbs to evaluate for associated neuropathy. Neuropathy, while not a feature of
• Spinal MRI examination to exclude any additional degenerative disorder can be considered if unusual symptoms or pain are present.
• Consultation with a clinical geneticist and/or genetic counselor is appropriate.
## Treatment of Manifestations
Treatment is symptomatic as there is still no curative or disease-modifying treatment for
Symptomatic treatment includes use of the following:
Antispastic drugs for leg spasticity
Anticholinergic antispasmodic drugs for urinary urgency
Regular physiotherapy for stretching of spastic muscles. Stretching should be done manually at all levels (hips, knees, ankles) and preceded by heat conditioning. Early regular physiotherapy can prevent contractures to a certain extent. Intensive and early physiotherapy delays the development of symptoms related to spasticity and prolongs the ability to walk [Author, personal observation]. To date, the effectiveness of physical therapy in individuals with HSP is only documented in a small number of case reports and uncontrolled studies.
Botulinum toxin and intrathecal baclofen can be proposed when oral drugs are ineffective and spasticity is severe and disabling. In children, orthopedic treatment and botulinum toxin injections may also contribute to better ambulatory function. A recent study of a mixed cohort of 33 individuals with HSP suggested that botulinum toxin-A injections provide some benefits, not only for spasticity, but also for fatigue [
Urodynamic evaluation should be performed early in all affected individuals complaining of urgency or other problems, such as voiding difficulties, urine retention, and/or frequent urinary infections. Such symptoms should be monitored and treated according to individual needs and disease evolution. Follow up of the sphincter disturbances is important to prevent bladder dysfunction. Treatment options include anticholinergic drugs and intravesical botulinum-toxin injections [
• Antispastic drugs for leg spasticity
• Anticholinergic antispasmodic drugs for urinary urgency
• Regular physiotherapy for stretching of spastic muscles. Stretching should be done manually at all levels (hips, knees, ankles) and preceded by heat conditioning. Early regular physiotherapy can prevent contractures to a certain extent. Intensive and early physiotherapy delays the development of symptoms related to spasticity and prolongs the ability to walk [Author, personal observation]. To date, the effectiveness of physical therapy in individuals with HSP is only documented in a small number of case reports and uncontrolled studies.
## Surveillance
Specialized outpatient evaluations are suggested every six to 12 months to update medications and physical rehabilitation.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
A double-blind crossover trial with gabapentin did not show improvement of spasticity in persons with
## Genetic Counseling
Spastic paraplegia 4 (
Individuals diagnosed with
An individual 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, possible explanations include a
The family history of some individuals diagnosed with
If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Note: Significant intrafamilial variability in age of onset and clinical severity is observed in
If the proband has a known
If the parents of a proband are clinically unaffected but have not undergone molecular genetic testing, sibs of the proband are still presumed to be at increased risk for
Predictive testing for at-risk relatives is possible once a
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 typically 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 a
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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Individuals diagnosed with
• An individual 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, possible explanations include a
• The family history of some individuals diagnosed with
• If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Note: Significant intrafamilial variability in age of onset and clinical severity is observed in
• If the proband has a known
• If the parents of a proband are clinically unaffected but have not undergone molecular genetic testing, sibs of the proband are still presumed to be at increased risk for
• Predictive testing for at-risk relatives is possible once a
• 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 typically 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.
## Mode of Inheritance
Spastic paraplegia 4 (
## Risk to Family Members
Individuals diagnosed with
An individual 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, possible explanations include a
The family history of some individuals diagnosed with
If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Note: Significant intrafamilial variability in age of onset and clinical severity is observed in
If the proband has a known
If the parents of a proband are clinically unaffected but have not undergone molecular genetic testing, sibs of the proband are still presumed to be at increased risk for
• Individuals diagnosed with
• An individual 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, possible explanations include a
• The family history of some individuals diagnosed with
• If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Note: Significant intrafamilial variability in age of onset and clinical severity is observed in
• If the proband has a known
• If the parents of a proband are clinically unaffected but have not undergone molecular genetic testing, sibs of the proband are still presumed to be at increased risk for
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once a
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 typically 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 a
• 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 typically 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.
## Prenatal Testing and Preimplantation Genetic Testing
Once a
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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
Australia
Tom Wahlig Stiftung
Germany
Associazione Italiana Vivere la Paraparesi Spastica
Italy
PO Box 9217
Oslo 0134
Norway
•
•
•
• Australia
•
•
•
•
• Tom Wahlig Stiftung
• Germany
•
•
• Associazione Italiana Vivere la Paraparesi Spastica
• Italy
•
•
•
•
•
• PO Box 9217
• Oslo 0134
• Norway
•
## Molecular Genetics
Spastic Paraplegia 4: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spastic Paraplegia 4 (
Spastin is widely expressed in the neurons of the central nervous system, including the cortex and striatum. Distal degeneration of long tracts in the spinal cord is associated with a microglial reaction [
Within the cells, spastin acts as a microtubule-severing protein and is responsible for different aspects of microtubule dynamics, such as their length, number, and mobility [
Spastin N-terminal domain is involved in both lipid metabolism [
The microtubule-interacting and trafficking domain (MIT) allows spastin to interact with CHIMP1 and IST1, two proteins belonging to the endosomal-sorting complex required for transport (ESCRT-III), being therefore involved in both cytokinesis and endosomal-tubule recycling [
The microtubule-binding domain (MTBD) and the AAA ATPase cassette are responsible for the microtubule binding and ATP hydrolysis [
An alternative to the loss-of-function model, the finding that
An additional alternative hypothesis was recently proposed by
In conclusion, the debate concerning
Both exon/multiexon deletions and duplications may be pathogenic
Notable
Variants listed in the table have been provided by the authors.
• Spastin N-terminal domain is involved in both lipid metabolism [
• The microtubule-interacting and trafficking domain (MIT) allows spastin to interact with CHIMP1 and IST1, two proteins belonging to the endosomal-sorting complex required for transport (ESCRT-III), being therefore involved in both cytokinesis and endosomal-tubule recycling [
• The microtubule-binding domain (MTBD) and the AAA ATPase cassette are responsible for the microtubule binding and ATP hydrolysis [
## Molecular Pathogenesis
Spastin is widely expressed in the neurons of the central nervous system, including the cortex and striatum. Distal degeneration of long tracts in the spinal cord is associated with a microglial reaction [
Within the cells, spastin acts as a microtubule-severing protein and is responsible for different aspects of microtubule dynamics, such as their length, number, and mobility [
Spastin N-terminal domain is involved in both lipid metabolism [
The microtubule-interacting and trafficking domain (MIT) allows spastin to interact with CHIMP1 and IST1, two proteins belonging to the endosomal-sorting complex required for transport (ESCRT-III), being therefore involved in both cytokinesis and endosomal-tubule recycling [
The microtubule-binding domain (MTBD) and the AAA ATPase cassette are responsible for the microtubule binding and ATP hydrolysis [
An alternative to the loss-of-function model, the finding that
An additional alternative hypothesis was recently proposed by
In conclusion, the debate concerning
Both exon/multiexon deletions and duplications may be pathogenic
Notable
Variants listed in the table have been provided by the authors.
• Spastin N-terminal domain is involved in both lipid metabolism [
• The microtubule-interacting and trafficking domain (MIT) allows spastin to interact with CHIMP1 and IST1, two proteins belonging to the endosomal-sorting complex required for transport (ESCRT-III), being therefore involved in both cytokinesis and endosomal-tubule recycling [
• The microtubule-binding domain (MTBD) and the AAA ATPase cassette are responsible for the microtubule binding and ATP hydrolysis [
## Chapter Notes
Christel Depienne, PhD; Hôpital Pitié Salpêtrière (2003-2019)Alexandra Durr, MD, PhD (2003-present)Livia Parodi, PhD (2019-present)Siri Lynne Rydning, MD (2019-present)Chantal Tallaksen, MD, PhD (2003-present)
13 June 2019 (sw) Comprehensive update posted live
16 August 2012 (me) Comprehensive update posted live
18 June 2009 (me) Comprehensive update posted live
10 August 2005 (me) Comprehensive update posted live
17 April 2003 (me) Review posted live
25 September 2002 (ct) Original submission
• 13 June 2019 (sw) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 18 June 2009 (me) Comprehensive update posted live
• 10 August 2005 (me) Comprehensive update posted live
• 17 April 2003 (me) Review posted live
• 25 September 2002 (ct) Original submission
## Author History
Christel Depienne, PhD; Hôpital Pitié Salpêtrière (2003-2019)Alexandra Durr, MD, PhD (2003-present)Livia Parodi, PhD (2019-present)Siri Lynne Rydning, MD (2019-present)Chantal Tallaksen, MD, PhD (2003-present)
## Revision History
13 June 2019 (sw) Comprehensive update posted live
16 August 2012 (me) Comprehensive update posted live
18 June 2009 (me) Comprehensive update posted live
10 August 2005 (me) Comprehensive update posted live
17 April 2003 (me) Review posted live
25 September 2002 (ct) Original submission
• 13 June 2019 (sw) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 18 June 2009 (me) Comprehensive update posted live
• 10 August 2005 (me) Comprehensive update posted live
• 17 April 2003 (me) Review posted live
• 25 September 2002 (ct) 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
|
[] |
17/4/2003
|
13/6/2019
|
23/4/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
spg7
|
spg7
|
[
"Hereditary Spastic Paraplegia, Paraplegin Type",
"Hereditary Spastic Paraplegia, Paraplegin Type",
"SPG7",
"Mitochondrial inner membrane m-AAA protease component paraplegin",
"SPG7",
"Spastic Paraplegia 7"
] |
Spastic Paraplegia 7
|
Giorgio Casari, Roberto Marconi
|
Summary Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral leg weakness and spasticity. Most affected individuals have decreased vibration sense and cerebellar signs. Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years. Additional features including ataxia (gait and limbs), spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, ptosis, hearing loss, motor and sensory neuropathy, amyotrophy, scoliosis, The diagnosis of SPG7 is established in a proband with typical clinical findings and biallelic pathogenic variants in SPG7 is inherited in an autosomal recessive manner. Heterozygotes (carriers) are usually asymptomatic. 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 increased risk and preimplantation genetic testing are possible if both pathogenic alleles have been identified in the family.
|
## Diagnosis
Spastic paraplegia 7 (SPG7)
Insidiously progressive bilateral leg weakness
Spasticity
Decreased vibratory sense
Cerebellar signs
Neurologic examination demonstrating EITHER of the following:
A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
Neuroimaging findings of cerebellar atrophy (MRI) or white matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem
Family history consistent with autosomal recessive inheritance
The diagnosis of SPG 7
Note: A single
Because the phenotype of SPG7 is indistinguishable from many other forms of hereditary spastic paraplegia, recommended molecular genetic testing approaches include use of a
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 Spastic Paraplegia 7
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.
• Insidiously progressive bilateral leg weakness
• Spasticity
• Decreased vibratory sense
• Cerebellar signs
• Neurologic examination demonstrating EITHER of the following:
• A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
• A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
• A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
• A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
• Neuroimaging findings of cerebellar atrophy (MRI) or white matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem
• Family history consistent with autosomal recessive inheritance
• A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
• A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Spastic paraplegia 7 (SPG7)
Insidiously progressive bilateral leg weakness
Spasticity
Decreased vibratory sense
Cerebellar signs
Neurologic examination demonstrating EITHER of the following:
A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
Neuroimaging findings of cerebellar atrophy (MRI) or white matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem
Family history consistent with autosomal recessive inheritance
• Insidiously progressive bilateral leg weakness
• Spasticity
• Decreased vibratory sense
• Cerebellar signs
• Neurologic examination demonstrating EITHER of the following:
• A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
• A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
• A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
• A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
• Neuroimaging findings of cerebellar atrophy (MRI) or white matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem
• Family history consistent with autosomal recessive inheritance
• A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
• A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis,
## Establishing the Diagnosis
The diagnosis of SPG 7
Note: A single
Because the phenotype of SPG7 is indistinguishable from many other forms of hereditary spastic paraplegia, recommended molecular genetic testing approaches include use of a
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 Spastic Paraplegia 7
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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral lower-limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense.
Cerebellar and motor signs
Ataxia (gait and limbs)
Spastic dysarthria
Dysphagia
Ophthalmic findings
Pale optic disks
Nystagmus
Strabismus
Ptosis
Hearing loss of conductive/neurosensory /mixed type
Peripheral neuromuscular findings
Motor and sensory neuropathy
Amyotrophy
Orthopedic issues
Scoliosis
Urinary sphincter disturbances
In a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [
White matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7.
Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the pontomedullary junction and of the cervical and dorsolumbar medulla.
Spinal evoked potentials may reveal delayed prolongation of the central conduction time [
Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.
Paired transcranial magnetic stimulation may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [
Optical coherence tomography is useful for detecting subclinical optic neuropathy [
A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [
Serum creatine kinase activity may be slightly above the normal range in some cases.
Muscle biopsy has revealed the following:
Changes of denervation with partial reinnervation
Atrophic, angulated fibers, predominantly type II
Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
No genotype-phenotype correlations can be proposed based on published studies.
The prevalence of SPG7 is estimated at between 1:100,000 and 9:100,000 for most countries (
• Cerebellar and motor signs
• Ataxia (gait and limbs)
• Spastic dysarthria
• Dysphagia
• Ataxia (gait and limbs)
• Spastic dysarthria
• Dysphagia
• Ophthalmic findings
• Pale optic disks
• Nystagmus
• Strabismus
• Ptosis
• Pale optic disks
• Nystagmus
• Strabismus
• Ptosis
• Hearing loss of conductive/neurosensory /mixed type
• Peripheral neuromuscular findings
• Motor and sensory neuropathy
• Amyotrophy
• Motor and sensory neuropathy
• Amyotrophy
• Orthopedic issues
• Scoliosis
•
• Scoliosis
•
• Urinary sphincter disturbances
• Ataxia (gait and limbs)
• Spastic dysarthria
• Dysphagia
• Pale optic disks
• Nystagmus
• Strabismus
• Ptosis
• Motor and sensory neuropathy
• Amyotrophy
• Scoliosis
•
• In a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [
• White matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7.
• Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the pontomedullary junction and of the cervical and dorsolumbar medulla.
• Spinal evoked potentials may reveal delayed prolongation of the central conduction time [
• Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.
• Paired transcranial magnetic stimulation may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [
• Optical coherence tomography is useful for detecting subclinical optic neuropathy [
• A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [
• Serum creatine kinase activity may be slightly above the normal range in some cases.
• Muscle biopsy has revealed the following:
• Changes of denervation with partial reinnervation
• Atrophic, angulated fibers, predominantly type II
• Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
• Changes of denervation with partial reinnervation
• Atrophic, angulated fibers, predominantly type II
• Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
• Changes of denervation with partial reinnervation
• Atrophic, angulated fibers, predominantly type II
• Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
## Clinical Description
Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral lower-limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense.
Cerebellar and motor signs
Ataxia (gait and limbs)
Spastic dysarthria
Dysphagia
Ophthalmic findings
Pale optic disks
Nystagmus
Strabismus
Ptosis
Hearing loss of conductive/neurosensory /mixed type
Peripheral neuromuscular findings
Motor and sensory neuropathy
Amyotrophy
Orthopedic issues
Scoliosis
Urinary sphincter disturbances
• Cerebellar and motor signs
• Ataxia (gait and limbs)
• Spastic dysarthria
• Dysphagia
• Ataxia (gait and limbs)
• Spastic dysarthria
• Dysphagia
• Ophthalmic findings
• Pale optic disks
• Nystagmus
• Strabismus
• Ptosis
• Pale optic disks
• Nystagmus
• Strabismus
• Ptosis
• Hearing loss of conductive/neurosensory /mixed type
• Peripheral neuromuscular findings
• Motor and sensory neuropathy
• Amyotrophy
• Motor and sensory neuropathy
• Amyotrophy
• Orthopedic issues
• Scoliosis
•
• Scoliosis
•
• Urinary sphincter disturbances
• Ataxia (gait and limbs)
• Spastic dysarthria
• Dysphagia
• Pale optic disks
• Nystagmus
• Strabismus
• Ptosis
• Motor and sensory neuropathy
• Amyotrophy
• Scoliosis
•
## Findings on Neuroimaging and Other Investigations
In a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [
White matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7.
Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the pontomedullary junction and of the cervical and dorsolumbar medulla.
Spinal evoked potentials may reveal delayed prolongation of the central conduction time [
Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.
Paired transcranial magnetic stimulation may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [
Optical coherence tomography is useful for detecting subclinical optic neuropathy [
A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [
Serum creatine kinase activity may be slightly above the normal range in some cases.
Muscle biopsy has revealed the following:
Changes of denervation with partial reinnervation
Atrophic, angulated fibers, predominantly type II
Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
• In a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [
• White matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7.
• Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the pontomedullary junction and of the cervical and dorsolumbar medulla.
• Spinal evoked potentials may reveal delayed prolongation of the central conduction time [
• Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.
• Paired transcranial magnetic stimulation may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [
• Optical coherence tomography is useful for detecting subclinical optic neuropathy [
• A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [
• Serum creatine kinase activity may be slightly above the normal range in some cases.
• Muscle biopsy has revealed the following:
• Changes of denervation with partial reinnervation
• Atrophic, angulated fibers, predominantly type II
• Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
• Changes of denervation with partial reinnervation
• Atrophic, angulated fibers, predominantly type II
• Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
• Changes of denervation with partial reinnervation
• Atrophic, angulated fibers, predominantly type II
• Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome
## Genotype-Phenotype Correlations
No genotype-phenotype correlations can be proposed based on published studies.
## Prevalence
The prevalence of SPG7 is estimated at between 1:100,000 and 9:100,000 for most countries (
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
No significant differences exist between spastic paraplegia 7 (SPG7) and other types of pure autosomal dominant and autosomal recessive spastic paraplegia [
Other conditions that need to be considered in the differential diagnosis of SPG7 are summarized in
Other Disorders to Consider in the Differential Diagnosis of SPG7
Dementia
On MRI: leukodystrophy, adrenal dysfunction, long-chain fatty acid accumulation
Young-onset dystonia parkinsonism responsive to levodopa
Diurnal variation
Epileptic seizures
Severe mental retardation
↑ plasma arginine
Hyperammonemia
Subacute combined degeneration
Improvement after vitamin B
MRI white matter changes
Oligoclonal IgG bands
↑ IgG index
External ophthalmoplegia
Proximal myopathy
No pyramidal signs
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; NA = not applicable; XL = X-linked
See
• Dementia
• On MRI: leukodystrophy, adrenal dysfunction, long-chain fatty acid accumulation
• Young-onset dystonia parkinsonism responsive to levodopa
• Diurnal variation
• Epileptic seizures
• Severe mental retardation
• ↑ plasma arginine
• Hyperammonemia
• Subacute combined degeneration
• Improvement after vitamin B
• MRI white matter changes
• Oligoclonal IgG bands
• ↑ IgG index
• External ophthalmoplegia
• Proximal myopathy
• No pyramidal signs
## Management
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 7 (SPG7), the following evaluations are recommended if they have not already been completed:
Ophthalmologic evaluation
Hearing testing
Urologic evaluation in case of bladder dysfunction
Consultation with a clinical geneticist and/or genetic counselor
Evaluation by a multidisciplinary team that includes a general practitioner, neurologist, physical therapist, social worker, and psychologist should be considered.
Neuropsychological testing may be suggested.
No specific drug treatments or cures for SPG7 exist.
Drugs to reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam – preferably administered one at a time.
Management of spasticity by intrathecal baclofen or intramuscular botulinum toxin injections may be an option in selected individuals [
A combination of physical therapy and assistive walking devices are often used to reduce contractures, provide support, and promote stability.
Occupational therapy and speech therapy are often helpful in managing activities of daily living.
Because individuals with advanced disease are bedridden they are at major risk of aspiration pneumonia, urinary tract infections and pulmonary embolism; careful monitoring is recommended to help avoid these complications.
Annual neurologic evaluation can help identify potential complications of spasticity that develop over time (e.g., contractures).
See
Search
• Ophthalmologic evaluation
• Hearing testing
• Urologic evaluation in case of bladder dysfunction
• 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 spastic paraplegia 7 (SPG7), the following evaluations are recommended if they have not already been completed:
Ophthalmologic evaluation
Hearing testing
Urologic evaluation in case of bladder dysfunction
Consultation with a clinical geneticist and/or genetic counselor
Evaluation by a multidisciplinary team that includes a general practitioner, neurologist, physical therapist, social worker, and psychologist should be considered.
Neuropsychological testing may be suggested.
• Ophthalmologic evaluation
• Hearing testing
• Urologic evaluation in case of bladder dysfunction
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No specific drug treatments or cures for SPG7 exist.
Drugs to reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam – preferably administered one at a time.
Management of spasticity by intrathecal baclofen or intramuscular botulinum toxin injections may be an option in selected individuals [
A combination of physical therapy and assistive walking devices are often used to reduce contractures, provide support, and promote stability.
Occupational therapy and speech therapy are often helpful in managing activities of daily living.
## Prevention of Secondary Complications
Because individuals with advanced disease are bedridden they are at major risk of aspiration pneumonia, urinary tract infections and pulmonary embolism; careful monitoring is recommended to help avoid these complications.
## Surveillance
Annual neurologic evaluation can help identify potential complications of spasticity that develop over time (e.g., contractures).
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spastic paraplegia 7 (SPG7) is inherited in an autosomal recessive manner.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Findings of a subtle reduction of white matter integrity in the corpus callosum on diffusion tensor imaging have been reported in individuals heterozygous for an
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 typically are not at risk of developing the disorder (see
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
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
• Findings of a subtle reduction of white matter integrity in the corpus callosum on diffusion tensor imaging have been reported in individuals heterozygous for an
• 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 typically are not at risk of developing the disorder (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 carriers.
## Mode of Inheritance
Spastic paraplegia 7 (SPG7) 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
Findings of a subtle reduction of white matter integrity in the corpus callosum on diffusion tensor imaging have been reported in individuals heterozygous for an
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 typically are not at risk of developing the disorder (see
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Findings of a subtle reduction of white matter integrity in the corpus callosum on diffusion tensor imaging have been reported in individuals heterozygous for an
• 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 typically are not at risk of developing the disorder (see
## 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 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
Australia
Tom Wahlig Stiftung
Germany
Associazione Italiana Vivere la Paraparesi Spastica
Italy
•
• Australia
•
•
•
•
•
•
• Tom Wahlig Stiftung
• Germany
•
•
• Associazione Italiana Vivere la Paraparesi Spastica
• Italy
•
## Molecular Genetics
Spastic Paraplegia 7: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spastic Paraplegia 7 (
Twenty-seven pathogenic variants have been reported in
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
In a recent paper paraplegin was identified as a molecular component/regulator of the mitochondrial permeability transition pore [
Biochemical analysis from two individuals with confirmed
In mouse,
## References
## Literature Cited
## Chapter Notes
25 October 2018 (ha) Comprehensive update posted live
23 December 2010 (me) Comprehensive update posted live
25 February 2008 (cd) Revision: deletion/duplication analysis available clinically
24 August 2006 (me) Review posted live
7 March 2005 (gc) Original submission
• 25 October 2018 (ha) Comprehensive update posted live
• 23 December 2010 (me) Comprehensive update posted live
• 25 February 2008 (cd) Revision: deletion/duplication analysis available clinically
• 24 August 2006 (me) Review posted live
• 7 March 2005 (gc) Original submission
## Revision History
25 October 2018 (ha) Comprehensive update posted live
23 December 2010 (me) Comprehensive update posted live
25 February 2008 (cd) Revision: deletion/duplication analysis available clinically
24 August 2006 (me) Review posted live
7 March 2005 (gc) Original submission
• 25 October 2018 (ha) Comprehensive update posted live
• 23 December 2010 (me) Comprehensive update posted live
• 25 February 2008 (cd) Revision: deletion/duplication analysis available clinically
• 24 August 2006 (me) Review posted live
• 7 March 2005 (gc) Original submission
|
[
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"C Tzoulis, PS Denora, FM Santorelli, LA Bindoff. Hereditary spastic paraplegia caused by the novel mutation 1047insC in the SPG7 gene.. J Neurol 2008;255:1142-4",
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"T Warnecke, T Duning, A Schirmacher, S Mohammadi, W Schwindt, H Lohmann, R Dziewas, M Deppe, EB Ringelstein, P Young. A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects.. Mov Disord 2010;25:413-20",
"IM Wedding, J Koht, GT Tran, D Misceo, KK Selmer, A Holmgren, E Frengen, L Bindoff, CM Tallaksen, C Tzoulis. Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions.. PLoS One 2014;9",
"PA Wilkinson, AH Crosby, C Turner, LJ Bradley, L Ginsberg, NW Wood, AH Schapira, TT Warner. A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia.. Brain. 2004;127:973-80",
"H Yahikozawa, K Yoshida, S Sato, N Hanyu, H Doi, S Miyatake, N Matsumoto. Predominant cerebellar phenotype in spastic paraplegia 7 (SPG7).. Hum Genome Var. 2015;2:15012",
"Y Yang, L Zhang, DR Lynch, T Lukas, K Ahmeti, PM Sleiman, E Ryan, KA Schadt, JH Newman, HX Deng, N Siddique, T Siddique. Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis.. Neurol Genet 2016;2",
"S Züchner, P De Jonghe, A Jordanova, KG Claeys, V Guergueltcheva, S Cherninkova, SR Hamilton, G Van Stavern, KM Krajewski, J Stajich, I Tournev, K Verhoeven, CT Langerhorst, M de Visser, F Baas, T Bird, V Timmerman, M Shy, JM Vance. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2.. Ann Neurol. 2006;59:276-81"
] |
24/8/2006
|
25/10/2018
|
25/2/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
spg8
|
spg8
|
[
"SPG8",
"SPG8",
"WASH complex subunit 5",
"WASHC5",
"Spastic Paraplegia 8"
] |
Spastic Paraplegia 8
|
Inge A Meijer, Paul N Valdmanis, Guy A Rouleau
|
Summary Hereditary spastic paraplegia 8 (SPG8) is a slowly progressive pure spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings). Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity. Onset is between ages ten and 59 years. Affected individuals often become wheelchair dependent. While intra- and interfamilial phenotypic variability is high, SPG8 is typically more severe than other types of hereditary spastic paraplegia. The diagnosis of SPG8 is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in SPG8 is inherited in an autosomal dominant manner. More than 90% of individuals with SPG8 have an affected parent. Each child of an individual with SPG8 has a 50% chance of inheriting the
|
## Diagnosis
Spastic paraplegia 8 (SPG8)
Onset in the 20s and 30s (range: age 20-60 years)
Slowly progressive "pure" spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings)
Mild distal decreased vibration sense
Urinary urgency
Cerebrospinal fluid
Electrophysiologic studies:
Nerve conduction velocity
Electromyography
Biochemical testing
Vitamin B
Very long chain fatty acids
Lactate [
The diagnosis of spastic paraplegia 8
Note: (1) Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous
Molecular genetic testing approaches 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
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 8
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 analysis detects deletions ranging from a single exon to the whole gene.
• Onset in the 20s and 30s (range: age 20-60 years)
• Slowly progressive "pure" spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings)
• Mild distal decreased vibration sense
• Urinary urgency
• Cerebrospinal fluid
• Electrophysiologic studies:
• Nerve conduction velocity
• Electromyography
• Nerve conduction velocity
• Electromyography
• Biochemical testing
• Vitamin B
• Very long chain fatty acids
• Lactate [
• Vitamin B
• Very long chain fatty acids
• Lactate [
• Nerve conduction velocity
• Electromyography
• Vitamin B
• Very long chain fatty acids
• Lactate [
## Suggestive Findings
Spastic paraplegia 8 (SPG8)
Onset in the 20s and 30s (range: age 20-60 years)
Slowly progressive "pure" spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings)
Mild distal decreased vibration sense
Urinary urgency
Cerebrospinal fluid
Electrophysiologic studies:
Nerve conduction velocity
Electromyography
Biochemical testing
Vitamin B
Very long chain fatty acids
Lactate [
• Onset in the 20s and 30s (range: age 20-60 years)
• Slowly progressive "pure" spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings)
• Mild distal decreased vibration sense
• Urinary urgency
• Cerebrospinal fluid
• Electrophysiologic studies:
• Nerve conduction velocity
• Electromyography
• Nerve conduction velocity
• Electromyography
• Biochemical testing
• Vitamin B
• Very long chain fatty acids
• Lactate [
• Vitamin B
• Very long chain fatty acids
• Lactate [
• Nerve conduction velocity
• Electromyography
• Vitamin B
• Very long chain fatty acids
• Lactate [
## Establishing the Diagnosis
The diagnosis of spastic paraplegia 8
Note: (1) Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous
Molecular genetic testing approaches 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
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 8
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 analysis detects deletions ranging from a single exon to the whole gene.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spastic Paraplegia 8
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 analysis detects deletions ranging from a single exon to the whole gene.
## Clinical Characteristics
Spastic paraplegia 8 (SPG8) is characterized by progressive lower-limb spasticity with hyperreflexia and extensor plantar reflexes. While intra- and interfamilial phenotypic variability is high, SPG8 is typically more severe than other types of hereditary spastic paraplegia.
Onset is between ages ten and 59 years (range: 18-26 years in 1 family [
SPG8 is more often associated with wheelchair dependence than other types of autosomal dominant hereditary spastic paraplegia. In one family of 15 affected individuals, insidiously progressive spastic paraparesis began between ages 22 and 60 years (average: 37.2 years); ten of the 15 were wheelchair bound by age 40 years [
Affected individuals also demonstrate weakness, a minor component that is probably secondary to reduced mobility.
Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity.
Decreased vibration sense is an additional finding on neurologic examination [
The number of pathogenic variants reported to date is too small to draw any genotype-phenotype correlations.
The penetrance for SPG8 is estimated between 90% and 100% [
The prevalence of all hereditary spastic paraplegia is 1-18:100,000 [
Pathogenic variants in
## Clinical Description
Spastic paraplegia 8 (SPG8) is characterized by progressive lower-limb spasticity with hyperreflexia and extensor plantar reflexes. While intra- and interfamilial phenotypic variability is high, SPG8 is typically more severe than other types of hereditary spastic paraplegia.
Onset is between ages ten and 59 years (range: 18-26 years in 1 family [
SPG8 is more often associated with wheelchair dependence than other types of autosomal dominant hereditary spastic paraplegia. In one family of 15 affected individuals, insidiously progressive spastic paraparesis began between ages 22 and 60 years (average: 37.2 years); ten of the 15 were wheelchair bound by age 40 years [
Affected individuals also demonstrate weakness, a minor component that is probably secondary to reduced mobility.
Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity.
Decreased vibration sense is an additional finding on neurologic examination [
## Genotype-Phenotype Correlations
The number of pathogenic variants reported to date is too small to draw any genotype-phenotype correlations.
## Nomenclature
## Penetrance
The penetrance for SPG8 is estimated between 90% and 100% [
## Prevalence
The prevalence of all hereditary spastic paraplegia is 1-18:100,000 [
Pathogenic variants in
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Hereditary spastic paraplegia 8 (SPG8) is indistinguishable clinically from other forms of autosomal dominant hereditary spastic paraplegia (see Hereditary Spastic Paraplegia Overview,
Other conditions that may be associated with spasticity include hereditary disorders (e.g.,
## Management
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 8 (SPG8), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 8
Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Fine motor function (e.g., hands, feet, face, fingers, & toes)
Activities of daily living
Speech disorder (dysarthria)
Swallowing disorder (dysphagia)
Use of
Social work involvement for caregiver support;
Home nursing referral.
Based on information provided by
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
No cures or specific drug treatments exist for hereditary spastic paraplegia; management is supportive (see
Treatment of Manifestations in Individuals with Spastic Paraplegia 8
Stretching exercises to improve flexibility, ↓ spasticity & maintain or improve joint range of motion & prevent joint contractures
Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination & balance
Strengthening exercises to improve posture; walking; arm strength to improve use of mobility aids; activites of daily living
Feet: appropriate footwear
Orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Training how to fall to minimize risk of injury
To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
To assist w/household modifications to meet special needs
OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor
Demonstrated by
Oral baclofen can be tried first, and can also be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.
Recommended Surveillance for Individuals with Spastic Paraplegia 8
OT = occupational therapy; PT = physical therapy
See
See
Of the two studies currently recruiting patients with hereditary spastic paraplegia, one involves a therapy. The NCT04180098 study will assess the effectiveness of the physical therapy intervention C-Mill in improving gait adaptability.
Search
• Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Fine motor function (e.g., hands, feet, face, fingers, & toes)
• Activities of daily living
• Speech disorder (dysarthria)
• Swallowing disorder (dysphagia)
• Use of
• Social work involvement for caregiver support;
• Home nursing referral.
• Stretching exercises to improve flexibility, ↓ spasticity & maintain or improve joint range of motion & prevent joint contractures
• Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination & balance
• Strengthening exercises to improve posture; walking; arm strength to improve use of mobility aids; activites of daily living
• Feet: appropriate footwear
• Orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
• Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Training how to fall to minimize risk of injury
• To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
• To assist w/household modifications to meet special needs
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 8 (SPG8), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spastic Paraplegia 8
Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Fine motor function (e.g., hands, feet, face, fingers, & toes)
Activities of daily living
Speech disorder (dysarthria)
Swallowing disorder (dysphagia)
Use of
Social work involvement for caregiver support;
Home nursing referral.
Based on information provided by
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Fine motor function (e.g., hands, feet, face, fingers, & toes)
• Activities of daily living
• Speech disorder (dysarthria)
• Swallowing disorder (dysphagia)
• Use of
• Social work involvement for caregiver support;
• Home nursing referral.
## Treatment of Manifestations
No cures or specific drug treatments exist for hereditary spastic paraplegia; management is supportive (see
Treatment of Manifestations in Individuals with Spastic Paraplegia 8
Stretching exercises to improve flexibility, ↓ spasticity & maintain or improve joint range of motion & prevent joint contractures
Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination & balance
Strengthening exercises to improve posture; walking; arm strength to improve use of mobility aids; activites of daily living
Feet: appropriate footwear
Orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
Transfers (e.g., from bed to wheelchair, wheelchair to car)
Training how to fall to minimize risk of injury
To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
To assist w/household modifications to meet special needs
OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor
Demonstrated by
Oral baclofen can be tried first, and can also be used with an intrathecal pump in some cases. The entire therapeutic range of doses in all four drugs is used. The drugs are administered before sleep if nocturnal cramps are problematic, otherwise three to four times per day. It usually takes a few days for their effects to become evident. No significant toxicity limits their use.
• Stretching exercises to improve flexibility, ↓ spasticity & maintain or improve joint range of motion & prevent joint contractures
• Aerobic exercise to improve cardiovascular fitness to maintain & improve muscle strength, coordination & balance
• Strengthening exercises to improve posture; walking; arm strength to improve use of mobility aids; activites of daily living
• Feet: appropriate footwear
• Orthotics (shoe inserts, splints, braces) to address gait problems, improve balance, relieve &/or improve pressure sores
• Gait training; use of assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
• Transfers (e.g., from bed to wheelchair, wheelchair to car)
• Training how to fall to minimize risk of injury
• To accomplish tasks such as mobility, washing, dressing, eating, cooking, grooming
• To assist w/household modifications to meet special needs
## Surveillance
Recommended Surveillance for Individuals with Spastic Paraplegia 8
OT = occupational therapy; PT = physical therapy
## Evaluation of Relatives at Risk
See
## Pregnancy Management
See
## Therapies Under Investigation
Of the two studies currently recruiting patients with hereditary spastic paraplegia, one involves a therapy. The NCT04180098 study will assess the effectiveness of the physical therapy intervention C-Mill in improving gait adaptability.
Search
## Genetic Counseling
Spastic paraplegia 8 (SPG8) is inherited in an autosomal dominant manner.
More than 90% of individuals diagnosed with SPG8 have an affected parent.
A proband with SPG8 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
If the
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with SPG8 may appear to be negative because of failure to recognize the disorder in family members with 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 unless molecular genetic testing has been performed on the parents of the proband.
Note: 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 is 50%. Note: Age of onset, severity, type of symptoms, and rate of disease progression may vary between family members heterozygous for the same
If the proband has a known
If the parents have not been tested for the
The optimal time for determination of genetic risk 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.
Predictive testing for at-risk relatives is possible once the SPG8-related pathogenic variant has 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 SPG8, 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.
• More than 90% of individuals diagnosed with SPG8 have an affected parent.
• A proband with SPG8 may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with SPG8 may appear to be negative because of failure to recognize the disorder in family members with 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 unless molecular genetic testing has been performed on the parents of the proband.
• Note: 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 is 50%. Note: Age of onset, severity, type of symptoms, and rate of disease progression may vary between family members heterozygous for the same
• If the proband has a known
• If the parents have not been tested for the
• The optimal time for determination of genetic risk 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.
• Predictive testing for at-risk relatives is possible once the SPG8-related pathogenic variant has 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
Spastic paraplegia 8 (SPG8) is inherited in an autosomal dominant manner.
## Risk to Family Members
More than 90% of individuals diagnosed with SPG8 have an affected parent.
A proband with SPG8 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
If the
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with SPG8 may appear to be negative because of failure to recognize the disorder in family members with 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 unless molecular genetic testing has been performed on the parents of the proband.
Note: 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 is 50%. Note: Age of onset, severity, type of symptoms, and rate of disease progression may vary between family members heterozygous for the same
If the proband has a known
If the parents have not been tested for the
• More than 90% of individuals diagnosed with SPG8 have an affected parent.
• A proband with SPG8 may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with SPG8 may appear to be negative because of failure to recognize the disorder in family members with 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 unless molecular genetic testing has been performed on the parents of the proband.
• Note: 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 is 50%. Note: Age of onset, severity, type of symptoms, and rate of disease progression may vary between family members heterozygous for the same
• If the proband has a known
• If the parents have not been tested for the
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk 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.
Predictive testing for at-risk relatives is possible once the SPG8-related pathogenic variant has 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 SPG8, it is appropriate to consider testing of symptomatic individuals regardless of age.
• The optimal time for determination of genetic risk 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.
• Predictive testing for at-risk relatives is possible once the SPG8-related pathogenic variant has 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
Australia
Tom Wahlig Stiftung
Germany
Associazione Italiana Vivere la Paraparesi Spastica
Italy
•
•
•
• Australia
•
•
•
•
•
•
• Tom Wahlig Stiftung
• Germany
•
•
• Associazione Italiana Vivere la Paraparesi Spastica
• Italy
•
## Molecular Genetics
Spastic Paraplegia 8: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spastic Paraplegia 8 (
Cells lacking strumpellin have abnormally enlarged lysosomes. Furthermore, defective endosomal tubule fission was found to cause these lysosomal abnormalities, a mechanism shared with spastin disease models (see
The p.Asn471Asp pathogenic variant, within the spectrin-binding domain, does not impair the interaction of strumpellin and VCP, but could impair interactions with other proteins [
Delivery of
A pathogenic heterozygous deletion of exon 11-15 includes the spectrin repeat domain and the conserved domain [
Finally, the pathogenic variants
A murine
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Cells lacking strumpellin have abnormally enlarged lysosomes. Furthermore, defective endosomal tubule fission was found to cause these lysosomal abnormalities, a mechanism shared with spastin disease models (see
• The p.Asn471Asp pathogenic variant, within the spectrin-binding domain, does not impair the interaction of strumpellin and VCP, but could impair interactions with other proteins [
• Delivery of
• A pathogenic heterozygous deletion of exon 11-15 includes the spectrin repeat domain and the conserved domain [
• Finally, the pathogenic variants
## Molecular Pathogenesis
Cells lacking strumpellin have abnormally enlarged lysosomes. Furthermore, defective endosomal tubule fission was found to cause these lysosomal abnormalities, a mechanism shared with spastin disease models (see
The p.Asn471Asp pathogenic variant, within the spectrin-binding domain, does not impair the interaction of strumpellin and VCP, but could impair interactions with other proteins [
Delivery of
A pathogenic heterozygous deletion of exon 11-15 includes the spectrin repeat domain and the conserved domain [
Finally, the pathogenic variants
A murine
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Cells lacking strumpellin have abnormally enlarged lysosomes. Furthermore, defective endosomal tubule fission was found to cause these lysosomal abnormalities, a mechanism shared with spastin disease models (see
• The p.Asn471Asp pathogenic variant, within the spectrin-binding domain, does not impair the interaction of strumpellin and VCP, but could impair interactions with other proteins [
• Delivery of
• A pathogenic heterozygous deletion of exon 11-15 includes the spectrin repeat domain and the conserved domain [
• Finally, the pathogenic variants
## Chapter Notes
21 May 2020 (bp) Comprehensive update posted live
25 July 2013 (me) Comprehensive update posted live
13 August 2008 (me) Review posted live
16 June 2008 (pnv) Original submission
• 21 May 2020 (bp) Comprehensive update posted live
• 25 July 2013 (me) Comprehensive update posted live
• 13 August 2008 (me) Review posted live
• 16 June 2008 (pnv) Original submission
## Revision History
21 May 2020 (bp) Comprehensive update posted live
25 July 2013 (me) Comprehensive update posted live
13 August 2008 (me) Review posted live
16 June 2008 (pnv) Original submission
• 21 May 2020 (bp) Comprehensive update posted live
• 25 July 2013 (me) Comprehensive update posted live
• 13 August 2008 (me) Review posted live
• 16 June 2008 (pnv) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
13/8/2008
|
21/5/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
spondylocostal-d
|
spondylocostal-d
|
[
"Costovertebral Dysplasia",
"Spondylocostal Dysplasia",
"Costovertebral Dysplasia",
"Spondylocostal Dysplasia",
"Beta-1,3-N-acetylglucosaminyltransferase lunatic fringe",
"Delta-like protein 3",
"Mesoderm posterior protein 2",
"Protein ripply2",
"T-box transcription factor TBX6",
"Transcription factor HES-7",
"DLL3",
"HES7",
"LFNG",
"MESP2",
"RIPPLY2",
"TBX6",
"Spondylocostal Dysostosis, Autosomal Recessive"
] |
Spondylocostal Dysostosis, Autosomal Recessive
|
Peter D Turnpenny, Melissa Sloman, Sally Dunwoodie
|
Summary Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae in combination with abnormalities of the ribs, is characterized clinically by a short trunk in proportion to height; short neck; and non-progressive mild scoliosis in most affected individuals – rarely, more significant scoliosis occurs. Respiratory function in neonates with severe disease may be compromised by reduced size of the thorax. By age two years lung growth may improve sufficiently to support relatively normal growth and development. In severely affected individuals with restricted pulmonary capacity, there is a possibility that pulmonary hypertension may eventually impact cardiac function. Males with SCDO appear to be at increased risk for inguinal hernia. The diagnosis of SCDO is based on radiographic features. Identification of biallelic pathogenic variants in SCDO caused by biallelic pathogenic variants in
|
## Diagnosis
Spondylocostal dysostosis (SCDO)
No major asymmetry to the shape of the thorax
The diagnosis of autosomal recessive SCDO
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
Sequence analysis of
Sequence analysis of
When the phenotype is indistinguishable from many other skeletal dysplasias, c
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Autosomal Recessive Spondylocostal Dysostosis
AR = autosomal recessive; SCDO = spondylocostal dysostosis
Genes are listed in alphabetic order.
See
The percentages in column two are estimates based on published reports [Authors, personal communication].
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 individual with a deletion of exons 2-4 (detected by an in-house-designed MLPA kit) and one individual with a whole-gene deletion (detected by array CGH and confirmed by in-house-designed MLPA) [Authors, personal communication]
Three reported families and an additional four unreported individuals [P Turnpenny, personal communication]
No deletions or duplications involving
Three known families with
Six families with
Large
One individual with an SCDO-like phenotype including multiple regional segmentation defects of the vertebrae and multiple intervertebral fusions of laminae, in addition to dysmorphic features and cleft palate, was homozygous for a
• No major asymmetry to the shape of the thorax
• Sequence analysis of
• Sequence analysis of
## Suggestive Findings
Spondylocostal dysostosis (SCDO)
No major asymmetry to the shape of the thorax
• No major asymmetry to the shape of the thorax
## Establishing the Diagnosis
The diagnosis of autosomal recessive SCDO
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
Sequence analysis of
Sequence analysis of
When the phenotype is indistinguishable from many other skeletal dysplasias, c
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Autosomal Recessive Spondylocostal Dysostosis
AR = autosomal recessive; SCDO = spondylocostal dysostosis
Genes are listed in alphabetic order.
See
The percentages in column two are estimates based on published reports [Authors, personal communication].
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 individual with a deletion of exons 2-4 (detected by an in-house-designed MLPA kit) and one individual with a whole-gene deletion (detected by array CGH and confirmed by in-house-designed MLPA) [Authors, personal communication]
Three reported families and an additional four unreported individuals [P Turnpenny, personal communication]
No deletions or duplications involving
Three known families with
Six families with
Large
One individual with an SCDO-like phenotype including multiple regional segmentation defects of the vertebrae and multiple intervertebral fusions of laminae, in addition to dysmorphic features and cleft palate, was homozygous for a
• Sequence analysis of
• Sequence analysis of
## Option 1
For an introduction to multigene panels click
Sequence analysis of
Sequence analysis of
• Sequence analysis of
• Sequence analysis of
## Option 2
When the phenotype is indistinguishable from many other skeletal dysplasias, c
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Autosomal Recessive Spondylocostal Dysostosis
AR = autosomal recessive; SCDO = spondylocostal dysostosis
Genes are listed in alphabetic order.
See
The percentages in column two are estimates based on published reports [Authors, personal communication].
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 individual with a deletion of exons 2-4 (detected by an in-house-designed MLPA kit) and one individual with a whole-gene deletion (detected by array CGH and confirmed by in-house-designed MLPA) [Authors, personal communication]
Three reported families and an additional four unreported individuals [P Turnpenny, personal communication]
No deletions or duplications involving
Three known families with
Six families with
Large
One individual with an SCDO-like phenotype including multiple regional segmentation defects of the vertebrae and multiple intervertebral fusions of laminae, in addition to dysmorphic features and cleft palate, was homozygous for a
## Clinical Characteristics
Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae that is usually generalized throughout the spine, is characterized clinically by a short trunk in proportion to height, short neck, and non-progressive mild scoliosis in most affected individuals. To date, nearly 100 individuals have been identified and/or reported with SCDO and biallelic pathogenic variants in one of the genes listed in
A short trunk in proportion to height. The extent varies and the data is very limited, but based on leg length measurements, individuals with SCDO are 10% shorter than projected adult height. Some individuals have severe short stature, with height up to four standard deviations below the mean [
Short neck. The extent varies, and the data is limited, but – similar to the decrease in overall spine length – the neck is likely to be shortened by approximately 10%. The range of limitation in neck mobility has not been formally assessed.
Non-progressive, or mildly progressive but self-limiting, scoliosis occurs in most affected individuals, usually apparent radiographically in infancy. More significant scoliosis, with a greater degree of progression, especially at the thoracolumbar region, is apparent in individuals with
In children requiring early respiratory support, lung growth may improve sufficiently to support relatively normal growth and development by age two years. However, life-threatening complications can occur, especially pulmonary hypertension and cardiac failure in individuals with severely restricted lung capacity from birth. There is no systematic review concerning susceptibility to pulmonary infection and pneumonia or incidence of pulmonary hypertension.
Cosegregation of dextrocardia was reported in a large consanguineous Middle Eastern kindred with
Solitary pelvic kidney, uterine dysgenesis, absence epilepsy, and inner ear (presumed sensorineural) deafness were reported in one individual with
See
No genotype-phenotype correlations for
To date, penetrance appears to be complete for the pathogenic variants implicated in autosomal recessive SCDO.
The term
All radiologic phenotypes that include segmentation defects of the vertebrae (SDV) and abnormal rib alignment, including reports of phenotypes that are neither similar to the case description of
STD in Puerto Ricans of Spanish descent (see
Use of the terms
"Costovertebral dysplasia" is now used less frequently.
"Spondylothoracic dysostosis/dysplasia" (STD) is recognized as being distinct from SCDO (see
Note: Spondylothoracic dysostosis is referred to as "vertebral segmentation defect (congenital scoliosis) with variable penetrance" in the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The wide range of radiologic phenotypes with multiple segmentation defects of the vertebrae (M-SDV) within SCDO has highlighted the need to rationalize nomenclature for these diverse and poorly understood disorders. The International Consortium for Vertebral Anomalies and Scoliosis (ICVAS), now subsumed into the International Consortium for Scoliosis Genetics Development and Disease (ICSGDD), proposed two algorithms:
The clinical algorithm, used for routine reporting of SDV, identifies seven broad categories (see
The research algorithm, used for more detailed documentation of SDV, employs ontology applicable to humans and animal models (see
• A short trunk in proportion to height. The extent varies and the data is very limited, but based on leg length measurements, individuals with SCDO are 10% shorter than projected adult height. Some individuals have severe short stature, with height up to four standard deviations below the mean [
• Short neck. The extent varies, and the data is limited, but – similar to the decrease in overall spine length – the neck is likely to be shortened by approximately 10%. The range of limitation in neck mobility has not been formally assessed.
• Non-progressive, or mildly progressive but self-limiting, scoliosis occurs in most affected individuals, usually apparent radiographically in infancy. More significant scoliosis, with a greater degree of progression, especially at the thoracolumbar region, is apparent in individuals with
• Cosegregation of dextrocardia was reported in a large consanguineous Middle Eastern kindred with
• Solitary pelvic kidney, uterine dysgenesis, absence epilepsy, and inner ear (presumed sensorineural) deafness were reported in one individual with
• All radiologic phenotypes that include segmentation defects of the vertebrae (SDV) and abnormal rib alignment, including reports of phenotypes that are neither similar to the case description of
• STD in Puerto Ricans of Spanish descent (see
• "Costovertebral dysplasia" is now used less frequently.
• "Spondylothoracic dysostosis/dysplasia" (STD) is recognized as being distinct from SCDO (see
• Note: Spondylothoracic dysostosis is referred to as "vertebral segmentation defect (congenital scoliosis) with variable penetrance" in the 2023 revision of the Nosology of Genetic Skeletal Disorders [
• The clinical algorithm, used for routine reporting of SDV, identifies seven broad categories (see
• The research algorithm, used for more detailed documentation of SDV, employs ontology applicable to humans and animal models (see
## Clinical Description
Spondylocostal dysostosis (SCDO), defined radiographically as multiple segmentation defects of the vertebrae that is usually generalized throughout the spine, is characterized clinically by a short trunk in proportion to height, short neck, and non-progressive mild scoliosis in most affected individuals. To date, nearly 100 individuals have been identified and/or reported with SCDO and biallelic pathogenic variants in one of the genes listed in
A short trunk in proportion to height. The extent varies and the data is very limited, but based on leg length measurements, individuals with SCDO are 10% shorter than projected adult height. Some individuals have severe short stature, with height up to four standard deviations below the mean [
Short neck. The extent varies, and the data is limited, but – similar to the decrease in overall spine length – the neck is likely to be shortened by approximately 10%. The range of limitation in neck mobility has not been formally assessed.
Non-progressive, or mildly progressive but self-limiting, scoliosis occurs in most affected individuals, usually apparent radiographically in infancy. More significant scoliosis, with a greater degree of progression, especially at the thoracolumbar region, is apparent in individuals with
In children requiring early respiratory support, lung growth may improve sufficiently to support relatively normal growth and development by age two years. However, life-threatening complications can occur, especially pulmonary hypertension and cardiac failure in individuals with severely restricted lung capacity from birth. There is no systematic review concerning susceptibility to pulmonary infection and pneumonia or incidence of pulmonary hypertension.
Cosegregation of dextrocardia was reported in a large consanguineous Middle Eastern kindred with
Solitary pelvic kidney, uterine dysgenesis, absence epilepsy, and inner ear (presumed sensorineural) deafness were reported in one individual with
• A short trunk in proportion to height. The extent varies and the data is very limited, but based on leg length measurements, individuals with SCDO are 10% shorter than projected adult height. Some individuals have severe short stature, with height up to four standard deviations below the mean [
• Short neck. The extent varies, and the data is limited, but – similar to the decrease in overall spine length – the neck is likely to be shortened by approximately 10%. The range of limitation in neck mobility has not been formally assessed.
• Non-progressive, or mildly progressive but self-limiting, scoliosis occurs in most affected individuals, usually apparent radiographically in infancy. More significant scoliosis, with a greater degree of progression, especially at the thoracolumbar region, is apparent in individuals with
• Cosegregation of dextrocardia was reported in a large consanguineous Middle Eastern kindred with
• Solitary pelvic kidney, uterine dysgenesis, absence epilepsy, and inner ear (presumed sensorineural) deafness were reported in one individual with
## Phenotype Correlations by Gene
See
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Penetrance
To date, penetrance appears to be complete for the pathogenic variants implicated in autosomal recessive SCDO.
## Nomenclature
The term
All radiologic phenotypes that include segmentation defects of the vertebrae (SDV) and abnormal rib alignment, including reports of phenotypes that are neither similar to the case description of
STD in Puerto Ricans of Spanish descent (see
Use of the terms
"Costovertebral dysplasia" is now used less frequently.
"Spondylothoracic dysostosis/dysplasia" (STD) is recognized as being distinct from SCDO (see
Note: Spondylothoracic dysostosis is referred to as "vertebral segmentation defect (congenital scoliosis) with variable penetrance" in the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The wide range of radiologic phenotypes with multiple segmentation defects of the vertebrae (M-SDV) within SCDO has highlighted the need to rationalize nomenclature for these diverse and poorly understood disorders. The International Consortium for Vertebral Anomalies and Scoliosis (ICVAS), now subsumed into the International Consortium for Scoliosis Genetics Development and Disease (ICSGDD), proposed two algorithms:
The clinical algorithm, used for routine reporting of SDV, identifies seven broad categories (see
The research algorithm, used for more detailed documentation of SDV, employs ontology applicable to humans and animal models (see
• All radiologic phenotypes that include segmentation defects of the vertebrae (SDV) and abnormal rib alignment, including reports of phenotypes that are neither similar to the case description of
• STD in Puerto Ricans of Spanish descent (see
• "Costovertebral dysplasia" is now used less frequently.
• "Spondylothoracic dysostosis/dysplasia" (STD) is recognized as being distinct from SCDO (see
• Note: Spondylothoracic dysostosis is referred to as "vertebral segmentation defect (congenital scoliosis) with variable penetrance" in the 2023 revision of the Nosology of Genetic Skeletal Disorders [
• The clinical algorithm, used for routine reporting of SDV, identifies seven broad categories (see
• The research algorithm, used for more detailed documentation of SDV, employs ontology applicable to humans and animal models (see
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Heterozygous
Autosomal dominant spondylocostal dysostosis (SCDO) was identified in a three-generation family. The widespread vertebral malformations consisted of a mixture of hemivertebrae and blocks of fused segments. There was relative sparing of rib involvement. Mild scoliosis was centered on the mid-thoracic region. No other anomalies were identified, and neurodevelopment was normal. A heterozygous
Variable segmentation anomalies, most commonly affecting the lower thoracic or upper lumbar regions and usually presenting as congenital scoliosis, have been reported. This may be due to deletion of
A distinct, very severe, lethal form of STD with müllerian duct anomalies was reported [P Turnpenny, unpublished data], more severe than the individual with severe
Müllerian aplasia / MURCS association / Mayer-Rokitansky-Küster-Hauser syndrome has been reported [
• Heterozygous
• Autosomal dominant spondylocostal dysostosis (SCDO) was identified in a three-generation family. The widespread vertebral malformations consisted of a mixture of hemivertebrae and blocks of fused segments. There was relative sparing of rib involvement. Mild scoliosis was centered on the mid-thoracic region. No other anomalies were identified, and neurodevelopment was normal. A heterozygous
• Variable segmentation anomalies, most commonly affecting the lower thoracic or upper lumbar regions and usually presenting as congenital scoliosis, have been reported. This may be due to deletion of
• A distinct, very severe, lethal form of STD with müllerian duct anomalies was reported [P Turnpenny, unpublished data], more severe than the individual with severe
• Müllerian aplasia / MURCS association / Mayer-Rokitansky-Küster-Hauser syndrome has been reported [
## Differential Diagnosis
Rarely, spondylocostal dysostosis (SCDO) occurs in association with chromosome abnormalities; however, apart from trisomy 8 mosaicism, no consistent genomic region has been involved, and the significance of these associations is unknown.
More severe shortening of the spine (all vertebral segments affected), especially the thoracic spine, leading to impaired respiratory function in infancy
Rib fusions typically occurring posteriorly at the costovertebral origins, where the spinal shortening is most severe. The ribs usually appear straight and neatly aligned without points of fusion along their length. On anteroposterior x-ray the ribs characteristically "fan out" from their costovertebral origins in a "crab-like" fashion.
A distinctive radiographic appearance called the "tramline sign" that results from early radiographic prominence of the vertebral pedicles, in contrast to the vertebral bodies, which have no regular form or layout [
Segmentation defects of the vertebrae (SDV) are estimated to occur in 0.5-1.0 in 1,000 live births, but in clinical practice the radiologic phenotypes and syndromic associations are extremely diverse. Syndromic forms of multiple segmentation defects of the vertebrae (M-SDV) should be considered if the diagnostic criteria for SCDO or STD are not met. For most individuals the underlying cause is not known, but an increasing number of genes are being identified. Some of the M-SDV syndromes to consider are listed in
Selected Genes Associated With M-SDV (SCDO and STD excluded)
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; M-SDV = multiple segmentation defects of the vertebrae; RAPADILINO = radial ray defect, patellae hypoplasia or aplasia and cleft or highly arched palate, diarrhea and dislocated joints, little size and limb malformation, nose slender and normal intelligence; SCDO = spondylocostal dysostosis; STD = spondylothoracic dysostosis; XL = X-linked
KBG syndrome is caused by either a heterozygous pathogenic variant in
Other Syndromes/Conditions That Include M-SDV (SCDO and STD excluded)
M-SDV = multiple segmentation defects of the vertebrae; SCDO = spondylocostal dysostosis; STD = spondylothoracic dysostosis
Note: A single individual with an SCDO-like phenotype with multiple regional segmentation defects of the vertebrae, multiple intervertebral fusions of laminae, dysmorphic features, and cleft palate has been reported in association with homozygosity for a start-loss variant in
• More severe shortening of the spine (all vertebral segments affected), especially the thoracic spine, leading to impaired respiratory function in infancy
• Rib fusions typically occurring posteriorly at the costovertebral origins, where the spinal shortening is most severe. The ribs usually appear straight and neatly aligned without points of fusion along their length. On anteroposterior x-ray the ribs characteristically "fan out" from their costovertebral origins in a "crab-like" fashion.
• A distinctive radiographic appearance called the "tramline sign" that results from early radiographic prominence of the vertebral pedicles, in contrast to the vertebral bodies, which have no regular form or layout [
## Management
No clinical practice guidelines for autosomal recessive spondylocostal dysostosis (SCDO) have been published.
To establish the extent of disease and needs in an individual diagnosed with autosomal recessive SCDO, the evaluations summarized in
Autosomal Recessive Spondylocostal Dysostosis: Recommended Evaluations Following Initial Diagnosis
Assessment of feeding
Eval of male child for presence of inguinal hernia
Community or
Social work involvement for parental support;
Home nursing referral.
AR = autosomal recessive; MOI = mode of inheritance; SCDO = spondylocostal dysostosis
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
In the majority of individuals, treatment is conservative because the clinical manifestations of the vertebral and rib malformations do not increase with age.
Autosomal Recessive Spondylocostal Dysostosis: Treatment of Manifestations
Respiratory support, depending on extent of pulmonary compromise (usually only necessary in severe disease)
Assessment for complications of respiratory disease, incl pulmonary hypertension & cardiac failure as indicated
Educate parents / care providers of young males of signs/symptoms of inguinal hernia & potential complications.
Routine mgmt of inguinal hernia per general surgeon
SCDO = spondylocostal dysostosis
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Autosomal Recessive Spondylocostal Dysostosis: Recommended Surveillance
SCDO = spondylocostal dysostosis
See
Virtually all individuals with SCDO have relative truncal shortening, and some have generalized short stature. For affected women, pregnancy may give rise to exaggerated intra-abdominal pressure problems, though there is no published research on this issue. As the spine is distorted, there are likely to be concerns with offering spinal and/or epidural anesthesia. However, spinal anesthesia has been successfully administered [
Search
• Assessment of feeding
• Eval of male child for presence of inguinal hernia
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Respiratory support, depending on extent of pulmonary compromise (usually only necessary in severe disease)
• Assessment for complications of respiratory disease, incl pulmonary hypertension & cardiac failure as indicated
• Educate parents / care providers of young males of signs/symptoms of inguinal hernia & potential complications.
• Routine mgmt of inguinal hernia per general surgeon
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with autosomal recessive SCDO, the evaluations summarized in
Autosomal Recessive Spondylocostal Dysostosis: Recommended Evaluations Following Initial Diagnosis
Assessment of feeding
Eval of male child for presence of inguinal hernia
Community or
Social work involvement for parental support;
Home nursing referral.
AR = autosomal recessive; MOI = mode of inheritance; SCDO = spondylocostal dysostosis
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assessment of feeding
• Eval of male child for presence of inguinal hernia
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
In the majority of individuals, treatment is conservative because the clinical manifestations of the vertebral and rib malformations do not increase with age.
Autosomal Recessive Spondylocostal Dysostosis: Treatment of Manifestations
Respiratory support, depending on extent of pulmonary compromise (usually only necessary in severe disease)
Assessment for complications of respiratory disease, incl pulmonary hypertension & cardiac failure as indicated
Educate parents / care providers of young males of signs/symptoms of inguinal hernia & potential complications.
Routine mgmt of inguinal hernia per general surgeon
SCDO = spondylocostal dysostosis
• Respiratory support, depending on extent of pulmonary compromise (usually only necessary in severe disease)
• Assessment for complications of respiratory disease, incl pulmonary hypertension & cardiac failure as indicated
• Educate parents / care providers of young males of signs/symptoms of inguinal hernia & potential complications.
• Routine mgmt of inguinal hernia per general surgeon
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Autosomal Recessive Spondylocostal Dysostosis: Recommended Surveillance
SCDO = spondylocostal dysostosis
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Virtually all individuals with SCDO have relative truncal shortening, and some have generalized short stature. For affected women, pregnancy may give rise to exaggerated intra-abdominal pressure problems, though there is no published research on this issue. As the spine is distorted, there are likely to be concerns with offering spinal and/or epidural anesthesia. However, spinal anesthesia has been successfully administered [
## Therapies Under Investigation
Search
## Genetic Counseling
Spondylocostal dysostosis (SCDO) caused by biallelic pathogenic variants in
Note: Autosomal dominant inheritance of
The parents of an affected child are presumed to be heterozygous for an autosomal recessive SCDO-causing 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 an autosomal recessive SCDO-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 SCDO-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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
* Molecular genetic testing for reproductive partners is appropriate, particularly if consanguinity is likely. Approximately 75% of individuals with autosomal recessive SCDO are from consanguineous families, usually from communities in which cousin partnerships are common.
Carrier testing for at-risk relatives requires prior identification of the autosomal recessive SCDO-causing pathogenic variants in the family. See
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 of being carriers.
Molecular genetic carrier testing of individuals from high-risk families, in which one or more individuals has been diagnosed with SCDO, may be helpful in identifying at-risk couples.
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 autosomal recessive SCDO-causing 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 an autosomal recessive SCDO-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 SCDO-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.
• 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 testing is before 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.
• Molecular genetic carrier testing of individuals from high-risk families, in which one or more individuals has been diagnosed with SCDO, may be helpful in identifying at-risk couples.
## Mode of Inheritance
Spondylocostal dysostosis (SCDO) caused by biallelic pathogenic variants in
Note: Autosomal dominant inheritance of
## Risk to Family Members (Autosomal Recessive Inheritance)
The parents of an affected child are presumed to be heterozygous for an autosomal recessive SCDO-causing 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 an autosomal recessive SCDO-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 SCDO-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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
* Molecular genetic testing for reproductive partners is appropriate, particularly if consanguinity is likely. Approximately 75% of individuals with autosomal recessive SCDO are from consanguineous families, usually from communities in which cousin partnerships are common.
• The parents of an affected child are presumed to be heterozygous for an autosomal recessive SCDO-causing 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 an autosomal recessive SCDO-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 SCDO-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.
• 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 autosomal recessive SCDO-causing pathogenic variants in the family. See
## 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, are carriers, or are at risk of being carriers.
Molecular genetic carrier testing of individuals from high-risk families, in which one or more individuals has been diagnosed with SCDO, may be helpful in identifying at-risk couples.
• 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 of being carriers.
• Molecular genetic carrier testing of individuals from high-risk families, in which one or more individuals has been diagnosed with SCDO, may be helpful in identifying at-risk couples.
## 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
Spondylocostal Dysostosis, Autosomal Recessive: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spondylocostal Dysostosis, Autosomal Recessive (
The six genes known to be associated with the six subtypes of autosomal recessive spondylocostal dysostosis (SCDO) encode proteins that are key components of the Notch signaling pathway, which (together with FGF and Wnt signaling) is one of the developmental pathways essential to normal somitogenesis [
Autosomal Recessive Spondylocostal Dysostosis: Gene-Specific Laboratory Considerations
Exon 1 contains a GQ poly tract consisting of 12 nucleotide repeats of type A, B, or C beginning at nucleotide 535. Repeat A: GGG CAG GGG CAA; repeat B: GGA CAG GGG CAA; repeat C: GGG CAG GGG CGC.
The reference sequence has an AABBC repeat. Bidirectional Sanger sequencing may be required.
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
• Exon 1 contains a GQ poly tract consisting of 12 nucleotide repeats of type A, B, or C beginning at nucleotide 535. Repeat A: GGG CAG GGG CAA; repeat B: GGA CAG GGG CAA; repeat C: GGG CAG GGG CGC.
• The reference sequence has an AABBC repeat. Bidirectional Sanger sequencing may be required.
## Molecular Pathogenesis
The six genes known to be associated with the six subtypes of autosomal recessive spondylocostal dysostosis (SCDO) encode proteins that are key components of the Notch signaling pathway, which (together with FGF and Wnt signaling) is one of the developmental pathways essential to normal somitogenesis [
Autosomal Recessive Spondylocostal Dysostosis: Gene-Specific Laboratory Considerations
Exon 1 contains a GQ poly tract consisting of 12 nucleotide repeats of type A, B, or C beginning at nucleotide 535. Repeat A: GGG CAG GGG CAA; repeat B: GGA CAG GGG CAA; repeat C: GGG CAG GGG CGC.
The reference sequence has an AABBC repeat. Bidirectional Sanger sequencing may be required.
Genes from
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
• Exon 1 contains a GQ poly tract consisting of 12 nucleotide repeats of type A, B, or C beginning at nucleotide 535. Repeat A: GGG CAG GGG CAA; repeat B: GGA CAG GGG CAA; repeat C: GGG CAG GGG CGC.
• The reference sequence has an AABBC repeat. Bidirectional Sanger sequencing may be required.
## Chapter Notes
Research on spondylocostal dysostosis (SCDO) in Exeter has been funded by Action Medical Research, British Scoliosis Research Foundation, and the Skeletal Dysplasia Group, to whom the authors are indebted. In the Exeter Molecular Genetics Laboratory the work was undertaken by Mike Bulman, June Duncan (deceased), Neil Whittock, and recently Melissa Sloman, all under the supervision of Sian Ellard. The work greatly benefited from collaboration with Kenro Kusumi, Sally Dunwoodie, and, more recently, Olivier Pourquié, Philip Giampietro, Alberto Cornier, Amaka Offiah, and Ben Alman, through the ICVAS consortium. Many clinicians have sent images of individuals with segmentation defects of the vertebrae (SDV), but for this review particular thanks are due to Dr Oivind Braaten, Oslo, Norway, and Drs Karin van Spaendonck-Zwarts and Mirjam M de Jong, Groningen, the Netherlands, Professor Eleni Fryysira and Dr Michael Christadoulou, Athens, Greece, and Dr Charles Shaw-Smith, Exeter, UK. Sally Dunwoodie received SCDO research funds from the National Health and Medical Research Council (ID142006, 404804,1044543, 1042002, 1135886).
Sally Dunwoodie, BSc PhD (2017-present)Melissa Sloman, BSc, DipRCPath (2017-present)Peter D Turnpenny, BSc, MB, ChB, FRCP, FRCPCH, FRCPath (2009-present)Elizabeth Young, PhD; Royal Devon & Exeter NHS Foundation Trust (2009-2017)
17 August 2023 (sw) Comprehensive update posted live
21 December 2017 (sw) Comprehensive update posted live
17 January 2013 (me) Comprehensive update posted live
25 August 2009 (et) Review posted live
6 February 2009 (pdt) Original submission
• 17 August 2023 (sw) Comprehensive update posted live
• 21 December 2017 (sw) Comprehensive update posted live
• 17 January 2013 (me) Comprehensive update posted live
• 25 August 2009 (et) Review posted live
• 6 February 2009 (pdt) Original submission
## Author Notes
## Acknowledgments
Research on spondylocostal dysostosis (SCDO) in Exeter has been funded by Action Medical Research, British Scoliosis Research Foundation, and the Skeletal Dysplasia Group, to whom the authors are indebted. In the Exeter Molecular Genetics Laboratory the work was undertaken by Mike Bulman, June Duncan (deceased), Neil Whittock, and recently Melissa Sloman, all under the supervision of Sian Ellard. The work greatly benefited from collaboration with Kenro Kusumi, Sally Dunwoodie, and, more recently, Olivier Pourquié, Philip Giampietro, Alberto Cornier, Amaka Offiah, and Ben Alman, through the ICVAS consortium. Many clinicians have sent images of individuals with segmentation defects of the vertebrae (SDV), but for this review particular thanks are due to Dr Oivind Braaten, Oslo, Norway, and Drs Karin van Spaendonck-Zwarts and Mirjam M de Jong, Groningen, the Netherlands, Professor Eleni Fryysira and Dr Michael Christadoulou, Athens, Greece, and Dr Charles Shaw-Smith, Exeter, UK. Sally Dunwoodie received SCDO research funds from the National Health and Medical Research Council (ID142006, 404804,1044543, 1042002, 1135886).
## Author History
Sally Dunwoodie, BSc PhD (2017-present)Melissa Sloman, BSc, DipRCPath (2017-present)Peter D Turnpenny, BSc, MB, ChB, FRCP, FRCPCH, FRCPath (2009-present)Elizabeth Young, PhD; Royal Devon & Exeter NHS Foundation Trust (2009-2017)
## Revision History
17 August 2023 (sw) Comprehensive update posted live
21 December 2017 (sw) Comprehensive update posted live
17 January 2013 (me) Comprehensive update posted live
25 August 2009 (et) Review posted live
6 February 2009 (pdt) Original submission
• 17 August 2023 (sw) Comprehensive update posted live
• 21 December 2017 (sw) Comprehensive update posted live
• 17 January 2013 (me) Comprehensive update posted live
• 25 August 2009 (et) Review posted live
• 6 February 2009 (pdt) Original submission
## References
The ICVAS classification system for congenital scoliosis and segmentation defects of the vertebrae has been published [
• The ICVAS classification system for congenital scoliosis and segmentation defects of the vertebrae has been published [
## Published Guidelines / Consensus Statements
The ICVAS classification system for congenital scoliosis and segmentation defects of the vertebrae has been published [
• The ICVAS classification system for congenital scoliosis and segmentation defects of the vertebrae has been published [
## Literature Cited
Typical axial skeletal features in an infant with
Individual with
Courtesy of Prof Eleni Fryssira, Athens, Greece.
individuals with
A & C. Individuals with
B. Unaffected individual
E, F, and G. Imaging of individuals with
Reproduced from
Radiograph of infant with
Radiograph of child with
Reproduced from
Radiographs of a child with
A. Spine radiograph as a neonate. The pattern of malsegmentation is not clearly distinguishable from typical findings in
B. Spine of same individual age six years nine months. The block-like appearance of the lumbar vertebrae is seen in this form of SCDO.
Segmentation defects of the vertebrae of the entire spine with angulated vertebral bodies (dotted lines) at birth in an individual with
Reprinted with permission from
Radiographs of a child with
Imaging of individuals with
A-C. 3D CT of male age 15 months with
D. AP radiograph of same male age 12 months, showing hemivertebrae and butterfly vertebrae situated between T2 and T7, resulting in a mild thoracic scoliosis
E & F. 3D CT of affected brother of A-D, age three years, showing complex craniocervical anomaly with deficiency of the posterior elements of C1-C3, left hemivertebrae at C4 and T9, and right hemivertebra at T4.
Reproduced from
Thoracic (A) and lumbar spine (B) radiographs of an infant with
Courtesy of Charles Shaw-Smith, Exeter, UK
Radiologic features for the different genes identified in a cohort of individuals with regional multiple segmentation defects of the vertebrae
A-D. An individual with
E & F. An individual with
G. An individual with
H. An individual with spondylothoracic dysostosis (STD) due to biallelic pathogenic variants in
I & J. An individual with
Reprinted with permission from
Radiograph of a child with a mild form of
ICVAS clinical classification algorithm
All forms of SDV can be placed in one of seven broad categories. The classification combines a descriptive approach for the diverse radiologic phenotypes encountered in clinical practice with specific diagnoses where the genotype and/or syndrome is clearly established. For any given case a radiologic report also includes a specific description of the site and nature of the vertebral anomalies.
G = generalized; M = multiple; R = regional; S = single; SDV = segmentation defect(s) of the vertebrae; U = undefined
ICVAS research classification algorithm: a more detailed, systematic analysis of radiographic anatomic features. Documentation of phenotypes in a systematic ontology facilitates direct interspecies comparison and stratification of patient cohorts for research.
Radiograph of an infant with
|
[] |
25/8/2009
|
17/8/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
spr-def
|
spr-def
|
[
"Dopa-Responsive Hypersomnia",
"DYT-SPR",
"SPR Deficiency",
"SPR Deficiency",
"Dopa-Responsive Hypersomnia",
"DYT-SPR",
"Sepiapterin reductase",
"SPR",
"Sepiapterin Reductase Deficiency"
] |
Sepiapterin Reductase Deficiency
|
Jennifer Friedman
|
Summary The phenotypic spectrum of sepiapterin reductase deficiency (SRD), which ranges from significant motor and cognitive deficits to only minimal findings, has not been completely elucidated. Clinical features in the majority of affected individuals include motor and speech delay, axial hypotonia, dystonia, weakness, and oculogyric crises; symptoms show diurnal fluctuation and sleep benefit. Other common features include parkinsonian signs (tremor, bradykinesia, masked facies, rigidity), limb hypertonia, hyperreflexia, intellectual disability, psychiatric and/or behavioral abnormalities, autonomic dysfunction, and sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, and drowsiness). Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia; other features develop over time. The diagnosis of sepiapterin reductase deficiency is established in a proband by detection of biallelic pathogenic variants in SRD 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
No formal diagnostic criteria for sepiapterin reductase deficiency (SRD) have been published. A diagnostic algorithm is presented in a recent review [
Sepiapterin reductase deficiency (SRD) should be suspected in individuals with characteristic clinical findings. The phenotypic spectrum is broad and suggestive signs are often nonspecific.
Core clinical features present in more than 65% of affected individuals:
Motor and speech delay
Axial hypotonia
Dystonia
Weakness
Oculogyric crises
Diurnal fluctuation and symptom improvement with sleep
Other common features:
Intellectual disability
Limb hypertonia and hyperreflexia
Parkinsonian signs (tremor, bradykinesia, masked facies, rigidity)
Psychiatric and/or behavioral abnormalities
Sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, drowsiness)
Autonomic dysfunction (excessive sweating, ptosis, nasal congestion, temperature instability)
Individuals with any of the following three broad sets of findings should be considered to possibly have SRD [
Developmental delays with axial hypotonia
Unexplained "cerebral palsy," especially if dystonia is present
An L-dopa-responsive motor disorder that may include dystonia. L-dopa responsiveness is evaluated in the following manner: L-dopa (in combination with 10%-25% carbidopa) may be introduced at 1 mg/kg/day and advanced slowly by 1 mg/kg/day over days/weeks monitoring for symptomatic improvement and side effects as the dose is raised. Although data are insufficient to provide precise dosing guidelines, benefit is most often achieved at low dose and is dramatic and rapid (hours to days). Because the response may be delayed or require a high dose (≥10 mg/kg/d) (as has been observed in
Note: Given the broad range of neurologic manifestations (from asymptomatic to severe global developmental delay) and dramatic response to L-dopa, clinicians should maintain a high index of suspicion for SRD or other monoamine neurotransmitter disorders (see
The diagnosis of sepiapterin reductase deficiency is established in a proband by detection of biallelic pathogenic (or likely pathogenic) variants in
Note: 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
Molecular Genetic Testing Used in Sepiapterin Reductase 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
A total of approximately 50 probands have been reported to date [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.
A single report of deletion involving
Decreased levels of homovanillic acid (HVA) and 5-hyroxyindolacetic acid (5-HIAA);
Normal to slightly increased levels of neopterin;
Increased levels of total biopterin, dihydrobiopterin (BH2), and sepiapterin [
Note: (1) CSF should be collected using standardized protocols and analyzed by a laboratory with appropriate age-related reference ranges [
• Motor and speech delay
• Axial hypotonia
• Dystonia
• Weakness
• Oculogyric crises
• Diurnal fluctuation and symptom improvement with sleep
• Intellectual disability
• Limb hypertonia and hyperreflexia
• Parkinsonian signs (tremor, bradykinesia, masked facies, rigidity)
• Psychiatric and/or behavioral abnormalities
• Sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, drowsiness)
• Autonomic dysfunction (excessive sweating, ptosis, nasal congestion, temperature instability)
• Developmental delays with axial hypotonia
• Unexplained "cerebral palsy," especially if dystonia is present
• An L-dopa-responsive motor disorder that may include dystonia. L-dopa responsiveness is evaluated in the following manner: L-dopa (in combination with 10%-25% carbidopa) may be introduced at 1 mg/kg/day and advanced slowly by 1 mg/kg/day over days/weeks monitoring for symptomatic improvement and side effects as the dose is raised. Although data are insufficient to provide precise dosing guidelines, benefit is most often achieved at low dose and is dramatic and rapid (hours to days). Because the response may be delayed or require a high dose (≥10 mg/kg/d) (as has been observed in
• For an introduction to multigene panels click
• Decreased levels of homovanillic acid (HVA) and 5-hyroxyindolacetic acid (5-HIAA);
• Normal to slightly increased levels of neopterin;
• Increased levels of total biopterin, dihydrobiopterin (BH2), and sepiapterin [
• Note: (1) CSF should be collected using standardized protocols and analyzed by a laboratory with appropriate age-related reference ranges [
## Suggestive Findings
Sepiapterin reductase deficiency (SRD) should be suspected in individuals with characteristic clinical findings. The phenotypic spectrum is broad and suggestive signs are often nonspecific.
Core clinical features present in more than 65% of affected individuals:
Motor and speech delay
Axial hypotonia
Dystonia
Weakness
Oculogyric crises
Diurnal fluctuation and symptom improvement with sleep
Other common features:
Intellectual disability
Limb hypertonia and hyperreflexia
Parkinsonian signs (tremor, bradykinesia, masked facies, rigidity)
Psychiatric and/or behavioral abnormalities
Sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, drowsiness)
Autonomic dysfunction (excessive sweating, ptosis, nasal congestion, temperature instability)
Individuals with any of the following three broad sets of findings should be considered to possibly have SRD [
Developmental delays with axial hypotonia
Unexplained "cerebral palsy," especially if dystonia is present
An L-dopa-responsive motor disorder that may include dystonia. L-dopa responsiveness is evaluated in the following manner: L-dopa (in combination with 10%-25% carbidopa) may be introduced at 1 mg/kg/day and advanced slowly by 1 mg/kg/day over days/weeks monitoring for symptomatic improvement and side effects as the dose is raised. Although data are insufficient to provide precise dosing guidelines, benefit is most often achieved at low dose and is dramatic and rapid (hours to days). Because the response may be delayed or require a high dose (≥10 mg/kg/d) (as has been observed in
Note: Given the broad range of neurologic manifestations (from asymptomatic to severe global developmental delay) and dramatic response to L-dopa, clinicians should maintain a high index of suspicion for SRD or other monoamine neurotransmitter disorders (see
• Motor and speech delay
• Axial hypotonia
• Dystonia
• Weakness
• Oculogyric crises
• Diurnal fluctuation and symptom improvement with sleep
• Intellectual disability
• Limb hypertonia and hyperreflexia
• Parkinsonian signs (tremor, bradykinesia, masked facies, rigidity)
• Psychiatric and/or behavioral abnormalities
• Sleep disturbances (hypersomnolence, difficulty initiating or maintaining sleep, drowsiness)
• Autonomic dysfunction (excessive sweating, ptosis, nasal congestion, temperature instability)
• Developmental delays with axial hypotonia
• Unexplained "cerebral palsy," especially if dystonia is present
• An L-dopa-responsive motor disorder that may include dystonia. L-dopa responsiveness is evaluated in the following manner: L-dopa (in combination with 10%-25% carbidopa) may be introduced at 1 mg/kg/day and advanced slowly by 1 mg/kg/day over days/weeks monitoring for symptomatic improvement and side effects as the dose is raised. Although data are insufficient to provide precise dosing guidelines, benefit is most often achieved at low dose and is dramatic and rapid (hours to days). Because the response may be delayed or require a high dose (≥10 mg/kg/d) (as has been observed in
## Establishing the Diagnosis
The diagnosis of sepiapterin reductase deficiency is established in a proband by detection of biallelic pathogenic (or likely pathogenic) variants in
Note: 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
Molecular Genetic Testing Used in Sepiapterin Reductase 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
A total of approximately 50 probands have been reported to date [
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications.
A single report of deletion involving
Decreased levels of homovanillic acid (HVA) and 5-hyroxyindolacetic acid (5-HIAA);
Normal to slightly increased levels of neopterin;
Increased levels of total biopterin, dihydrobiopterin (BH2), and sepiapterin [
Note: (1) CSF should be collected using standardized protocols and analyzed by a laboratory with appropriate age-related reference ranges [
• For an introduction to multigene panels click
• Decreased levels of homovanillic acid (HVA) and 5-hyroxyindolacetic acid (5-HIAA);
• Normal to slightly increased levels of neopterin;
• Increased levels of total biopterin, dihydrobiopterin (BH2), and sepiapterin [
• Note: (1) CSF should be collected using standardized protocols and analyzed by a laboratory with appropriate age-related reference ranges [
## Clinical Characteristics
The phenotypic spectrum of sepiapterin reductase deficiency (SRD) has not been completely elucidated due to the small number of affected individuals reported to date, lack of systematic diagnostic evaluation and long-term follow up, and the absence of data on the prevalence and natural history of findings in untreated individuals. Of particular note, severity varies: some individuals manifest significant motor and cognitive deficits and others only minimal findings. Those with minimal findings may present at an older age or be identified because of the diagnosis of SRD in a sib [
Clinical features in 38 individuals with SRD are summarized by
Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia. In the next few years other features that may develop include limb hypertonia, hyperreflexia, dystonia, and more apparent diurnal fluctuation and sleep disturbance.
In some instances, dystonia may present as paroxysmal stiffening of limbs and/or trunk with gaze deviation and tremor of the tongue, limbs, and/ or head [
Seizures (mostly febrile) occasionally occur, though frequency may be over-reported as oculogyric crises and paroxysmal stiffening episodes may be confused with seizures.
A few reports note low birth weight [
During later childhood, abnormalities in behavior and cognition become more apparent. These may be under-reported due to the prominence of the motor features.
While many affected individuals have intellectual disability, others with mild learning disabilities or normal cognition have been reported.
Psychiatric and/or behavioral findings most commonly include inattention, irritability, and anxiety; however, a wide range of symptoms may occur. It is hypothesized (though not yet proven) that early treatment may mitigate cognitive or psychiatric/behavioral abnormalities.
Although several possible genotype-phenotype correlations have been suggested in individuals with biallelic
One individual heterozygous for a
Two individuals originally reported as having "central" dihydropteridine reductase (DHPR) deficiency [
No data are available on the prevalence of SRD.
A total of approximately 50 probands have been reported to date [
SRD may be under-recognized due to lack of awareness.
## Clinical Description
The phenotypic spectrum of sepiapterin reductase deficiency (SRD) has not been completely elucidated due to the small number of affected individuals reported to date, lack of systematic diagnostic evaluation and long-term follow up, and the absence of data on the prevalence and natural history of findings in untreated individuals. Of particular note, severity varies: some individuals manifest significant motor and cognitive deficits and others only minimal findings. Those with minimal findings may present at an older age or be identified because of the diagnosis of SRD in a sib [
Clinical features in 38 individuals with SRD are summarized by
Most affected individuals have nonspecific features in infancy including developmental delays and axial hypotonia. In the next few years other features that may develop include limb hypertonia, hyperreflexia, dystonia, and more apparent diurnal fluctuation and sleep disturbance.
In some instances, dystonia may present as paroxysmal stiffening of limbs and/or trunk with gaze deviation and tremor of the tongue, limbs, and/ or head [
Seizures (mostly febrile) occasionally occur, though frequency may be over-reported as oculogyric crises and paroxysmal stiffening episodes may be confused with seizures.
A few reports note low birth weight [
During later childhood, abnormalities in behavior and cognition become more apparent. These may be under-reported due to the prominence of the motor features.
While many affected individuals have intellectual disability, others with mild learning disabilities or normal cognition have been reported.
Psychiatric and/or behavioral findings most commonly include inattention, irritability, and anxiety; however, a wide range of symptoms may occur. It is hypothesized (though not yet proven) that early treatment may mitigate cognitive or psychiatric/behavioral abnormalities.
## Genotype-Phenotype Correlations
Although several possible genotype-phenotype correlations have been suggested in individuals with biallelic
One individual heterozygous for a
## Nomenclature
Two individuals originally reported as having "central" dihydropteridine reductase (DHPR) deficiency [
## Prevalence
No data are available on the prevalence of SRD.
A total of approximately 50 probands have been reported to date [
SRD may be under-recognized due to lack of awareness.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
A suggested algorithm for evaluation of patients with global delay with hypotonia, dystonia, or L-dopa-responsive motor disorder may be found in
Tetrahydrobiopterin (BH
Symptoms, which result from impaired phenylalanine homeostasis and serotonin and catecholamine biosynthesis, overlap significantly with SRD. Unlike SRD, these conditions typically (though not always) present with hyperphenylalaninemia detected on newborn screening. More information on the BH
## Management
To establish the extent of disease and needs in an individual diagnosed with sepiapterin reductase deficiency (SRD), the following evaluations are recommended:
Consultation with a neurologist
Physical therapy, occupational therapy, and speech therapy evaluations depending on severity of manifestations
Neuropsychological evaluation depending on the severity of manifestations
Social services consultation depending on the severity of manifestations
Consultation with a clinical geneticist and/or genetic counselor
Therapy is aimed at correcting central nervous system (CNS) neurotransmitter deficits.
Recommended treatments are based on the few reported cases in the literature and extrapolation from strategies employed in treatment of other neurotransmitter disorders.
While the medications discussed below reduce manifestations of SRD, response can range from complete resolution to partial improvement. These medications most consistently correct motor abnormalities while in some cognitive manifestations remain more refractory.
Often, medications must be prescribed "off-label" without established pediatric dose ranges [
Note: (1) Dose-related dyskinesias may occur [
Monoamine oxidase inhibitors (selegeline)
Serotonin reuptake inhibitors (sertraline)
Melatonin
Dopamine agonists (bromocriptine, pramipexole)
Anticholinergics
Methylphenidate
Physical, occupational, and speech therapy may improve or maintain function.
Data are insufficient to determine how frequently CSF levels of dopamine and serotonin metabolites should be evaluated and whether these levels should be used to adjust medication doses. Practices range from at least annual assessment of CNS neurotransmitter metabolites to adjustment of neurotransmitter precursor therapy based solely on clinical manifestations.
Because clinical manifestations are more difficult to assess in children, it would seem prudent to evaluate CSF neurotransmitter metabolites two to four times yearly in children younger than age two years and at least yearly in children younger than age ten years.
Note: Plasma prolactin levels may inversely correlate with CNS dopamine levels but are neither a sensitive nor specific marker [
Although adverse events with specific agents have not been reported in persons with SRD, several should be avoided on a theoretic basis including:
Sulfa drugs, which impair BH
Methotrexate, which inhibits dihydropteridine reductase, an enzyme involved in BH
Nitrous oxide, which may impair folate metabolism [
Neuroleptics and other dopamine antagonists (e.g., metoclopramide)
While no data on outcomes are available, it is appropriate to use molecular genetic testing for the
See
No pregnancies have been reported to date in women with SRD.
Based on reports that suggest that L-dopa may be advantageous during pregnancy in women with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (
Search
• Consultation with a neurologist
• Physical therapy, occupational therapy, and speech therapy evaluations depending on severity of manifestations
• Neuropsychological evaluation depending on the severity of manifestations
• Social services consultation depending on the severity of manifestations
• Consultation with a clinical geneticist and/or genetic counselor
• Note: (1) Dose-related dyskinesias may occur [
• Monoamine oxidase inhibitors (selegeline)
• Serotonin reuptake inhibitors (sertraline)
• Melatonin
• Dopamine agonists (bromocriptine, pramipexole)
• Anticholinergics
• Methylphenidate
• Monoamine oxidase inhibitors (selegeline)
• Serotonin reuptake inhibitors (sertraline)
• Melatonin
• Dopamine agonists (bromocriptine, pramipexole)
• Anticholinergics
• Methylphenidate
• Monoamine oxidase inhibitors (selegeline)
• Serotonin reuptake inhibitors (sertraline)
• Melatonin
• Dopamine agonists (bromocriptine, pramipexole)
• Anticholinergics
• Methylphenidate
• Sulfa drugs, which impair BH
• Methotrexate, which inhibits dihydropteridine reductase, an enzyme involved in BH
• Nitrous oxide, which may impair folate metabolism [
• Neuroleptics and other dopamine antagonists (e.g., metoclopramide)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with sepiapterin reductase deficiency (SRD), the following evaluations are recommended:
Consultation with a neurologist
Physical therapy, occupational therapy, and speech therapy evaluations depending on severity of manifestations
Neuropsychological evaluation depending on the severity of manifestations
Social services consultation depending on the severity of manifestations
Consultation with a clinical geneticist and/or genetic counselor
• Consultation with a neurologist
• Physical therapy, occupational therapy, and speech therapy evaluations depending on severity of manifestations
• Neuropsychological evaluation depending on the severity of manifestations
• Social services consultation depending on the severity of manifestations
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Therapy is aimed at correcting central nervous system (CNS) neurotransmitter deficits.
Recommended treatments are based on the few reported cases in the literature and extrapolation from strategies employed in treatment of other neurotransmitter disorders.
While the medications discussed below reduce manifestations of SRD, response can range from complete resolution to partial improvement. These medications most consistently correct motor abnormalities while in some cognitive manifestations remain more refractory.
Often, medications must be prescribed "off-label" without established pediatric dose ranges [
Note: (1) Dose-related dyskinesias may occur [
Monoamine oxidase inhibitors (selegeline)
Serotonin reuptake inhibitors (sertraline)
Melatonin
Dopamine agonists (bromocriptine, pramipexole)
Anticholinergics
Methylphenidate
• Note: (1) Dose-related dyskinesias may occur [
• Monoamine oxidase inhibitors (selegeline)
• Serotonin reuptake inhibitors (sertraline)
• Melatonin
• Dopamine agonists (bromocriptine, pramipexole)
• Anticholinergics
• Methylphenidate
• Monoamine oxidase inhibitors (selegeline)
• Serotonin reuptake inhibitors (sertraline)
• Melatonin
• Dopamine agonists (bromocriptine, pramipexole)
• Anticholinergics
• Methylphenidate
• Monoamine oxidase inhibitors (selegeline)
• Serotonin reuptake inhibitors (sertraline)
• Melatonin
• Dopamine agonists (bromocriptine, pramipexole)
• Anticholinergics
• Methylphenidate
## Prevention of Secondary Complications
Physical, occupational, and speech therapy may improve or maintain function.
## Surveillance
Data are insufficient to determine how frequently CSF levels of dopamine and serotonin metabolites should be evaluated and whether these levels should be used to adjust medication doses. Practices range from at least annual assessment of CNS neurotransmitter metabolites to adjustment of neurotransmitter precursor therapy based solely on clinical manifestations.
Because clinical manifestations are more difficult to assess in children, it would seem prudent to evaluate CSF neurotransmitter metabolites two to four times yearly in children younger than age two years and at least yearly in children younger than age ten years.
Note: Plasma prolactin levels may inversely correlate with CNS dopamine levels but are neither a sensitive nor specific marker [
## Agents/Circumstances to Avoid
Although adverse events with specific agents have not been reported in persons with SRD, several should be avoided on a theoretic basis including:
Sulfa drugs, which impair BH
Methotrexate, which inhibits dihydropteridine reductase, an enzyme involved in BH
Nitrous oxide, which may impair folate metabolism [
Neuroleptics and other dopamine antagonists (e.g., metoclopramide)
• Sulfa drugs, which impair BH
• Methotrexate, which inhibits dihydropteridine reductase, an enzyme involved in BH
• Nitrous oxide, which may impair folate metabolism [
• Neuroleptics and other dopamine antagonists (e.g., metoclopramide)
## Evaluation of Relatives at Risk
While no data on outcomes are available, it is appropriate to use molecular genetic testing for the
See
## Pregnancy Management
No pregnancies have been reported to date in women with SRD.
Based on reports that suggest that L-dopa may be advantageous during pregnancy in women with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (
## Therapies Under Investigation
Search
## Genetic Counseling
Sepiapterin reductase deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes are generally asymptomatic and are not at risk of developing the disorder. Current data are insufficient to associate clinical manifestations with heterozygosity for an
An individual with a heterozygous
Fibromyalgia which segregated with carrier status in one small pedigree [
The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
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 the sib being a carrier of a
Heterozygotes (carriers) are asymptomatic and are usually not at risk of developing the disorder (see
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 have or are at risk of having one or more
Once the
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes are generally asymptomatic and are not at risk of developing the disorder. Current data are insufficient to associate clinical manifestations with heterozygosity for an
• An individual with a heterozygous
• Fibromyalgia which segregated with carrier status in one small pedigree [
• The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
• An individual with a heterozygous
• Fibromyalgia which segregated with carrier status in one small pedigree [
• The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
• An individual with a heterozygous
• Fibromyalgia which segregated with carrier status in one small pedigree [
• The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
• 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 the sib being a carrier of a
• Heterozygotes (carriers) are asymptomatic and are usually not at risk of developing the disorder (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 have or are at risk of having one or more
## Mode of Inheritance
Sepiapterin reductase 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
Heterozygotes are generally asymptomatic and are not at risk of developing the disorder. Current data are insufficient to associate clinical manifestations with heterozygosity for an
An individual with a heterozygous
Fibromyalgia which segregated with carrier status in one small pedigree [
The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
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 the sib being a carrier of a
Heterozygotes (carriers) are asymptomatic and are usually not at risk of developing the disorder (see
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes are generally asymptomatic and are not at risk of developing the disorder. Current data are insufficient to associate clinical manifestations with heterozygosity for an
• An individual with a heterozygous
• Fibromyalgia which segregated with carrier status in one small pedigree [
• The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
• An individual with a heterozygous
• Fibromyalgia which segregated with carrier status in one small pedigree [
• The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
• An individual with a heterozygous
• Fibromyalgia which segregated with carrier status in one small pedigree [
• The presence of other manifestations including dystonia and parkinsonism in relatives (who had not undergone molecular genetic testing) of individuals with SRD [
• 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 the sib being a carrier of a
• Heterozygotes (carriers) are asymptomatic and are usually not at risk of developing the disorder (see
## Carrier (Heterozygote) 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 have or are at risk of having one or more
• 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 have or are at risk of having one or more
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
United Kingdom
Spanish Neurotransmitter Diseases Association
Spain
Germany
Serbia
United Kingdom
Dystonia Medical Research Foundation
•
• United Kingdom
•
•
• Spanish Neurotransmitter Diseases Association
• Spain
•
•
• Germany
•
•
•
•
• Serbia
•
•
• United Kingdom
•
•
•
•
• Dystonia Medical Research Foundation
•
•
•
## Molecular Genetics
Sepiapterin Reductase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sepiapterin Reductase Deficiency (
Known pathogenic variants are missense, nonsense, and frameshift. Pathogenic variants have been found in all three exons, the 5’ untranslated region, and the intronic region in the splicing acceptor consensus sequence preceding exon 3 [
Homozygosity for the intronic variant c.596-2A>G was the most common genotype found in a cohort of affected individuals from Malta, suggesting a possible founder effect [
Variants listed in the table have been provided by the author.
Symptoms arise primarily from impaired central nervous system serotonin and catecholamine production. Reduced neurotransmitter production is the result of both reduced activity of tyrosine and tryptophan hydroxylases due to reduced levels of BH
Neurotransmitter deficiency is primarily responsible for clinical manifestations; however, several lines of evidence suggest that sepiapterin reductase deficiency may also affect maturation of the dopaminergic system as well as stabilization of the protein tyrosine hydroxylase [
## Chapter Notes
Thank you to patients and families whose participation has enabled us to learn about sepiapterin reductase deficiency and bring benefit to individuals identified with this condition in the future.
1 July 2015 (me) Review posted live
26 January 2015 (jf) Original submission
• 1 July 2015 (me) Review posted live
• 26 January 2015 (jf) Original submission
## Acknowledgments
Thank you to patients and families whose participation has enabled us to learn about sepiapterin reductase deficiency and bring benefit to individuals identified with this condition in the future.
## Revision History
1 July 2015 (me) Review posted live
26 January 2015 (jf) Original submission
• 1 July 2015 (me) Review posted live
• 26 January 2015 (jf) Original submission
## References
## Literature Cited
## Suggested Reading
|
[] |
1/7/2015
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sptbn4
|
sptbn4
|
[
"Neurodevelopmental Disorder with Hypotonia, Neuropathy, and Deafness (NEDHND)",
"Neurodevelopmental Disorder With Hypotonia, Neuropathy, and Deafness (NEDHND)",
"Spectrin beta chain, non-erythrocytic 4",
"SPTBN4",
"SPTBN4 Disorder"
] |
Xilma Ortiz-Gonzalez, Klaas Wierenga
|
Summary The diagnosis of
|
## Diagnosis
Formal clinical diagnostic criteria for
Severe-to-profound developmental delay / intellectual disability
Congenital hypotonia
Neuromuscular weakness
Loss of deep tendon reflexes indicative of neuropathy
Epilepsy, including both focal and/or generalized seizures (infantile spasms)
Cortical visual impairment
Hearing impairment characterized as central deafness or auditory neuropathy
Respiratory difficulties
Feeding difficulties
Normal serum CK level
Muscle biopsy findings consistent with a neurogenic process with evidence of denervation, including fiber type disproportion and/or neurogenic changes
Note: Muscle biopsy is not required to establish the diagnosis.
Electromyography (EMG) / nerve conduction studies (NCS) demonstrating an axonal motor neuropathy/neuronopathy
Abnormal auditory brain stem response (ABR) suggestive of auditory neuropathy
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: 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
To date, 14 different pathogenic variants have been described in 12 families; 8 are truncating variants, 4 are missense, and 2 are splice variants. The majority of affected individuals reported to date are homozygous (12/14).
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 [
• Severe-to-profound developmental delay / intellectual disability
• Congenital hypotonia
• Neuromuscular weakness
• Loss of deep tendon reflexes indicative of neuropathy
• Epilepsy, including both focal and/or generalized seizures (infantile spasms)
• Cortical visual impairment
• Hearing impairment characterized as central deafness or auditory neuropathy
• Respiratory difficulties
• Feeding difficulties
• Normal serum CK level
• Muscle biopsy findings consistent with a neurogenic process with evidence of denervation, including fiber type disproportion and/or neurogenic changes
• Note: Muscle biopsy is not required to establish the diagnosis.
• Electromyography (EMG) / nerve conduction studies (NCS) demonstrating an axonal motor neuropathy/neuronopathy
• Abnormal auditory brain stem response (ABR) suggestive of auditory neuropathy
## Suggestive Findings
Severe-to-profound developmental delay / intellectual disability
Congenital hypotonia
Neuromuscular weakness
Loss of deep tendon reflexes indicative of neuropathy
Epilepsy, including both focal and/or generalized seizures (infantile spasms)
Cortical visual impairment
Hearing impairment characterized as central deafness or auditory neuropathy
Respiratory difficulties
Feeding difficulties
Normal serum CK level
Muscle biopsy findings consistent with a neurogenic process with evidence of denervation, including fiber type disproportion and/or neurogenic changes
Note: Muscle biopsy is not required to establish the diagnosis.
Electromyography (EMG) / nerve conduction studies (NCS) demonstrating an axonal motor neuropathy/neuronopathy
Abnormal auditory brain stem response (ABR) suggestive of auditory neuropathy
• Severe-to-profound developmental delay / intellectual disability
• Congenital hypotonia
• Neuromuscular weakness
• Loss of deep tendon reflexes indicative of neuropathy
• Epilepsy, including both focal and/or generalized seizures (infantile spasms)
• Cortical visual impairment
• Hearing impairment characterized as central deafness or auditory neuropathy
• Respiratory difficulties
• Feeding difficulties
• Normal serum CK level
• Muscle biopsy findings consistent with a neurogenic process with evidence of denervation, including fiber type disproportion and/or neurogenic changes
• Note: Muscle biopsy is not required to establish the diagnosis.
• Electromyography (EMG) / nerve conduction studies (NCS) demonstrating an axonal motor neuropathy/neuronopathy
• Abnormal auditory brain stem response (ABR) suggestive of auditory neuropathy
## 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: 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
To date, 14 different pathogenic variants have been described in 12 families; 8 are truncating variants, 4 are missense, and 2 are splice variants. The majority of affected individuals reported to date are homozygous (12/14).
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
To date, 14 individuals from 12 families have been reported with pathogenic variants in
Features of
Typically severe to profound
1 affected person reported w/normal cognitive development & 1 w/mild gross motor & speech delay at age 2 yrs 5 mos
Time of onset variable
Congenital arthrogryposis in at least 2 persons
Progressive spasticity & contractures also observed in at least 2 persons [
In most reports the phenotypic details were limited and pertinent negatives were often not provided. Therefore, the number of individuals with a specific clinical feature likely represents a minimum proportion.
No clinically relevant genotype-phenotype correlations have been identified.
The prevalence of this condition is unknown. To date, only 14 individuals from 12 families have been reported in the literature. Most affected individuals reported to date have been from consanguineous families.
• Typically severe to profound
• 1 affected person reported w/normal cognitive development & 1 w/mild gross motor & speech delay at age 2 yrs 5 mos
• Time of onset variable
• Congenital arthrogryposis in at least 2 persons
• Progressive spasticity & contractures also observed in at least 2 persons [
## Clinical Description
To date, 14 individuals from 12 families have been reported with pathogenic variants in
Features of
Typically severe to profound
1 affected person reported w/normal cognitive development & 1 w/mild gross motor & speech delay at age 2 yrs 5 mos
Time of onset variable
Congenital arthrogryposis in at least 2 persons
Progressive spasticity & contractures also observed in at least 2 persons [
In most reports the phenotypic details were limited and pertinent negatives were often not provided. Therefore, the number of individuals with a specific clinical feature likely represents a minimum proportion.
• Typically severe to profound
• 1 affected person reported w/normal cognitive development & 1 w/mild gross motor & speech delay at age 2 yrs 5 mos
• Time of onset variable
• Congenital arthrogryposis in at least 2 persons
• Progressive spasticity & contractures also observed in at least 2 persons [
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
## Prevalence
The prevalence of this condition is unknown. To date, only 14 individuals from 12 families have been reported in the literature. Most affected individuals reported to date have been from consanguineous families.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
↑ CK
Congenital brain malformations on MRI
Typically normal hearing
White matter changes on MRI
Normal hearing
AR = autosomal recessive; AD = autosomal dominant; MOI = mode of inheritance
Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). 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.
Listed genes represent a subset of those associated with muscular dystrophy-dystroglycanopathy, type A; for other genes associated with this phenotype in OMIM see
See
• ↑ CK
• Congenital brain malformations on MRI
• Typically normal hearing
• White matter changes on MRI
• Normal hearing
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl motor, adaptive, cognitive, & speech-language eval.
Evaluate for early intervention / special education.
Incl BAER/ABR.
To assess for hearing loss & auditory neuropathy
Risk of nocturnal hypoventilation due to neuromuscular weakness
May require ventilatory support
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement if concern for dysphagia &/or aspiration risk.
Gross motor & fine motor skills;
Contractures, clubfoot, & kyphoscoliosis;
Need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
ABR = auditory brain stem response; BAER = brain stem auditory evoked potential; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
A ketogenic diet has been used safely in at least 1 affected person [X Ortiz-Gonzalez, personal experience].
Education of parents/caregivers
No specific treatment
Early intervention to help stimulate visual development
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
To help avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard.
Ensure 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
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for parents or caregivers of 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 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 the teen years, a transition plan should 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, consider involving appropriate specialists to aid in management of baclofen, Botox
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures & changes in tone.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
See
Search
• Incl motor, adaptive, cognitive, & speech-language eval.
• Evaluate for early intervention / special education.
• Incl BAER/ABR.
• To assess for hearing loss & auditory neuropathy
• Risk of nocturnal hypoventilation due to neuromuscular weakness
• May require ventilatory support
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement if concern for dysphagia &/or aspiration risk.
• Gross motor & fine motor skills;
• Contractures, clubfoot, & kyphoscoliosis;
• Need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Use of community or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• A ketogenic diet has been used safely in at least 1 affected person [X Ortiz-Gonzalez, personal experience].
• Education of parents/caregivers
• No specific treatment
• Early intervention to help stimulate visual development
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• To help avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard.
• Ensure 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
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• 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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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, consider involving appropriate specialists to aid in management of baclofen, Botox
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures & changes in tone.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## 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
Incl motor, adaptive, cognitive, & speech-language eval.
Evaluate for early intervention / special education.
Incl BAER/ABR.
To assess for hearing loss & auditory neuropathy
Risk of nocturnal hypoventilation due to neuromuscular weakness
May require ventilatory support
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement if concern for dysphagia &/or aspiration risk.
Gross motor & fine motor skills;
Contractures, clubfoot, & kyphoscoliosis;
Need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
Use of community or
Need for social work involvement for parental support;
Need for home nursing referral.
ABR = auditory brain stem response; BAER = brain stem auditory evoked potential; OT = occupational therapy; PT = physical therapy
• Incl motor, adaptive, cognitive, & speech-language eval.
• Evaluate for early intervention / special education.
• Incl BAER/ABR.
• To assess for hearing loss & auditory neuropathy
• Risk of nocturnal hypoventilation due to neuromuscular weakness
• May require ventilatory support
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement if concern for dysphagia &/or aspiration risk.
• Gross motor & fine motor skills;
• Contractures, clubfoot, & kyphoscoliosis;
• Need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• Use of community or
• Need for social work involvement for parental support;
• Need for 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.
A ketogenic diet has been used safely in at least 1 affected person [X Ortiz-Gonzalez, personal experience].
Education of parents/caregivers
No specific treatment
Early intervention to help stimulate visual development
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
To help avoid contractures & falls
Consider need for positioning & mobility devices, disability parking placard.
Ensure 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
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of parents regarding common seizure presentations is appropriate. For information on nonmedical interventions and coping strategies for parents or caregivers of 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 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 the teen years, a transition plan should 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, consider involving appropriate specialists to aid in management of baclofen, Botox
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• A ketogenic diet has been used safely in at least 1 affected person [X Ortiz-Gonzalez, personal experience].
• Education of parents/caregivers
• No specific treatment
• Early intervention to help stimulate visual development
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• To help avoid contractures & falls
• Consider need for positioning & mobility devices, disability parking placard.
• Ensure 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
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• 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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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, 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.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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 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 the teen years, a transition plan should 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, consider involving appropriate specialists to aid in management of baclofen, 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, consider involving appropriate specialists to aid in management of baclofen, Botox
## Surveillance
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures & changes in tone.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures & changes in tone.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## 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 an
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.
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 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
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an
• 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 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
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
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 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
• 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.
## 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 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
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•
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•
•
• Canada
•
•
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•
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•
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• Speaking out for People with Intellectual and Developmental Disabilities
•
## Molecular Genetics
SPTBN4 Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SPTBN4 Disorder (
Spectrin proteins are actin cross-linking and molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and function in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. A spectrin molecule is a tetramer consisting of two alpha and two beta subunits.
## Molecular Pathogenesis
Spectrin proteins are actin cross-linking and molecular scaffold proteins that link the plasma membrane to the actin cytoskeleton and function in the determination of cell shape, arrangement of transmembrane proteins, and organization of organelles. A spectrin molecule is a tetramer consisting of two alpha and two beta subunits.
## Chapter Notes
16 July 2020 (ma) Review posted live
24 October 2019 (kw) Original submission
• 16 July 2020 (ma) Review posted live
• 24 October 2019 (kw) Original submission
## Revision History
16 July 2020 (ma) Review posted live
24 October 2019 (kw) Original submission
• 16 July 2020 (ma) Review posted live
• 24 October 2019 (kw) Original submission
## References
## Literature Cited
|
[] |
16/7/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
srns-ov
|
srns-ov
|
[
"Genetic Steroid-Resistant Nephrotic Syndrome",
"Overview"
] |
Genetic Steroid-Resistant Nephrotic Syndrome Overview
|
Beata S Lipska-Ziętkiewicz
|
Summary The purpose of this overview is to: Describe the Review the Provide an Review Review Inform
|
## Clinical Characteristics of Genetic Steroid-Resistant Nephrotic Syndrome
The initial manifestation of nephrotic syndrome is severe proteinuria defined as presence of the following [
Urine protein/creatinine ratio (UPCR) ≥200 mg/mmol (2 mg/mg) in the first morning void; OR 24-h urine sample ≥1000 mg/m
Hypoalbuminemia (serum albumin <30 g/L)
Edema
About 85% of nephrotic syndrome is steroid sensitive (SSNS), defined as complete remission of proteinuria following glucocorticoid treatment. SSNS will not be discussed further in this overview.
About 15% of nephrotic syndrome is steroid resistant (SRNS), defined as proteinuria that does not remit within four to six weeks of glucocorticoid treatment. About 50% of individuals with SRNS achieve sustained remission with intensified immunosuppressive treatment, whereas the rest have multi-drug resistance and progress to chronic kidney disease (CKD) and eventually to kidney failure.
Although most non-genetic SRNS is steroid resistant at the onset, a few individuals may initially respond to standard steroid therapy but subsequently demonstrate secondary steroid resistance. About 70% of individuals with non-genetic SRNS experience rapid post-transplantation recurrence of nephrotic syndrome in the graft [
In SRNS, about 30% of individuals with childhood-onset disease and 10%-15% of individuals with adult-onset disease have an underlying genetic alteration in one of the roughly 60 genes associated with genetic SRNS (see
• Urine protein/creatinine ratio (UPCR) ≥200 mg/mmol (2 mg/mg) in the first morning void; OR 24-h urine sample ≥1000 mg/m
• Hypoalbuminemia (serum albumin <30 g/L)
• Edema
## Causes of Genetic Steroid-Resistant Nephrotic Syndrome
Identification of a genetic SRNS can be particularly useful in individuals with syndromic genetic SRNS (see
Note: The following genes are listed in both
Syndromic Genetic SRNS: Genes and Clinical Features
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; CKD = chronic kidney disease; CMT = Charcot-Marie-Tooth disease; CNS = central nervous system; DD = developmental delay; ID = intellectual disability; Mat = maternal; MELAS =
Genes are listed alphabetically
Also associated with nonsyndromic SRNS
C3 glomerulopathy is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. Multiple affected persons within a single nuclear family are reported only occasionally, with both autosomal dominant and autosomal recessive inheritance being described.
Preliminary data suggest that
Nonsyndromic Genetic SRNS: Genes and Distinguishing Clinical Features
AD = autosomal dominant; AR = autosomal recessive; CNS = congenital nephrotic syndrome; MOI = mode of inheritance; SRNS = steroid-resistant nephrotic syndrome; XL = X-linked
Genes are listed alphabetically
13% of African Americans have the
Also associated with syndromic genetic SRNS.
Preliminary data suggest that
Genetic SRNS may also be referred to as "hereditary SRNS" or "monogenic SRNS."
Nonsyndromic genetic SRNS may also be referred to as "hereditary podocytopathy/glomerulopathy." Glomerulopathy is the preferred term as a subset of individuals with a hereditary podocytopathy never receive steroids, and, thus, their renal disease cannot be classified as steroid resistant.
In the context of genetic SRNS, use of the terms "idiopathic SRNS" and "primary SRNS" is controversial as these terms may imply absence of molecularly confirmed diagnosis.
## Nomenclature
Genetic SRNS may also be referred to as "hereditary SRNS" or "monogenic SRNS."
Nonsyndromic genetic SRNS may also be referred to as "hereditary podocytopathy/glomerulopathy." Glomerulopathy is the preferred term as a subset of individuals with a hereditary podocytopathy never receive steroids, and, thus, their renal disease cannot be classified as steroid resistant.
In the context of genetic SRNS, use of the terms "idiopathic SRNS" and "primary SRNS" is controversial as these terms may imply absence of molecularly confirmed diagnosis.
## Evaluation Strategies to Identify the Cause of Genetic Steroid-Resistant Nephrotic Syndrome in a Proband
Establishing a specific cause of genetic steroid-resistant nephrotic syndrome usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.
The age at first disease manifestation and the rate of chronic kidney disease (CKD) progression will strongly depend on the gene affected and the type of causative pathogenic variant.
Variants in
Variants in
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Variants in
• Variants in
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Phenocopies of Genetic Steroid-Resistant Nephrotic Syndrome
Phenocopies of Genetic SRNS Usually Presenting As Persistent Proteinuria
AD = autosomal dominant; AR = autosomal recessive; CKD = chronic kidney disease; DD = developmental delay; ID = intellectual disability; LMW = low-molecular-weight; MOI = mode of inheritance; SRNS = steroid-resistant nephrotic syndrome; TMA = thrombotic microangiopathy; XL = X-linked
Genes are listed alphabetically
Simultaneous kidney & liver transplantation in young children w/
C3 glomerulopathy (C3G) is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. In most persons with C3G, inheritance is complex and incompletely understood. For these reasons, recurrence risk to family members is not known but likely very low.
C-terminal variants associate with chronic proteinuria and normal renal function [
## Management of Genetic Steroid-Resistant Nephrotic Syndrome
In 2020 the International Pediatric Nephrology Association developed comprehensive clinical practice recommendations for the diagnosis and management of SRNS in children [
See also the detailed genetic and clinical guidelines for management of congenital nephrotic syndrome [
Once the diagnosis of SRNS is established, ineffective prednisolone/prednisone treatment should be avoided. Instead affected individuals should be treated with renin-angiotensin-aldosterone system inhibitors (RAASi) to reduce proteinuria.
While recent recommendations also suggest withholding calcineurin inhibitors and other immunosuppressive agents in individuals with evidence for genetic SRNS, the final decision should be made on an individual basis (for details see
Clinical management also includes the following:
Prompt detection and treatment of hypertension
Cautious use of diuretics, vitamin D, and thyroid hormone substitution
Conservative management of chronic kidney disease (CKD)
Kidney replacement therapy including preemptive transplantation in selected disorders (e.g.,
• Prompt detection and treatment of hypertension
• Cautious use of diuretics, vitamin D, and thyroid hormone substitution
• Conservative management of chronic kidney disease (CKD)
• Kidney replacement therapy including preemptive transplantation in selected disorders (e.g.,
## Risk Assessment and Surveillance of At-Risk Relatives for Early Detection and Treatment of Genetic Steroid-Resistant Nephrotic Syndrome
Screening of asymptomatic first-degree family members (see
Clarification of the genetic status of first-degree family members can also help to identify potential organ donors. (Note: Molecular genetic testing for the familial pathogenic variant is obligatory for genetic SRNS with autosomal dominant transmission and in certain entities with significant intra- and interfamilial variability and reduced or age-dependent penetrance [e.g., genetic SRNS associated with pathogenic variants in
Note: Given the complexity of the genetics and surveillance recommendations for genetic SRNS, health care providers should consider referring at-risk asymptomatic relatives to a nephrology genetics center or a genetic counselor specializing in nephrology genetics (see
If a proband has a specific genetic syndrome associated with SRNS (e.g.,
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive genetic SRNS-causing pathogenic variant based on family history).
Molecular genetic testing of the parents for the pathogenic variants identified in the proband is recommended to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, 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.
In some families, a parent of the proband is found to have biallelic genetic SRNS-causing pathogenic variants (rather than a heterozygous pathogenic variant). This is more likely to occur in families segregating a relatively common non-neutral variant such as the p.Arg229Gln
Heterozygotes (carriers) are asymptomatic and are not at risk of developing autosomal recessive genetic SRNS. A parent who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
If both parents are known to be heterozygous for an autosomal recessive SRNS-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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. A sib who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
Some individuals diagnosed with autosomal dominant genetic SRNS have an affected parent. The frequency of probands with an affected parent is highest in individuals with a heterozygous pathogenic variant in
Most individuals diagnosed with autosomal dominant genetic SRNS have 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 confirm their genetic status and to allow reliable recurrence risk counseling. Note: Molecular genetic testing is obligatory for relatives considering organ donation.
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 an autosomal dominant genetic SRNS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, and/or 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 of inheriting the pathogenic variant is 50%.
If the proband has a known genetic SRNS-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 possibility of parental germline mosaicism [
If the parents have not been tested for the pathogenic variant identified in the proband but 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 autosomal dominant genetic SRNS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
First degree relatives, including sibs, should be offered urine analysis for proteinuria. This testing should be offered to at-risk family members as soon as possible and should not be delayed pending molecular confirmation that the proband has genetic SRNS.
Family members found to have proteinuria should undergo detailed clinical evaluation by a nephrologist to either confirm a diagnosis of genetic SRNS or detect any other cause of proteinuria (see
Once the genetic SRNS-causing pathogenic variant(s) have been identified in the proband, it is appropriate to clarify the genetic status of at-risk relatives to identify individuals with the familial pathogenic variant(s) as early as possible.
Early identification of a genetic predisposition may result in successful delay of disease progression, not only by avoiding ineffective therapies and their substantial side effects, but also by the following: initiation of treatment with RAASi to reduce proteinuria; prompt detection and treatment of hypertension; cautious use of diuretics, vaccination, vitamin D, and thyroid hormone substitution; and early start of targeted treatment such as ubiquinone supplementation in COQ
Early intervention may also include surveillance for extrarenal manifestations (e.g., endocrinologic, oncologic, immune, or neurologic; see
Members of the family found negative on genetic testing may be discharged from surveillance and are no longer considered at increased risk for genetic SRNS.
Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the potential donor's genetic status. Screening of the potential donor with molecular genetic testing is obligatory for families segregating autosomal dominant or X-linked genetic SRNS and in certain entities with significant intra- and interfamilial variability and reduced or age-dependent penetrance (e.g., genetic SRNS associated with pathogenic variants in
Family members who are found to have a pathogenic variant associated with autosomal dominant or X-linked genetic SRNS cannot serve as kidney donors regardless of clinical status [
Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive genetic SRNS and individuals who do not have the familial genetic SRNS-related pathogenic variant can be evaluated further as possible kidney donors.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive genetic SRNS-causing pathogenic variant based on family history).
• Molecular genetic testing of the parents for the pathogenic variants identified in the proband is recommended to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, 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.
• In some families, a parent of the proband is found to have biallelic genetic SRNS-causing pathogenic variants (rather than a heterozygous pathogenic variant). This is more likely to occur in families segregating a relatively common non-neutral variant such as the p.Arg229Gln
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing autosomal recessive genetic SRNS. A parent who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
• 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 autosomal recessive SRNS-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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. A sib who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
• Some individuals diagnosed with autosomal dominant genetic SRNS have an affected parent. The frequency of probands with an affected parent is highest in individuals with a heterozygous pathogenic variant in
• Most individuals diagnosed with autosomal dominant genetic SRNS have 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 confirm their genetic status and to allow reliable recurrence risk counseling. Note: Molecular genetic testing is obligatory for relatives considering organ donation.
• 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 an autosomal dominant genetic SRNS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, and/or 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.
• 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 proband has a known genetic SRNS-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 possibility of parental germline mosaicism [
• If the parents have not been tested for the pathogenic variant identified in the proband but 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 autosomal dominant genetic SRNS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• First degree relatives, including sibs, should be offered urine analysis for proteinuria. This testing should be offered to at-risk family members as soon as possible and should not be delayed pending molecular confirmation that the proband has genetic SRNS.
• Family members found to have proteinuria should undergo detailed clinical evaluation by a nephrologist to either confirm a diagnosis of genetic SRNS or detect any other cause of proteinuria (see
• Once the genetic SRNS-causing pathogenic variant(s) have been identified in the proband, it is appropriate to clarify the genetic status of at-risk relatives to identify individuals with the familial pathogenic variant(s) as early as possible.
• Early identification of a genetic predisposition may result in successful delay of disease progression, not only by avoiding ineffective therapies and their substantial side effects, but also by the following: initiation of treatment with RAASi to reduce proteinuria; prompt detection and treatment of hypertension; cautious use of diuretics, vaccination, vitamin D, and thyroid hormone substitution; and early start of targeted treatment such as ubiquinone supplementation in COQ
• Early intervention may also include surveillance for extrarenal manifestations (e.g., endocrinologic, oncologic, immune, or neurologic; see
• Members of the family found negative on genetic testing may be discharged from surveillance and are no longer considered at increased risk for genetic SRNS.
• Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the potential donor's genetic status. Screening of the potential donor with molecular genetic testing is obligatory for families segregating autosomal dominant or X-linked genetic SRNS and in certain entities with significant intra- and interfamilial variability and reduced or age-dependent penetrance (e.g., genetic SRNS associated with pathogenic variants in
• Family members who are found to have a pathogenic variant associated with autosomal dominant or X-linked genetic SRNS cannot serve as kidney donors regardless of clinical status [
• Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive genetic SRNS and individuals who do not have the familial genetic SRNS-related pathogenic variant can be evaluated further as possible kidney donors.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive genetic SRNS-causing pathogenic variant based on family history).
Molecular genetic testing of the parents for the pathogenic variants identified in the proband is recommended to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, 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.
In some families, a parent of the proband is found to have biallelic genetic SRNS-causing pathogenic variants (rather than a heterozygous pathogenic variant). This is more likely to occur in families segregating a relatively common non-neutral variant such as the p.Arg229Gln
Heterozygotes (carriers) are asymptomatic and are not at risk of developing autosomal recessive genetic SRNS. A parent who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
If both parents are known to be heterozygous for an autosomal recessive SRNS-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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. A sib who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one autosomal recessive genetic SRNS-causing pathogenic variant based on family history).
• Molecular genetic testing of the parents for the pathogenic variants identified in the proband is recommended to confirm that both parents are heterozygous for a causative pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent, 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.
• In some families, a parent of the proband is found to have biallelic genetic SRNS-causing pathogenic variants (rather than a heterozygous pathogenic variant). This is more likely to occur in families segregating a relatively common non-neutral variant such as the p.Arg229Gln
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing autosomal recessive genetic SRNS. A parent who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
• 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 autosomal recessive SRNS-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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. A sib who is heterozygous for autosomal recessive genetic SRNS may be able to serve as a kidney donor.
## Autosomal Dominant Inheritance – Risk to Family Members
Some individuals diagnosed with autosomal dominant genetic SRNS have an affected parent. The frequency of probands with an affected parent is highest in individuals with a heterozygous pathogenic variant in
Most individuals diagnosed with autosomal dominant genetic SRNS have 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 confirm their genetic status and to allow reliable recurrence risk counseling. Note: Molecular genetic testing is obligatory for relatives considering organ donation.
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 an autosomal dominant genetic SRNS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, and/or 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 of inheriting the pathogenic variant is 50%.
If the proband has a known genetic SRNS-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 possibility of parental germline mosaicism [
If the parents have not been tested for the pathogenic variant identified in the proband but 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 autosomal dominant genetic SRNS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• Some individuals diagnosed with autosomal dominant genetic SRNS have an affected parent. The frequency of probands with an affected parent is highest in individuals with a heterozygous pathogenic variant in
• Most individuals diagnosed with autosomal dominant genetic SRNS have 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 confirm their genetic status and to allow reliable recurrence risk counseling. Note: Molecular genetic testing is obligatory for relatives considering organ donation.
• 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 an autosomal dominant genetic SRNS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, and/or 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.
• 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 proband has a known genetic SRNS-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 possibility of parental germline mosaicism [
• If the parents have not been tested for the pathogenic variant identified in the proband but 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 autosomal dominant genetic SRNS because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
## Surveillance of At-Risk Relatives for Early Detection and Treatment of Genetic Steroid-Resistant Nephrotic Syndrome
First degree relatives, including sibs, should be offered urine analysis for proteinuria. This testing should be offered to at-risk family members as soon as possible and should not be delayed pending molecular confirmation that the proband has genetic SRNS.
Family members found to have proteinuria should undergo detailed clinical evaluation by a nephrologist to either confirm a diagnosis of genetic SRNS or detect any other cause of proteinuria (see
Once the genetic SRNS-causing pathogenic variant(s) have been identified in the proband, it is appropriate to clarify the genetic status of at-risk relatives to identify individuals with the familial pathogenic variant(s) as early as possible.
Early identification of a genetic predisposition may result in successful delay of disease progression, not only by avoiding ineffective therapies and their substantial side effects, but also by the following: initiation of treatment with RAASi to reduce proteinuria; prompt detection and treatment of hypertension; cautious use of diuretics, vaccination, vitamin D, and thyroid hormone substitution; and early start of targeted treatment such as ubiquinone supplementation in COQ
Early intervention may also include surveillance for extrarenal manifestations (e.g., endocrinologic, oncologic, immune, or neurologic; see
Members of the family found negative on genetic testing may be discharged from surveillance and are no longer considered at increased risk for genetic SRNS.
Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the potential donor's genetic status. Screening of the potential donor with molecular genetic testing is obligatory for families segregating autosomal dominant or X-linked genetic SRNS and in certain entities with significant intra- and interfamilial variability and reduced or age-dependent penetrance (e.g., genetic SRNS associated with pathogenic variants in
Family members who are found to have a pathogenic variant associated with autosomal dominant or X-linked genetic SRNS cannot serve as kidney donors regardless of clinical status [
Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive genetic SRNS and individuals who do not have the familial genetic SRNS-related pathogenic variant can be evaluated further as possible kidney donors.
• First degree relatives, including sibs, should be offered urine analysis for proteinuria. This testing should be offered to at-risk family members as soon as possible and should not be delayed pending molecular confirmation that the proband has genetic SRNS.
• Family members found to have proteinuria should undergo detailed clinical evaluation by a nephrologist to either confirm a diagnosis of genetic SRNS or detect any other cause of proteinuria (see
• Once the genetic SRNS-causing pathogenic variant(s) have been identified in the proband, it is appropriate to clarify the genetic status of at-risk relatives to identify individuals with the familial pathogenic variant(s) as early as possible.
• Early identification of a genetic predisposition may result in successful delay of disease progression, not only by avoiding ineffective therapies and their substantial side effects, but also by the following: initiation of treatment with RAASi to reduce proteinuria; prompt detection and treatment of hypertension; cautious use of diuretics, vaccination, vitamin D, and thyroid hormone substitution; and early start of targeted treatment such as ubiquinone supplementation in COQ
• Early intervention may also include surveillance for extrarenal manifestations (e.g., endocrinologic, oncologic, immune, or neurologic; see
• Members of the family found negative on genetic testing may be discharged from surveillance and are no longer considered at increased risk for genetic SRNS.
• Any relative who is a potential kidney donor should undergo molecular genetic testing to clarify the potential donor's genetic status. Screening of the potential donor with molecular genetic testing is obligatory for families segregating autosomal dominant or X-linked genetic SRNS and in certain entities with significant intra- and interfamilial variability and reduced or age-dependent penetrance (e.g., genetic SRNS associated with pathogenic variants in
• Family members who are found to have a pathogenic variant associated with autosomal dominant or X-linked genetic SRNS cannot serve as kidney donors regardless of clinical status [
• Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive genetic SRNS and individuals who do not have the familial genetic SRNS-related pathogenic variant can be evaluated further as possible kidney donors.
## Resources
Canada
Clinical, Genetic and Experimental Research into Hereditary Disease of the Podocyte
•
•
•
•
•
• Canada
•
•
•
•
•
•
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• Clinical, Genetic and Experimental Research into Hereditary Disease of the Podocyte
•
## Chapter Notes
Beata S Lipska-Ziętkiewicz is the genetic coordinator at PodoNet (
26 August 2021 (bp) Review posted live
11 January 2021 (blz) Original submission
• 26 August 2021 (bp) Review posted live
• 11 January 2021 (blz) Original submission
## Author Notes
Beata S Lipska-Ziętkiewicz is the genetic coordinator at PodoNet (
## Revision History
26 August 2021 (bp) Review posted live
11 January 2021 (blz) Original submission
• 26 August 2021 (bp) Review posted live
• 11 January 2021 (blz) Original submission
## References
## Literature Cited
|
[] |
26/8/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ss-def
|
ss-def
|
[
"Squalene synthase",
"FDFT1",
"Squalene Synthase Deficiency"
] |
Squalene Synthase Deficiency
|
David Coman, Lisenka Vissers, Hans Waterham, John Christodoulou, Ron A Wevers, James Pitt
|
Summary Squalene synthase deficiency (SQSD) is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to Smith-Lemli-Optiz syndrome. Key clinical features include facial dysmorphism, a generalized seizure disorder presenting in the neonatal period, nonspecific structural brain malformations, cortical visual impairment, optic nerve hypoplasia, profound developmental delay / intellectual disability, dry skin with photosensitivity, and genital malformations in males. Individuals with SQSD have a unique urine metabolic profile with increased saturated and unsaturated branched-chain dicarboxylic acids and glucuronides derived from farnesol. The diagnosis of squalene synthase deficiency is established in a proband with characteristic urine metabolites on urine organic acids analysis or by the identification of biallelic pathogenic variants in SQSD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% change 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
Formal clinical diagnostic criteria for squalene synthase deficiency (SQSD) have not been established. However, the urine metabolic profile with increased saturated and unsaturated branched-chain dicarboxylic acids and glucuronides derived from farnesol in the appropriate clinical setting is specific for SQSD.
Squalene synthase deficiency
Dysmorphic features (See
Neonatal generalized seizure disorder
Profound developmental delay
Cortical visual impairment
Genital malformations in males
Dry skin with photosensitivity
Typical Urine Metabolite Profile in Squalene Synthase Deficiency
Methylsuccinic acid
Mevalonic lactone
3-methylhex-2-enedioic acid
2,6-dimethylhept-2-enedioic acid
3,7-dimethyl-2,6-dienedioic
3-methylhex-2,4-dienedioic acid
3-methylhex-3,4-dienedioic acid
GC-MS = gas chromatography-mass spectroscopy; NMRS = nuclear magnetic resonance spectroscopy
Note: A similar metabolite profile is also found in the urine of humans treated with pharmacologic inhibitors of squalene synthase or those who have taken farnesol [
Increased plasma farnesol levels
Plasma squalene levels that are either reduced or normal
Fasting cholesterol studies demonstrating:
Low normal total cholesterol level
Reduced low-density lipoprotein cholesterol level
Hypoplastic corpus callosum
Reduced white matter volume
Polymicrogyria involving the frontal, parietal, and temporal lobes
Optic nerve hypoplasia
The diagnosis of SQSD
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 squalene synthase deficiency may be broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of squalene synthase deficiency molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of squalene synthase deficiency is not considered because the phenotypic association with SQSD was not recognized or an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Squalene Synthase 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
Note that of the three described disease-associated variants to date, one –
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
• Dysmorphic features (See
• Neonatal generalized seizure disorder
• Profound developmental delay
• Cortical visual impairment
• Genital malformations in males
• Dry skin with photosensitivity
• Methylsuccinic acid
• Mevalonic lactone
• 3-methylhex-2-enedioic acid
• 2,6-dimethylhept-2-enedioic acid
• 3,7-dimethyl-2,6-dienedioic
• 3-methylhex-2,4-dienedioic acid
• 3-methylhex-3,4-dienedioic acid
• Increased plasma farnesol levels
• Plasma squalene levels that are either reduced or normal
• Fasting cholesterol studies demonstrating:
• Low normal total cholesterol level
• Reduced low-density lipoprotein cholesterol level
• Low normal total cholesterol level
• Reduced low-density lipoprotein cholesterol level
• Low normal total cholesterol level
• Reduced low-density lipoprotein cholesterol level
• Hypoplastic corpus callosum
• Reduced white matter volume
• Polymicrogyria involving the frontal, parietal, and temporal lobes
• Optic nerve hypoplasia
• For an introduction to multigene panels click
## Suggestive Findings
Squalene synthase deficiency
Dysmorphic features (See
Neonatal generalized seizure disorder
Profound developmental delay
Cortical visual impairment
Genital malformations in males
Dry skin with photosensitivity
Typical Urine Metabolite Profile in Squalene Synthase Deficiency
Methylsuccinic acid
Mevalonic lactone
3-methylhex-2-enedioic acid
2,6-dimethylhept-2-enedioic acid
3,7-dimethyl-2,6-dienedioic
3-methylhex-2,4-dienedioic acid
3-methylhex-3,4-dienedioic acid
GC-MS = gas chromatography-mass spectroscopy; NMRS = nuclear magnetic resonance spectroscopy
Note: A similar metabolite profile is also found in the urine of humans treated with pharmacologic inhibitors of squalene synthase or those who have taken farnesol [
Increased plasma farnesol levels
Plasma squalene levels that are either reduced or normal
Fasting cholesterol studies demonstrating:
Low normal total cholesterol level
Reduced low-density lipoprotein cholesterol level
Hypoplastic corpus callosum
Reduced white matter volume
Polymicrogyria involving the frontal, parietal, and temporal lobes
Optic nerve hypoplasia
• Dysmorphic features (See
• Neonatal generalized seizure disorder
• Profound developmental delay
• Cortical visual impairment
• Genital malformations in males
• Dry skin with photosensitivity
• Methylsuccinic acid
• Mevalonic lactone
• 3-methylhex-2-enedioic acid
• 2,6-dimethylhept-2-enedioic acid
• 3,7-dimethyl-2,6-dienedioic
• 3-methylhex-2,4-dienedioic acid
• 3-methylhex-3,4-dienedioic acid
• Increased plasma farnesol levels
• Plasma squalene levels that are either reduced or normal
• Fasting cholesterol studies demonstrating:
• Low normal total cholesterol level
• Reduced low-density lipoprotein cholesterol level
• Low normal total cholesterol level
• Reduced low-density lipoprotein cholesterol level
• Low normal total cholesterol level
• Reduced low-density lipoprotein cholesterol level
• Hypoplastic corpus callosum
• Reduced white matter volume
• Polymicrogyria involving the frontal, parietal, and temporal lobes
• Optic nerve hypoplasia
## Establishing the Diagnosis
The diagnosis of SQSD
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 squalene synthase deficiency may be broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of squalene synthase deficiency molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of squalene synthase deficiency is not considered because the phenotypic association with SQSD was not recognized or an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Squalene Synthase 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
Note that of the three described disease-associated variants to date, one –
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
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of squalene synthase deficiency 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 squalene synthase deficiency is not considered because the phenotypic association with SQSD was not recognized or an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Squalene Synthase 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
Note that of the three described disease-associated variants to date, one –
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
## Clinical Characteristics
Squalene synthase deficiency (SQSD) is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to
Small for gestational age, including one individual with a birth weight at the tenth centile and another with an occipital frontal circumference at birth at the tenth centile
Generalized seizures, typically presenting in the first week of life
Neonatal hepatitis consisting of unconjugated hyperbilirubinemia and elevated liver function enzymes with normal hepatic synthetic function
Coarse facial features
Narrow forehead
Epicanthus
Depressed nasal bridge
Low-set and posteriorly rotated ears
Squared nasal tip
Micrognathia and retrognathia
2-3 toe syndactyly
Generalized tonic-colonic seizures that present in the neonatal period
Profound developmental delay. The limited number of affected individuals identified to date have been:
Able to sit independently
Nonambulatory
Nonverbal
Not able to perform any self-care
Affected individuals have varying degrees of nonverbal social communication skills ranging from no meaningful nonverbal communication/interactions to use of eye contact.
Autistic features
Habitual eye poking
Irritability
Central hypotonia, typically present at birth
Hyperreflexia, typically present at birth
Hypersalivation
Hypoplastic corpus callosum in two sibs
Reduced white matter volume
Polymicrogyria involving the frontal, parietal, and temporal lobes in one affected individual
Thin gracile bones in two sibs
Reduced bone mineralization in two sibs
Fixed flexion joint contractures at the knees in two sibs and of the elbows in one unrelated affected individual
Plasma total cholesterol is mildly decreased.
Plasma HDL- and LDL-cholesterol levels are decreased or low normal range.
Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) are significantly increased.
Plasma squalene levels are reduced or normal.
Pathognomonic urine metabolic profile (See
Thus far, pathogenic variants have included a contiguous gene deletion, a splice acceptor site variant, and an intronic deletion in three individuals with similar features. Therefore, no clear genotype-phenotype correlations exist.
The prevalence is unknown. Currently three affected individuals from two kindreds have been described [
• Small for gestational age, including one individual with a birth weight at the tenth centile and another with an occipital frontal circumference at birth at the tenth centile
• Generalized seizures, typically presenting in the first week of life
• Neonatal hepatitis consisting of unconjugated hyperbilirubinemia and elevated liver function enzymes with normal hepatic synthetic function
• Coarse facial features
• Narrow forehead
• Epicanthus
• Depressed nasal bridge
• Low-set and posteriorly rotated ears
• Squared nasal tip
• Micrognathia and retrognathia
• 2-3 toe syndactyly
• Generalized tonic-colonic seizures that present in the neonatal period
• Profound developmental delay. The limited number of affected individuals identified to date have been:
• Able to sit independently
• Nonambulatory
• Nonverbal
• Not able to perform any self-care
• Affected individuals have varying degrees of nonverbal social communication skills ranging from no meaningful nonverbal communication/interactions to use of eye contact.
• Able to sit independently
• Nonambulatory
• Nonverbal
• Not able to perform any self-care
• Autistic features
• Habitual eye poking
• Irritability
• Central hypotonia, typically present at birth
• Hyperreflexia, typically present at birth
• Hypersalivation
• Able to sit independently
• Nonambulatory
• Nonverbal
• Not able to perform any self-care
• Hypoplastic corpus callosum in two sibs
• Reduced white matter volume
• Polymicrogyria involving the frontal, parietal, and temporal lobes in one affected individual
• Thin gracile bones in two sibs
• Reduced bone mineralization in two sibs
• Fixed flexion joint contractures at the knees in two sibs and of the elbows in one unrelated affected individual
• Plasma total cholesterol is mildly decreased.
• Plasma HDL- and LDL-cholesterol levels are decreased or low normal range.
• Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) are significantly increased.
• Plasma squalene levels are reduced or normal.
• Pathognomonic urine metabolic profile (See
## Clinical Description
Squalene synthase deficiency (SQSD) is a rare inborn error of cholesterol biosynthesis with multisystem clinical manifestations similar to
Small for gestational age, including one individual with a birth weight at the tenth centile and another with an occipital frontal circumference at birth at the tenth centile
Generalized seizures, typically presenting in the first week of life
Neonatal hepatitis consisting of unconjugated hyperbilirubinemia and elevated liver function enzymes with normal hepatic synthetic function
Coarse facial features
Narrow forehead
Epicanthus
Depressed nasal bridge
Low-set and posteriorly rotated ears
Squared nasal tip
Micrognathia and retrognathia
2-3 toe syndactyly
Generalized tonic-colonic seizures that present in the neonatal period
Profound developmental delay. The limited number of affected individuals identified to date have been:
Able to sit independently
Nonambulatory
Nonverbal
Not able to perform any self-care
Affected individuals have varying degrees of nonverbal social communication skills ranging from no meaningful nonverbal communication/interactions to use of eye contact.
Autistic features
Habitual eye poking
Irritability
Central hypotonia, typically present at birth
Hyperreflexia, typically present at birth
Hypersalivation
Hypoplastic corpus callosum in two sibs
Reduced white matter volume
Polymicrogyria involving the frontal, parietal, and temporal lobes in one affected individual
Thin gracile bones in two sibs
Reduced bone mineralization in two sibs
Fixed flexion joint contractures at the knees in two sibs and of the elbows in one unrelated affected individual
Plasma total cholesterol is mildly decreased.
Plasma HDL- and LDL-cholesterol levels are decreased or low normal range.
Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) are significantly increased.
Plasma squalene levels are reduced or normal.
Pathognomonic urine metabolic profile (See
• Small for gestational age, including one individual with a birth weight at the tenth centile and another with an occipital frontal circumference at birth at the tenth centile
• Generalized seizures, typically presenting in the first week of life
• Neonatal hepatitis consisting of unconjugated hyperbilirubinemia and elevated liver function enzymes with normal hepatic synthetic function
• Coarse facial features
• Narrow forehead
• Epicanthus
• Depressed nasal bridge
• Low-set and posteriorly rotated ears
• Squared nasal tip
• Micrognathia and retrognathia
• 2-3 toe syndactyly
• Generalized tonic-colonic seizures that present in the neonatal period
• Profound developmental delay. The limited number of affected individuals identified to date have been:
• Able to sit independently
• Nonambulatory
• Nonverbal
• Not able to perform any self-care
• Affected individuals have varying degrees of nonverbal social communication skills ranging from no meaningful nonverbal communication/interactions to use of eye contact.
• Able to sit independently
• Nonambulatory
• Nonverbal
• Not able to perform any self-care
• Autistic features
• Habitual eye poking
• Irritability
• Central hypotonia, typically present at birth
• Hyperreflexia, typically present at birth
• Hypersalivation
• Able to sit independently
• Nonambulatory
• Nonverbal
• Not able to perform any self-care
• Hypoplastic corpus callosum in two sibs
• Reduced white matter volume
• Polymicrogyria involving the frontal, parietal, and temporal lobes in one affected individual
• Thin gracile bones in two sibs
• Reduced bone mineralization in two sibs
• Fixed flexion joint contractures at the knees in two sibs and of the elbows in one unrelated affected individual
• Plasma total cholesterol is mildly decreased.
• Plasma HDL- and LDL-cholesterol levels are decreased or low normal range.
• Plasma total farnesol levels (the sum of free farnesol and farnesyl-pyrophosphate) are significantly increased.
• Plasma squalene levels are reduced or normal.
• Pathognomonic urine metabolic profile (See
## Genotype-Phenotype Correlations
Thus far, pathogenic variants have included a contiguous gene deletion, a splice acceptor site variant, and an intronic deletion in three individuals with similar features. Therefore, no clear genotype-phenotype correlations exist.
## Prevalence
The prevalence is unknown. Currently three affected individuals from two kindreds have been described [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Currently, ten mendelian disorders of cholesterol biosynthesis have been characterized. Of these, four overlap clinically with squalene synthase deficiency (SQSD): lanosterol synthase deficiency,
Cholesterol Biosynthesis Disordersof Interest in the Differential Diagnosis of Squalene Synthase Deficiency
Facial dysmorphism
Congenital heart defects
Microcephaly
DD & ID
Structural brain malformations
↑ desmosterol
Normal urine organic acids
2-3 toe syndactyly
DD & ID
Facial dysmorphism
Genital abnormalities
Structural brain malformations
Congenital heart defects
Dry skin / photosensitivity
Autism
Low-normal plasma TC levels
↑ 7-dehydrocholesterol
Normal urine organic acids
Seizures
DD & ID
Structural brain malformations
Congenital cataracts
Hypotrichosis simplex
Normal urine organic acids
Microcephaly
DD & ID
Structural brain malformations
Genital abnormalities
Cataracts
Normal urine organic acids
AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; GC-MS = gas chromatography-mass spectrometry; ID = intellectual disability; MOI = mode of inheritance; NMRS = nuclear magnetic resonance spectroscopy; SQSD = squalene synthase deficiency; TC = total cholesterol
• Facial dysmorphism
• Congenital heart defects
• Microcephaly
• DD & ID
• Structural brain malformations
• ↑ desmosterol
• Normal urine organic acids
• 2-3 toe syndactyly
• DD & ID
• Facial dysmorphism
• Genital abnormalities
• Structural brain malformations
• Congenital heart defects
• Dry skin / photosensitivity
• Autism
• Low-normal plasma TC levels
• ↑ 7-dehydrocholesterol
• Normal urine organic acids
• Seizures
• DD & ID
• Structural brain malformations
• Congenital cataracts
• Hypotrichosis simplex
• Normal urine organic acids
• Microcephaly
• DD & ID
• Structural brain malformations
• Genital abnormalities
• Cataracts
• Normal urine organic acids
## Management
To establish the extent of disease and needs in an individual diagnosed with squalene synthase deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Squalene Synthase Deficiency
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 aspiration risk, nutritional status, & for constipation
Consider eval for gastrostomy tube placement in those w/failure to thrive, dysphagia, &/or aspiration risk.
Gross motor & fine motor skills
Contractures
Mobility & activities of daily living & 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.
ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; US = ultrasound
Hearing loss has not been described as a primary feature in this condition; however, this recommendation is based on the fact that the affected individuals have intellectual impairment, which makes clinical assessment for hearing loss difficult.
No structural renal anomalies have as yet been described in affected individuals.
There are currently no specific disease modifying treatments for SQSD.
Treatment of Manifestations in Individuals with Squalene Synthase Deficiency
To date, no one ASM has been demonstrated effective specifically for SQSD.
Education of parents/caregivers
ASM = anti-seizure medication; DD = developmental delay; 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 (US); standard recommendations may vary from country to country
An IEP provides specially designed instruction and related services to children who qualify.
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.
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 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.
The authors recommend general care as outlined in
Recommended Surveillance for Individuals with Squalene Synthase Deficiency
Aspiration or respiratory insufficiency;
Sleep disorder.
Measurement of growth parameters
Evaluation of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
The skin photosensitivity has produced clinically significant UV-related sunburns within ten minutes of direct sunlight exposure. Skin care and UV protection is recommended (see
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 incl eval of aspiration risk, nutritional status, & for constipation
• Consider eval for gastrostomy tube placement in those w/failure to thrive, dysphagia, &/or aspiration risk.
• Gross motor & fine motor skills
• Contractures
• Mobility & activities of daily living & 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.
• To date, no one ASM has been demonstrated effective specifically for SQSD.
• Education of parents/caregivers
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• 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
• Aspiration or respiratory insufficiency;
• Sleep disorder.
• Measurement of growth parameters
• Evaluation of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with squalene synthase deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Squalene Synthase Deficiency
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 aspiration risk, nutritional status, & for constipation
Consider eval for gastrostomy tube placement in those w/failure to thrive, dysphagia, &/or aspiration risk.
Gross motor & fine motor skills
Contractures
Mobility & activities of daily living & 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.
ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; US = ultrasound
Hearing loss has not been described as a primary feature in this condition; however, this recommendation is based on the fact that the affected individuals have intellectual impairment, which makes clinical assessment for hearing loss difficult.
No structural renal anomalies have as yet been described in affected individuals.
• 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 aspiration risk, nutritional status, & for constipation
• Consider eval for gastrostomy tube placement in those w/failure to thrive, dysphagia, &/or aspiration risk.
• Gross motor & fine motor skills
• Contractures
• Mobility & activities of daily living & 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 are currently no specific disease modifying treatments for SQSD.
Treatment of Manifestations in Individuals with Squalene Synthase Deficiency
To date, no one ASM has been demonstrated effective specifically for SQSD.
Education of parents/caregivers
ASM = anti-seizure medication; DD = developmental delay; 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 (US); standard recommendations may vary from country to country
An IEP provides specially designed instruction and related services to children who qualify.
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.
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 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.
• To date, no one ASM has been demonstrated effective specifically for SQSD.
• Education of parents/caregivers
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• 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 (US); standard recommendations may vary from country to country
An IEP provides specially designed instruction and related services to children who qualify.
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.
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
## 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 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
The authors recommend general care as outlined in
Recommended Surveillance for Individuals with Squalene Synthase Deficiency
Aspiration or respiratory insufficiency;
Sleep disorder.
Measurement of growth parameters
Evaluation of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
• Aspiration or respiratory insufficiency;
• Sleep disorder.
• Measurement of growth parameters
• Evaluation of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
The skin photosensitivity has produced clinically significant UV-related sunburns within ten minutes of direct sunlight exposure. Skin care and UV protection is recommended (see
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Squalene synthase deficiency (SQSD) 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.
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 the parents of an affected child.
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.
• 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 the parents of an affected child.
## Mode of Inheritance
Squalene synthase deficiency (SQSD) 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.
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 the parents of an affected child.
• 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 the parents of an affected child.
## 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
PO Box 138
Mentone Victoria 3194
Australia
•
• PO Box 138
• Mentone Victoria 3194
• Australia
•
•
•
## Molecular Genetics
Squalene Synthase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Squalene Synthase Deficiency (
Mammalian SS is a conserved ~47-kd protein containing ~416 amino acids; it forms an alpha-helical structure which is located in the endoplasmic reticulum, where it is anchored by a C-terminal membrane-spanning domain, with the N-terminal catalytic domain facing the cytosol [
Plasma total farnesol levels are elevated and plasma squalene levels may be reduced or normal. The accumulation of farnesyl pyrophosphate initiates a complex metabolic cascade involving glucuronidation, hydroxylation, and oxidation to shorter chain molecules [
Notable
NA = not applicable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Mammalian SS is a conserved ~47-kd protein containing ~416 amino acids; it forms an alpha-helical structure which is located in the endoplasmic reticulum, where it is anchored by a C-terminal membrane-spanning domain, with the N-terminal catalytic domain facing the cytosol [
Plasma total farnesol levels are elevated and plasma squalene levels may be reduced or normal. The accumulation of farnesyl pyrophosphate initiates a complex metabolic cascade involving glucuronidation, hydroxylation, and oxidation to shorter chain molecules [
Notable
NA = not applicable
Variants listed in the table have been provided by the authors.
## Chapter Notes
6 February 2020 (ma) Review posted live
24 June 2019 (dc) Original submission
• 6 February 2020 (ma) Review posted live
• 24 June 2019 (dc) Original submission
## Revision History
6 February 2020 (ma) Review posted live
24 June 2019 (dc) Original submission
• 6 February 2020 (ma) Review posted live
• 24 June 2019 (dc) Original submission
## References
## Literature Cited
|
[] |
6/2/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ssadh
|
ssadh
|
[
"4-Hydroxybutyric Aciduria",
"Gamma-Hydroxybutyric Aciduria",
"SSADH Deficiency",
"4-Hydroxybutyric Aciduria",
"Gamma-Hydroxybutyric Aciduria",
"SSADH Deficiency",
"Succinate-semialdehyde dehydrogenase, mitochondrial",
"ALDH5A1",
"Succinic Semialdehyde Dehydrogenase Deficiency"
] |
Succinic Semialdehyde Dehydrogenase Deficiency
|
Itay Tokatly Latzer, Phillip L Pearl, Jean-Baptiste Roullet
|
Summary Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence. Affected individuals do not usually have episodic decompensation following metabolic stressors, as is typical of other organic acidemias and metabolic encephalopathies, although some have been diagnosed after having unanticipated difficulty recovering from otherwise ordinary childhood illnesses. Clinical presentation with acute onset of generalized hypotonia and choreiform movement following upper-respiratory tract infection has been observed. Increased gamma-hydroxybutyric aciduria (GHB) on a urinary organic acid analysis is suggestive of the condition; however, the diagnosis of SSADH deficiency is established in a proband with consistent analyte findings and/or suggestive clinical features by identification of biallelic pathogenic variants in SSADH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
Succinic semialdehyde dehydrogenase (SSADH) deficiency
Developmental delay and/or cognitive deficiency, often with prominent expressive language deficit
Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and behavioral issues, including obsessive-compulsive disorder, anxiety, and affective issues
Hypotonia
Epilepsy
Hyporeflexia
Movement disorders, such as ataxia, dystonia, and exertional dyskinesia
Sleep disturbances
Cranial MRI that demonstrates:
A pallidodentatoluysian pattern, showing increased T
T
Cerebral atrophy
Cerebellar atrophy
Delayed myelination
Magnetic resonance spectroscopy that demonstrates elevated levels of gamma-aminobutyric acid (GABA) and related compounds in the Glx peak (e.g., gamma-hydroxybutyrate [GHB], also known as 4-hydroxybutyric acid], glutamate, and homocarnosine)
Absence of metabolic acidosis
Suggestive pattern of findings on urine organic acid, plasma amino/organic acid, and cerebrospinal fluid (CSF) analyses (see Establishing the Diagnosis,
Note: Newborn screening is not routinely done for this disorder at this time. However, ongoing efforts to develop targeted genetic therapies for SSADH deficiency may provide a more substantial justification for newborn screening for this disorder in the future.
The following
Urine organic analysis demonstrating:
4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
Significant amounts of dicarboxylic acids
Increased glycine concentration
Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [
The molecular diagnosis of SSADH 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
When the phenotypic and laboratory findings suggest the diagnosis of SSADH deficiency, 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 Succinic Semialdehyde Dehydrogenase 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
Sixty-two families [
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.
• Developmental delay and/or cognitive deficiency, often with prominent expressive language deficit
• Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and behavioral issues, including obsessive-compulsive disorder, anxiety, and affective issues
• Hypotonia
• Epilepsy
• Hyporeflexia
• Movement disorders, such as ataxia, dystonia, and exertional dyskinesia
• Sleep disturbances
• Cranial MRI that demonstrates:
• A pallidodentatoluysian pattern, showing increased T
• T
• Cerebral atrophy
• Cerebellar atrophy
• Delayed myelination
• A pallidodentatoluysian pattern, showing increased T
• T
• Cerebral atrophy
• Cerebellar atrophy
• Delayed myelination
• Magnetic resonance spectroscopy that demonstrates elevated levels of gamma-aminobutyric acid (GABA) and related compounds in the Glx peak (e.g., gamma-hydroxybutyrate [GHB], also known as 4-hydroxybutyric acid], glutamate, and homocarnosine)
• A pallidodentatoluysian pattern, showing increased T
• T
• Cerebral atrophy
• Cerebellar atrophy
• Delayed myelination
• Absence of metabolic acidosis
• Suggestive pattern of findings on urine organic acid, plasma amino/organic acid, and cerebrospinal fluid (CSF) analyses (see Establishing the Diagnosis,
• Urine organic analysis demonstrating:
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
• Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
## Suggestive Findings
Succinic semialdehyde dehydrogenase (SSADH) deficiency
Developmental delay and/or cognitive deficiency, often with prominent expressive language deficit
Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and behavioral issues, including obsessive-compulsive disorder, anxiety, and affective issues
Hypotonia
Epilepsy
Hyporeflexia
Movement disorders, such as ataxia, dystonia, and exertional dyskinesia
Sleep disturbances
Cranial MRI that demonstrates:
A pallidodentatoluysian pattern, showing increased T
T
Cerebral atrophy
Cerebellar atrophy
Delayed myelination
Magnetic resonance spectroscopy that demonstrates elevated levels of gamma-aminobutyric acid (GABA) and related compounds in the Glx peak (e.g., gamma-hydroxybutyrate [GHB], also known as 4-hydroxybutyric acid], glutamate, and homocarnosine)
Absence of metabolic acidosis
Suggestive pattern of findings on urine organic acid, plasma amino/organic acid, and cerebrospinal fluid (CSF) analyses (see Establishing the Diagnosis,
Note: Newborn screening is not routinely done for this disorder at this time. However, ongoing efforts to develop targeted genetic therapies for SSADH deficiency may provide a more substantial justification for newborn screening for this disorder in the future.
• Developmental delay and/or cognitive deficiency, often with prominent expressive language deficit
• Neurobehavioral/psychiatric manifestations, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and behavioral issues, including obsessive-compulsive disorder, anxiety, and affective issues
• Hypotonia
• Epilepsy
• Hyporeflexia
• Movement disorders, such as ataxia, dystonia, and exertional dyskinesia
• Sleep disturbances
• Cranial MRI that demonstrates:
• A pallidodentatoluysian pattern, showing increased T
• T
• Cerebral atrophy
• Cerebellar atrophy
• Delayed myelination
• A pallidodentatoluysian pattern, showing increased T
• T
• Cerebral atrophy
• Cerebellar atrophy
• Delayed myelination
• Magnetic resonance spectroscopy that demonstrates elevated levels of gamma-aminobutyric acid (GABA) and related compounds in the Glx peak (e.g., gamma-hydroxybutyrate [GHB], also known as 4-hydroxybutyric acid], glutamate, and homocarnosine)
• A pallidodentatoluysian pattern, showing increased T
• T
• Cerebral atrophy
• Cerebellar atrophy
• Delayed myelination
• Absence of metabolic acidosis
• Suggestive pattern of findings on urine organic acid, plasma amino/organic acid, and cerebrospinal fluid (CSF) analyses (see Establishing the Diagnosis,
## Establishing the Diagnosis
The following
Urine organic analysis demonstrating:
4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
Significant amounts of dicarboxylic acids
Increased glycine concentration
Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [
The molecular diagnosis of SSADH 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
When the phenotypic and laboratory findings suggest the diagnosis of SSADH deficiency, 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 Succinic Semialdehyde Dehydrogenase 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
Sixty-two families [
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.
• Urine organic analysis demonstrating:
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
• Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
## Analyte Diagnosis
The following
Urine organic analysis demonstrating:
4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
Significant amounts of dicarboxylic acids
Increased glycine concentration
Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [
• Urine organic analysis demonstrating:
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
• Note: (1) Specific ion monitoring may be required for the detection of GHB, as its presence is sometimes obscured by a large normal urea peak on routine organic acid qualitative studies. (2) Falsely elevated urinary concentrations of GHB have been reported in individuals in whom the urine sample was obtained using Coloplast SpeediCath catheters, which have been found to have GHB concentrations as high as 11 mmol/L [
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
• 4-hydroxybutyric acid (GHB) concentration of 100-1200 mmol/mol creatinine (normal: >0-7 mmol/mol creatinine)
• Small amounts of 4,5-dihydroxyhexanoic acid and 3-hydroxyproprionic acid
• Significant amounts of dicarboxylic acids
• Increased glycine concentration
## Molecular Diagnosis
The molecular diagnosis of SSADH 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
When the phenotypic and laboratory findings suggest the diagnosis of SSADH deficiency, 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 Succinic Semialdehyde Dehydrogenase 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
Sixty-two families [
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.
##
When the phenotypic and laboratory findings suggest the diagnosis of SSADH deficiency, 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 Succinic Semialdehyde Dehydrogenase 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
Sixty-two families [
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
Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence [
Succinic Semialdehyde Dehydrogenase Deficiency: Frequency of Select Features
Based on
ADHD = attention-deficit/hyperactivity disorder
The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
Hypotonia is present in roughly 65% of individuals, tends to improve over time, and is typically not severe enough to require a feeding tube.
Ataxia occurs in about 40% of individuals and does not tend to improve with age.
Movement disorders, such as dystonia and dyskinesia, occur in 20%-30% of individuals, with exertional dyskinesias, including ballismus, appearing in late adolescence [
Ten affected individuals studied with overnight polysomnography and daytime multiple sleep latency testing (MLST) had prolonged REM latency (mean: 272±89 min) and reduced stage REM percentage (mean: 8.9%; range: 0.3%-13.8%) [
Half of these individuals showed a decrease in daytime mean sleep latency on MSLT, indicating excessive daytime somnolence.
Overall, REM sleep appears to be reduced.
Notably, the severity of glymphatic dysfunction, as reflected by an increased burden of perivascular spaces, is associated with worse sleeping disturbances (such as parasomnias, sleep-disordered breathing problems, and daytime sleepiness) [
SSADH deficiency is caused by biallelic pathogenic variants and SSADH is an oligomeric protein; therefore, knowledge of the
In general, individuals with pathogenic
While the actual incidence and prevalence of SSADH deficiency are currently unknown, at least 450 individuals have been described worldwide [
•
• The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
• The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
• The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
• The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
• Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
• However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
• Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
• However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
• The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
• The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
• Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
• However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
• Hypotonia is present in roughly 65% of individuals, tends to improve over time, and is typically not severe enough to require a feeding tube.
• Ataxia occurs in about 40% of individuals and does not tend to improve with age.
• Movement disorders, such as dystonia and dyskinesia, occur in 20%-30% of individuals, with exertional dyskinesias, including ballismus, appearing in late adolescence [
• Ten affected individuals studied with overnight polysomnography and daytime multiple sleep latency testing (MLST) had prolonged REM latency (mean: 272±89 min) and reduced stage REM percentage (mean: 8.9%; range: 0.3%-13.8%) [
• Half of these individuals showed a decrease in daytime mean sleep latency on MSLT, indicating excessive daytime somnolence.
• Overall, REM sleep appears to be reduced.
• Notably, the severity of glymphatic dysfunction, as reflected by an increased burden of perivascular spaces, is associated with worse sleeping disturbances (such as parasomnias, sleep-disordered breathing problems, and daytime sleepiness) [
## Clinical Description
Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by a relatively non-progressive encephalopathy typically presenting with hypotonia and delayed acquisition of motor and language developmental milestones in the first two years of life. Common clinical features include an almost universal intellectual disability and adaptive function deficits, as well as epilepsy, autism spectrum disorder, movement disorders (such as ataxia, dystonia, and exertional dyskinesia), sleep disturbances, attention problems, anxiety, and obsessive-compulsive behaviors. Notably, seizures, autism spectrum disorder features, and behavioral problems tend to worsen around the time of late childhood or early adolescence [
Succinic Semialdehyde Dehydrogenase Deficiency: Frequency of Select Features
Based on
ADHD = attention-deficit/hyperactivity disorder
The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
Hypotonia is present in roughly 65% of individuals, tends to improve over time, and is typically not severe enough to require a feeding tube.
Ataxia occurs in about 40% of individuals and does not tend to improve with age.
Movement disorders, such as dystonia and dyskinesia, occur in 20%-30% of individuals, with exertional dyskinesias, including ballismus, appearing in late adolescence [
Ten affected individuals studied with overnight polysomnography and daytime multiple sleep latency testing (MLST) had prolonged REM latency (mean: 272±89 min) and reduced stage REM percentage (mean: 8.9%; range: 0.3%-13.8%) [
Half of these individuals showed a decrease in daytime mean sleep latency on MSLT, indicating excessive daytime somnolence.
Overall, REM sleep appears to be reduced.
Notably, the severity of glymphatic dysfunction, as reflected by an increased burden of perivascular spaces, is associated with worse sleeping disturbances (such as parasomnias, sleep-disordered breathing problems, and daytime sleepiness) [
•
• The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
• The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
• The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
• The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
• Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
• However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
• Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
• However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
• The majority of individuals with SSADH deficiency attain head control (98%), can sit unsupported (97%), and walk unsupported (90%) at median (IQR) ages of 6 months (4-7 months), 11 months (7-12 months), and 19 months (16-30 months), respectively.
• The vast majority of affected individuals are only mildly delayed in motor abilities, and only 10% require support for walking [
• Roughly 90% of individuals acquire the ability to express some words, and the median (IQR) age of the first expressed word is 28 (20-48) months (see
• However, both expressive and receptive language deficits are almost universal, with expressive language deficits more pronounced than receptive language deficits.
• Hypotonia is present in roughly 65% of individuals, tends to improve over time, and is typically not severe enough to require a feeding tube.
• Ataxia occurs in about 40% of individuals and does not tend to improve with age.
• Movement disorders, such as dystonia and dyskinesia, occur in 20%-30% of individuals, with exertional dyskinesias, including ballismus, appearing in late adolescence [
• Ten affected individuals studied with overnight polysomnography and daytime multiple sleep latency testing (MLST) had prolonged REM latency (mean: 272±89 min) and reduced stage REM percentage (mean: 8.9%; range: 0.3%-13.8%) [
• Half of these individuals showed a decrease in daytime mean sleep latency on MSLT, indicating excessive daytime somnolence.
• Overall, REM sleep appears to be reduced.
• Notably, the severity of glymphatic dysfunction, as reflected by an increased burden of perivascular spaces, is associated with worse sleeping disturbances (such as parasomnias, sleep-disordered breathing problems, and daytime sleepiness) [
## Genotype-Phenotype Correlations
SSADH deficiency is caused by biallelic pathogenic variants and SSADH is an oligomeric protein; therefore, knowledge of the
In general, individuals with pathogenic
## Prevalence
While the actual incidence and prevalence of SSADH deficiency are currently unknown, at least 450 individuals have been described worldwide [
## Genetically Related (Allelic) Disorders
No phenotypes other than those described in this
## Differential Diagnosis
•
•
•
•
## Management
Consensus clinical management guidelines for succinic semialdehyde dehydrogenase (SSADH) deficiency have been published [
To establish the extent of disease and needs in an individual diagnosed with SSADH deficiency, the evaluations summarized in
Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis
Neuroimaging is not specifically indicated for SSADH deficiency, unless neurologic signs warranting a neuroimaging assessment are present.
An EEG is indicated in SSADH deficiency only if there is clinical suspicion of seizures.
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 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; OT = occupational therapy; PT = physical therapy; SSADH = succinic semialdehyde dehydrogenase
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for SSADH 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
Succinic Semialdehyde Dehydrogenase Deficiency: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Valproate is avoided when possible because of inhibition of potential residual enzymatic activity. However, it may be considered in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective.
Vigabatrin is not generally recommended as an ASM for persons w/SSADH deficiency.
Ketogenic diet is not clearly indicated as standard therapy in persons w/SSADH deficiency; however, if adherence is possible, it is not contraindicated & may be attempted.
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; 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.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
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. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for the treatment of increased anxiety, aggressiveness, and inattention [
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Surveillance
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, ataxia, or movement disorders.
ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder
Vigabatrin could be a rational therapy in people with SSADH deficiency due to its property of gamma-aminobutyric acid transaminase (GABA-T) inhibition leading to decreased 4-hydroxybutyric acid (GHB) levels. However, it may result in elevated GABA and the exacerbation of manifestations, and its clinical utility has been inconsistent. For these reasons and its potential for retinal toxicity, vigabatrin is not generally recommended as an anti-seizure medication (ASM) for individuals with SSADH deficiency.
Tiagabine could also lead to an increase in GABA levels and is not recommended for individuals with SSADH deficiency.
Valproate may lead to inhibition of residual SSADH activity; however, its efficacy in individuals with SSADH deficiency has been occasionally described. Valproate is not recommended as a first-line ASM in those with SSADH deficiency, but it may be considered in drug-resistant epilepsy or generalized spike-wave epilepsy [
See
Ongoing work on gene replacement therapy for people with SSADH deficiency involves disease-specific modeling, viral vector testing, and development of clinical biomarkers assessing indices of cortical inhibition such as transcranial magnetic stimulation [
Search
• Neuroimaging is not specifically indicated for SSADH deficiency, unless neurologic signs warranting a neuroimaging assessment are present.
• An EEG is indicated in SSADH deficiency only if there is clinical suspicion of seizures.
• 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 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.
• Valproate is avoided when possible because of inhibition of potential residual enzymatic activity. However, it may be considered in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective.
• Vigabatrin is not generally recommended as an ASM for persons w/SSADH deficiency.
• Ketogenic diet is not clearly indicated as standard therapy in persons w/SSADH deficiency; however, if adherence is possible, it is not contraindicated & may be attempted.
• 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 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).
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, ataxia, or movement disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SSADH deficiency, the evaluations summarized in
Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Evaluations Following Initial Diagnosis
Neuroimaging is not specifically indicated for SSADH deficiency, unless neurologic signs warranting a neuroimaging assessment are present.
An EEG is indicated in SSADH deficiency only if there is clinical suspicion of seizures.
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 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; OT = occupational therapy; PT = physical therapy; SSADH = succinic semialdehyde dehydrogenase
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Neuroimaging is not specifically indicated for SSADH deficiency, unless neurologic signs warranting a neuroimaging assessment are present.
• An EEG is indicated in SSADH deficiency only if there is clinical suspicion of seizures.
• 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 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 SSADH 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
Succinic Semialdehyde Dehydrogenase Deficiency: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Valproate is avoided when possible because of inhibition of potential residual enzymatic activity. However, it may be considered in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective.
Vigabatrin is not generally recommended as an ASM for persons w/SSADH deficiency.
Ketogenic diet is not clearly indicated as standard therapy in persons w/SSADH deficiency; however, if adherence is possible, it is not contraindicated & may be attempted.
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; 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.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
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. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for the treatment of increased anxiety, aggressiveness, and inattention [
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Valproate is avoided when possible because of inhibition of potential residual enzymatic activity. However, it may be considered in circumstances such as drug-resistant generalized spike-wave EEG pattern when other ASMs are ineffective.
• Vigabatrin is not generally recommended as an ASM for persons w/SSADH deficiency.
• Ketogenic diet is not clearly indicated as standard therapy in persons w/SSADH deficiency; however, if adherence is possible, it is not contraindicated & may be attempted.
• 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 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
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. Methylphenidate, thioridazine, risperidal, fluoxetine, and benzodiazepines have been used for the treatment of increased anxiety, aggressiveness, and inattention [
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Succinic Semialdehyde Dehydrogenase Deficiency: Recommended Surveillance
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, ataxia, or movement disorders.
ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, ataxia, or movement disorders.
## Agents/Circumstances to Avoid
Vigabatrin could be a rational therapy in people with SSADH deficiency due to its property of gamma-aminobutyric acid transaminase (GABA-T) inhibition leading to decreased 4-hydroxybutyric acid (GHB) levels. However, it may result in elevated GABA and the exacerbation of manifestations, and its clinical utility has been inconsistent. For these reasons and its potential for retinal toxicity, vigabatrin is not generally recommended as an anti-seizure medication (ASM) for individuals with SSADH deficiency.
Tiagabine could also lead to an increase in GABA levels and is not recommended for individuals with SSADH deficiency.
Valproate may lead to inhibition of residual SSADH activity; however, its efficacy in individuals with SSADH deficiency has been occasionally described. Valproate is not recommended as a first-line ASM in those with SSADH deficiency, but it may be considered in drug-resistant epilepsy or generalized spike-wave epilepsy [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Ongoing work on gene replacement therapy for people with SSADH deficiency involves disease-specific modeling, viral vector testing, and development of clinical biomarkers assessing indices of cortical inhibition such as transcranial magnetic stimulation [
Search
## Genetic Counseling
Succinic semialdehyde dehydrogenase (SSADH) deficiency 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
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.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Biochemical testing is not accurate or reliable for carrier determination.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
It is appropriate to offer
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
• 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.
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
• It is appropriate to offer
## Mode of Inheritance
Succinic semialdehyde dehydrogenase (SSADH) deficiency 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
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.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic.
• 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.
• 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.
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Biochemical testing is not accurate or reliable for carrier determination.
## 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.
It is appropriate to offer
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
• It is appropriate to offer
## 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
•
•
•
• United Kingdom
•
## Molecular Genetics
Succinic Semialdehyde Dehydrogenase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Succinic Semialdehyde Dehydrogenase Deficiency (
In the absence of SSADH, the transamination of GABA to succinic semialdehyde is interrupted, leading to a pathologic accumulation of GABA and 4-hydroxybutyric acid (GHB). Persistent levels of GABA lead to user-dependent down-regulation of GABA
## Molecular Pathogenesis
In the absence of SSADH, the transamination of GABA to succinic semialdehyde is interrupted, leading to a pathologic accumulation of GABA and 4-hydroxybutyric acid (GHB). Persistent levels of GABA lead to user-dependent down-regulation of GABA
## Chapter Notes
Boston Children's Hospital, Boston, Massachusetts, USA, is leading a natural history study of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. For more information and to contact the study team, see
Itay Tokatly Latzer, MD (
Supported in part by the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant (1R01HD091142), a Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC) grant (P50 HD105351), an exploratory/developmental research grant award (R21NS121858), and the SSADH Association.
Emily S Barrios; Children's National Medical Center (2013-2016)Jessica L Cabalza; George Washington University (2006-2010) Philip K Capp; George Washington University (2004-2006) Adrianne M Dorsey; Children's National Medical Center (2013-2016)Ian Drillings; Children's National Medical Center (2010-2013)Maciej Gasior, MD, PhD; National Institutes of Health (2004-2006) K Michael Gibson, PhD, FACMG; Washington State University (2004-2025) Thomas R Hartka, MS; George Washington University (2006-2010) Phillip L Pearl, MD (2004-present) Tom Reehal; Sheffield University (2010-2013)Jean-Baptiste Roullet, PhD (2016-present)Emily Robbins; George Washington University (2004-2006) Itay Tokatly Latzer, MD (2024-present)Natrujee Wiwattanadittakul, MD; Chiang Mai University (2016-2025)
9 January 2025 (ma) Comprehensive update posted live
28 April 2016 (ma) Comprehensive update posted live
19 September 2013 (me) Comprehensive update posted live
5 October 2010 (me) Comprehensive update posted live
25 July 2006 (me) Comprehensive update posted live
5 May 2004 (ca) Review posted live
16 September 2003 (pp) Original submission
• 9 January 2025 (ma) Comprehensive update posted live
• 28 April 2016 (ma) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 5 October 2010 (me) Comprehensive update posted live
• 25 July 2006 (me) Comprehensive update posted live
• 5 May 2004 (ca) Review posted live
• 16 September 2003 (pp) Original submission
## Author Notes
Boston Children's Hospital, Boston, Massachusetts, USA, is leading a natural history study of patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. For more information and to contact the study team, see
Itay Tokatly Latzer, MD (
## Acknowledgments
Supported in part by the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) grant (1R01HD091142), a Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC) grant (P50 HD105351), an exploratory/developmental research grant award (R21NS121858), and the SSADH Association.
## Author History
Emily S Barrios; Children's National Medical Center (2013-2016)Jessica L Cabalza; George Washington University (2006-2010) Philip K Capp; George Washington University (2004-2006) Adrianne M Dorsey; Children's National Medical Center (2013-2016)Ian Drillings; Children's National Medical Center (2010-2013)Maciej Gasior, MD, PhD; National Institutes of Health (2004-2006) K Michael Gibson, PhD, FACMG; Washington State University (2004-2025) Thomas R Hartka, MS; George Washington University (2006-2010) Phillip L Pearl, MD (2004-present) Tom Reehal; Sheffield University (2010-2013)Jean-Baptiste Roullet, PhD (2016-present)Emily Robbins; George Washington University (2004-2006) Itay Tokatly Latzer, MD (2024-present)Natrujee Wiwattanadittakul, MD; Chiang Mai University (2016-2025)
## Revision History
9 January 2025 (ma) Comprehensive update posted live
28 April 2016 (ma) Comprehensive update posted live
19 September 2013 (me) Comprehensive update posted live
5 October 2010 (me) Comprehensive update posted live
25 July 2006 (me) Comprehensive update posted live
5 May 2004 (ca) Review posted live
16 September 2003 (pp) Original submission
• 9 January 2025 (ma) Comprehensive update posted live
• 28 April 2016 (ma) Comprehensive update posted live
• 19 September 2013 (me) Comprehensive update posted live
• 5 October 2010 (me) Comprehensive update posted live
• 25 July 2006 (me) Comprehensive update posted live
• 5 May 2004 (ca) Review posted live
• 16 September 2003 (pp) Original submission
## References
## Literature Cited
In the absence of succinic semialdehyde dehydrogenase (SSADH), transamination of gamma-aminobutyric acid (GABA) to succinic semialdehyde is followed by reduction to 4-hydroxybutyric acid (gamma-hydroxybutyrate [GHB]). SSADH deficiency leads to significant accumulation of GHB and GABA.
|
[] |
5/5/2004
|
9/1/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
stac3-dis
|
stac3-dis
|
[
"Native American Myopathy",
"Native American Myopathy",
"SH3 and cysteine-rich domain-containing protein 3",
"STAC3",
"STAC3 Disorder"
] |
Bryn D Webb, Irini Manoli, Ethylin Wang Jabs
|
Summary The diagnosis of Occupational and physical therapy needs regarding range of motion and mobility Use of adaptive devices for mobility and activities of daily living Feeding difficulties Speech delays Scoliosis Respiratory insufficiency Due to the medical comorbidities in
|
## Diagnosis
Formal diagnostic criteria for
Congenital weakness
Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
Scoliosis, kyphosis, or kyphoscoliosis
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. Because the phenotype of
When the phenotypic findings suggest the diagnosis of
Note: Targeted analysis for the
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date no large
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.
•
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
•
• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
• Scoliosis, kyphosis, or kyphoscoliosis
• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
• Scoliosis, kyphosis, or kyphoscoliosis
•
•
•
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
• Scoliosis, kyphosis, or kyphoscoliosis
• Note: Targeted analysis for the
• For an introduction to multigene panels click
## Suggestive Findings
Congenital weakness
Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
Scoliosis, kyphosis, or kyphoscoliosis
•
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
•
• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
• Scoliosis, kyphosis, or kyphoscoliosis
• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
• Scoliosis, kyphosis, or kyphoscoliosis
•
•
•
• Congenital weakness
• Myopathic facies, characterized by ptosis, inability to raise corners of mouth, and (in some individuals) hollowed-out cheeks from loss of facial musculature, which may cause an open-mouthed expressionless appearance with downturned corners of the mouth. Over time, the face often becomes long and narrow.
• Congenital contractures ranging from talipes equinovarus (bilateral or unilateral) with or without other joint contractures to arthrogryposis (i.e., multiple contractures of the joints in more than one area of the body present at birth) [
• Scoliosis, kyphosis, or kyphoscoliosis
## 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. Because the phenotype of
When the phenotypic findings suggest the diagnosis of
Note: Targeted analysis for the
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date no large
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.
• Note: Targeted analysis for the
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of
Note: Targeted analysis for the
For an introduction to multigene panels click
• Note: Targeted analysis for the
• For an introduction to multigene panels click
## Option 2
When the diagnosis of
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date no large
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
Prior to knowledge of its genetic cause,
Following the identification of biallelic pathogenic variants in
The findings of all individuals reported to date with molecularly confirmed
Clinical Findings in Individuals with
6/6 patients in Stewart et at [1988] had short stature; 2/2 adults in
At least two individuals in
Motor delays are most often present by infancy or very early childhood. The maximum motor ability in 15 individuals old enough for evaluation was walking (11), short walk (2), running (1), and sitting independently (1) [
Ptosis refers to downward placement (i.e., drooping) of the upper eyelids. In children, ptosis that obstructs the pupil may result in vision impairment or amblyopia. Ptosis may also cause loss of peripheral vision and blurred vision. To maximize vision individuals with ptosis may assume a posture with head tilted backwards and chin pointed upwards.
Joint laxity has been seen in individuals with or without contractures.
Spinal involvement, including scoliosis, kyphosis, or kyphoscoliosis, is often present by early childhood and is often progressive.
Abnormal palatal formation, including cleft palate
Abnormal tongue movement
Compensatory misarticulation
Velopharyngeal insufficiency
Neurologic factors
Atypical resonance
Respiratory insufficiency
Apraxia
Although MH has been reported in a significant number of individuals, the true frequency of MH susceptibility is likely higher as not all reported individuals had prior surgery or had been exposed to an MH-provoking anesthetic.
Conductive hearing loss is common.
Facial hemangiomas may also be present.
Electromyogram revealed normal results in some individuals and evidence of myopathy in others [
To date no genotype-phenotype correlations are known.
See
• Abnormal palatal formation, including cleft palate
• Abnormal tongue movement
• Compensatory misarticulation
• Velopharyngeal insufficiency
• Neurologic factors
• Atypical resonance
• Respiratory insufficiency
• Apraxia
## Clinical Description
Prior to knowledge of its genetic cause,
Following the identification of biallelic pathogenic variants in
The findings of all individuals reported to date with molecularly confirmed
Clinical Findings in Individuals with
6/6 patients in Stewart et at [1988] had short stature; 2/2 adults in
At least two individuals in
Motor delays are most often present by infancy or very early childhood. The maximum motor ability in 15 individuals old enough for evaluation was walking (11), short walk (2), running (1), and sitting independently (1) [
Ptosis refers to downward placement (i.e., drooping) of the upper eyelids. In children, ptosis that obstructs the pupil may result in vision impairment or amblyopia. Ptosis may also cause loss of peripheral vision and blurred vision. To maximize vision individuals with ptosis may assume a posture with head tilted backwards and chin pointed upwards.
Joint laxity has been seen in individuals with or without contractures.
Spinal involvement, including scoliosis, kyphosis, or kyphoscoliosis, is often present by early childhood and is often progressive.
Abnormal palatal formation, including cleft palate
Abnormal tongue movement
Compensatory misarticulation
Velopharyngeal insufficiency
Neurologic factors
Atypical resonance
Respiratory insufficiency
Apraxia
Although MH has been reported in a significant number of individuals, the true frequency of MH susceptibility is likely higher as not all reported individuals had prior surgery or had been exposed to an MH-provoking anesthetic.
Conductive hearing loss is common.
Facial hemangiomas may also be present.
Electromyogram revealed normal results in some individuals and evidence of myopathy in others [
• Abnormal palatal formation, including cleft palate
• Abnormal tongue movement
• Compensatory misarticulation
• Velopharyngeal insufficiency
• Neurologic factors
• Atypical resonance
• Respiratory insufficiency
• Apraxia
## Genotype-Phenotype Correlations
To date no genotype-phenotype correlations are known.
## Prevalence
See
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with Facial Weakness and Hypotonia to Consider in the Differential Diagnosis of
Respiratory insufficiency
Contractures
Arthrogryposis
Susceptibility to MH
External ophthalmoplegia may be present.
Serum CK may be ↑ in King-Denborough syndrome.
Upturned/broad nasal tip
Micro/retrognathia
Generalized muscle hypoplasia
Delayed motor milestones
Normal cognition
Cleft palate
Talipes equinovarus
Short stature
Scoliosis
Joint contractures
Impairment in ocular abduction is obligatory.
Variably present:
Cranial nerve abnormalities
Hearing loss
Poland anomaly
Limb reduction defects
DD, ASD
AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; DiffDx = differential diagnosis; MH = malignant hyperthermia; MOI = mode of inheritance; XL = X-linked
Moebius syndrome was defined by the Moebius Syndrome Foundation Research Conference with the minimum criteria of congenital, nonprogressive facial weakness with limited abduction of one or both eyes [
Both genetic and environmental etiologies have been proposed. Additionally, prenatal exposure to misoprostol and other agents has been known to cause a Moebius syndrome phenotype.
Heterozygous
• Respiratory insufficiency
• Contractures
• Arthrogryposis
• Susceptibility to MH
• External ophthalmoplegia may be present.
• Serum CK may be ↑ in King-Denborough syndrome.
• Upturned/broad nasal tip
• Micro/retrognathia
• Generalized muscle hypoplasia
• Delayed motor milestones
• Normal cognition
• Cleft palate
• Talipes equinovarus
• Short stature
• Scoliosis
• Joint contractures
• Impairment in ocular abduction is obligatory.
• Variably present:
• Cranial nerve abnormalities
• Hearing loss
• Poland anomaly
• Limb reduction defects
• DD, ASD
• Cranial nerve abnormalities
• Hearing loss
• Poland anomaly
• Limb reduction defects
• DD, ASD
• Cranial nerve abnormalities
• Hearing loss
• Poland anomaly
• Limb reduction defects
• DD, ASD
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Physical exam
Clinical feeding eval using different types of nipples
Video fluoroscopic swallow study
Lab eval (e.g., total carbon dioxide level)
Chest x-ray
Upper GI series
Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia
Spirometry + measurement of maximal inspiratory & expiratory pressures & cough peak flow
For older children & adults, pulmonary function tests may be helpful.
If concern for ascending or descending microaspiration, evaluate for chronic lung disease.
Evaluate severely affected infants for pulmonary hypoplasia.
GI = gastrointestinal; MH = malignant hyperthermia; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy
At present, no treatment halts or reverses the manifestations of
Treatment of Manifestations in Individuals with
PT to improve range of motion;
Stretching, night splints, or serial casts.
Invasive or noninvasive ventilatory support, mechanical cough assist (in exsufflator)
As per recommendations of pulmonary & craniofacial team
Aggressive treatment & prevention of lower respiratory tract infections (influenza & PCV-23 vaccines)
May incl need for noninvasive or invasive positive pressure ventilation (e.g., CPAP, BiPAP via mask, tracheostomy w/ventilation); assessment for ascending or descending microaspiration w/appropriate interventions
OT = occupational therapy; PT = physical therapy
Enteral feeding tubes may be needed if there is concern for aspiration or if the affected individual is unable to take in adequate calories for growth. Some children with more significant respiratory issues may require surgical feeding tubes and/or procedures to protect their lungs from microaspiration.
Due to the complexity of speech evaluation in children with myopathic facies, structural differences with or without cleft palate, a speech-language pathologist on a multidisciplinary craniofacial team will be needed to determine the contributing factors in most children.
Recommended Surveillance for Individuals with
Respiratory status, speech development, swallowing function
Musculoskeletal complications (e.g., scoliosis &/or joint contractures)
Infants age <12 mos: every 3-4 mos
Older children & adults: every 6-12 mos
Equipment & techniques for feeding infants w/cleft palate
Surgical repair timing & type of procedure determined by team
Anesthesiologist should be aware of risk of MH.
Audiologic eval as part of craniofacial team as needed
Infants: visit frequency determined by feeding & respiratory issues
Children: varies depending on comorbidities; at least annually
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
Consider clinical feeding eval &/or video fluoroscopic swallow study.
Assessment of pulmonary status & pulmonary function testing
Polysomnography
Evaluate for signs of ascending or descending aspiration.
Speech assessment by speech-language pathologist familiar w/cleft palate & neuromuscular contributors to speech issues
Consider speech therapy, surgical interventions, & augmentative communication devices.
MH = malignant hyperthermia; PCP = primary care physician
Persons with
See
Search
• Physical exam
• Clinical feeding eval using different types of nipples
• Video fluoroscopic swallow study
• Lab eval (e.g., total carbon dioxide level)
• Chest x-ray
• Upper GI series
• Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia
• Spirometry + measurement of maximal inspiratory & expiratory pressures & cough peak flow
• For older children & adults, pulmonary function tests may be helpful.
• If concern for ascending or descending microaspiration, evaluate for chronic lung disease.
• Evaluate severely affected infants for pulmonary hypoplasia.
• PT to improve range of motion;
• Stretching, night splints, or serial casts.
• Invasive or noninvasive ventilatory support, mechanical cough assist (in exsufflator)
• As per recommendations of pulmonary & craniofacial team
• Aggressive treatment & prevention of lower respiratory tract infections (influenza & PCV-23 vaccines)
• May incl need for noninvasive or invasive positive pressure ventilation (e.g., CPAP, BiPAP via mask, tracheostomy w/ventilation); assessment for ascending or descending microaspiration w/appropriate interventions
• Respiratory status, speech development, swallowing function
• Musculoskeletal complications (e.g., scoliosis &/or joint contractures)
• Infants age <12 mos: every 3-4 mos
• Older children & adults: every 6-12 mos
• Equipment & techniques for feeding infants w/cleft palate
• Surgical repair timing & type of procedure determined by team
• Anesthesiologist should be aware of risk of MH.
• Audiologic eval as part of craniofacial team as needed
• Infants: visit frequency determined by feeding & respiratory issues
• Children: varies depending on comorbidities; at least annually
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
• Consider clinical feeding eval &/or video fluoroscopic swallow study.
• Assessment of pulmonary status & pulmonary function testing
• Polysomnography
• Evaluate for signs of ascending or descending aspiration.
• Speech assessment by speech-language pathologist familiar w/cleft palate & neuromuscular contributors to speech issues
• Consider speech therapy, surgical interventions, & augmentative communication devices.
## 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
Physical exam
Clinical feeding eval using different types of nipples
Video fluoroscopic swallow study
Lab eval (e.g., total carbon dioxide level)
Chest x-ray
Upper GI series
Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia
Spirometry + measurement of maximal inspiratory & expiratory pressures & cough peak flow
For older children & adults, pulmonary function tests may be helpful.
If concern for ascending or descending microaspiration, evaluate for chronic lung disease.
Evaluate severely affected infants for pulmonary hypoplasia.
GI = gastrointestinal; MH = malignant hyperthermia; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy
• Physical exam
• Clinical feeding eval using different types of nipples
• Video fluoroscopic swallow study
• Lab eval (e.g., total carbon dioxide level)
• Chest x-ray
• Upper GI series
• Polysomnography needed to evaluate for central &/or obstructive sleep apnea as well as hypoxia
• Spirometry + measurement of maximal inspiratory & expiratory pressures & cough peak flow
• For older children & adults, pulmonary function tests may be helpful.
• If concern for ascending or descending microaspiration, evaluate for chronic lung disease.
• Evaluate severely affected infants for pulmonary hypoplasia.
## Treatment of Manifestations
At present, no treatment halts or reverses the manifestations of
Treatment of Manifestations in Individuals with
PT to improve range of motion;
Stretching, night splints, or serial casts.
Invasive or noninvasive ventilatory support, mechanical cough assist (in exsufflator)
As per recommendations of pulmonary & craniofacial team
Aggressive treatment & prevention of lower respiratory tract infections (influenza & PCV-23 vaccines)
May incl need for noninvasive or invasive positive pressure ventilation (e.g., CPAP, BiPAP via mask, tracheostomy w/ventilation); assessment for ascending or descending microaspiration w/appropriate interventions
OT = occupational therapy; PT = physical therapy
Enteral feeding tubes may be needed if there is concern for aspiration or if the affected individual is unable to take in adequate calories for growth. Some children with more significant respiratory issues may require surgical feeding tubes and/or procedures to protect their lungs from microaspiration.
Due to the complexity of speech evaluation in children with myopathic facies, structural differences with or without cleft palate, a speech-language pathologist on a multidisciplinary craniofacial team will be needed to determine the contributing factors in most children.
• PT to improve range of motion;
• Stretching, night splints, or serial casts.
• Invasive or noninvasive ventilatory support, mechanical cough assist (in exsufflator)
• As per recommendations of pulmonary & craniofacial team
• Aggressive treatment & prevention of lower respiratory tract infections (influenza & PCV-23 vaccines)
• May incl need for noninvasive or invasive positive pressure ventilation (e.g., CPAP, BiPAP via mask, tracheostomy w/ventilation); assessment for ascending or descending microaspiration w/appropriate interventions
## Surveillance
Recommended Surveillance for Individuals with
Respiratory status, speech development, swallowing function
Musculoskeletal complications (e.g., scoliosis &/or joint contractures)
Infants age <12 mos: every 3-4 mos
Older children & adults: every 6-12 mos
Equipment & techniques for feeding infants w/cleft palate
Surgical repair timing & type of procedure determined by team
Anesthesiologist should be aware of risk of MH.
Audiologic eval as part of craniofacial team as needed
Infants: visit frequency determined by feeding & respiratory issues
Children: varies depending on comorbidities; at least annually
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
Consider clinical feeding eval &/or video fluoroscopic swallow study.
Assessment of pulmonary status & pulmonary function testing
Polysomnography
Evaluate for signs of ascending or descending aspiration.
Speech assessment by speech-language pathologist familiar w/cleft palate & neuromuscular contributors to speech issues
Consider speech therapy, surgical interventions, & augmentative communication devices.
MH = malignant hyperthermia; PCP = primary care physician
• Respiratory status, speech development, swallowing function
• Musculoskeletal complications (e.g., scoliosis &/or joint contractures)
• Infants age <12 mos: every 3-4 mos
• Older children & adults: every 6-12 mos
• Equipment & techniques for feeding infants w/cleft palate
• Surgical repair timing & type of procedure determined by team
• Anesthesiologist should be aware of risk of MH.
• Audiologic eval as part of craniofacial team as needed
• Infants: visit frequency determined by feeding & respiratory issues
• Children: varies depending on comorbidities; at least annually
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
• Consider clinical feeding eval &/or video fluoroscopic swallow study.
• Assessment of pulmonary status & pulmonary function testing
• Polysomnography
• Evaluate for signs of ascending or descending aspiration.
• Speech assessment by speech-language pathologist familiar w/cleft palate & neuromuscular contributors to speech issues
• Consider speech therapy, surgical interventions, & augmentative communication devices.
## Agents/Circumstances to Avoid
Persons 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 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., 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 affected, 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 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
United Kingdom
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
STAC3 Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for STAC3 Disorder (
See
Variants listed in the table have been provided by the authors.
STAC3 contains an N-terminal cysteine-rich domain and two SH3 domains.
STAC3 is a component of the excitation-contraction coupling machinery of muscles and biochemically associates with dihydropyridine receptor (DHPR) and ryanodine receptor 1 (RYR1) at triadic complexes, which are required for normal calcium release from the sarcoplasmic reticulum in skeletal muscle that leads to muscle contraction.
The c.851G>C missense variant identified in Lumbee Native American families leads to decreases in the quantity, organization, stability, and voltage sensitivity of Ca
cDNA studies confirmed two aberrant transcription products for the
For the c.997-1G>T variant, cDNA studies confirmed activation of a cryptic acceptor site within exon 12 leading to deletion of 12 nucleotides from mature
• The c.851G>C missense variant identified in Lumbee Native American families leads to decreases in the quantity, organization, stability, and voltage sensitivity of Ca
• cDNA studies confirmed two aberrant transcription products for the
• For the c.997-1G>T variant, cDNA studies confirmed activation of a cryptic acceptor site within exon 12 leading to deletion of 12 nucleotides from mature
## Chapter Notes
Bryn Webb is a clinical geneticist, clinical molecular geneticist, and pediatrician specializing in genetic studies of rare congenital anomalies. She is co-director of the Cleft and Craniofacial Program at the Icahn School of Medicine at Mount Sinai.
Irini Manoli is a clinical and biochemical geneticist and pediatrician with a focus on clinical and translational research in rare genetic syndromes and inborn errors of metabolism. She works at the National Human Genome Research Institute of the National Institutes of Health.
Ethylin Wang Jabs is a medical geneticist with a clinical focus in dysmorphology and a clinical, translational, and basic research interest in developmental genetics, in particular craniofacial disorders.
20 June 2019 (bp) Review posted live
13 August 2018 (bw) Original submission
• 20 June 2019 (bp) Review posted live
• 13 August 2018 (bw) Original submission
## Author Notes
Bryn Webb is a clinical geneticist, clinical molecular geneticist, and pediatrician specializing in genetic studies of rare congenital anomalies. She is co-director of the Cleft and Craniofacial Program at the Icahn School of Medicine at Mount Sinai.
Irini Manoli is a clinical and biochemical geneticist and pediatrician with a focus on clinical and translational research in rare genetic syndromes and inborn errors of metabolism. She works at the National Human Genome Research Institute of the National Institutes of Health.
Ethylin Wang Jabs is a medical geneticist with a clinical focus in dysmorphology and a clinical, translational, and basic research interest in developmental genetics, in particular craniofacial disorders.
## Revision History
20 June 2019 (bp) Review posted live
13 August 2018 (bw) Original submission
• 20 June 2019 (bp) Review posted live
• 13 August 2018 (bw) Original submission
## References
## Literature Cited
|
[
"H Alrohaif, A Töpf, T Evangelista, M Lek, D McArthur, H Lochmüller. Whole-exome sequencing identifies mutations in MYMK in a mild form of Carey-Fineman-Ziter syndrome.. Neurol Genet. 2018;4",
"AG Bailey, EC Bloch. Malignant hyperthermia in a three-month-old American Indian infant.. Anesth Analg. 1987;66:1043-5",
"JC Carey, RM Fineman, FA Ziter. The Robin sequence as a consequence of malformation, dysplasia, and neuromuscular syndromes.. J Pediatr. 1982;101:858-64",
"CE D'Arcy, A Bjorksten, EM Yiu, A Bankier, R Gillies, CA McLean, LK Shield, MM Ryan. King-Denborough syndrome caused by a novel mutation in the ryanodine receptor gene.. Neurology. 2008;71:776-7",
"SA Di Gioia, S Connors, N Matsunami, J Cannavino, MF Rose, NM Gilette, P Artoni, NL de Macena Sobreira, WM Chan, BD Webb, CD Robson, L Cheng, C Van Ryzin, A Ramirez-Martinez, P Mohassel, M Leppert, MB Scholand, C Grunseich, CR Ferreira, T Hartman, IM Hayes, T Morgan, DM Markie, M Fagiolini, A Swift, PS Chines, CE Speck-Martins, FS Collins, EW Jabs, CG Bönnemann, EN Olson, JC Carey, SP Robertson, I Manoli, EC Engle. A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome.. Nat Commun. 2017;8:16077",
"JJ Dowling, S Lillis, K Amburgey, H Zhou, S Al-Sarraj, SJ Buk, E Wraige, G Chow, S Abbs, S Leber, K Lachlan, D Baralle, A Taylor, C Sewry, F Muntoni, H Jungbluth. King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene.. Neuromuscul Disord. 2011;21:420-7",
"M Grzybowski, A Schänzer, A Pepler, C Heller, BA Neubauer, A Hahn. Novel STAC3 mutations in the first non-Amerindian patient with Native American myopathy.. Neuropediatrics. 2017;48:451-5",
"C Hedberg-Oldfors, C Lindberg, A Oldfors. Carey-Fineman-Ziter syndrome with mutations in the myomaker gene and muscle fiber hypertrophy.. Neurol Genet. 2018;4",
"EJ Horstick, JW Linsley, JJ Dowling, MA Hauser, KK McDonald, A Ashley-Koch, L Saint-Amant, A Satish, WW Cui, W Zhou, SM Sprague, DS Stamm, CM Powell, MC Speer, C Franzini-Armstrong, H Hirata, JY Kuwada. Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy.. Nat Commun. 2013;4:1952",
"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",
"JO King, MA Denborough. Anesthetic-induced malignant hyperpyrexia in children.. J Pediatr. 1973;83:37-40",
"G. Miller. Neurological disorders. The mystery of the missing smile.. Science. 2007;316:826-7",
"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",
"DS Stamm, AS Aylsworth, JM Stajich, SG Kahler, LB Thorne, MC Speer, CM Powell. Native American myopathy: congenital myopathy with cleft palate, skeletal anomalies, and susceptibility to malignant hyperthermia.. Am J Med Genet A. 2008a;146A:1832-41",
"DS Stamm, CM Powell, JM Stajich, VL Zismann, DA Stephan, B Chesnut, AS Aylsworth, SG Kahler, KL Deak, JR Gilbert, MC Speer. Novel congenital myopathy locus identified in Native American Indians at 12q13.13-14.1.. Neurology. 2008b;71:1764-9",
"CR Stewart, SG Kahler, JM Gilchrist. Congenital myopathy with cleft palate and increased susceptibility to malignant hyperthermia: King syndrome?. Pediatr Neurol. 1988;4:371-4",
"A Telegrafi, BD Webb, SM Robbins, CE Speck-Martins, D FitzPatrick, L Fleming, R Redett, A Dufke, G Houge, JJT van Harssel, A Verloes, A Robles, I Manoli, EC Engle, EW Jabs, D Valle, J Carey, JE Hoover-Fong, NLM Sobreira. Identification of STAC3 variants in non-Native American families with overlapping features of Carey-Fineman-Ziter syndrome and Moebius syndrome.. Am J Med Genet A. 2017;173:2763-71",
"L Tomas-Roca, A Tsaalbi-Shtylik, JG Jansen, MK Singh, JA Epstein, U Altunoglu, H Verzijl, L Soria, E van Beusekom, T Roscioli, Z Iqbal, C Gilissen, A Hoischen, AP de Brouwer, C Erasmus, D Schubert, H Brunner, A Pérez Aytés, F Marin, P Aroca, H Kayserili, A Carta, N de Wind, GW Padberg, H van Bokhoven. De novo mutations in PLXND1 and REV3L cause Möbius syndrome.. Nat Commun. 2015;6:7199",
"CH Wang, JJ Dowling, K North, MK Schroth, T Sejersen, F Shapiro, J Bellini, H Weiss, M Guillet, K Amburgey, S Apkon, E Bertini, C Bonnemann, N Clarke, AM Connolly, B Estournet-Mathiaud, D Fitzgerald, JM Florence, R Gee, J Gurgel-Giannetti, AM Glanzman, B Hofmeister, H Jungbluth, AC Koumbourlis, NG Laing, M Main, LA Morrison, C Munns, K Rose, PM Schuler, C Sewry, K Storhaug, M Vainzof, N Yuan. Consensus statement on standard of care for congenital myopathies.. J Child Neurol. 2012;27:363-82",
"IT Zaharieva, A Sarkozy, P Munot, A Manzur, G O'Grady, J Rendu, E Malfatti, H Amthor, L Servais, JA Urtizberea, OA Neto, E Zanoteli, S Donkervoort, J Taylor, J Dixon, G Poke, AR Foley, C Holmes, G Williams, M Holder, S Yum, L Medne, S Quijano-Roy, NB Romero, J Fauré, L Feng, L Bastaki, MR Davis, R Phadke, CA Sewry, CG Bönnemann, H Jungbluth, C Bachmann, S Treves, F Muntoni. STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.. Hum Mutat. 2018;39:1980-94"
] |
20/6/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
stickler
|
stickler
|
[
"Arthroophthalmopathy",
"Arthroophthalmopathy",
"Collagen alpha-1(II) chain",
"Collagen alpha-1(IX) chain",
"Collagen alpha-1(XI) chain",
"Collagen alpha-2(IX) chain",
"Collagen alpha-2(XI) chain",
"Collagen alpha-3(IX) chain",
"COL11A1",
"COL11A2",
"COL2A1",
"COL9A1",
"COL9A2",
"COL9A3",
"Stickler Syndrome"
] |
Stickler Syndrome
|
Geert Mortier
|
Summary Stickler syndrome is a connective tissue disorder that can include ocular findings of myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Pierre Robin sequence); and early-onset degenerative joint disease. Variable phenotypic expression of Stickler syndrome occurs both within and among families; interfamilial variability is in part explained by locus and allelic heterogeneity. The diagnosis of Stickler syndrome can be established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in Stickler syndrome caused by pathogenic variants in Once the Stickler syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
No consensus clinical diagnostic criteria for Stickler syndrome have been published.
Stickler syndrome
Cleft palate (open cleft, submucous cleft, or bifid uvula)
Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro- or retrognathia
Ocular manifestations including high myopia, vitreous abnormalities, cataracts, and/or retinal abnormalities
Sensorineural hearing loss with or without conductive hearing loss
Osteoarticular manifestations with joint pain in childhood and early-onset degenerative joint disease in adulthood
Signs of mild spondyloepiphyseal involvement can be present on radiographs: mild flattening of the vertebrae with or without end plate irregularities; small or dysplastic epiphyses, especially at the hips or knees; Legg-Calvé-Perthes-like changes in the hips [
Early-onset degenerative joint disease
The diagnosis of Stickler syndrome can be
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 Stickler Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; 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
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 [
Rarely, biallelic
To date, large exon or multiexon deletions or duplications in
Pathogenic variants in
• Cleft palate (open cleft, submucous cleft, or bifid uvula)
• Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro- or retrognathia
• Ocular manifestations including high myopia, vitreous abnormalities, cataracts, and/or retinal abnormalities
• Sensorineural hearing loss with or without conductive hearing loss
• Osteoarticular manifestations with joint pain in childhood and early-onset degenerative joint disease in adulthood
• Signs of mild spondyloepiphyseal involvement can be present on radiographs: mild flattening of the vertebrae with or without end plate irregularities; small or dysplastic epiphyses, especially at the hips or knees; Legg-Calvé-Perthes-like changes in the hips [
• Early-onset degenerative joint disease
## Suggestive Findings
Stickler syndrome
Cleft palate (open cleft, submucous cleft, or bifid uvula)
Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro- or retrognathia
Ocular manifestations including high myopia, vitreous abnormalities, cataracts, and/or retinal abnormalities
Sensorineural hearing loss with or without conductive hearing loss
Osteoarticular manifestations with joint pain in childhood and early-onset degenerative joint disease in adulthood
Signs of mild spondyloepiphyseal involvement can be present on radiographs: mild flattening of the vertebrae with or without end plate irregularities; small or dysplastic epiphyses, especially at the hips or knees; Legg-Calvé-Perthes-like changes in the hips [
Early-onset degenerative joint disease
• Cleft palate (open cleft, submucous cleft, or bifid uvula)
• Characteristic facial features including malar hypoplasia, broad or flat nasal bridge, and micro- or retrognathia
• Ocular manifestations including high myopia, vitreous abnormalities, cataracts, and/or retinal abnormalities
• Sensorineural hearing loss with or without conductive hearing loss
• Osteoarticular manifestations with joint pain in childhood and early-onset degenerative joint disease in adulthood
• Signs of mild spondyloepiphyseal involvement can be present on radiographs: mild flattening of the vertebrae with or without end plate irregularities; small or dysplastic epiphyses, especially at the hips or knees; Legg-Calvé-Perthes-like changes in the hips [
• Early-onset degenerative joint disease
## Establishing the Diagnosis
The diagnosis of Stickler syndrome can be
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 Stickler Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; 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
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 [
Rarely, biallelic
To date, large exon or multiexon deletions or duplications in
Pathogenic variants 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 Stickler Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; 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
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 [
Rarely, biallelic
To date, large exon or multiexon deletions or duplications in
Pathogenic variants in
## Clinical Characteristics
Stickler syndrome is characterized by typical craniofacial features, ocular manifestations, hearing impairment, and osteoarticular problems. To date, more than 1,000 individuals have been identified with Stickler syndrome due to a pathogenic variant(s) in one of the genes listed in
Stickler Syndrome: Frequency of Select Features by Related Gene
-- = not reported; HL = hearing loss; SNHL = sensorineural hearing loss; SS = Stickler syndrome
Includes mainly early-onset degenerative joint disease
Micrognathia is common and may be associated with cleft palate as part of the Pierre Robin sequence (micrognathia, glossoptosis, cleft palate). The degree of micrognathia may compromise the upper airway, necessitating tracheostomy in the neonatal period.
Cleft palate may be seen in the absence of micrognathia. Cleft palate may range from open cleft to submucous cleft or just bifid uvula.
High myopia (greater than −3 diopters) is common; myopia may be progressive and is detectable in the newborn period.
Two types of vitreous abnormalities are observed:
Type 1 ("membranous"), which is much more common, is characterized by a persistence of vestigial vitreous gel in the retrolental space that is bordered by a folded membrane.
Type 2 ("beaded"), much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.
The development of a retinal tear and subsequent retinal detachment is increased in individuals with Stickler syndrome. Prophylactic retinopexy is recommended, as surgical repair of retinal detachment in individuals with Stickler syndrome is often not successful [
Posterior chorioretinal atrophy was described in a family with vitreoretinal dystrophy, systemic features of Stickler syndrome, and a novel pathogenic variant in
Cataracts were reported to be more common in individuals with
Conductive hearing loss can also be seen. This may be secondary to recurrent ear infections that are often associated with cleft palate and/or may be secondary to a defect of the ossicles of the middle ear.
Early-onset osteoarthrosis is common and may be severe, leading to the need for surgical joint replacement even as early as the third or fourth decade. More commonly, the arthropathy is mild with mild joint pain and nonspecific joint stiffness.
Spinal abnormalities sometimes observed in Stickler syndrome that result in chronic back pain are scoliosis and kyphosis [
Although inter- and intrafamilial variation is common, some generalities can be made regarding genotype-phenotype correlations.
Penetrance is complete.
The prevalence of Stickler syndrome is unknown.
• Type 1 ("membranous"), which is much more common, is characterized by a persistence of vestigial vitreous gel in the retrolental space that is bordered by a folded membrane.
• Type 2 ("beaded"), much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.
## Clinical Description
Stickler syndrome is characterized by typical craniofacial features, ocular manifestations, hearing impairment, and osteoarticular problems. To date, more than 1,000 individuals have been identified with Stickler syndrome due to a pathogenic variant(s) in one of the genes listed in
Stickler Syndrome: Frequency of Select Features by Related Gene
-- = not reported; HL = hearing loss; SNHL = sensorineural hearing loss; SS = Stickler syndrome
Includes mainly early-onset degenerative joint disease
Micrognathia is common and may be associated with cleft palate as part of the Pierre Robin sequence (micrognathia, glossoptosis, cleft palate). The degree of micrognathia may compromise the upper airway, necessitating tracheostomy in the neonatal period.
Cleft palate may be seen in the absence of micrognathia. Cleft palate may range from open cleft to submucous cleft or just bifid uvula.
High myopia (greater than −3 diopters) is common; myopia may be progressive and is detectable in the newborn period.
Two types of vitreous abnormalities are observed:
Type 1 ("membranous"), which is much more common, is characterized by a persistence of vestigial vitreous gel in the retrolental space that is bordered by a folded membrane.
Type 2 ("beaded"), much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.
The development of a retinal tear and subsequent retinal detachment is increased in individuals with Stickler syndrome. Prophylactic retinopexy is recommended, as surgical repair of retinal detachment in individuals with Stickler syndrome is often not successful [
Posterior chorioretinal atrophy was described in a family with vitreoretinal dystrophy, systemic features of Stickler syndrome, and a novel pathogenic variant in
Cataracts were reported to be more common in individuals with
Conductive hearing loss can also be seen. This may be secondary to recurrent ear infections that are often associated with cleft palate and/or may be secondary to a defect of the ossicles of the middle ear.
Early-onset osteoarthrosis is common and may be severe, leading to the need for surgical joint replacement even as early as the third or fourth decade. More commonly, the arthropathy is mild with mild joint pain and nonspecific joint stiffness.
Spinal abnormalities sometimes observed in Stickler syndrome that result in chronic back pain are scoliosis and kyphosis [
• Type 1 ("membranous"), which is much more common, is characterized by a persistence of vestigial vitreous gel in the retrolental space that is bordered by a folded membrane.
• Type 2 ("beaded"), much less common, is characterized by sparse and irregularly thickened bundles throughout the vitreous cavity.
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
Although inter- and intrafamilial variation is common, some generalities can be made regarding genotype-phenotype correlations.
## Penetrance
Penetrance is complete.
## Nomenclature
## Prevalence
The prevalence of Stickler syndrome is unknown.
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in Stickler syndrome-related genes are summarized in
Stickler Syndrome: Selected Allelic Disorders
MED = multiple epiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia; SMD = spondylometaphyseal dysplasia
Phenotype names are based on the 2023 revision of the Nosology of Genetic Skeletal Disorders [
See OMIM
## Differential Diagnosis
A number of disorders have features that overlap with those of Stickler syndrome.
Genes of Interest in the Differential Diagnosis of Stickler Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Pathogenic variants in
## Management
No clinical practice guidelines for Stickler syndrome have been published.
To establish the extent of disease and needs in an individual diagnosed with Stickler syndrome, the evaluations summarized in
Stickler Syndrome: Recommended Evaluations Following Initial Diagnosis
Eval of palate by craniofacial specialist
Feeding assessment
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; PRS = Pierre Robin sequence
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Stickler Syndrome: Treatment of Manifestations
Laser therapy for prevention of retinal detachment
Education on risk & symptoms of retinal detachment & need for immediate eval & treatment
Refractive errors should be corrected w/spectacles.
See
Prompt treatment of otitis media
Consider myringotomy tubes for recurrent otitis media.
PRS = Pierre Robin sequence
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Stickler Syndrome: Recommended Surveillance
Affected individuals should be advised to avoid activities that may lead to traumatic retinal detachment (e.g., contact sports).
Some physicians recommend avoiding physical activities that involve high impact to the joints to delay the onset of the arthropathy. While this recommendation seems logical, there are no data to support it.
Because of the variable expression of Stickler syndrome, it is appropriate to evaluate the older and younger sibs of a proband as well as other at-risk relatives in order to identify those who warrant ongoing evaluation (see
Documentation of medical history, physical examination, and ophthalmologic, audiologic, and radiographic assessments. The examination of childhood photographs may be helpful in the assessment of craniofacial findings of adults, since the craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.
Molecular genetic testing if the pathogenic variant(s) in the family are known
It is recommended that relatives at risk in whom the diagnosis of Stickler syndrome cannot be excluded with certainty be followed for potential complications.
See
Search
• Eval of palate by craniofacial specialist
• Feeding assessment
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Laser therapy for prevention of retinal detachment
• Education on risk & symptoms of retinal detachment & need for immediate eval & treatment
• Refractive errors should be corrected w/spectacles.
• See
• Prompt treatment of otitis media
• Consider myringotomy tubes for recurrent otitis media.
• Documentation of medical history, physical examination, and ophthalmologic, audiologic, and radiographic assessments. The examination of childhood photographs may be helpful in the assessment of craniofacial findings of adults, since the craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.
• 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 in an individual diagnosed with Stickler syndrome, the evaluations summarized in
Stickler Syndrome: Recommended Evaluations Following Initial Diagnosis
Eval of palate by craniofacial specialist
Feeding assessment
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; PRS = Pierre Robin sequence
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Eval of palate by craniofacial specialist
• Feeding assessment
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Stickler Syndrome: Treatment of Manifestations
Laser therapy for prevention of retinal detachment
Education on risk & symptoms of retinal detachment & need for immediate eval & treatment
Refractive errors should be corrected w/spectacles.
See
Prompt treatment of otitis media
Consider myringotomy tubes for recurrent otitis media.
PRS = Pierre Robin sequence
• Laser therapy for prevention of retinal detachment
• Education on risk & symptoms of retinal detachment & need for immediate eval & treatment
• Refractive errors should be corrected w/spectacles.
• See
• Prompt treatment of otitis media
• Consider myringotomy tubes for recurrent otitis media.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Stickler Syndrome: Recommended Surveillance
## Agents/Circumstances to Avoid
Affected individuals should be advised to avoid activities that may lead to traumatic retinal detachment (e.g., contact sports).
Some physicians recommend avoiding physical activities that involve high impact to the joints to delay the onset of the arthropathy. While this recommendation seems logical, there are no data to support it.
## Evaluation of Relatives at Risk
Because of the variable expression of Stickler syndrome, it is appropriate to evaluate the older and younger sibs of a proband as well as other at-risk relatives in order to identify those who warrant ongoing evaluation (see
Documentation of medical history, physical examination, and ophthalmologic, audiologic, and radiographic assessments. The examination of childhood photographs may be helpful in the assessment of craniofacial findings of adults, since the craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.
Molecular genetic testing if the pathogenic variant(s) in the family are known
It is recommended that relatives at risk in whom the diagnosis of Stickler syndrome cannot be excluded with certainty be followed for potential complications.
See
• Documentation of medical history, physical examination, and ophthalmologic, audiologic, and radiographic assessments. The examination of childhood photographs may be helpful in the assessment of craniofacial findings of adults, since the craniofacial findings characteristic of Stickler syndrome may become less distinctive with age.
• Molecular genetic testing if the pathogenic variant(s) in the family are known
## Therapies Under Investigation
Search
## Genetic Counseling
Stickler syndrome caused by a heterozygous pathogenic variant in
Stickler syndrome caused by biallelic pathogenic variants in
The majority of individuals with autosomal dominant Stickler syndrome have an affected parent.
A proband with Stickler syndrome 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:
Evaluation of both parents for manifestations of Stickler syndrome (see
If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
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 * [
* A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant may be mildly/minimally affected [
If a parent has autosomal dominant Stickler syndrome, the risk to each sib of a proband is 50%. Clinical variability is common among affected family members; however, some generalities can be made regarding genotype-phenotype correlation (see
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 germline mosaicism.
The parents of a child with Stickler syndrome caused by biallelic pathogenic variants in
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 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.
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 with Stickler syndrome or are carriers (or are at risk of being carriers) of autosomal recessive Stickler syndrome.
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 majority of individuals with autosomal dominant Stickler syndrome have an affected parent.
• A proband with Stickler syndrome 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:
• Evaluation of both parents for manifestations of Stickler syndrome (see
• If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• Evaluation of both parents for manifestations of Stickler syndrome (see
• If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• 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 * [
• * A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant 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 * [
• * A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant may be mildly/minimally affected [
• Evaluation of both parents for manifestations of Stickler syndrome (see
• If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant may be mildly/minimally affected [
• If a parent has autosomal dominant Stickler syndrome, the risk to each sib of a proband is 50%. Clinical variability is common among affected family members; however, some generalities can be made regarding genotype-phenotype correlation (see
• 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 germline mosaicism.
• The parents of a child with Stickler syndrome caused by biallelic pathogenic variants in
• 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 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 with Stickler syndrome or are carriers (or are at risk of being carriers) of autosomal recessive Stickler syndrome.
## Mode of Inheritance
Stickler syndrome caused by a heterozygous pathogenic variant in
Stickler syndrome caused by biallelic pathogenic variants in
## Autosomal Dominant Inheritance – Risk to Family Members
The majority of individuals with autosomal dominant Stickler syndrome have an affected parent.
A proband with Stickler syndrome 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:
Evaluation of both parents for manifestations of Stickler syndrome (see
If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
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 * [
* A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant may be mildly/minimally affected [
If a parent has autosomal dominant Stickler syndrome, the risk to each sib of a proband is 50%. Clinical variability is common among affected family members; however, some generalities can be made regarding genotype-phenotype correlation (see
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 germline mosaicism.
• The majority of individuals with autosomal dominant Stickler syndrome have an affected parent.
• A proband with Stickler syndrome 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:
• Evaluation of both parents for manifestations of Stickler syndrome (see
• If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• Evaluation of both parents for manifestations of Stickler syndrome (see
• If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• 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 * [
• * A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant 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 * [
• * A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant may be mildly/minimally affected [
• Evaluation of both parents for manifestations of Stickler syndrome (see
• If a molecular diagnosis has been established in the proband, molecular genetic testing to confirm the genetic status of the parents and to allow reliable recurrence risk counseling.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism * [
• * A parent with somatic and germline mosaicism for a Stickler syndrome-related pathogenic variant may be mildly/minimally affected [
• If a parent has autosomal dominant Stickler syndrome, the risk to each sib of a proband is 50%. Clinical variability is common among affected family members; however, some generalities can be made regarding genotype-phenotype correlation (see
• 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 germline mosaicism.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with Stickler syndrome caused by biallelic pathogenic variants in
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 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 a child with Stickler syndrome caused by biallelic pathogenic variants in
• 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 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.
## 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 with Stickler syndrome or are carriers (or are at risk of being carriers) of autosomal recessive Stickler syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected with Stickler syndrome or are carriers (or are at risk of being carriers) of autosomal recessive Stickler syndrome.
## 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
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Stickler Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Stickler Syndrome (
Stickler Syndrome: Gene-Specific Mechanism of Disease Causation
Genes are in alphabetic order.
Stickler Syndrome: Gene-Specific Laboratory Considerations
Genes are in alphabetic order.
## Molecular Pathogenesis
Stickler Syndrome: Gene-Specific Mechanism of Disease Causation
Genes are in alphabetic order.
Stickler Syndrome: Gene-Specific Laboratory Considerations
Genes are in alphabetic order.
## Chapter Notes
Leena Ala-Kokko, MD, PhD; Connective Tissue Gene Tests (2000-2023)Rocio T Moran, MD, The MetroHealth System (2000-2023)Geert Mortier, MD, PhD (2023-present) Nathaniel H Robin, MD; University of Alabama (2000-2023)Matthew Warman, MD; Children's Hospital Boston (2000-2011)
7 September 2023 (sw) Comprehensive update posted live
16 March 2017 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
3 November 2011 (me) Comprehensive update posted live
20 August 2009 (me) Comprehensive update posted live
2 August 2005 (me) Comprehensive update posted live
16 June 2003 (ca) Comprehensive update posted live
9 June 2000 (me) Review posted live
31 August 1999 (nr) Original submission
• 7 September 2023 (sw) Comprehensive update posted live
• 16 March 2017 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 20 August 2009 (me) Comprehensive update posted live
• 2 August 2005 (me) Comprehensive update posted live
• 16 June 2003 (ca) Comprehensive update posted live
• 9 June 2000 (me) Review posted live
• 31 August 1999 (nr) Original submission
## Author History
Leena Ala-Kokko, MD, PhD; Connective Tissue Gene Tests (2000-2023)Rocio T Moran, MD, The MetroHealth System (2000-2023)Geert Mortier, MD, PhD (2023-present) Nathaniel H Robin, MD; University of Alabama (2000-2023)Matthew Warman, MD; Children's Hospital Boston (2000-2011)
## Revision History
7 September 2023 (sw) Comprehensive update posted live
16 March 2017 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
3 November 2011 (me) Comprehensive update posted live
20 August 2009 (me) Comprehensive update posted live
2 August 2005 (me) Comprehensive update posted live
16 June 2003 (ca) Comprehensive update posted live
9 June 2000 (me) Review posted live
31 August 1999 (nr) Original submission
• 7 September 2023 (sw) Comprehensive update posted live
• 16 March 2017 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 3 November 2011 (me) Comprehensive update posted live
• 20 August 2009 (me) Comprehensive update posted live
• 2 August 2005 (me) Comprehensive update posted live
• 16 June 2003 (ca) Comprehensive update posted live
• 9 June 2000 (me) Review posted live
• 31 August 1999 (nr) Original submission
## References
## Literature Cited
|
[] |
9/6/2000
|
7/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
strc-hearing-loss
|
strc-hearing-loss
|
[
"STRC-Related Sensorineural Hearing Loss",
"STRC-Related Sensorineural Hearing Loss",
"STRC-Related Nonsyndromic Sensorineural Hearing Loss",
"STRC-Related Sensorineural Hearing Loss With Decreased Fertility in Males",
"Cation channel sperm-associated protein 2",
"Stereocilin",
"CATSPER2",
"STRC",
"STRC-Related Autosomal Recessive Hearing Loss"
] |
Shelby Redfield, A Eliot Shearer
|
Summary Males with biallelic contiguous gene deletions involving The diagnosis of When males with biallelic contiguous gene deletions involving
|
For synonyms and outdated names, see
For other genetic causes of this phenotype, see
## Diagnosis
The diagnosis of
Universal newborn hearing screening (NBHS) uses physiologic screening, either otoacoustic emissions (OAEs), which measure the response of the cochlea to auditory stimuli, or automated auditory brain stem response (AABR) testing, which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. NBHS, required by law or rule in all 50 states in the United States, is performed on >98% of children in the US typically within days after birth (see
On receipt of an abnormal NBHS result, the following medical interventions will begin:
First, diagnostic audiometric testing (typically an initial auditory brain stem response [ABR] test) is performed followed by a confirmatory ABR test, to establish the diagnosis of hearing loss. Note: Evoked otoacoustic emissions (EOAEs) are generally absent [
After diagnostic testing, medical evaluation by an otolaryngologist (often the first point of contact for children with newly diagnosed hearing loss) is typically performed. This includes:
Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
Physical examination to identify:
Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
Features related to an underlying syndrome associated with hearing loss
Next steps may involve consideration of additional audiometric testing and/or genetic tests to establish the underlying diagnosis (see
Hearing is measured in
Severity of Hearing Loss in Decibels (dB)
Based on
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
Biallelic
OR
One
OR
Biallelic contiguous gene deletions 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 [
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
CNV = copy number variant;
See
See
Provided figures are estimates based on
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
Provided figures are estimates based on
Supplementing standard next-generation sequencing (NGS) methods with long-range PCR-based sequencing or NGS assays increases the yield of pathogenic
Most reported
Provided figures are estimates based on
Based on published reports to date, biallelic contiguous gene deletions involving
• First, diagnostic audiometric testing (typically an initial auditory brain stem response [ABR] test) is performed followed by a confirmatory ABR test, to establish the diagnosis of hearing loss. Note: Evoked otoacoustic emissions (EOAEs) are generally absent [
• After diagnostic testing, medical evaluation by an otolaryngologist (often the first point of contact for children with newly diagnosed hearing loss) is typically performed. This includes:
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Next steps may involve consideration of additional audiometric testing and/or genetic tests to establish the underlying diagnosis (see
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Biallelic
• OR
• One
• OR
• Biallelic contiguous gene deletions involving
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
The diagnosis of
Universal newborn hearing screening (NBHS) uses physiologic screening, either otoacoustic emissions (OAEs), which measure the response of the cochlea to auditory stimuli, or automated auditory brain stem response (AABR) testing, which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. NBHS, required by law or rule in all 50 states in the United States, is performed on >98% of children in the US typically within days after birth (see
On receipt of an abnormal NBHS result, the following medical interventions will begin:
First, diagnostic audiometric testing (typically an initial auditory brain stem response [ABR] test) is performed followed by a confirmatory ABR test, to establish the diagnosis of hearing loss. Note: Evoked otoacoustic emissions (EOAEs) are generally absent [
After diagnostic testing, medical evaluation by an otolaryngologist (often the first point of contact for children with newly diagnosed hearing loss) is typically performed. This includes:
Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
Physical examination to identify:
Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
Features related to an underlying syndrome associated with hearing loss
Next steps may involve consideration of additional audiometric testing and/or genetic tests to establish the underlying diagnosis (see
Hearing is measured in
Severity of Hearing Loss in Decibels (dB)
Based on
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.
• First, diagnostic audiometric testing (typically an initial auditory brain stem response [ABR] test) is performed followed by a confirmatory ABR test, to establish the diagnosis of hearing loss. Note: Evoked otoacoustic emissions (EOAEs) are generally absent [
• After diagnostic testing, medical evaluation by an otolaryngologist (often the first point of contact for children with newly diagnosed hearing loss) is typically performed. This includes:
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Next steps may involve consideration of additional audiometric testing and/or genetic tests to establish the underlying diagnosis (see
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
## Scenario 1: Abnormal Newborn Hearing Screening (NBHS) Result
Universal newborn hearing screening (NBHS) uses physiologic screening, either otoacoustic emissions (OAEs), which measure the response of the cochlea to auditory stimuli, or automated auditory brain stem response (AABR) testing, which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. NBHS, required by law or rule in all 50 states in the United States, is performed on >98% of children in the US typically within days after birth (see
On receipt of an abnormal NBHS result, the following medical interventions will begin:
First, diagnostic audiometric testing (typically an initial auditory brain stem response [ABR] test) is performed followed by a confirmatory ABR test, to establish the diagnosis of hearing loss. Note: Evoked otoacoustic emissions (EOAEs) are generally absent [
After diagnostic testing, medical evaluation by an otolaryngologist (often the first point of contact for children with newly diagnosed hearing loss) is typically performed. This includes:
Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
Physical examination to identify:
Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
Features related to an underlying syndrome associated with hearing loss
Next steps may involve consideration of additional audiometric testing and/or genetic tests to establish the underlying diagnosis (see
• First, diagnostic audiometric testing (typically an initial auditory brain stem response [ABR] test) is performed followed by a confirmatory ABR test, to establish the diagnosis of hearing loss. Note: Evoked otoacoustic emissions (EOAEs) are generally absent [
• After diagnostic testing, medical evaluation by an otolaryngologist (often the first point of contact for children with newly diagnosed hearing loss) is typically performed. This includes:
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Next steps may involve consideration of additional audiometric testing and/or genetic tests to establish the underlying diagnosis (see
• Prenatal and perinatal history (with risk factors for hearing loss including viral infection in utero, such as cytomegalovirus and rubella, prematurity, aminoglycoside exposure, hyperbilirubinemia)
• Physical examination to identify:
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
• Non-permanent causes (like otitis media, i.e., fluid in the middle ear)
• Outer and middle ear abnormalities causing conductive hearing loss (which may include imaging studies of the middle/inner ear)
• Note: Imaging by computed tomography or magnetic resonance imaging shows no abnormalities of the brain and temporal bones for individuals with
• Features related to an underlying syndrome associated with hearing loss
## Scenario 2: Symptomatic Individual
Hearing is measured in
Severity of Hearing Loss in Decibels (dB)
Based on
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.
##
Hearing is measured in
Severity of Hearing Loss in Decibels (dB)
Based on
##
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
Biallelic
OR
One
OR
Biallelic contiguous gene deletions 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 [
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
CNV = copy number variant;
See
See
Provided figures are estimates based on
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
Provided figures are estimates based on
Supplementing standard next-generation sequencing (NGS) methods with long-range PCR-based sequencing or NGS assays increases the yield of pathogenic
Most reported
Provided figures are estimates based on
Based on published reports to date, biallelic contiguous gene deletions involving
• Biallelic
• OR
• One
• OR
• Biallelic contiguous gene deletions involving
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Mean pure tone average at the time of the diagnosis of
Rarely phenotypic variability has been noted in
A gradual progression of hearing loss, at a rate of 0.6 dB per year on average across frequencies, was documented in a cohort of individuals with
Progression of Hearing Loss in
Mean period 6.1 years
With the degree of hearing loss and rate of progression documented by
While
Males with biallelic contiguous gene deletions involving
Females with contiguous gene deletions involving
No genotype-phenotype correlations have been identified that distinguish between the hearing loss associated in persons with the following two genotypes:
Biallelic intragenic
Compound heterozygosity for one intragenic
Males with biallelic contiguous gene deletions involving
Nonsyndromic hearing impairment may be referred to by the gene involved (e.g.,
Nonsyndromic deafness loci are designated DFN (for
In a large meta-analysis, the overall prevalence of
Based on published data to date, an estimated 27,000 individuals in the United States have biallelic
• Biallelic intragenic
• Compound heterozygosity for one intragenic
## Clinical Description
Mean pure tone average at the time of the diagnosis of
Rarely phenotypic variability has been noted in
A gradual progression of hearing loss, at a rate of 0.6 dB per year on average across frequencies, was documented in a cohort of individuals with
Progression of Hearing Loss in
Mean period 6.1 years
With the degree of hearing loss and rate of progression documented by
While
Males with biallelic contiguous gene deletions involving
Females with contiguous gene deletions involving
Mean pure tone average at the time of the diagnosis of
Rarely phenotypic variability has been noted in
A gradual progression of hearing loss, at a rate of 0.6 dB per year on average across frequencies, was documented in a cohort of individuals with
Progression of Hearing Loss in
Mean period 6.1 years
With the degree of hearing loss and rate of progression documented by
While
## Decreased Male Fertility
Males with biallelic contiguous gene deletions involving
Females with contiguous gene deletions involving
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified that distinguish between the hearing loss associated in persons with the following two genotypes:
Biallelic intragenic
Compound heterozygosity for one intragenic
Males with biallelic contiguous gene deletions involving
• Biallelic intragenic
• Compound heterozygosity for one intragenic
## Nomenclature
Nonsyndromic hearing impairment may be referred to by the gene involved (e.g.,
Nonsyndromic deafness loci are designated DFN (for
## Prevalence
In a large meta-analysis, the overall prevalence of
Based on published data to date, an estimated 27,000 individuals in the United States have biallelic
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Selected Genes of Interest in the Differential Diagnosis of Nonsyndromic Mild-to-Moderate
Most common genetic cause of congenital severe-to-profound non-progressive sensorineural HL in many world populations
Some
Usher syndrome overall (i.e., Usher syndrome types I, II, & III) is the most common type of AR syndromic HL & is a nonsyndromic HL mimic (HL is congenital w/later onset of retinitis pigmentosa in adolescence or early adulthood).
Usher syndrome type II is assoc w/congenital, bilateral sensorineural HL that is mild to moderate in the low frequencies & severe to profound in the high frequencies.
May be assoc w/mid-frequency HL in moderate range (but is often severe to profound)
Gene deletions are common causative variants.
Non-progressive moderate HL
Occasional vestibular hypofunction
AD = autosomal dominant; AR = autosomal recessive; NSHL = nonsyndromic hearing loss; HL = hearing loss; MOI = mode of inheritance; XL = X-linked
• Most common genetic cause of congenital severe-to-profound non-progressive sensorineural HL in many world populations
• Some
• Usher syndrome overall (i.e., Usher syndrome types I, II, & III) is the most common type of AR syndromic HL & is a nonsyndromic HL mimic (HL is congenital w/later onset of retinitis pigmentosa in adolescence or early adulthood).
• Usher syndrome type II is assoc w/congenital, bilateral sensorineural HL that is mild to moderate in the low frequencies & severe to profound in the high frequencies.
• May be assoc w/mid-frequency HL in moderate range (but is often severe to profound)
• Gene deletions are common causative variants.
• Non-progressive moderate HL
• Occasional vestibular hypofunction
## Management
To establish the extent of involvement and needs of an individual diagnosed with
Complete assessment of auditory acuity using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
Evaluation by an otolaryngologist to assess ear health (e.g., middle ear status, cerumen management), dizziness and vertigo (which could be an indication of benign paroxysmal positional vertigo [BPPV]), medical appropriateness of amplification/hearing aids, need for hearing support in a school setting, and overall well-being
Evaluation by a speech-language pathologist for assessment of communication needs (through early intervention, in a school setting, or privately)
Complete ophthalmologic examination to assess visual acuity. Although
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
Assess need for family support and resources including community or online
Hearing aids (i.e., sound amplification), customized by an audiologist to the degree and frequency of hearing loss, are often recommended in individuals with mild-to-moderate hearing loss.
See
To monitor the degree of hearing loss, the individual's response to use of hearing aids, and development of speech and language, the following evaluations are recommended:
Annual examination by an otolaryngologist familiar with genetic hearing loss to assure that no other reversible factors may be contributing to hearing loss, such as otitis media or cerumen impaction. This visit also ensures health of the ears in the presence of hearing aids.
Repeat audiometry to identify any change in hearing. In general, audiologic evaluation is recommended every three months between birth and age two years and every six months between the ages of two and five years. Hearing tests can occur annually for children age five years and older if hearing is stable and there are no additional otologic concerns. Audiologic scheduling and follow up will be determined by the individual's managing audiologist.
Evaluation of speech and language and/or communication as recommended by a speech-language pathologist
Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided. There is no established "safe" noise level; however, the United States Occupational Safety and Health Administration (OSHA) and National Institute for Occupational Safety and Health (NIOSH) have identified a permissible noise exposure limit of 85 decibels (dB) over an eight-hour work day.
One of the primary sources of loud noise exposure in our environment is sound from headphones and earbuds. An 85-dB limit on earbuds and headphones may provide a reasonable way to reduce loud noise exposure. The headphone safety feature built into most smartphones can be set to limit noise level.
Headphone/earbud safety features can be found in the phone settings menu:
In iPhones, under Settings > Sounds & Haptics > Headphone Safety
In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit
Also see these general resources on noise reduction:
It is appropriate to clarify the genetic status of sibs of a proband with
A newborn sib has an abnormal result on universal newborn hearing screening (NBHS);
A newborn sib has a normal result on NBHS (as NBHS may miss newborns with milder hearing loss); or
A sib did not undergo NBHS and/or NBHS results are unknown.
Early identification of infants and children with hearing loss allows appropriate support and management to be provided to the child and family.
See
Using a mouse model with a targeted deletion of
Search
• Complete assessment of auditory acuity using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
• Evaluation by an otolaryngologist to assess ear health (e.g., middle ear status, cerumen management), dizziness and vertigo (which could be an indication of benign paroxysmal positional vertigo [BPPV]), medical appropriateness of amplification/hearing aids, need for hearing support in a school setting, and overall well-being
• Evaluation by a speech-language pathologist for assessment of communication needs (through early intervention, in a school setting, or privately)
• Complete ophthalmologic examination to assess visual acuity. Although
• 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
• Assess need for family support and resources including community or online
• Annual examination by an otolaryngologist familiar with genetic hearing loss to assure that no other reversible factors may be contributing to hearing loss, such as otitis media or cerumen impaction. This visit also ensures health of the ears in the presence of hearing aids.
• Repeat audiometry to identify any change in hearing. In general, audiologic evaluation is recommended every three months between birth and age two years and every six months between the ages of two and five years. Hearing tests can occur annually for children age five years and older if hearing is stable and there are no additional otologic concerns. Audiologic scheduling and follow up will be determined by the individual's managing audiologist.
• Evaluation of speech and language and/or communication as recommended by a speech-language pathologist
• In iPhones, under Settings > Sounds & Haptics > Headphone Safety
• In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit
•
•
• A newborn sib has an abnormal result on universal newborn hearing screening (NBHS);
• A newborn sib has a normal result on NBHS (as NBHS may miss newborns with milder hearing loss); or
• A sib did not undergo NBHS and/or NBHS results are unknown.
## Evaluations Following Initial Diagnosis
To establish the extent of involvement and needs of an individual diagnosed with
Complete assessment of auditory acuity using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
Evaluation by an otolaryngologist to assess ear health (e.g., middle ear status, cerumen management), dizziness and vertigo (which could be an indication of benign paroxysmal positional vertigo [BPPV]), medical appropriateness of amplification/hearing aids, need for hearing support in a school setting, and overall well-being
Evaluation by a speech-language pathologist for assessment of communication needs (through early intervention, in a school setting, or privately)
Complete ophthalmologic examination to assess visual acuity. Although
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
Assess need for family support and resources including community or online
• Complete assessment of auditory acuity using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure tone audiometry
• Evaluation by an otolaryngologist to assess ear health (e.g., middle ear status, cerumen management), dizziness and vertigo (which could be an indication of benign paroxysmal positional vertigo [BPPV]), medical appropriateness of amplification/hearing aids, need for hearing support in a school setting, and overall well-being
• Evaluation by a speech-language pathologist for assessment of communication needs (through early intervention, in a school setting, or privately)
• Complete ophthalmologic examination to assess visual acuity. Although
• 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
• Assess need for family support and resources including community or online
## Treatment of Manifestations
Hearing aids (i.e., sound amplification), customized by an audiologist to the degree and frequency of hearing loss, are often recommended in individuals with mild-to-moderate hearing loss.
See
## Surveillance
To monitor the degree of hearing loss, the individual's response to use of hearing aids, and development of speech and language, the following evaluations are recommended:
Annual examination by an otolaryngologist familiar with genetic hearing loss to assure that no other reversible factors may be contributing to hearing loss, such as otitis media or cerumen impaction. This visit also ensures health of the ears in the presence of hearing aids.
Repeat audiometry to identify any change in hearing. In general, audiologic evaluation is recommended every three months between birth and age two years and every six months between the ages of two and five years. Hearing tests can occur annually for children age five years and older if hearing is stable and there are no additional otologic concerns. Audiologic scheduling and follow up will be determined by the individual's managing audiologist.
Evaluation of speech and language and/or communication as recommended by a speech-language pathologist
• Annual examination by an otolaryngologist familiar with genetic hearing loss to assure that no other reversible factors may be contributing to hearing loss, such as otitis media or cerumen impaction. This visit also ensures health of the ears in the presence of hearing aids.
• Repeat audiometry to identify any change in hearing. In general, audiologic evaluation is recommended every three months between birth and age two years and every six months between the ages of two and five years. Hearing tests can occur annually for children age five years and older if hearing is stable and there are no additional otologic concerns. Audiologic scheduling and follow up will be determined by the individual's managing audiologist.
• Evaluation of speech and language and/or communication as recommended by a speech-language pathologist
## Agents/Circumstances to Avoid
Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, persons with documented hearing loss should be counseled appropriately and repeated overexposure to loud noises should be avoided. There is no established "safe" noise level; however, the United States Occupational Safety and Health Administration (OSHA) and National Institute for Occupational Safety and Health (NIOSH) have identified a permissible noise exposure limit of 85 decibels (dB) over an eight-hour work day.
One of the primary sources of loud noise exposure in our environment is sound from headphones and earbuds. An 85-dB limit on earbuds and headphones may provide a reasonable way to reduce loud noise exposure. The headphone safety feature built into most smartphones can be set to limit noise level.
Headphone/earbud safety features can be found in the phone settings menu:
In iPhones, under Settings > Sounds & Haptics > Headphone Safety
In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit
Also see these general resources on noise reduction:
• In iPhones, under Settings > Sounds & Haptics > Headphone Safety
• In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit
•
•
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of sibs of a proband with
A newborn sib has an abnormal result on universal newborn hearing screening (NBHS);
A newborn sib has a normal result on NBHS (as NBHS may miss newborns with milder hearing loss); or
A sib did not undergo NBHS and/or NBHS results are unknown.
Early identification of infants and children with hearing loss allows appropriate support and management to be provided to the child and family.
See
• A newborn sib has an abnormal result on universal newborn hearing screening (NBHS);
• A newborn sib has a normal result on NBHS (as NBHS may miss newborns with milder hearing loss); or
• A sib did not undergo NBHS and/or NBHS results are unknown.
## Therapies Under Investigation
Using a mouse model with a targeted deletion of
Search
## Genetic Counseling
The parents of an individual with
Molecular genetic testing capable of detecting the genetic alterations identified in the proband is recommended for the parents to confirm that both parents are heterozygous for a genetic alteration involving
If a genetic alteration is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the genetic alterations identified in the proband occurred as a
If the proband appears to have homozygous genetic alterations (i.e., the same two genetic alterations), additional possibilities to consider include:
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 genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a genetic alteration involving
If both parents are known to be heterozygous for a genetic alteration involving
Individuals who are heterozygous for a genetic alteration involving
See Management,
The optimal time for determination 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 the probability of deafness in offspring and reproductive options) to young adults who are deaf.
Males with biallelic contiguous gene deletions involving
Once the genetic alterations involving
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
• Molecular genetic testing capable of detecting the genetic alterations identified in the proband is recommended for the parents to confirm that both parents are heterozygous for a genetic alteration involving
• If a genetic alteration is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the genetic alterations identified in the proband occurred as a
• If the proband appears to have homozygous genetic alterations (i.e., the same two genetic alterations), additional possibilities to consider include:
• 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 genetic alteration 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 genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a genetic alteration involving
• 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 genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a genetic alteration involving
• Individuals who are heterozygous for a genetic alteration involving
• The optimal time for determination 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 the probability of deafness in offspring and reproductive options) to young adults who are deaf.
• Males with biallelic contiguous gene deletions involving
## Mode of Inheritance
## Risk to Family Members
The parents of an individual with
Molecular genetic testing capable of detecting the genetic alterations identified in the proband is recommended for the parents to confirm that both parents are heterozygous for a genetic alteration involving
If a genetic alteration is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the genetic alterations identified in the proband occurred as a
If the proband appears to have homozygous genetic alterations (i.e., the same two genetic alterations), additional possibilities to consider include:
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 genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
Individuals who are heterozygous for a genetic alteration involving
If both parents are known to be heterozygous for a genetic alteration involving
Individuals who are heterozygous for a genetic alteration involving
• The parents of an individual with
• Molecular genetic testing capable of detecting the genetic alterations identified in the proband is recommended for the parents to confirm that both parents are heterozygous for a genetic alteration involving
• If a genetic alteration is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the genetic alterations identified in the proband occurred as a
• If the proband appears to have homozygous genetic alterations (i.e., the same two genetic alterations), additional possibilities to consider include:
• 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 genetic alteration 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 genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
• Individuals who are heterozygous for a genetic alteration involving
• 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 genetic alteration that resulted in homozygosity for the pathogenic variant in the proband.
• If both parents are known to be heterozygous for a genetic alteration involving
• Individuals who are heterozygous for a genetic alteration involving
## Related Genetic Counseling Issues
See Management,
The optimal time for determination 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 the probability of deafness in offspring and reproductive options) to young adults who are deaf.
Males with biallelic contiguous gene deletions involving
• The optimal time for determination 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 the probability of deafness in offspring and reproductive options) to young adults who are deaf.
• Males with biallelic contiguous gene deletions involving
## Prenatal Testing and Preimplantation Genetic Testing
Once the genetic alterations involving
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
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• Health Resources & Services Administration
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## Molecular Genetics
STRC-Related Autosomal Recessive Hearing Loss: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for STRC-Related Autosomal Recessive Hearing Loss (
The delicate molecular machinery of the cochlea that permits hearing in humans involves hundreds of genes.
In addition, the
## Molecular Pathogenesis
The delicate molecular machinery of the cochlea that permits hearing in humans involves hundreds of genes.
In addition, the
## Chapter Notes
Dr Shearer is also interested in hearing from clinicians treating families affected by hereditary hearing loss 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 Shearer to inquire about review of
14 December 2023 (bp) Review posted live
7 July 2023 (aes) Original submission
• 14 December 2023 (bp) Review posted live
• 7 July 2023 (aes) Original submission
## Author Notes
Dr Shearer is also interested in hearing from clinicians treating families affected by hereditary hearing loss 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 Shearer to inquire about review of
## Revision History
14 December 2023 (bp) Review posted live
7 July 2023 (aes) Original submission
• 14 December 2023 (bp) Review posted live
• 7 July 2023 (aes) Original submission
## References
## Literature Cited
|
[] |
14/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
stromme
|
stromme
|
[
"Apple Peel Syndrome with Microcephaly and Ocular Anomalies",
"Jejunal Atresia with Microcephaly and Ocular Anomalies",
"Apple Peel Syndrome with Microcephaly and Ocular Anomalies",
"Jejunal Atresia with Microcephaly and Ocular Anomalies",
"Centromere protein F",
"CENPF",
"Strømme Syndrome"
] |
Strømme Syndrome
|
Stephanie KL Ho, Lai Ting Leung, Ho-ming Luk, Ivan FM Lo
|
Summary Strømme syndrome is a clinically variable disorder characterized primarily by small bowel intestinal atresia (including apple peel intestinal atresia), microcephaly, developmental delay and/or intellectual disability, structural brain anomalies, and ocular, genitourinary, and cardiac anomalies. A highly variable clinical presentation is observed among affected individuals that may range from mid-gestation lethality, to multisystem involvement with features implicated in the ciliopathies, to nonsyndromic microcephaly with developmental delay. Apple peel intestinal atresia, a rare form of small bowel atresia involving the proximal jejunum near the ligament of Treitz, occurs in some individuals. Intestinal atresia in individuals with Strømme syndrome can involve the duodenum, jejunum, or multiple segments. The diagnosis of Strømme syndrome is established in a proband with characteristic features and biallelic Strømme syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for Strømme syndrome have been published.
Strømme syndrome
Small bowel intestinal atresia, in particular apple peel intestinal atresia
Microcephaly
Mild-to-moderate developmental delay and/or intellectual disability
Various ocular anomalies including anterior segment anomalies and microphthalmia
Genitourinary anomalies including hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or cryptorchidism
Brain MRI may reveal corpus callosum agenesis, hydrocephalus, pachygyria, lissencephaly, holoprosencephaly, cerebral and cerebellar hypoplasia.
Abdominal imaging findings may include hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or accessory spleen.
The diagnosis of Strømme 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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Strømme 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.
To date, no large exon or multiexon deletions or duplications have been reported.
• Small bowel intestinal atresia, in particular apple peel intestinal atresia
• Microcephaly
• Mild-to-moderate developmental delay and/or intellectual disability
• Various ocular anomalies including anterior segment anomalies and microphthalmia
• Genitourinary anomalies including hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or cryptorchidism
• Brain MRI may reveal corpus callosum agenesis, hydrocephalus, pachygyria, lissencephaly, holoprosencephaly, cerebral and cerebellar hypoplasia.
• Abdominal imaging findings may include hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or accessory spleen.
## Suggestive Findings
Strømme syndrome
Small bowel intestinal atresia, in particular apple peel intestinal atresia
Microcephaly
Mild-to-moderate developmental delay and/or intellectual disability
Various ocular anomalies including anterior segment anomalies and microphthalmia
Genitourinary anomalies including hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or cryptorchidism
Brain MRI may reveal corpus callosum agenesis, hydrocephalus, pachygyria, lissencephaly, holoprosencephaly, cerebral and cerebellar hypoplasia.
Abdominal imaging findings may include hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or accessory spleen.
• Small bowel intestinal atresia, in particular apple peel intestinal atresia
• Microcephaly
• Mild-to-moderate developmental delay and/or intellectual disability
• Various ocular anomalies including anterior segment anomalies and microphthalmia
• Genitourinary anomalies including hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or cryptorchidism
• Brain MRI may reveal corpus callosum agenesis, hydrocephalus, pachygyria, lissencephaly, holoprosencephaly, cerebral and cerebellar hypoplasia.
• Abdominal imaging findings may include hypoplastic kidney, horseshoe kidney, hydroureteronephrosis, and/or accessory spleen.
## Establishing the Diagnosis
The diagnosis of Strømme 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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Strømme 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.
To date, no large exon or multiexon deletions or duplications have been reported.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Strømme 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.
To date, no large exon or multiexon deletions or duplications have been reported.
## Clinical Characteristics
Initially believed to be pathognomonic of Strømme syndrome, small intestine atresia is now considered a distinctive but nonobligatory feature. A highly variable clinical presentation is observed among affected individuals that may range from mid-gestation lethality, to multisystem involvement with features implicated in the ciliopathies, to nonsyndromic microcephaly with developmental delay.
To date, at least 26 individuals have been identified with pathogenic variants in
Strømme Syndrome: Frequency of Select Features
Three of the individuals with intestinal atresia reported in the literature did not have the affected segment specified and are therefore excluded from the denominator.
Physiologic patent ductus arteriosus due to prematurity is not included.
Apple peel intestinal atresia is managed by resection of the atretic segment with subsequent anastomosis. The underlying insecure vasculature and the need for bowel preservation have contributed to challenges in surgical treatment, unfavorable prognosis, and a higher risk of short bowel syndrome. Affected individuals may require prolonged total parental nutrition, which may be complicated by cholestasis, sepsis, and multisystem organ failure. Persistent malabsorption and poor weight gain after surgical intervention have been described in individuals with Strømme syndrome-related small bowel atresia [
The renal phenotype observed in Strømme syndrome is highly variable. Structural renal anomalies reported include single kidney, hypoplastic kidneys, horseshoe kidneys, and hydroureteronephrosis [
Undescended and retractile testis have been reported in affected individuals [
No genotype-phenotype correlations have been identified.
Strømme syndrome has also been referred to as primary ciliary dyskinesia 31 (CILD31).
Strømme syndrome is rare, and the exact prevalence is unknown. To date, at least 26 individuals with molecularly confirmed Strømme syndrome have been reported.
## Clinical Description
Initially believed to be pathognomonic of Strømme syndrome, small intestine atresia is now considered a distinctive but nonobligatory feature. A highly variable clinical presentation is observed among affected individuals that may range from mid-gestation lethality, to multisystem involvement with features implicated in the ciliopathies, to nonsyndromic microcephaly with developmental delay.
To date, at least 26 individuals have been identified with pathogenic variants in
Strømme Syndrome: Frequency of Select Features
Three of the individuals with intestinal atresia reported in the literature did not have the affected segment specified and are therefore excluded from the denominator.
Physiologic patent ductus arteriosus due to prematurity is not included.
Apple peel intestinal atresia is managed by resection of the atretic segment with subsequent anastomosis. The underlying insecure vasculature and the need for bowel preservation have contributed to challenges in surgical treatment, unfavorable prognosis, and a higher risk of short bowel syndrome. Affected individuals may require prolonged total parental nutrition, which may be complicated by cholestasis, sepsis, and multisystem organ failure. Persistent malabsorption and poor weight gain after surgical intervention have been described in individuals with Strømme syndrome-related small bowel atresia [
The renal phenotype observed in Strømme syndrome is highly variable. Structural renal anomalies reported include single kidney, hypoplastic kidneys, horseshoe kidneys, and hydroureteronephrosis [
Undescended and retractile testis have been reported in affected individuals [
## Gastrointestinal Features
Apple peel intestinal atresia is managed by resection of the atretic segment with subsequent anastomosis. The underlying insecure vasculature and the need for bowel preservation have contributed to challenges in surgical treatment, unfavorable prognosis, and a higher risk of short bowel syndrome. Affected individuals may require prolonged total parental nutrition, which may be complicated by cholestasis, sepsis, and multisystem organ failure. Persistent malabsorption and poor weight gain after surgical intervention have been described in individuals with Strømme syndrome-related small bowel atresia [
## Ophthalmologic Features
## Neurodevelopmental Features
## Genitourinary Features
The renal phenotype observed in Strømme syndrome is highly variable. Structural renal anomalies reported include single kidney, hypoplastic kidneys, horseshoe kidneys, and hydroureteronephrosis [
Undescended and retractile testis have been reported in affected individuals [
## Other Features
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
Strømme syndrome has also been referred to as primary ciliary dyskinesia 31 (CILD31).
## Prevalence
Strømme syndrome is rare, and the exact prevalence is unknown. To date, at least 26 individuals with molecularly confirmed Strømme syndrome have been reported.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Intestinal Atresia
Digital anomalies incl toe syndactyly, thumb hypoplasia, & brachymesophalangy;
Tracheoesophageal atresia.
GI involvement incl cholestasis, gallbladder aplasia or hypoplasia, & hypoplastic or annular pancreas;
Neonatal or childhood onset diabetes.
GI involvement (e.g., hepatitis, omphalocele);
Immunodeficiency w/thymus hypoplasia.
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; MOI = mode of inheritance
• Digital anomalies incl toe syndactyly, thumb hypoplasia, & brachymesophalangy;
• Tracheoesophageal atresia.
• GI involvement incl cholestasis, gallbladder aplasia or hypoplasia, & hypoplastic or annular pancreas;
• Neonatal or childhood onset diabetes.
• GI involvement (e.g., hepatitis, omphalocele);
• Immunodeficiency w/thymus hypoplasia.
## Management
No clinical practice guidelines for Strømme syndrome have been published.
To establish the extent of disease and needs in an individual diagnosed with Strømme syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Strømme Syndrome
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Renal ultrasound eval for structural anomalies & parenchymal disease
Physical exam for undescended testes in males
Lab assessment of renal function incl CBC, BUN, creatinine, & electrolytes
Community or
Social work involvement for parental support;
Home nursing referral.
BUN = blood urea nitrogen; CBC = complete blood count; DD = developmental delay; GI = gastrointestinal; 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 can include multidisciplinary care by specialists in neurology, speech-language pathology, occupational therapy, physical therapy, feeding, ophthalmology, surgery, nephrology, developmental pediatrics, and clinical genetics (see
Treatment of Manifestations in Individuals with Strømme Syndrome
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.
GI = gastrointestinal
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).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
Recommended Surveillance for Individuals with Strømme Syndrome
Measurement of growth parameters
Eval of nutritional status & oral intake
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Renal ultrasound eval for structural anomalies & parenchymal disease
• Physical exam for undescended testes in males
• Lab assessment of renal function incl CBC, BUN, creatinine, & electrolytes
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• 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 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 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 & oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Strømme syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Strømme Syndrome
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Renal ultrasound eval for structural anomalies & parenchymal disease
Physical exam for undescended testes in males
Lab assessment of renal function incl CBC, BUN, creatinine, & electrolytes
Community or
Social work involvement for parental support;
Home nursing referral.
BUN = blood urea nitrogen; CBC = complete blood count; DD = developmental delay; GI = gastrointestinal; 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
• Renal ultrasound eval for structural anomalies & parenchymal disease
• Physical exam for undescended testes in males
• Lab assessment of renal function incl CBC, BUN, creatinine, & electrolytes
• 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 can include multidisciplinary care by specialists in neurology, speech-language pathology, occupational therapy, physical therapy, feeding, ophthalmology, surgery, nephrology, developmental pediatrics, and clinical genetics (see
Treatment of Manifestations in Individuals with Strømme Syndrome
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.
GI = gastrointestinal
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).
For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• 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 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 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 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 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
## Surveillance
Recommended Surveillance for Individuals with Strømme Syndrome
Measurement of growth parameters
Eval of nutritional status & oral intake
• Measurement of growth parameters
• Eval of nutritional status & oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Strømme syndrome 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.
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 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 optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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
Strømme 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
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 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.
## 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
No specific resources for Strømme Syndrome have been identified by
## Molecular Genetics
Strømme Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Strømme Syndrome (
## Molecular Pathogenesis
## Chapter Notes
We would like to thank the families of individuals with Strømme syndrome for their generous participation in research studies.
10 November 2022 (sw) Review posted live
25 July 2022 (sh) Original submission
• 10 November 2022 (sw) Review posted live
• 25 July 2022 (sh) Original submission
## Acknowledgments
We would like to thank the families of individuals with Strømme syndrome for their generous participation in research studies.
## Revision History
10 November 2022 (sw) Review posted live
25 July 2022 (sh) Original submission
• 10 November 2022 (sw) Review posted live
• 25 July 2022 (sh) Original submission
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"F Palombo, C Graziano, N Al Wardy, N Nouri, C Marconi, P Magini, G Severi, C La Morgia, G Cantalupo, DM Cordelli, S Gangarossa, MN Al Kindi, M Al Khabouri, M Salehi, E Giorgio, A Brusco, F Pisani, G Romeo, V Carelli, T Pippucci, M Seri. Autozygosity-driven genetic diagnosis in consanguineous families from Italy and the Greater Middle East.. Hum Genet. 2020;139:1429-41",
"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",
"AM Waters, R Asfahani, P Carroll, L Bicknell, F Lescai, A Bright, E Chanudet, A Brooks, S Christou-Savina, G Osman, P Walsh, C Bacchelli, A Chapgier, B Vernay, DM Bader, C Deshpande, M O' Sullivan, L Ocaka, H Stanescu, HS Stewart, F Hildebrandt, E Otto, CA Johnson, K Szymanska, N Katsanis, E Davis, R Kleta, M Hubank, S Doxsey, A Jackson, E Stupka, M Winey, PL Beales. The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes.. J Med Genet. 2015;52:147-56"
] |
10/11/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
stsl
|
stsl
|
[
"Beta-Sitosterolemia",
"Phytosterolæmia",
"Phytosterolemia",
"Sitosterolæmia",
"Beta-Sitosterolemia",
"Phytosterolæmia",
"Phytosterolemia",
"Sitosterolæmia",
"ATP-binding cassette sub-family G member 5",
"ATP-binding cassette sub-family G member 8",
"ABCG5",
"ABCG8",
"Sitosterolemia"
] |
Sitosterolemia
|
Semone B Myrie, Robert D Steiner, David Mymin
|
Summary Sitosterolemia is characterized by: Hypercholesterolemia (especially in children) which (1) shows an unexpected significant lowering of plasma cholesterol level in response to low-fat diet modification or to bile acid sequestrant therapy; or (2) does not respond to statin therapy; Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows, and buttocks); Premature atherosclerosis, which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet. In an individual with sitosterolemia, increased plasma concentrations of plant sterols (especially sitosterol, campesterol, and stigmasterol) are observed – if the diet includes plant-derived food, which contain plant sterols – once the plant sterols have accumulated in the body. The diagnosis of sitosterolemia is established in a proband with greatly increased plant sterol concentrations in plasma and/or by identification of biallelic pathogenic (or likely pathogenic) variants in Sitosterolemia 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. Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol. Once the sitosterolemia-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.
|
## Diagnosis
Formal diagnostic criteria for sitosterolemia have not been established.
Sitosterolemia
Hypercholesterolemia (especially in children) that shows unexpected significant response (i.e., lowering of plasma cholesterol level) to low-fat diet modification (e.g., low saturated fat/low cholesterol/low plant-derived foods) or to bile acid sequestrant (e.g. cholestyramine) therapy [
Hypercholesterolemia that does not respond to statin therapy [
Tendon xanthomas or tuberous xanthomas, which may occur in childhood and in unusual locations (heels, knees, elbows, and buttocks) [
Premature atherosclerosis, which may lead to angina, myocardial infarction, and sudden death [
Hemolytic anemia usually associated with abnormally shaped erythrocytes (stomatocytes) and/or thrombocytopenia usually associated with large platelets (macrothrombocytopenia)
Note: The hematologic abnormalities can be the initial presentation [
Note: The complete clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis. Furthermore, the phenotype in infants is likely to be highly dependent on diet.
The diagnosis of sitosterolemia
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 [
Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography / mass spectrometry (GC/MS), high-pressure liquid chromatography (HPLC) or separation with tandem mass spectrometry (LC-MS/MS).
In untreated individuals with sitosterolemia the sitosterol concentration can be 30- to 100-fold increased (i.e., as high as 10 to 65 mg/dL) [
Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by
False positive results have been observed:
Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [
Patients with cholestasis or liver disease receiving parenteral nutrition (which often contains plant sterols in intralipids) may be unable to effectively clear the plant sterols [
Heterozygotes (carriers of one
False negative results can be observed in:
Individuals using ezetimibe or ezetimibe combinations, or bile acid-binding resin;
AND/OR
Individuals on a diet low in plant-derived foods.
Note: (1) In general plasma cholesterol concentration is not diagnostic because it can be normal in individuals with sitosterolemia, and elevations of plasma cholesterol concentration can be seen in numerous common disorders. (2) In sitosterolemia, plasma concentrations of cholesterol in children can be high, even in the range seen in homozygous familial hypercholesterolemia [
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 laboratory findings suggest the diagnosis of sitosterolemia, the molecular genetic testing approach is use of a
For an introduction to multigene panels click
When the diagnosis of sitosterolemia is not considered because an individual has atypical phenotypic features or laboratory results,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sitosterolemia
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.
From 40 publications [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Although no deletions or duplications of
• Hypercholesterolemia (especially in children) that shows unexpected significant response (i.e., lowering of plasma cholesterol level) to low-fat diet modification (e.g., low saturated fat/low cholesterol/low plant-derived foods) or to bile acid sequestrant (e.g. cholestyramine) therapy [
• Hypercholesterolemia that does not respond to statin therapy [
• Tendon xanthomas or tuberous xanthomas, which may occur in childhood and in unusual locations (heels, knees, elbows, and buttocks) [
• Premature atherosclerosis, which may lead to angina, myocardial infarction, and sudden death [
• Hemolytic anemia usually associated with abnormally shaped erythrocytes (stomatocytes) and/or thrombocytopenia usually associated with large platelets (macrothrombocytopenia)
• Note: The hematologic abnormalities can be the initial presentation [
• Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography / mass spectrometry (GC/MS), high-pressure liquid chromatography (HPLC) or separation with tandem mass spectrometry (LC-MS/MS).
• In untreated individuals with sitosterolemia the sitosterol concentration can be 30- to 100-fold increased (i.e., as high as 10 to 65 mg/dL) [
• Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by
• Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [
• Patients with cholestasis or liver disease receiving parenteral nutrition (which often contains plant sterols in intralipids) may be unable to effectively clear the plant sterols [
• Heterozygotes (carriers of one
• Individuals using ezetimibe or ezetimibe combinations, or bile acid-binding resin;
• AND/OR
• Individuals on a diet low in plant-derived foods.
## Suggestive Findings
Sitosterolemia
Hypercholesterolemia (especially in children) that shows unexpected significant response (i.e., lowering of plasma cholesterol level) to low-fat diet modification (e.g., low saturated fat/low cholesterol/low plant-derived foods) or to bile acid sequestrant (e.g. cholestyramine) therapy [
Hypercholesterolemia that does not respond to statin therapy [
Tendon xanthomas or tuberous xanthomas, which may occur in childhood and in unusual locations (heels, knees, elbows, and buttocks) [
Premature atherosclerosis, which may lead to angina, myocardial infarction, and sudden death [
Hemolytic anemia usually associated with abnormally shaped erythrocytes (stomatocytes) and/or thrombocytopenia usually associated with large platelets (macrothrombocytopenia)
Note: The hematologic abnormalities can be the initial presentation [
Note: The complete clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis. Furthermore, the phenotype in infants is likely to be highly dependent on diet.
• Hypercholesterolemia (especially in children) that shows unexpected significant response (i.e., lowering of plasma cholesterol level) to low-fat diet modification (e.g., low saturated fat/low cholesterol/low plant-derived foods) or to bile acid sequestrant (e.g. cholestyramine) therapy [
• Hypercholesterolemia that does not respond to statin therapy [
• Tendon xanthomas or tuberous xanthomas, which may occur in childhood and in unusual locations (heels, knees, elbows, and buttocks) [
• Premature atherosclerosis, which may lead to angina, myocardial infarction, and sudden death [
• Hemolytic anemia usually associated with abnormally shaped erythrocytes (stomatocytes) and/or thrombocytopenia usually associated with large platelets (macrothrombocytopenia)
• Note: The hematologic abnormalities can be the initial presentation [
## Establishing the Diagnosis
The diagnosis of sitosterolemia
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 [
Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography / mass spectrometry (GC/MS), high-pressure liquid chromatography (HPLC) or separation with tandem mass spectrometry (LC-MS/MS).
In untreated individuals with sitosterolemia the sitosterol concentration can be 30- to 100-fold increased (i.e., as high as 10 to 65 mg/dL) [
Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by
False positive results have been observed:
Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [
Patients with cholestasis or liver disease receiving parenteral nutrition (which often contains plant sterols in intralipids) may be unable to effectively clear the plant sterols [
Heterozygotes (carriers of one
False negative results can be observed in:
Individuals using ezetimibe or ezetimibe combinations, or bile acid-binding resin;
AND/OR
Individuals on a diet low in plant-derived foods.
Note: (1) In general plasma cholesterol concentration is not diagnostic because it can be normal in individuals with sitosterolemia, and elevations of plasma cholesterol concentration can be seen in numerous common disorders. (2) In sitosterolemia, plasma concentrations of cholesterol in children can be high, even in the range seen in homozygous familial hypercholesterolemia [
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 laboratory findings suggest the diagnosis of sitosterolemia, the molecular genetic testing approach is use of a
For an introduction to multigene panels click
When the diagnosis of sitosterolemia is not considered because an individual has atypical phenotypic features or laboratory results,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sitosterolemia
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.
From 40 publications [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Although no deletions or duplications of
• Typical plant sterol concentrations in healthy individuals are 100 times lower than cholesterol (0.21 ± 0.7 mg/dL); thus, their contribution to the total sterol concentration is negligible. These plant sterols and shellfish sterols are not detected by standard laboratory methods of cholesterol measurement and require specialized analysis typically utilizing gas chromatography (GC), gas chromatography / mass spectrometry (GC/MS), high-pressure liquid chromatography (HPLC) or separation with tandem mass spectrometry (LC-MS/MS).
• In untreated individuals with sitosterolemia the sitosterol concentration can be 30- to 100-fold increased (i.e., as high as 10 to 65 mg/dL) [
• Note: (1) In individuals with sitosterolemia the plant sterol transporters sterolin-1 (encoded by
• Normal infants ingesting commercial infant formula (which contains plant sterols) may have a transient increase in plasma plant sterols, probably due to immature transporters [
• Patients with cholestasis or liver disease receiving parenteral nutrition (which often contains plant sterols in intralipids) may be unable to effectively clear the plant sterols [
• Heterozygotes (carriers of one
• Individuals using ezetimibe or ezetimibe combinations, or bile acid-binding resin;
• AND/OR
• Individuals on a diet low in plant-derived foods.
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of sitosterolemia, the molecular genetic testing approach is use of a
For an introduction to multigene panels click
## Option 2
When the diagnosis of sitosterolemia is not considered because an individual has atypical phenotypic features or laboratory results,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sitosterolemia
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.
From 40 publications [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Although no deletions or duplications of
## Clinical Characteristics
To date, approximately 110 individuals with biallelic pathogenic variants in
There is evidence of an age-related change in sterol homeostasis in sitosterolemia, where plasma concentrations of cholesterol in children with sitosterolemia can be in the hypercholesterolemia range and decrease to normal cholesterol levels by adulthood [
Assessment for premature atherosclerosis should include noninvasive imaging to exclude coronary and carotid plaque as well as atherosclerotic manifestations (e.g., heart murmurs and vascular bruits).
Because of the limited number of reports, the incidence of coronary artery disease is not known.
On occasion arthritis, arthralgias, and splenomegaly are also seen.
In one family, phenotypic variablilty was seen in three affected sibs and one affected first cousin with the same genotype [
In another family the mother and brother of the proband were homozygous for the same nucleotide change in
No genotype-phenotype correlations for
The disorder was named β-sitosterolemia by the investigators who first described it [
To date, about 110 individuals with molecularly confirmed sitosterolemia have been reported worldwide [
Because the usual clinical test for plasma concentration of cholesterol does not measure plant sterols, sitosterolemia is likely to be underdiagnosed. In a population-based study, the data suggest a much higher prevalence than that indicated by the small number of known cases [
Sitosterolemia has been described in persons of Hutterite, Amish, Japanese, and Chinese ancestry as well as in other populations [
The Old Order Amish. Carrier frequency up to 4%
North American Hutterites. Carrier frequency 8% [
The inhabitants of Kosrae (Micronesia). Adult carrier frequency 13% [
A founder effect is evident in certain populations [
Northern Europeans / individuals of northern European ancestry more frequently have pathogenic variants in
Chinese, Japanese, and Indian individuals tend to have pathogenic variants in
• Assessment for premature atherosclerosis should include noninvasive imaging to exclude coronary and carotid plaque as well as atherosclerotic manifestations (e.g., heart murmurs and vascular bruits).
• Because of the limited number of reports, the incidence of coronary artery disease is not known.
• On occasion arthritis, arthralgias, and splenomegaly are also seen.
• In one family, phenotypic variablilty was seen in three affected sibs and one affected first cousin with the same genotype [
• In another family the mother and brother of the proband were homozygous for the same nucleotide change in
• The Old Order Amish. Carrier frequency up to 4%
• North American Hutterites. Carrier frequency 8% [
• The inhabitants of Kosrae (Micronesia). Adult carrier frequency 13% [
• Northern Europeans / individuals of northern European ancestry more frequently have pathogenic variants in
• Chinese, Japanese, and Indian individuals tend to have pathogenic variants in
## Clinical Description
To date, approximately 110 individuals with biallelic pathogenic variants in
There is evidence of an age-related change in sterol homeostasis in sitosterolemia, where plasma concentrations of cholesterol in children with sitosterolemia can be in the hypercholesterolemia range and decrease to normal cholesterol levels by adulthood [
Assessment for premature atherosclerosis should include noninvasive imaging to exclude coronary and carotid plaque as well as atherosclerotic manifestations (e.g., heart murmurs and vascular bruits).
Because of the limited number of reports, the incidence of coronary artery disease is not known.
On occasion arthritis, arthralgias, and splenomegaly are also seen.
In one family, phenotypic variablilty was seen in three affected sibs and one affected first cousin with the same genotype [
In another family the mother and brother of the proband were homozygous for the same nucleotide change in
• Assessment for premature atherosclerosis should include noninvasive imaging to exclude coronary and carotid plaque as well as atherosclerotic manifestations (e.g., heart murmurs and vascular bruits).
• Because of the limited number of reports, the incidence of coronary artery disease is not known.
• On occasion arthritis, arthralgias, and splenomegaly are also seen.
• In one family, phenotypic variablilty was seen in three affected sibs and one affected first cousin with the same genotype [
• In another family the mother and brother of the proband were homozygous for the same nucleotide change in
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Nomenclature
The disorder was named β-sitosterolemia by the investigators who first described it [
## Prevalence
To date, about 110 individuals with molecularly confirmed sitosterolemia have been reported worldwide [
Because the usual clinical test for plasma concentration of cholesterol does not measure plant sterols, sitosterolemia is likely to be underdiagnosed. In a population-based study, the data suggest a much higher prevalence than that indicated by the small number of known cases [
Sitosterolemia has been described in persons of Hutterite, Amish, Japanese, and Chinese ancestry as well as in other populations [
The Old Order Amish. Carrier frequency up to 4%
North American Hutterites. Carrier frequency 8% [
The inhabitants of Kosrae (Micronesia). Adult carrier frequency 13% [
A founder effect is evident in certain populations [
Northern Europeans / individuals of northern European ancestry more frequently have pathogenic variants in
Chinese, Japanese, and Indian individuals tend to have pathogenic variants in
• The Old Order Amish. Carrier frequency up to 4%
• North American Hutterites. Carrier frequency 8% [
• The inhabitants of Kosrae (Micronesia). Adult carrier frequency 13% [
• Northern Europeans / individuals of northern European ancestry more frequently have pathogenic variants in
• Chinese, Japanese, and Indian individuals tend to have pathogenic variants in
## Genetically Related (Allelic) Disorders
No phenotypes other than those described in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Sitosterolemia
Extreme ↓ circulating HDL-C levels (<1-2 mg/dL)
Extreme hypercholesterolemia
Extreme hypercholesterolemia: LDL-C levels >190 mg/dL in untreated adults
LDL-C levels >130 mg/dL in untreated children/adolescents
Not assoc w/macro-thrombocytopenia
Both parents of affected child have hypercholesterolemia.
LDL-C levels are generally >500 mg/dL in untreated adults (levels can be lower in children).
Not assoc w/macro-thrombocytopenia
↑ concentrations of plasma cholestanol, childhood-onset protracted diarrhea, & cataracts
Typically, neurologic involvment in affected adults
Extreme ↓ circulating HDL-C levels (<10 mg/dL)
↑ VLDL-C & triglycerides
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance; VLDL-C = very low-density lipoprotein cholesterol
FH results from a heterozygous pathogenic variant in
Homozygous FH results from biallelic (homozygous or compound heterozygous) pathogenic variants in
The combination of
Liver disease
Thrombotic thrombocytopenic purpura
Systemic lupus erythematosus (SLE)
• Extreme ↓ circulating HDL-C levels (<1-2 mg/dL)
• Extreme hypercholesterolemia
• Extreme hypercholesterolemia: LDL-C levels >190 mg/dL in untreated adults
• LDL-C levels >130 mg/dL in untreated children/adolescents
• Not assoc w/macro-thrombocytopenia
• Both parents of affected child have hypercholesterolemia.
• LDL-C levels are generally >500 mg/dL in untreated adults (levels can be lower in children).
• Not assoc w/macro-thrombocytopenia
• ↑ concentrations of plasma cholestanol, childhood-onset protracted diarrhea, & cataracts
• Typically, neurologic involvment in affected adults
• Extreme ↓ circulating HDL-C levels (<10 mg/dL)
• ↑ VLDL-C & triglycerides
• Liver disease
• Thrombotic thrombocytopenic purpura
• Systemic lupus erythematosus (SLE)
## Hereditary Disorders in the Differential Diagnosis of Sitosterolemia
Genes of Interest in the Differential Diagnosis of Sitosterolemia
Extreme ↓ circulating HDL-C levels (<1-2 mg/dL)
Extreme hypercholesterolemia
Extreme hypercholesterolemia: LDL-C levels >190 mg/dL in untreated adults
LDL-C levels >130 mg/dL in untreated children/adolescents
Not assoc w/macro-thrombocytopenia
Both parents of affected child have hypercholesterolemia.
LDL-C levels are generally >500 mg/dL in untreated adults (levels can be lower in children).
Not assoc w/macro-thrombocytopenia
↑ concentrations of plasma cholestanol, childhood-onset protracted diarrhea, & cataracts
Typically, neurologic involvment in affected adults
Extreme ↓ circulating HDL-C levels (<10 mg/dL)
↑ VLDL-C & triglycerides
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; FH = familial hypercholesterolemia; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MOI = mode of inheritance; VLDL-C = very low-density lipoprotein cholesterol
FH results from a heterozygous pathogenic variant in
Homozygous FH results from biallelic (homozygous or compound heterozygous) pathogenic variants in
• Extreme ↓ circulating HDL-C levels (<1-2 mg/dL)
• Extreme hypercholesterolemia
• Extreme hypercholesterolemia: LDL-C levels >190 mg/dL in untreated adults
• LDL-C levels >130 mg/dL in untreated children/adolescents
• Not assoc w/macro-thrombocytopenia
• Both parents of affected child have hypercholesterolemia.
• LDL-C levels are generally >500 mg/dL in untreated adults (levels can be lower in children).
• Not assoc w/macro-thrombocytopenia
• ↑ concentrations of plasma cholestanol, childhood-onset protracted diarrhea, & cataracts
• Typically, neurologic involvment in affected adults
• Extreme ↓ circulating HDL-C levels (<10 mg/dL)
• ↑ VLDL-C & triglycerides
## Other Disorders in the Differential Diagnosis of Sitosterolemia
The combination of
Liver disease
Thrombotic thrombocytopenic purpura
Systemic lupus erythematosus (SLE)
• Liver disease
• Thrombotic thrombocytopenic purpura
• Systemic lupus erythematosus (SLE)
## Management
Recommended Evaluations Following Initial Diagnosis in Individuals with Sitosterolemia
CBC w/smear to look for platelet abnormalities &/or thrombocytopenia
Eval for possible hemolysis/ hemolytic anemia
CBC = complete blood count; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease the plasma concentrations of cholesterol and sitosterol by 10% to 50%. Existing xanthomas often regress.
Arthritis, arthralgias, anemia, thromobocytopenia, and/or splenomegaly require treatment, the first step being management of the sitosterolemia, followed by routine management of the finding (by the appropriate consultants) as needed.
Note: Sitosterolemia does not respond to standard statin treatment.
Treatment of Manifestations in Individuals with Sitosterolemia
Diet low in shellfish sterols & plant sterols (i.e., avoidance of vegetable oils, margarine, nuts, seeds, avocados, chocolate, & shellfish)
Treatment w/sterol absorption inhibitor ezetimibe (10 mg/day in adults)
Bile acid sequestrants such as cholestryramine (8-15 g/day) may be considered in those w/incomplete response to ezetimibe.
Recommended Annual Surveillance for Individuals with Sitosterolemia
Plasma concentrations of plant sterols (primarily beta-sitosterol & campesterol) & cholesterol
Evaluate size, number, & distribution of xanthomas.
CBC = complete blood count
Margarines and other products containing stanols (e.g., campestanol and sitostanol), which are recommended for use by persons with hypercholesterolemia, are contraindicated in those with sitosterolemia as they can exacerbate plant stanol accumulation [
Note: Foods with high plant sterol content including shellfish, vegetable oils, margarine, nuts, avocados, and chocolate should be taken in moderation due to increased intestinal absorption of plant sterols in those with sitosterolemia [
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 institution of treatment and surveillance. Evaluations include the following:
Molecular genetic testing if the
Measurement of plasma concentrations of plant sterols if the family-specific pathogenic variants are not known
See
Guidelines for the management of women with sitosterolemia during pregnancy have not been established.
There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justify the risk to the fetus (
See
Search
• CBC w/smear to look for platelet abnormalities &/or thrombocytopenia
• Eval for possible hemolysis/ hemolytic anemia
• Diet low in shellfish sterols & plant sterols (i.e., avoidance of vegetable oils, margarine, nuts, seeds, avocados, chocolate, & shellfish)
• Treatment w/sterol absorption inhibitor ezetimibe (10 mg/day in adults)
• Bile acid sequestrants such as cholestryramine (8-15 g/day) may be considered in those w/incomplete response to ezetimibe.
• Plasma concentrations of plant sterols (primarily beta-sitosterol & campesterol) & cholesterol
• Evaluate size, number, & distribution of xanthomas.
• Molecular genetic testing if the
• Measurement of plasma concentrations of plant sterols if the family-specific pathogenic variants are not known
## Evaluations Following Initial Diagnosis
Recommended Evaluations Following Initial Diagnosis in Individuals with Sitosterolemia
CBC w/smear to look for platelet abnormalities &/or thrombocytopenia
Eval for possible hemolysis/ hemolytic anemia
CBC = complete blood count; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• CBC w/smear to look for platelet abnormalities &/or thrombocytopenia
• Eval for possible hemolysis/ hemolytic anemia
## Treatment of Manifestations
Treatment should begin at the time of diagnosis, though there is little experience treating children younger than age two years. Treatment can decrease the plasma concentrations of cholesterol and sitosterol by 10% to 50%. Existing xanthomas often regress.
Arthritis, arthralgias, anemia, thromobocytopenia, and/or splenomegaly require treatment, the first step being management of the sitosterolemia, followed by routine management of the finding (by the appropriate consultants) as needed.
Note: Sitosterolemia does not respond to standard statin treatment.
Treatment of Manifestations in Individuals with Sitosterolemia
Diet low in shellfish sterols & plant sterols (i.e., avoidance of vegetable oils, margarine, nuts, seeds, avocados, chocolate, & shellfish)
Treatment w/sterol absorption inhibitor ezetimibe (10 mg/day in adults)
Bile acid sequestrants such as cholestryramine (8-15 g/day) may be considered in those w/incomplete response to ezetimibe.
• Diet low in shellfish sterols & plant sterols (i.e., avoidance of vegetable oils, margarine, nuts, seeds, avocados, chocolate, & shellfish)
• Treatment w/sterol absorption inhibitor ezetimibe (10 mg/day in adults)
• Bile acid sequestrants such as cholestryramine (8-15 g/day) may be considered in those w/incomplete response to ezetimibe.
## Surveillance
Recommended Annual Surveillance for Individuals with Sitosterolemia
Plasma concentrations of plant sterols (primarily beta-sitosterol & campesterol) & cholesterol
Evaluate size, number, & distribution of xanthomas.
CBC = complete blood count
• Plasma concentrations of plant sterols (primarily beta-sitosterol & campesterol) & cholesterol
• Evaluate size, number, & distribution of xanthomas.
## Agents/Circumstances to Avoid
Margarines and other products containing stanols (e.g., campestanol and sitostanol), which are recommended for use by persons with hypercholesterolemia, are contraindicated in those with sitosterolemia as they can exacerbate plant stanol accumulation [
Note: Foods with high plant sterol content including shellfish, vegetable oils, margarine, nuts, avocados, and chocolate should be taken in moderation due to increased intestinal absorption of plant sterols in those with sitosterolemia [
## 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 institution of treatment and surveillance. Evaluations include the following:
Molecular genetic testing if the
Measurement of plasma concentrations of plant sterols if the family-specific pathogenic variants are not known
See
• Molecular genetic testing if the
• Measurement of plasma concentrations of plant sterols if the family-specific pathogenic variants are not known
## Pregnancy Management
Guidelines for the management of women with sitosterolemia during pregnancy have not been established.
There are no adequate and well-controlled studies of ezetimibe in pregnant women; ezetimibe can be used during pregnancy only if the potential benefits justify the risk to the fetus (
See
## Therapies Under Investigation
Search
## Genetic Counseling
Sitosterolemia 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
Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol [
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol.
Molecular genetic carrier testing for at-risk family members requires prior identification of the
Note: Carriers cannot be reliably detected by analyte testing.
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 carriers.
Once the sitosterolemia-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing is possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would regard use of prenatal and preimplantation genetic testing to be a personal choice, 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
• Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol [
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol.
• 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
Sitosterolemia 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
Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol [
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol.
• 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
• Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol [
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic but may occasionally have a mildly elevated concentration of sitosterol.
## Carrier Detection
Molecular genetic carrier testing for at-risk family members requires prior identification of the
Note: Carriers cannot be reliably detected by analyte testing.
## Related Genetic Counseling Issues
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 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 sitosterolemia-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing is possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would regard use of prenatal and preimplantation genetic testing to be a personal choice, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
•
•
## Molecular Genetics
Sitosterolemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sitosterolemia (
Sterolin-1 (encoded by
Defective sterolin heterodimer transporter function increases cholesterol and sitosterol absorption and decreases sitosterol and cholesterol excretion into the bile.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Sterolin-1 (encoded by
Defective sterolin heterodimer transporter function increases cholesterol and sitosterol absorption and decreases sitosterol and cholesterol excretion into the bile.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Analyte clinical diagnostic testing for sitosterolemia is available
The authors conduct research studies on sitosterolemia as part of the Rare Diseases Clinical Research Network:
The current authors would like to acknowledge Louise S Merkens, PhD, retired from Oregon Health & Science University in Portland, Oregon, as an original author whose contributions to the original content of this
Louise S Merkens, PhD; Oregon Health & Science University (2012-2020)David Mymin, MBBCh, FRCP (2012-present)Semone B Myrie, PhD (2012-present)Robert D Steiner, MD (2012-present)
16 July 2020 (ha) Comprehensive update posted live
4 April 2013 (me) Review posted live
21 February 2012 (lm) Original submission
• 16 July 2020 (ha) Comprehensive update posted live
• 4 April 2013 (me) Review posted live
• 21 February 2012 (lm) Original submission
## Author Notes
Analyte clinical diagnostic testing for sitosterolemia is available
The authors conduct research studies on sitosterolemia as part of the Rare Diseases Clinical Research Network:
## Acknowledgments
The current authors would like to acknowledge Louise S Merkens, PhD, retired from Oregon Health & Science University in Portland, Oregon, as an original author whose contributions to the original content of this
## Author History
Louise S Merkens, PhD; Oregon Health & Science University (2012-2020)David Mymin, MBBCh, FRCP (2012-present)Semone B Myrie, PhD (2012-present)Robert D Steiner, MD (2012-present)
## Revision History
16 July 2020 (ha) Comprehensive update posted live
4 April 2013 (me) Review posted live
21 February 2012 (lm) Original submission
• 16 July 2020 (ha) Comprehensive update posted live
• 4 April 2013 (me) Review posted live
• 21 February 2012 (lm) Original submission
## References
## Literature Cited
|
[] |
4/4/2013
|
16/7/2020
|
17/5/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
stxbp1-ee
|
stxbp1-ee
|
[
"Early-Infantile Epileptic Encephalopathy 4 (EIEE4)",
"STXBP1 Epileptic Encephalopathy",
"STXBP1-Related Developmental and Epileptic Encephalopathy (STXBP1-DEE)",
"STXBP1 Epileptic Encephalopathy",
"Early-Infantile Epileptic Encephalopathy 4 (EIEE4)",
"STXBP1-Related Developmental and Epileptic Encephalopathy (STXBP1-DEE)",
"Syntaxin-binding protein 1",
"STXBP1",
"STXBP1 Encephalopathy with Epilepsy"
] |
Saadet Mercimek-Andrews
|
Summary The diagnosis is established in a proband with a heterozygous
|
## Diagnosis
Median age of onset six weeks (range: 1 day to 13 years)
EEG characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves
Infantile spasms
Generalized tonic-clonic, clonic, or tonic seizures
Myoclonic seizures
Atonic seizures
Absence seizures
Focal seizures
Mild-to-profound intellectual disability
Tone abnormalities: spasticity, hypotonia
Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis
Behavioral issues
Autism spectrum disorder
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 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 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.
• Median age of onset six weeks (range: 1 day to 13 years)
• EEG characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves
• Infantile spasms
• Generalized tonic-clonic, clonic, or tonic seizures
• Myoclonic seizures
• Atonic seizures
• Absence seizures
• Focal seizures
• Mild-to-profound intellectual disability
• Tone abnormalities: spasticity, hypotonia
• Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis
• Behavioral issues
• Autism spectrum disorder
## Suggestive Findings
Median age of onset six weeks (range: 1 day to 13 years)
EEG characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves
Infantile spasms
Generalized tonic-clonic, clonic, or tonic seizures
Myoclonic seizures
Atonic seizures
Absence seizures
Focal seizures
Mild-to-profound intellectual disability
Tone abnormalities: spasticity, hypotonia
Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis
Behavioral issues
Autism spectrum disorder
• Median age of onset six weeks (range: 1 day to 13 years)
• EEG characterized by focal epileptic activity, burst suppression, hypsarrhythmia, or generalized spike-and-slow waves
• Infantile spasms
• Generalized tonic-clonic, clonic, or tonic seizures
• Myoclonic seizures
• Atonic seizures
• Absence seizures
• Focal seizures
• Mild-to-profound intellectual disability
• Tone abnormalities: spasticity, hypotonia
• Movement disorders including ataxia, dystonia, dyskinesia, tremor, or choreoathetosis
• Behavioral issues
• Autism spectrum disorder
## 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
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 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 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 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 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
In a natural history study of adults with
Episodic developmental regression was reported in 59% of adults with
Focal-onset seizures, generalized-onset seizures, and infantile spasms were the most common seizure types [
Epilepsy course was reported for 48 individuals with
In about 1% of affected individuals, the ketogenic diet was used for seizure management. Response to the ketogenic diet ranged from a mild reduction in seizure frequency to no response in early studies [
Epilepsy surgery was the treatment of choice in two affected individuals: one became seizure-free following corpuscallosotomy [
In 30 adults with
Other EEG abnormalities included focal and multifocal discharges, spike-and-slow waves, polyspike waves, theta and delta waves, paroxysmal activity, and low-amplitude fast rhythms. Background activity was frequently described as slow or poorly organized.
Scoliosis (4 individuals) [
Joint laxity (3 individuals) [
Strabismus (2 individuals) [
In more than 50 individuals with
In a study of recurrent pathogenic variants (
More than 500 individuals with an
• Scoliosis (4 individuals) [
• Joint laxity (3 individuals) [
• Strabismus (2 individuals) [
## Clinical Description
In a natural history study of adults with
Episodic developmental regression was reported in 59% of adults with
Focal-onset seizures, generalized-onset seizures, and infantile spasms were the most common seizure types [
Epilepsy course was reported for 48 individuals with
In about 1% of affected individuals, the ketogenic diet was used for seizure management. Response to the ketogenic diet ranged from a mild reduction in seizure frequency to no response in early studies [
Epilepsy surgery was the treatment of choice in two affected individuals: one became seizure-free following corpuscallosotomy [
In 30 adults with
Other EEG abnormalities included focal and multifocal discharges, spike-and-slow waves, polyspike waves, theta and delta waves, paroxysmal activity, and low-amplitude fast rhythms. Background activity was frequently described as slow or poorly organized.
Scoliosis (4 individuals) [
Joint laxity (3 individuals) [
Strabismus (2 individuals) [
• Scoliosis (4 individuals) [
• Joint laxity (3 individuals) [
• Strabismus (2 individuals) [
## Genotype-Phenotype Correlations
In more than 50 individuals with
In a study of recurrent pathogenic variants (
## Penetrance
## Prevalence
More than 500 individuals with an
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Absent thumbnails and hypoplastic second fingernails (1 individual) [
Cleft lip and palate, ventricular septal defect, overlapping fingers, small penis (1 individual) [
Short and broad fingers and broad feet [
Dysplastic right kidney, ureterocele, umbilical hernia (1 individual) [
Cleft lip/palate, umbilical hernia, mild dysmorphic facial features, dilated renal pelvis, microcephaly (1 individual) [
• Absent thumbnails and hypoplastic second fingernails (1 individual) [
• Cleft lip and palate, ventricular septal defect, overlapping fingers, small penis (1 individual) [
• Short and broad fingers and broad feet [
• Dysplastic right kidney, ureterocele, umbilical hernia (1 individual) [
• Cleft lip/palate, umbilical hernia, mild dysmorphic facial features, dilated renal pelvis, microcephaly (1 individual) [
## Differential Diagnosis
The phenotypic features (both clinical and electrophysiologic) associated with
Treatable neurometabolic disorders causing early infantile-onset epileptic encephalopathy should be included in the differential diagnosis. These disorders include:
Vitamin B
Holocarboxylase synthetase deficiency (OMIM
• Vitamin B
•
•
• Holocarboxylase synthetase deficiency (OMIM
## Management
No clinical practice guidelines for
To establish the extent of disease and needs of an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI
Consider EEG if seizures are a concern.
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.
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, certified advanced genetic nurse
There is no cure for
Treatment by experienced neurologist. Options incl ASMs, ketogenic diet, & epilepsy surgery.
Education of parents/caregivers
Response to vigabatrin, carbamazepine, phenobarbital, or valproic acid & levetiracetam have been reported.
Response to phenobarbital (focal seizures), ACTH (infantile spasms), clobazam, & ketogenic diet have also been reported.
≥2 ASMs were used in ≥20% of affected persons. ~25% were refractory to ASM therapy.
Severe dystonia, dyskinesia, or choreoathetosis can be treated w/monoamine-depleting or dopaminergic agents.
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
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; 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
There are no published guidelines for surveillance of individuals diagnosed with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures,
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
38% of individuals who became seizure-free in childhood or adolescence had seizure recurrence later in life.
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI
• Consider EEG if seizures are a concern.
• 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 by experienced neurologist. Options incl ASMs, ketogenic diet, & epilepsy surgery.
• Education of parents/caregivers
• Response to vigabatrin, carbamazepine, phenobarbital, or valproic acid & levetiracetam have been reported.
• Response to phenobarbital (focal seizures), ACTH (infantile spasms), clobazam, & ketogenic diet have also been reported.
• ≥2 ASMs were used in ≥20% of affected persons. ~25% were refractory to ASM therapy.
• Severe dystonia, dyskinesia, or choreoathetosis can be treated w/monoamine-depleting or dopaminergic agents.
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures,
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI
Consider EEG if seizures are a concern.
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.
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, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI
• Consider EEG if seizures are a concern.
• 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
Treatment by experienced neurologist. Options incl ASMs, ketogenic diet, & epilepsy surgery.
Education of parents/caregivers
Response to vigabatrin, carbamazepine, phenobarbital, or valproic acid & levetiracetam have been reported.
Response to phenobarbital (focal seizures), ACTH (infantile spasms), clobazam, & ketogenic diet have also been reported.
≥2 ASMs were used in ≥20% of affected persons. ~25% were refractory to ASM therapy.
Severe dystonia, dyskinesia, or choreoathetosis can be treated w/monoamine-depleting or dopaminergic agents.
Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
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; 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
• Treatment by experienced neurologist. Options incl ASMs, ketogenic diet, & epilepsy surgery.
• Education of parents/caregivers
• Response to vigabatrin, carbamazepine, phenobarbital, or valproic acid & levetiracetam have been reported.
• Response to phenobarbital (focal seizures), ACTH (infantile spasms), clobazam, & ketogenic diet have also been reported.
• ≥2 ASMs were used in ≥20% of affected persons. ~25% were refractory to ASM therapy.
• Severe dystonia, dyskinesia, or choreoathetosis can be treated w/monoamine-depleting or dopaminergic agents.
• Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
## 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
There are no published guidelines for surveillance of individuals diagnosed with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures,
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
38% of individuals who became seizure-free in childhood or adolescence had seizure recurrence later in life.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures,
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Parents of a proband
Most individuals reported to date with
Rarely, a proband with
Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
Presumed parental germline mosaicism was reported in a family in which the
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 [
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 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.
• Most individuals reported to date with
• Rarely, a proband with
• Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
• Presumed parental germline mosaicism was reported in a family in which the
• Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
• Presumed parental germline mosaicism was reported in a family in which the
• 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 [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
• Presumed parental germline mosaicism was reported in a family in which the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• 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 parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Parents of a proband
Most individuals reported to date with
Rarely, a proband with
Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
Presumed parental germline mosaicism was reported in a family in which the
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 [
If a parent of the proband has the
If the
If the parents have not been tested for the
• Most individuals reported to date with
• Rarely, a proband with
• Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
• Presumed parental germline mosaicism was reported in a family in which the
• Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
• Presumed parental germline mosaicism was reported in a family in which the
• 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 [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• Parental somatic and germline mosaicism was reported in the asymptomatic father of a child diagnosed with Ohtahara syndrome [
• Presumed parental germline mosaicism was reported in a family in which the
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• If a parent of the proband has the
• 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 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
STXBP1 Encephalopathy with Epilepsy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for STXBP1 Encephalopathy with Epilepsy (
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Variants listed in the table have been provided by the author.
## Chapter Notes
Dr Saadet Mercimek-Andrews's areas of focus are neurometabolic disorders, epilepsy genetics, and neurogenetics. See:
Saadet Mercimek-Andrews, MD, PhD, FCCMG, FRCPC (2016-present)
Yannay Khaikin, BSc; The Hospital for Sick Children (2016-2023)
28 September 2023 (sw) Comprehensive update posted live
1 December 2016 (bp) Review posted live
23 February 2016 (smm) Original submission
•
•
• 28 September 2023 (sw) Comprehensive update posted live
• 1 December 2016 (bp) Review posted live
• 23 February 2016 (smm) Original submission
## Author Notes
Dr Saadet Mercimek-Andrews's areas of focus are neurometabolic disorders, epilepsy genetics, and neurogenetics. See:
•
•
## Author History
Saadet Mercimek-Andrews, MD, PhD, FCCMG, FRCPC (2016-present)
Yannay Khaikin, BSc; The Hospital for Sick Children (2016-2023)
## Revision History
28 September 2023 (sw) Comprehensive update posted live
1 December 2016 (bp) Review posted live
23 February 2016 (smm) Original submission
• 28 September 2023 (sw) Comprehensive update posted live
• 1 December 2016 (bp) Review posted live
• 23 February 2016 (smm) Original submission
## References
## Literature Cited
|
[] |
1/12/2016
|
28/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sucla2-def
|
sucla2-def
|
[
"SUCLA2 Deficiency",
"SUCLA2 Deficiency",
"Succinate--CoA ligase [ADP-forming] subunit beta, mitochondrial",
"SUCLA2",
"SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria"
] |
Ayman W El-Hattab, Fernando Scaglia
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Hypotonia, axial or generalized
Dystonia
Muscle atrophy
Feeding difficulties
Growth deficiency affecting both weight gain and linear growth
Basal ganglia hyperintensities
Cerebral atrophy
Leukoencephalopathy
Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
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 [
When the phenotypic and laboratory findings suggest the diagnosis of
Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see
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.
•
• Hypotonia, axial or generalized
• Dystonia
• Muscle atrophy
• Hypotonia, axial or generalized
• Dystonia
• Muscle atrophy
•
•
• Feeding difficulties
• Growth deficiency affecting both weight gain and linear growth
• Feeding difficulties
• Growth deficiency affecting both weight gain and linear growth
• Hypotonia, axial or generalized
• Dystonia
• Muscle atrophy
• Feeding difficulties
• Growth deficiency affecting both weight gain and linear growth
• Basal ganglia hyperintensities
• Cerebral atrophy
• Leukoencephalopathy
• Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
• Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
• Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
• Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
• Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
• Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
• Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see
• For an introduction to multigene panels click
## Suggestive Findings
Hypotonia, axial or generalized
Dystonia
Muscle atrophy
Feeding difficulties
Growth deficiency affecting both weight gain and linear growth
Basal ganglia hyperintensities
Cerebral atrophy
Leukoencephalopathy
Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
•
• Hypotonia, axial or generalized
• Dystonia
• Muscle atrophy
• Hypotonia, axial or generalized
• Dystonia
• Muscle atrophy
•
•
• Feeding difficulties
• Growth deficiency affecting both weight gain and linear growth
• Feeding difficulties
• Growth deficiency affecting both weight gain and linear growth
• Hypotonia, axial or generalized
• Dystonia
• Muscle atrophy
• Feeding difficulties
• Growth deficiency affecting both weight gain and linear growth
• Basal ganglia hyperintensities
• Cerebral atrophy
• Leukoencephalopathy
• Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
• Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
• Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
• Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
• Elevation of methylmalonic acid (MMA) in most affected children. However, the MMA level is considerably less pronounced than in classic methylmalonic aciduria and can be only marginally elevated or even normal on rare occasions.
• Other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates such as succinate, fumarate, and 2-ketoglutarate.
## 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 [
When the phenotypic and laboratory findings suggest the diagnosis of
Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see
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.
• Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see
For an introduction to multigene panels click
• Note: Targeted analysis for the c.534+1G>A pathogenic founder variant can be performed first in probands of Faroese ancestry (see
• 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
To date, 61individuals have been identified with biallelic pathogenic variants in
Children with
Brain MRI typically shows basal ganglia hyperintensities (70%), cerebral atrophy (70%), and leukoencephalopathy (15%) [
Hyperhidrosis [
Neonatal hypoglycemia [
Biallelic
A founder pathogenic variant in families of Faroese ancestry has been identified (see
• Hyperhidrosis [
• Neonatal hypoglycemia [
## Clinical Description
To date, 61individuals have been identified with biallelic pathogenic variants in
Children with
Brain MRI typically shows basal ganglia hyperintensities (70%), cerebral atrophy (70%), and leukoencephalopathy (15%) [
Hyperhidrosis [
Neonatal hypoglycemia [
• Hyperhidrosis [
• Neonatal hypoglycemia [
## Genotype-Phenotype Correlations
Biallelic
## Prevalence
A founder pathogenic variant in families of Faroese ancestry has been identified (see
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
A contiguous gene deletion involving
## Differential Diagnosis
Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (
The phenotype of
Mitochondrial DNA Depletion Syndromes
CSF = cerebrospinal fluid; DD = developmental delay; GABA = gamma-aminobutyric acid; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; MDMD = mitochondrial DNA maintenance defect; MMA = methylmalonic acid; MNGIE = mitochondrial neurogastrointestinal encephalopathy
Within each phenotypic category, mitochondrial DNA depletion syndromes are ordered by relative prevalence.
Common manifestations seen in addition to the primary phenotype (i.e., in addition to encephalohepatopathy, encephalomyopathy, etc.)
Leukoencephalopathy is not present in
## 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
To incl assessment for hypotonia, dystonia, hypertonia, muscle weakness, muscle atrophy, movement disorders, & clinical signs of seizures
Brain MRI
Consider EMG to assess myopathy.
Consider EEG if seizures are a concern.
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 swallowing function / aspiration risk, nutritional status, & GERD
Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Joint contractures & kyphoscoliosis
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; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; mtDNA = mitochondrial DNA; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Nutritional support by dietitian
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Intervention for GERD/vomiting as indicated
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Chest physiotherapy
Aggressive antibiotic treatment of chest infections
PT to help maintain muscle function & prevent joint contractures
Bracing or surgery for kyphoscoliosis per orthopedist
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 health care decisions in the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
ASM = antiseizure medication; GERD = gastroesophageal reflux disease; 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.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Eval of safety of oral intake
Monitor for GERD/vomiting.
Measurement of growth parameters
Eval of nutritional status
Monitor for new development of kyphoscoliosis or joint contractures.
Physical medicine, OT/PT assessment of mobility, self-help skills
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl assessment for hypotonia, dystonia, hypertonia, muscle weakness, muscle atrophy, movement disorders, & clinical signs of seizures
• Brain MRI
• Consider EMG to assess myopathy.
• Consider EEG if seizures are a concern.
• 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 swallowing function / aspiration risk, nutritional status, & GERD
• Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Joint contractures & kyphoscoliosis
• 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
• Nutritional support by dietitian
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Intervention for GERD/vomiting as indicated
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Chest physiotherapy
• Aggressive antibiotic treatment of chest infections
• PT to help maintain muscle function & prevent joint contractures
• Bracing or surgery for kyphoscoliosis per orthopedist
• 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 health care decisions in the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
• 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.
• Eval of safety of oral intake
• Monitor for GERD/vomiting.
• Measurement of growth parameters
• Eval of nutritional status
• Monitor for new development of kyphoscoliosis or joint contractures.
• Physical medicine, OT/PT assessment of mobility, self-help skills
## 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
To incl assessment for hypotonia, dystonia, hypertonia, muscle weakness, muscle atrophy, movement disorders, & clinical signs of seizures
Brain MRI
Consider EMG to assess myopathy.
Consider EEG if seizures are a concern.
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 swallowing function / aspiration risk, nutritional status, & GERD
Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Joint contractures & kyphoscoliosis
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; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; mtDNA = mitochondrial DNA; OT = occupational therapy; PT = physical therapy
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 assessment for hypotonia, dystonia, hypertonia, muscle weakness, muscle atrophy, movement disorders, & clinical signs of seizures
• Brain MRI
• Consider EMG to assess myopathy.
• Consider EEG if seizures are a concern.
• 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 swallowing function / aspiration risk, nutritional status, & GERD
• Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Joint contractures & kyphoscoliosis
• 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
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Nutritional support by dietitian
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
Intervention for GERD/vomiting as indicated
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / OT / mobility services
Chest physiotherapy
Aggressive antibiotic treatment of chest infections
PT to help maintain muscle function & prevent joint contractures
Bracing or surgery for kyphoscoliosis per orthopedist
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 health care decisions in the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
ASM = antiseizure medication; GERD = gastroesophageal reflux disease; 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.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Nutritional support by dietitian
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Low threshold for clinical feeding eval &/or radiographic swallowing study when showing clinical signs or symptoms of dysphagia
• Intervention for GERD/vomiting as indicated
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / OT / mobility services
• Chest physiotherapy
• Aggressive antibiotic treatment of chest infections
• PT to help maintain muscle function & prevent joint contractures
• Bracing or surgery for kyphoscoliosis per orthopedist
• 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 health care decisions in the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
• 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
Eval of safety of oral intake
Monitor for GERD/vomiting.
Measurement of growth parameters
Eval of nutritional status
Monitor for new development of kyphoscoliosis or joint contractures.
Physical medicine, OT/PT assessment of mobility, self-help skills
GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Eval of safety of oral intake
• Monitor for GERD/vomiting.
• Measurement of growth parameters
• Eval of nutritional status
• Monitor for new development of kyphoscoliosis or joint contractures.
• Physical medicine, OT/PT assessment of mobility, self-help skills
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
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
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.
Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder pathogenic variant in families of Faroese origin has been identified; the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands (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
• 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 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.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder pathogenic variant in families of Faroese origin has been identified; the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands (see
## Mode of Inheritance
## 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
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 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
• 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.
Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder pathogenic variant in families of Faroese origin has been identified; the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands (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 carriers or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder pathogenic variant in families of Faroese origin has been identified; the disorder has a high incidence (1:1,700) and a carrier frequency of 1:33 in the Faroe Islands (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
United Kingdom
•
• United Kingdom
•
•
•
•
•
•
•
## Molecular Genetics
SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SUCLA2-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria (
The pathogenic variants lead to dysfunctional SUCL protein. As SUCL forms a complex with the mitochondrial nucleoside diphosphate kinase, the lack of this complex formation in SUCL deficiency can disturb the kinase function, resulting in decreased mitochondrial nucleotide synthesis and therefore decreased mitochondrial DNA (mtDNA) synthesis leading to mtDNA depletion [
Electron microscopic findings of increased fiber size variability, atrophic fibers, intracellular lipid accumulation, COX-deficient fibers, and structurally altered mitochondria with abnormal cristae.
Deficiencies in electron transport chain activity in combined complex I and IV; in combined complex I, III, and IV; and in isolated complex IV.
Mitochondrial DNA content in affected muscle tissue typically reduced to 20%-60% of that in tissue- and age-matched controls.
Variants listed in the table have been provided by the authors.
• Electron microscopic findings of increased fiber size variability, atrophic fibers, intracellular lipid accumulation, COX-deficient fibers, and structurally altered mitochondria with abnormal cristae.
• Deficiencies in electron transport chain activity in combined complex I and IV; in combined complex I, III, and IV; and in isolated complex IV.
• Mitochondrial DNA content in affected muscle tissue typically reduced to 20%-60% of that in tissue- and age-matched controls.
## Molecular Pathogenesis
The pathogenic variants lead to dysfunctional SUCL protein. As SUCL forms a complex with the mitochondrial nucleoside diphosphate kinase, the lack of this complex formation in SUCL deficiency can disturb the kinase function, resulting in decreased mitochondrial nucleotide synthesis and therefore decreased mitochondrial DNA (mtDNA) synthesis leading to mtDNA depletion [
Electron microscopic findings of increased fiber size variability, atrophic fibers, intracellular lipid accumulation, COX-deficient fibers, and structurally altered mitochondria with abnormal cristae.
Deficiencies in electron transport chain activity in combined complex I and IV; in combined complex I, III, and IV; and in isolated complex IV.
Mitochondrial DNA content in affected muscle tissue typically reduced to 20%-60% of that in tissue- and age-matched controls.
Variants listed in the table have been provided by the authors.
• Electron microscopic findings of increased fiber size variability, atrophic fibers, intracellular lipid accumulation, COX-deficient fibers, and structurally altered mitochondria with abnormal cristae.
• Deficiencies in electron transport chain activity in combined complex I and IV; in combined complex I, III, and IV; and in isolated complex IV.
• Mitochondrial DNA content in affected muscle tissue typically reduced to 20%-60% of that in tissue- and age-matched controls.
## Chapter Notes
Dr El-Hattab is also interested in hearing from clinicians treating families affected by mitochondrial disorders 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 El-Hattab to inquire about review of
Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)Elsebet Ostergaard, MD, PhD; National University Hospital Rigshospitalet (2009-2016)Fernando Scaglia, MD, FAAP, FACMG (2016-present)
28 September 2023 (bp) Comprehensive update posted live
30 June 2016 (ma) Comprehensive update posted live
26 May 2009 (et) Review posted live
16 January 2009 (eo) Original submission
• 28 September 2023 (bp) Comprehensive update posted live
• 30 June 2016 (ma) Comprehensive update posted live
• 26 May 2009 (et) Review posted live
• 16 January 2009 (eo) Original submission
## Author Notes
Dr El-Hattab is also interested in hearing from clinicians treating families affected by mitochondrial disorders 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 El-Hattab to inquire about review of
## Author History
Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)Elsebet Ostergaard, MD, PhD; National University Hospital Rigshospitalet (2009-2016)Fernando Scaglia, MD, FAAP, FACMG (2016-present)
## Revision History
28 September 2023 (bp) Comprehensive update posted live
30 June 2016 (ma) Comprehensive update posted live
26 May 2009 (et) Review posted live
16 January 2009 (eo) Original submission
• 28 September 2023 (bp) Comprehensive update posted live
• 30 June 2016 (ma) Comprehensive update posted live
• 26 May 2009 (et) Review posted live
• 16 January 2009 (eo) Original submission
## References
## Literature Cited
|
[] |
26/5/2009
|
28/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
suclg1-mtddepl
|
suclg1-mtddepl
|
[
"SUCLG1 Deficiency",
"SUCLG1-Related Succinyl-CoA Ligase Deficiency",
"SUCLG1 Deficiency",
"SUCLG1-Related Succinyl-CoA Ligase Deficiency",
"Succinate--CoA ligase [ADP/GDP-forming] subunit alpha, mitochondrial",
"SUCLG1",
"SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria"
] |
Ayman W El-Hattab, Fernando Scaglia
|
Summary The diagnosis of
|
## Diagnosis
Present in >50%:
Developmental delay and cognitive impairment
Hypotonia
Muscle atrophy
Feeding difficulties
Present in 20%-50%:
Growth retardation / failure to thrive
Hepatopathy
Sensorineural hearing impairment
Dystonia
Hypertonia
Present in <20%:
Hypertrophic cardiomyopathy
Recurrent respiratory infections, respiratory distress, and apnea
Recurrent vomiting and gastroesophageal reflux disease
Ptosis and strabismus
Epilepsy, myoclonus, and microcephaly
Hyperhidrosis
Sleep disturbance
Rhabdomyolysis
Contractures
Hypothermia
Basal ganglia hyperintensities (80%)
Cerebral atrophy (30%)
Leukoencephalopathy (20%)
Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
Note: In classic
Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
Increased fiber size variability, atrophic fibers, intracellular lipid accumulation, ragged-red fibers (RRF), and COX-deficient fibers
Structurally altered mitochondria with abnormal cristae on electron microscopy
Abnormal electron transport chain activity. The most common abnormalities are combined complex I and IV deficiencies, combined complex I, III, and IV deficiencies, and isolated complex IV deficiency.
Reduced mtDNA content; typically 15%-50% of tissue- and age-matched controls [
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. Because the phenotype of
The phenotypes of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other
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.
• Developmental delay and cognitive impairment
• Hypotonia
• Muscle atrophy
• Feeding difficulties
• Growth retardation / failure to thrive
• Hepatopathy
• Sensorineural hearing impairment
• Dystonia
• Hypertonia
• Hypertrophic cardiomyopathy
• Recurrent respiratory infections, respiratory distress, and apnea
• Recurrent vomiting and gastroesophageal reflux disease
• Ptosis and strabismus
• Epilepsy, myoclonus, and microcephaly
• Hyperhidrosis
• Sleep disturbance
• Rhabdomyolysis
• Contractures
• Hypothermia
• Basal ganglia hyperintensities (80%)
• Cerebral atrophy (30%)
• Leukoencephalopathy (20%)
•
• Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
• Note: In classic
• Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
• Note: In classic
• Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
• Note: In classic
• Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Increased fiber size variability, atrophic fibers, intracellular lipid accumulation, ragged-red fibers (RRF), and COX-deficient fibers
• Structurally altered mitochondria with abnormal cristae on electron microscopy
• Abnormal electron transport chain activity. The most common abnormalities are combined complex I and IV deficiencies, combined complex I, III, and IV deficiencies, and isolated complex IV deficiency.
• Reduced mtDNA content; typically 15%-50% of tissue- and age-matched controls [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Present in >50%:
Developmental delay and cognitive impairment
Hypotonia
Muscle atrophy
Feeding difficulties
Present in 20%-50%:
Growth retardation / failure to thrive
Hepatopathy
Sensorineural hearing impairment
Dystonia
Hypertonia
Present in <20%:
Hypertrophic cardiomyopathy
Recurrent respiratory infections, respiratory distress, and apnea
Recurrent vomiting and gastroesophageal reflux disease
Ptosis and strabismus
Epilepsy, myoclonus, and microcephaly
Hyperhidrosis
Sleep disturbance
Rhabdomyolysis
Contractures
Hypothermia
Basal ganglia hyperintensities (80%)
Cerebral atrophy (30%)
Leukoencephalopathy (20%)
Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
Note: In classic
Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
Increased fiber size variability, atrophic fibers, intracellular lipid accumulation, ragged-red fibers (RRF), and COX-deficient fibers
Structurally altered mitochondria with abnormal cristae on electron microscopy
Abnormal electron transport chain activity. The most common abnormalities are combined complex I and IV deficiencies, combined complex I, III, and IV deficiencies, and isolated complex IV deficiency.
Reduced mtDNA content; typically 15%-50% of tissue- and age-matched controls [
• Developmental delay and cognitive impairment
• Hypotonia
• Muscle atrophy
• Feeding difficulties
• Growth retardation / failure to thrive
• Hepatopathy
• Sensorineural hearing impairment
• Dystonia
• Hypertonia
• Hypertrophic cardiomyopathy
• Recurrent respiratory infections, respiratory distress, and apnea
• Recurrent vomiting and gastroesophageal reflux disease
• Ptosis and strabismus
• Epilepsy, myoclonus, and microcephaly
• Hyperhidrosis
• Sleep disturbance
• Rhabdomyolysis
• Contractures
• Hypothermia
• Basal ganglia hyperintensities (80%)
• Cerebral atrophy (30%)
• Leukoencephalopathy (20%)
•
• Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
• Note: In classic
• Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
• Note: In classic
• Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Elevation of urinary methylmalonic acid (MMA) in all affected children. Urinary MMA ranges from 10 to 500 mmol/mol creatinine (normal <3 mmol/mol creatinine).
• Note: In classic
• Several other metabolites that may be elevated in urine include methylcitrate, 3-methylglutaconic acid, 3-hydroxyisovaleric acid, and Krebs cycle intermediates (e.g., succinate, fumarate, 2-ketoglutarate).
• Increased fiber size variability, atrophic fibers, intracellular lipid accumulation, ragged-red fibers (RRF), and COX-deficient fibers
• Structurally altered mitochondria with abnormal cristae on electron microscopy
• Abnormal electron transport chain activity. The most common abnormalities are combined complex I and IV deficiencies, combined complex I, III, and IV deficiencies, and isolated complex IV deficiency.
• Reduced mtDNA content; typically 15%-50% of tissue- and age-matched controls [
## 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. Because the phenotype of
The phenotypes of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other
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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Option 1
The phenotypes 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
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.
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date 29 individuals with
The clinical description here is based on the findings reported in these 29 individuals. The common clinical manifestations are summarized in
Clinical Manifestations of
Developmental delay & cognitive impairment
Hypotonia
Muscle atrophy
Feeding difficulties
Lactic acidosis
Growth retardation / failure to thrive
Hepatopathy
Sensorineural hearing impairment
Dystonia
Hypertonia
Hypertrophic cardiomyopathy
Recurrent respiratory infections
Respiratory distress
Apnea
Recurrent vomiting
Gastroesophageal reflux disease
Ptosis
Strabismus
Epilepsy
Myoclonus
Microcephaly
Choreoathetosis
Hyperhidrosis
Sleep disturbance
Rhabdomyolysis
Contractures
Hypothermia
Hypoglycemia
The majority have an uncomplicated pregnancy and normal birth weight; however, five neonates had intrauterine growth restriction (IUGR) or were small for gestational age (SGA) [
The majority of affected infants present with early-onset encephalomyopathy and neurocognitive problems as well as hepatopathy, feeding and growth problems, and cardiorespiratory complications.
Death from severe metabolic acidosis during the neonatal period (fatal infantile lactic acidosis) has been reported in five infants [
Other congenital anomalies reported in single infants each are interrupted aortic arch, polydactyly, and hypospadias [
Pathogenic
Succinyl-CoA ligase deficiency can result from either biallelic pathogenic variants in
• Developmental delay & cognitive impairment
• Hypotonia
• Muscle atrophy
• Feeding difficulties
• Lactic acidosis
• Growth retardation / failure to thrive
• Hepatopathy
• Sensorineural hearing impairment
• Dystonia
• Hypertonia
• Hypertrophic cardiomyopathy
• Recurrent respiratory infections
• Respiratory distress
• Apnea
• Recurrent vomiting
• Gastroesophageal reflux disease
• Ptosis
• Strabismus
• Epilepsy
• Myoclonus
• Microcephaly
• Choreoathetosis
• Hyperhidrosis
• Sleep disturbance
• Rhabdomyolysis
• Contractures
• Hypothermia
• Hypoglycemia
## Clinical Description
To date 29 individuals with
The clinical description here is based on the findings reported in these 29 individuals. The common clinical manifestations are summarized in
Clinical Manifestations of
Developmental delay & cognitive impairment
Hypotonia
Muscle atrophy
Feeding difficulties
Lactic acidosis
Growth retardation / failure to thrive
Hepatopathy
Sensorineural hearing impairment
Dystonia
Hypertonia
Hypertrophic cardiomyopathy
Recurrent respiratory infections
Respiratory distress
Apnea
Recurrent vomiting
Gastroesophageal reflux disease
Ptosis
Strabismus
Epilepsy
Myoclonus
Microcephaly
Choreoathetosis
Hyperhidrosis
Sleep disturbance
Rhabdomyolysis
Contractures
Hypothermia
Hypoglycemia
The majority have an uncomplicated pregnancy and normal birth weight; however, five neonates had intrauterine growth restriction (IUGR) or were small for gestational age (SGA) [
The majority of affected infants present with early-onset encephalomyopathy and neurocognitive problems as well as hepatopathy, feeding and growth problems, and cardiorespiratory complications.
Death from severe metabolic acidosis during the neonatal period (fatal infantile lactic acidosis) has been reported in five infants [
Other congenital anomalies reported in single infants each are interrupted aortic arch, polydactyly, and hypospadias [
• Developmental delay & cognitive impairment
• Hypotonia
• Muscle atrophy
• Feeding difficulties
• Lactic acidosis
• Growth retardation / failure to thrive
• Hepatopathy
• Sensorineural hearing impairment
• Dystonia
• Hypertonia
• Hypertrophic cardiomyopathy
• Recurrent respiratory infections
• Respiratory distress
• Apnea
• Recurrent vomiting
• Gastroesophageal reflux disease
• Ptosis
• Strabismus
• Epilepsy
• Myoclonus
• Microcephaly
• Choreoathetosis
• Hyperhidrosis
• Sleep disturbance
• Rhabdomyolysis
• Contractures
• Hypothermia
• Hypoglycemia
## Genotype-Phenotype Correlations
Pathogenic
## Nomenclature
Succinyl-CoA ligase deficiency can result from either biallelic pathogenic variants in
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Mitochondrial DNA depletion syndromes occur as a result of defects in mtDNA maintenance caused by pathogenic variants in nuclear genes that function in either mitochondrial nucleotide synthesis (e.g.,
Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral, encephalomyopathic, neurogastrointestinal, and myopathic forms [
Mitochondrial DNA Depletion Syndromes
Within each phenotypic category, mtDNA depletion syndromes are ordered by relative prevalence.
See hyperlinked
Among mtDNA depletion syndromes, methylmalonic acid (MMA) is elevated only in
The phenotypes of
Comparison of the Phenotypes of
## Management
To establish the extent of disease and needs in an individual diagnosed with
Comprehensive neurologic examination and developmental/cognitive assessment. The following diagnostic modalities can be considered to assess the degree of neurologic involvement:
Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
EEG if seizures are suspected
Echocardiogram to assess for cardiomyopathy
Liver function tests including transaminases, albumin, total and direct bilirubin, and coagulation profile
Audiologic evaluation
Ophthalmologic examination for evidence of ptosis and/or strabismus
Nutritional evaluation and swallowing assessment for feeding difficulties and growth failure
Consultation with a clinical geneticist and/or genetic counselor
Management is best provided by a multidisciplinary team including specialists in neurology, audiology, child development, gastroenterology, cardiology, nutrition, and clinical genetics. Treatments include the following:
Physical therapy to help maintain muscle function and prevent joint contractures
Standard treatment with anti-seizure medication for seizures
Nutritional support by a dietitian and the use of a nasogastric tube or gastrostomy tube feedings to address feeding difficulties and failure to thrive
Chest physiotherapy, aggressive antibiotic treatment of chest infections, and artificial ventilation (including assisted nasal ventilation or intubation and the use of a tracheostomy and ventilator) for respiratory insufficiency
Hypertrophic cardiomyopathy and hepatopathy, when present, require standard management by cardiologists and hepatologists, respectively.
No clinical guidelines for surveillance are available.
The following evaluations are suggested, with frequency varying according to the needs of the child:
Developmental and neurologic assessment
Nutritional and growth assessment
Echocardiogram
Liver function tests
Hearing evaluation
Ophthalmologic examination
See
A group of mtDNA depletion syndromes is caused by defects in genes encoding proteins involved in maintenance of the mitochondrial deoxyribonucleotide pool. Because in vitro experimental studies have demonstrated improved mtDNA content following deoxyribonucleotide supplementation, this could potentially be a treatment for some mtDNA depletion syndromes [
Search
• Comprehensive neurologic examination and developmental/cognitive assessment. The following diagnostic modalities can be considered to assess the degree of neurologic involvement:
• Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
• EEG if seizures are suspected
• Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
• EEG if seizures are suspected
• Echocardiogram to assess for cardiomyopathy
• Liver function tests including transaminases, albumin, total and direct bilirubin, and coagulation profile
• Audiologic evaluation
• Ophthalmologic examination for evidence of ptosis and/or strabismus
• Nutritional evaluation and swallowing assessment for feeding difficulties and growth failure
• Consultation with a clinical geneticist and/or genetic counselor
• Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
• EEG if seizures are suspected
• Physical therapy to help maintain muscle function and prevent joint contractures
• Standard treatment with anti-seizure medication for seizures
• Nutritional support by a dietitian and the use of a nasogastric tube or gastrostomy tube feedings to address feeding difficulties and failure to thrive
• Chest physiotherapy, aggressive antibiotic treatment of chest infections, and artificial ventilation (including assisted nasal ventilation or intubation and the use of a tracheostomy and ventilator) for respiratory insufficiency
• Hypertrophic cardiomyopathy and hepatopathy, when present, require standard management by cardiologists and hepatologists, respectively.
• Developmental and neurologic assessment
• Nutritional and growth assessment
• Echocardiogram
• Liver function tests
• Hearing evaluation
• Ophthalmologic examination
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Comprehensive neurologic examination and developmental/cognitive assessment. The following diagnostic modalities can be considered to assess the degree of neurologic involvement:
Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
EEG if seizures are suspected
Echocardiogram to assess for cardiomyopathy
Liver function tests including transaminases, albumin, total and direct bilirubin, and coagulation profile
Audiologic evaluation
Ophthalmologic examination for evidence of ptosis and/or strabismus
Nutritional evaluation and swallowing assessment for feeding difficulties and growth failure
Consultation with a clinical geneticist and/or genetic counselor
• Comprehensive neurologic examination and developmental/cognitive assessment. The following diagnostic modalities can be considered to assess the degree of neurologic involvement:
• Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
• EEG if seizures are suspected
• Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
• EEG if seizures are suspected
• Echocardiogram to assess for cardiomyopathy
• Liver function tests including transaminases, albumin, total and direct bilirubin, and coagulation profile
• Audiologic evaluation
• Ophthalmologic examination for evidence of ptosis and/or strabismus
• Nutritional evaluation and swallowing assessment for feeding difficulties and growth failure
• Consultation with a clinical geneticist and/or genetic counselor
• Brain MRI (if not performed during the diagnostic evaluation) to establish the degree of central nervous system involvement
• EEG if seizures are suspected
## Treatment of Manifestations
Management is best provided by a multidisciplinary team including specialists in neurology, audiology, child development, gastroenterology, cardiology, nutrition, and clinical genetics. Treatments include the following:
Physical therapy to help maintain muscle function and prevent joint contractures
Standard treatment with anti-seizure medication for seizures
Nutritional support by a dietitian and the use of a nasogastric tube or gastrostomy tube feedings to address feeding difficulties and failure to thrive
Chest physiotherapy, aggressive antibiotic treatment of chest infections, and artificial ventilation (including assisted nasal ventilation or intubation and the use of a tracheostomy and ventilator) for respiratory insufficiency
Hypertrophic cardiomyopathy and hepatopathy, when present, require standard management by cardiologists and hepatologists, respectively.
• Physical therapy to help maintain muscle function and prevent joint contractures
• Standard treatment with anti-seizure medication for seizures
• Nutritional support by a dietitian and the use of a nasogastric tube or gastrostomy tube feedings to address feeding difficulties and failure to thrive
• Chest physiotherapy, aggressive antibiotic treatment of chest infections, and artificial ventilation (including assisted nasal ventilation or intubation and the use of a tracheostomy and ventilator) for respiratory insufficiency
• Hypertrophic cardiomyopathy and hepatopathy, when present, require standard management by cardiologists and hepatologists, respectively.
## Surveillance
No clinical guidelines for surveillance are available.
The following evaluations are suggested, with frequency varying according to the needs of the child:
Developmental and neurologic assessment
Nutritional and growth assessment
Echocardiogram
Liver function tests
Hearing evaluation
Ophthalmologic examination
• Developmental and neurologic assessment
• Nutritional and growth assessment
• Echocardiogram
• Liver function tests
• Hearing evaluation
• Ophthalmologic examination
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
A group of mtDNA depletion syndromes is caused by defects in genes encoding proteins involved in maintenance of the mitochondrial deoxyribonucleotide pool. Because in vitro experimental studies have demonstrated improved mtDNA content following deoxyribonucleotide supplementation, this could potentially be a treatment for some mtDNA depletion syndromes [
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
• 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
## Resources
United Kingdom
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SUCLG1-Related Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Methylmalonic Aciduria (
Succinyl-CoA ligase (SUCL) is a mitochondrial heterodimeric enzyme of the Krebs cycle that is composed of an alpha subunit, encoded by
SUCL also forms a complex with the mitochondrial nucleoside diphosphate kinase (see
## Molecular Pathogenesis
Succinyl-CoA ligase (SUCL) is a mitochondrial heterodimeric enzyme of the Krebs cycle that is composed of an alpha subunit, encoded by
SUCL also forms a complex with the mitochondrial nucleoside diphosphate kinase (see
## Chapter Notes
30 March 2017 (bp) Review posted live
20 October 2016 (aeh) Original submission
• 30 March 2017 (bp) Review posted live
• 20 October 2016 (aeh) Original submission
## Revision History
30 March 2017 (bp) Review posted live
20 October 2016 (aeh) Original submission
• 30 March 2017 (bp) Review posted live
• 20 October 2016 (aeh) Original submission
## References
## Literature Cited
|
[
"Y Cámara, E González-Vioque, M Scarpelli, J Torres-Torronteras, A Caballero, M Hirano, R Martí. Administration of deoxyribonucleosides or inhibition of their catabolism as a pharmacological approach for mitochondrial DNA depletion syndrome.. Hum Mol Genet. 2014;23:2459-67",
"R Carrozzo, D Verrigni, M Rasmussen, R de Coo, H Amartino, M Bianchi, D Buhas, S Mesli, K Naess, AP Born, B Woldseth, P Prontera, M Batbayli, K Ravn, F Joensen, DM Cordelli, FM Santorelli, M Tulinius, N Darin, M Duno, P Jouvencel, A Burlina, G Stangoni, E Bertini, I Redonnet-Vernhet, F Wibrand, C Dionisi-Vici, J Uusimaa, P Vieira, AN Osorio, R McFarland, RW Taylor, E Holme, E Ostergaard. Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG1: phenotype and genotype correlations in 71 patients.. J Inherit Metab Dis. 2016;39:243-52",
"J Chu, M Pupavac, D Watkins, X Tian, Y Feng, S Chen, R Fenter, VW Zhang, J Wang, LJ Wong, DS Rosenblatt. Next generation sequencing of patients with mut methylmalonic aciduria: Validation of somatic cell studies and identification of 16 novel mutations.. Mol Genet Metab. 2016;118:264-71",
"TR Donti, R Masand, DA Scott, WJ Craigen, BH Graham. Expanding the phenotypic spectrum of Succinyl-CoA ligase deficiency through functional validation of a new SUCLG1 variant.. Mol Genet Metab. 2016;119:68-74",
"AW El-Hattab, F Scaglia. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options.. Neurotherapeutics. 2013;10:186-98",
"T Honzik, M Tesarova, M Magner, J Mayr, P Jesina, K Vesela, L Wenchich, K Szentivanyi, H Hansikova, W Sperl, J Zeman. Neonatal onset of mitochondrial disorders in 129 patients: clinical and laboratory characteristics and a new approach to diagnosis.. J Inherit Metab Dis. 2012;35:749-59",
"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",
"Y Liu, X Li, Q Wang, Y Ding, J Song, Y. Yang. Five novel SUCLG1 mutations in three Chinese patients with succinate-CoA ligase deficiency noticed by mild methylmalonic aciduria.. Brain Dev. 2016;38:61-7",
"A Navarro-Sastre, F Tort, J Garcia-Villoria, MR Pons, A Nascimento, J Colomer, J Campistol, ME Yoldi, E López-Gallardo, J Montoya, M Unceta, MJ Martinez, P Briones, A Ribes. Mitochondrial DNA depletion syndrome: new descriptions and the use of citrate synthase as a helpful tool to better characterise the patients.. Mol Genet Metab. 2012;107:409-15",
"E Ostergaard, E Christensen, E Kristensen, B Mogensen, M Duno, EA Shoubridge, F Wibrand. Deficiency of the alpha subunit of succinate-coenzyme A ligase causes fatal infantile lactic acidosis with mitochondrial DNA depletion.. Am J Hum Genet. 2007;81:383-7",
"E Ostergaard, M Schwartz, M Batbayli, E Christensen, O Hjalmarson, G Kollberg, E. Holme. A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria.. Eur J Pediatr. 2010;169:201-5",
"M Pupavac, X Tian, J Chu, G Wang, Y Feng, S Chen, R Fenter, VW Zhang, J Wang, D Watkins, LJ Wong, DS Rosenblatt. Added value of next generation gene panel analysis for patients with elevated methylmalonic acid and no clinical diagnosis following functional studies of vitamin B12 metabolism.. Mol Genet Metab. 2016;117:363-8",
"LM Randolph, HA Jackson, J Wang, H Shimada, PA Sanchez-Lara, DA Wong, LJ Wong, RG Boles. Fatal infantile lactic acidosis and a novel homozygous mutation in the SUCLG1 gene: a mitochondrial DNA depletion disorder.. Mol Genet Metab. 2011;102:149-52",
"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",
"H Rivera, B Merinero, M Martinez-Pardo, I Arroyo, P Ruiz-Sala, B Bornstein, C Serra-Suhe, E Gallardo, R Marti, MJ Moran, C Ugalde, LA Perez-Jurado, AL Andreu, R Garesse, M Ugarte, J Arenas, MA Martin. Marked mitochondrial DNA depletion associated with a novel SUCLG1 gene mutation resulting in lethal neonatal acidosis, multi-organ failure, and interrupted aortic arch.. Mitochondrion. 2010;10:362-8",
"C Rouzier, S Le Guédard-Méreuze, K Fragaki, V Serre, J Miro, S Tuffery-Giraud, A Chaussenot, S Bannwarth, C Caruba, E Ostergaard, JF Pellissier, C Richelme, C Espil, B Chabrol, V Paquis-Flucklinger. The severity of phenotype linked to SUCLG1 mutations could be correlated with residual amount of SUCLG1 protein.. J Med Genet. 2010;47:670-6",
"O Sakamoto, T Ohura, K Murayama, A Ohtake, H Harashima, D Abukawa, J Takeyama, K Haginoya, S Miyabayashi, S Kure. Neonatal lactic acidosis with methylmalonic aciduria due to novel mutations in the SUCLG1 gene.. Pediatr Int. 2011;53:921-5",
"V Valayannopoulos, C Haudry, V Serre, M Barth, N Boddaert, JB Arnoux, V Cormier-Daire, M Rio, D Rabier, A Vassault, A Munnich, JP Bonnefont, P de Lonlay, A Rötig, AS Lebre. New SUCLG1 patients expanding the phenotypic spectrum of this rare cause of mild methylmalonic aciduria.. Mitochondrion. 2010;10:335-41",
"JL Van Hove, MS Saenz, JA Thomas, RC Gallagher, MA Lovell, LZ Fenton, S Shanske, SM Myers, RJ Wanders, J Ruiter, M Turkenburg, HR Waterham. Succinyl-CoA ligase deficiency: a mitochondrial hepatoencephalomyopathy.. Pediatr Res. 2010;68:159-64"
] |
30/3/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
syne1ca-ar
|
syne1ca-ar
|
[
"SYNE1 Cerebellar Ataxia (Autosomal Recessive Cerebellar Ataxia 1 [ARCA1])",
"SYNE1-Deficient Arthrogryposis Multiplex Congenita (AMC)",
"Nesprin-1",
"SYNE1",
"SYNE1 Deficiency"
] |
SYNE1 Deficiency
|
Marie Beaudin, Pierre-Luc Gamache, François Gros-Louis, Nicolas Dupré
|
Summary SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia at the mild end to arthrogryposis multiplex congenita (AMC) at the severe end. SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years). While some individuals have a pure cerebellar syndrome (i.e., cerebellar ataxia, dysarthria, dysmetria, abnormalities in ocular saccades and smooth pursuit), many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations). Most individuals develop features of the cerebellar cognitive and affective syndrome (i.e., significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills). The two less common phenotypes are SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability) and SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot). The diagnosis of SYNE1 deficiency is established in a proband with suggestive findings and biallelic SYNE1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
|
SYNE1-deficient arthrogryposis multiplex congenita (AMC)
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• SYNE1-deficient arthrogryposis multiplex congenita (AMC)
## Diagnosis
SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia to arthrogryposis multiplex congenita (AMC).
SYNE1 deficiency
Cerebellar ataxia
Progressive ataxia of gait
Clumsiness of hands
Dysmetria
Dysarthria
Abnormalities in ocular saccades and smooth pursuit
Upper and/or lower motor neuron involvement
Spasticity, hyperactive deep tendon reflexes, extensor plantar response
Muscle atrophy, diminished deep tendon reflexes, fasciculations
Cognitive impairment
Delayed motor milestones in infancy
Intellectual disability
Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
Skeletal involvement
Scoliosis or kyphosis
Pes cavus
Arthrogryposis with distal joint contractures
Brain MRI in individuals with childhood-onset multisystem disease or adult-onset ataxia usually shows marked diffuse cerebellar atrophy with no other abnormalities (
Brain stem atrophy has been reported in one individual with childhood-onset multisystem disease [
White matter abnormalities in the brain and spinal cord that mimicked findings in multiple sclerosis have been reported in two individuals with adult-onset ataxia [
The diagnosis of SYNE1 deficiency
Because the phenotype of SYNE1 deficiency is indistinguishable from many other inherited disorders with similar complex neurologic and neuromuscular phenotypes, molecular genetic testing approaches include
Note: Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in SYNE1 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.
• Cerebellar ataxia
• Progressive ataxia of gait
• Clumsiness of hands
• Dysmetria
• Dysarthria
• Abnormalities in ocular saccades and smooth pursuit
• Progressive ataxia of gait
• Clumsiness of hands
• Dysmetria
• Dysarthria
• Abnormalities in ocular saccades and smooth pursuit
• Upper and/or lower motor neuron involvement
• Spasticity, hyperactive deep tendon reflexes, extensor plantar response
• Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Spasticity, hyperactive deep tendon reflexes, extensor plantar response
• Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Cognitive impairment
• Delayed motor milestones in infancy
• Intellectual disability
• Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Delayed motor milestones in infancy
• Intellectual disability
• Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Skeletal involvement
• Scoliosis or kyphosis
• Pes cavus
• Arthrogryposis with distal joint contractures
• Scoliosis or kyphosis
• Pes cavus
• Arthrogryposis with distal joint contractures
• Progressive ataxia of gait
• Clumsiness of hands
• Dysmetria
• Dysarthria
• Abnormalities in ocular saccades and smooth pursuit
• Spasticity, hyperactive deep tendon reflexes, extensor plantar response
• Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Delayed motor milestones in infancy
• Intellectual disability
• Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Scoliosis or kyphosis
• Pes cavus
• Arthrogryposis with distal joint contractures
• Brain stem atrophy has been reported in one individual with childhood-onset multisystem disease [
• White matter abnormalities in the brain and spinal cord that mimicked findings in multiple sclerosis have been reported in two individuals with adult-onset ataxia [
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
SYNE1 deficiency
Cerebellar ataxia
Progressive ataxia of gait
Clumsiness of hands
Dysmetria
Dysarthria
Abnormalities in ocular saccades and smooth pursuit
Upper and/or lower motor neuron involvement
Spasticity, hyperactive deep tendon reflexes, extensor plantar response
Muscle atrophy, diminished deep tendon reflexes, fasciculations
Cognitive impairment
Delayed motor milestones in infancy
Intellectual disability
Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
Skeletal involvement
Scoliosis or kyphosis
Pes cavus
Arthrogryposis with distal joint contractures
• Cerebellar ataxia
• Progressive ataxia of gait
• Clumsiness of hands
• Dysmetria
• Dysarthria
• Abnormalities in ocular saccades and smooth pursuit
• Progressive ataxia of gait
• Clumsiness of hands
• Dysmetria
• Dysarthria
• Abnormalities in ocular saccades and smooth pursuit
• Upper and/or lower motor neuron involvement
• Spasticity, hyperactive deep tendon reflexes, extensor plantar response
• Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Spasticity, hyperactive deep tendon reflexes, extensor plantar response
• Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Cognitive impairment
• Delayed motor milestones in infancy
• Intellectual disability
• Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Delayed motor milestones in infancy
• Intellectual disability
• Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Skeletal involvement
• Scoliosis or kyphosis
• Pes cavus
• Arthrogryposis with distal joint contractures
• Scoliosis or kyphosis
• Pes cavus
• Arthrogryposis with distal joint contractures
• Progressive ataxia of gait
• Clumsiness of hands
• Dysmetria
• Dysarthria
• Abnormalities in ocular saccades and smooth pursuit
• Spasticity, hyperactive deep tendon reflexes, extensor plantar response
• Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Delayed motor milestones in infancy
• Intellectual disability
• Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Scoliosis or kyphosis
• Pes cavus
• Arthrogryposis with distal joint contractures
## Electrophysiologic Studies
## Brain Imaging
Brain MRI in individuals with childhood-onset multisystem disease or adult-onset ataxia usually shows marked diffuse cerebellar atrophy with no other abnormalities (
Brain stem atrophy has been reported in one individual with childhood-onset multisystem disease [
White matter abnormalities in the brain and spinal cord that mimicked findings in multiple sclerosis have been reported in two individuals with adult-onset ataxia [
• Brain stem atrophy has been reported in one individual with childhood-onset multisystem disease [
• White matter abnormalities in the brain and spinal cord that mimicked findings in multiple sclerosis have been reported in two individuals with adult-onset ataxia [
## Establishing the Diagnosis
The diagnosis of SYNE1 deficiency
Because the phenotype of SYNE1 deficiency is indistinguishable from many other inherited disorders with similar complex neurologic and neuromuscular phenotypes, molecular genetic testing approaches include
Note: Single-gene testing (sequence analysis of
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in SYNE1 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.
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
The phenotype and severity of SYNE1 deficiency vary widely and span a spectrum ranging from adult-onset cerebellar ataxia at the milder end to childhood-onset multisystem disease and prenatal-onset arthrogryposis multiplex congenita at the more severe end.
SYNE1-deficient cerebellar ataxia, also known as autosomal recessive cerebellar ataxia 1 (ARCA1), typically begins in adulthood (mean age at onset: 31.6 years [
The initial description of ARCA1 was that of a pure cerebellar syndrome characterized by cerebellar ataxia, dysarthria, dysmetria, and abnormalities in ocular saccades and smooth pursuit [
Individuals with SYNE1-deficient cerebellar ataxia show typical findings of the cerebellar cognitive and affective syndrome: significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills [
The disease course is usually slowly progressive, resulting in a moderate degree of disability but normal life expectancy [
A rarer phenotype is childhood-onset complex and severe multisystem disease with ataxia, upper and lower motor neuron dysfunction, pes cavus, intellectual disability, and findings suggestive of muscle disease (weakness, muscle wasting, elevated creatine kinase values, respiratory insufficiency) [
One individual had developmental abnormalities of the visceral organs (i.e., malrotation of the colon and unilateral position of both kidneys) [
Brain MRI may show brain stem atrophy in addition to cerebellar atrophy [
Death between ages 36 and 44 years has been reported in a few individuals [
SYNE1-deficient arthrogryposis multiplex congenita is characterized by decreased fetal movements in the absence of polyhydramnios, intrauterine growth restriction, or associated malformations [
Cerebellar involvement and pyramidal signs have not been reported. Intellectual development is borderline to normal. Growth deficiency worsens with advancing age despite adequate weight gain. Hyperopia with intermittent strabismus has been reported.
Early death has been reported in two individuals: one age 22 years with severe kyphoscoliosis and restrictive lung disease who died of pneumonia and sepsis [
In SYNE1-deficient AMC, muscle biopsy may show variations in the size of muscle fibers without increased number of muscle fibers with central nuclei. Creatine kinase values are normal.
Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain. Most – but not all –
In this
Note: Autosomal recessive cerebellar ataxia 1 (ARCA1) has also been referred to as "recessive ataxia of Beauce" and "spinocerebellar ataxia recessive 8" (SCAR8).
Most recently, the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders suggested the term "ATX-SYNE1" [
ARCA1, initially described in the French Canadian population, has now been reported worldwide, notably in Japan, Europe, the Middle East, and Brazil. Although its exact prevalence is not known, it is highly prevalent in the French Canadian population, which is a homogeneous founder population [
When Friedreich ataxia has been excluded, SYNE1 deficiency represents 5.3%-6% of unexplained early-onset (i.e., age <40 years) autosomal recessive ataxias [
The prevalence of SYNE1-deficient arthrogryposis multiplex congenita cannot be evaluated as it has only been reported in a few families to date.
## Clinical Description
The phenotype and severity of SYNE1 deficiency vary widely and span a spectrum ranging from adult-onset cerebellar ataxia at the milder end to childhood-onset multisystem disease and prenatal-onset arthrogryposis multiplex congenita at the more severe end.
SYNE1-deficient cerebellar ataxia, also known as autosomal recessive cerebellar ataxia 1 (ARCA1), typically begins in adulthood (mean age at onset: 31.6 years [
The initial description of ARCA1 was that of a pure cerebellar syndrome characterized by cerebellar ataxia, dysarthria, dysmetria, and abnormalities in ocular saccades and smooth pursuit [
Individuals with SYNE1-deficient cerebellar ataxia show typical findings of the cerebellar cognitive and affective syndrome: significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills [
The disease course is usually slowly progressive, resulting in a moderate degree of disability but normal life expectancy [
A rarer phenotype is childhood-onset complex and severe multisystem disease with ataxia, upper and lower motor neuron dysfunction, pes cavus, intellectual disability, and findings suggestive of muscle disease (weakness, muscle wasting, elevated creatine kinase values, respiratory insufficiency) [
One individual had developmental abnormalities of the visceral organs (i.e., malrotation of the colon and unilateral position of both kidneys) [
Brain MRI may show brain stem atrophy in addition to cerebellar atrophy [
Death between ages 36 and 44 years has been reported in a few individuals [
SYNE1-deficient arthrogryposis multiplex congenita is characterized by decreased fetal movements in the absence of polyhydramnios, intrauterine growth restriction, or associated malformations [
Cerebellar involvement and pyramidal signs have not been reported. Intellectual development is borderline to normal. Growth deficiency worsens with advancing age despite adequate weight gain. Hyperopia with intermittent strabismus has been reported.
Early death has been reported in two individuals: one age 22 years with severe kyphoscoliosis and restrictive lung disease who died of pneumonia and sepsis [
In SYNE1-deficient AMC, muscle biopsy may show variations in the size of muscle fibers without increased number of muscle fibers with central nuclei. Creatine kinase values are normal.
SYNE1-deficient cerebellar ataxia, also known as autosomal recessive cerebellar ataxia 1 (ARCA1), typically begins in adulthood (mean age at onset: 31.6 years [
The initial description of ARCA1 was that of a pure cerebellar syndrome characterized by cerebellar ataxia, dysarthria, dysmetria, and abnormalities in ocular saccades and smooth pursuit [
Individuals with SYNE1-deficient cerebellar ataxia show typical findings of the cerebellar cognitive and affective syndrome: significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills [
The disease course is usually slowly progressive, resulting in a moderate degree of disability but normal life expectancy [
A rarer phenotype is childhood-onset complex and severe multisystem disease with ataxia, upper and lower motor neuron dysfunction, pes cavus, intellectual disability, and findings suggestive of muscle disease (weakness, muscle wasting, elevated creatine kinase values, respiratory insufficiency) [
One individual had developmental abnormalities of the visceral organs (i.e., malrotation of the colon and unilateral position of both kidneys) [
Brain MRI may show brain stem atrophy in addition to cerebellar atrophy [
Death between ages 36 and 44 years has been reported in a few individuals [
SYNE1-deficient arthrogryposis multiplex congenita is characterized by decreased fetal movements in the absence of polyhydramnios, intrauterine growth restriction, or associated malformations [
Cerebellar involvement and pyramidal signs have not been reported. Intellectual development is borderline to normal. Growth deficiency worsens with advancing age despite adequate weight gain. Hyperopia with intermittent strabismus has been reported.
Early death has been reported in two individuals: one age 22 years with severe kyphoscoliosis and restrictive lung disease who died of pneumonia and sepsis [
In SYNE1-deficient AMC, muscle biopsy may show variations in the size of muscle fibers without increased number of muscle fibers with central nuclei. Creatine kinase values are normal.
## Genotype-Phenotype Correlations
Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain. Most – but not all –
## Nomenclature
In this
Note: Autosomal recessive cerebellar ataxia 1 (ARCA1) has also been referred to as "recessive ataxia of Beauce" and "spinocerebellar ataxia recessive 8" (SCAR8).
Most recently, the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders suggested the term "ATX-SYNE1" [
## Prevalence
ARCA1, initially described in the French Canadian population, has now been reported worldwide, notably in Japan, Europe, the Middle East, and Brazil. Although its exact prevalence is not known, it is highly prevalent in the French Canadian population, which is a homogeneous founder population [
When Friedreich ataxia has been excluded, SYNE1 deficiency represents 5.3%-6% of unexplained early-onset (i.e., age <40 years) autosomal recessive ataxias [
The prevalence of SYNE1-deficient arthrogryposis multiplex congenita cannot be evaluated as it has only been reported in a few families to date.
## Genetically Related (Allelic) Disorders
Heterozygous
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of SYNE1 Deficiency
Very similar clinically
Pure cerebellar ataxia w/occasional UMN signs
Cognitive impairment
Absence of polyneuropathy
Marked cerebellar atrophy
Exercise intolerance
Epilepsy
Myoclonus
Occasional stroke-like cerebral lesions
Absence of UMN &/or LMN signs
Cerebellar ataxia
Positive Babinski signs
Sensory involvement w/spinal cord atrophy
Abolished reflexes
Square-wave jerks
Hypertrophic cardiomyopathy
Childhood to teenage onset
Absence of cerebellar atrophy
Cerebellar ataxia
Spasticity
Hyperreflexia
Hypogonadotropic hypogonadism
Chorioretinal dystrophy
Childhood onset
Pontine atrophy
Ataxia
Dysarthria
Eye movement abnormalities
UMN signs
Seen worldwide but high prevalence in French Canadians
Infantile or childhood onset
Sensorimotor neuropathy
Retinal striation
Frequent mitral valve prolapse
Pyramidal signs w/spasticity
Cerebellar ataxia w/cerebellar atrophy
Spastic paraparesis more predominant
Optic neuropathy
Ptosis
Cerebellar ataxia
UMN signs w/occasional amyotrophy & fasciculations
Cognitive impairment
Extrapyramidal features w/dystonia, rigidity, parkinsonism
Progressive external ophthalmoparesis
Cerebellar ataxia w/adult onset & slow progression
Occasional UMN signs
Cerebellar ataxia of adult onset
Cognitive impairment
Predominant tremor
Parkinsonism
MRI: White matter lesions in cerebellar peduncles & brain stem
AD = autosomal dominant; AR = autosomal recessive; LMN = lower motor neuron; MOI = mode of inheritance; SCA = spinocerebellar ataxia; UMN = upper motor neuron; XL = X-linked
Within a MOI, genes are in alphabetic order.
• Very similar clinically
• Pure cerebellar ataxia w/occasional UMN signs
• Cognitive impairment
• Absence of polyneuropathy
• Marked cerebellar atrophy
• Exercise intolerance
• Epilepsy
• Myoclonus
• Occasional stroke-like cerebral lesions
• Absence of UMN &/or LMN signs
• Cerebellar ataxia
• Positive Babinski signs
• Sensory involvement w/spinal cord atrophy
• Abolished reflexes
• Square-wave jerks
• Hypertrophic cardiomyopathy
• Childhood to teenage onset
• Absence of cerebellar atrophy
• Cerebellar ataxia
• Spasticity
• Hyperreflexia
• Hypogonadotropic hypogonadism
• Chorioretinal dystrophy
• Childhood onset
• Pontine atrophy
• Ataxia
• Dysarthria
• Eye movement abnormalities
• UMN signs
• Seen worldwide but high prevalence in French Canadians
• Infantile or childhood onset
• Sensorimotor neuropathy
• Retinal striation
• Frequent mitral valve prolapse
• Pyramidal signs w/spasticity
• Cerebellar ataxia w/cerebellar atrophy
• Spastic paraparesis more predominant
• Optic neuropathy
• Ptosis
• Cerebellar ataxia
• UMN signs w/occasional amyotrophy & fasciculations
• Cognitive impairment
• Extrapyramidal features w/dystonia, rigidity, parkinsonism
• Progressive external ophthalmoparesis
• Cerebellar ataxia w/adult onset & slow progression
• Occasional UMN signs
• Cerebellar ataxia of adult onset
• Cognitive impairment
• Predominant tremor
• Parkinsonism
• MRI: White matter lesions in cerebellar peduncles & brain stem
## Management
To establish the extent of disease and needs of an individual diagnosed with SYNE1 deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Recommended Evaluations Following Initial Diagnosis in Individuals with SYNE1-Deficient Cerebellar Ataxia
Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
Vibration loss or polyneuropathy based on clinical findings
Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy.
Brain MRI to evaluate presence & severity of cerebellar atrophy
Nutritional status
Aspiration risk
CCAS scale
Psychiatrist, psychologist, neuropsychologist if needed
BARS = Brief Ataxia Rating Scale; CCAS = cerebellar cognitive affective syndrome; EMG = electromyogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; NCS = nerve conduction study; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Recommended Evaluations Following Initial Diagnosis in Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita
Tone, primitive reflexes, deep tendon reflexes
Progression of motor milestones
Muscular involvement (e.g., proximal weakness, facial weakness)
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
Nutritional status
Aspiration risk
Gastroenterologist
Nutritionist
Feeding team
Involve pulmonary specialist / respiratory therapist
Assess for pulmonary insufficiency
To include motor, speech/language evaluation, & general cognitive skills
Evaluation for early intervention / special education
OT = occupational therapy/therapist; PT = physical therapy/therapist
There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications. Each affected individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists (OT), physical therapists (PT), physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists depending on the clinical manifestations.
Treatment of Manifestations in Individuals with SYNE1-Deficient Cerebellar Ataxia
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks)
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Inpatient rehabilitation w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
Treatment of Manifestations in Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita
NG = nasogastric; OT = occupational therapy; PT = physical therapy
There are no published surveillance guidelines for individuals with SYNE1 deficiency or for degenerative ataxias in general.
Recommended Surveillance for Individuals with SYNE1 Deficient Cerebellar Ataxia
Neurologic assessment for progression of ataxia; UMN or LMN signs
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS)
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Recommended Surveillance for Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita
Progression of kyphoscoliosis
Clubfoot relapse
Other complications that limit function
Speech & language development;
Need for alternative communication method.
Aspiration risk;
Nutritional status.
See
Search
• Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
• UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
• Vibration loss or polyneuropathy based on clinical findings
• Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
• Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy.
• Brain MRI to evaluate presence & severity of cerebellar atrophy
• Nutritional status
• Aspiration risk
• CCAS scale
• Psychiatrist, psychologist, neuropsychologist if needed
• Tone, primitive reflexes, deep tendon reflexes
• Progression of motor milestones
• Muscular involvement (e.g., proximal weakness, facial weakness)
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
• Nutritional status
• Aspiration risk
• Gastroenterologist
• Nutritionist
• Feeding team
• Involve pulmonary specialist / respiratory therapist
• Assess for pulmonary insufficiency
• To include motor, speech/language evaluation, & general cognitive skills
• Evaluation for early intervention / special education
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks)
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Inpatient rehabilitation w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Neurologic assessment for progression of ataxia; UMN or LMN signs
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS)
• Progression of kyphoscoliosis
• Clubfoot relapse
• Other complications that limit function
• Speech & language development;
• Need for alternative communication method.
• Aspiration risk;
• Nutritional status.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with SYNE1 deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Recommended Evaluations Following Initial Diagnosis in Individuals with SYNE1-Deficient Cerebellar Ataxia
Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
Vibration loss or polyneuropathy based on clinical findings
Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy.
Brain MRI to evaluate presence & severity of cerebellar atrophy
Nutritional status
Aspiration risk
CCAS scale
Psychiatrist, psychologist, neuropsychologist if needed
BARS = Brief Ataxia Rating Scale; CCAS = cerebellar cognitive affective syndrome; EMG = electromyogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; NCS = nerve conduction study; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Recommended Evaluations Following Initial Diagnosis in Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita
Tone, primitive reflexes, deep tendon reflexes
Progression of motor milestones
Muscular involvement (e.g., proximal weakness, facial weakness)
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
Nutritional status
Aspiration risk
Gastroenterologist
Nutritionist
Feeding team
Involve pulmonary specialist / respiratory therapist
Assess for pulmonary insufficiency
To include motor, speech/language evaluation, & general cognitive skills
Evaluation for early intervention / special education
OT = occupational therapy/therapist; PT = physical therapy/therapist
• Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
• UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
• Vibration loss or polyneuropathy based on clinical findings
• Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
• Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy.
• Brain MRI to evaluate presence & severity of cerebellar atrophy
• Nutritional status
• Aspiration risk
• CCAS scale
• Psychiatrist, psychologist, neuropsychologist if needed
• Tone, primitive reflexes, deep tendon reflexes
• Progression of motor milestones
• Muscular involvement (e.g., proximal weakness, facial weakness)
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• Need for PT (for improving gross motor skills) &/or OT (for improving fine motor skills)
• Nutritional status
• Aspiration risk
• Gastroenterologist
• Nutritionist
• Feeding team
• Involve pulmonary specialist / respiratory therapist
• Assess for pulmonary insufficiency
• To include motor, speech/language evaluation, & general cognitive skills
• Evaluation for early intervention / special education
## Treatment of Manifestations
There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications. Each affected individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists (OT), physical therapists (PT), physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists depending on the clinical manifestations.
Treatment of Manifestations in Individuals with SYNE1-Deficient Cerebellar Ataxia
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks)
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Inpatient rehabilitation w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
Treatment of Manifestations in Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita
NG = nasogastric; OT = occupational therapy; PT = physical therapy
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs), feeding (e.g., weighted eating utensils), dressing (e.g., dressing hooks)
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Inpatient rehabilitation w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
## Surveillance
There are no published surveillance guidelines for individuals with SYNE1 deficiency or for degenerative ataxias in general.
Recommended Surveillance for Individuals with SYNE1 Deficient Cerebellar Ataxia
Neurologic assessment for progression of ataxia; UMN or LMN signs
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS)
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Recommended Surveillance for Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita
Progression of kyphoscoliosis
Clubfoot relapse
Other complications that limit function
Speech & language development;
Need for alternative communication method.
Aspiration risk;
Nutritional status.
• Neurologic assessment for progression of ataxia; UMN or LMN signs
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS)
• Progression of kyphoscoliosis
• Clubfoot relapse
• Other complications that limit function
• Speech & language development;
• Need for alternative communication method.
• Aspiration risk;
• Nutritional status.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
SYNE1 deficiency 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 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 testing is before 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, 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.
• The parents of an affected individual 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 testing is before 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
SYNE1 deficiency 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 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 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 (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 testing is before 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
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
P.O. Box 6291
Spartanburg SC 29304
United Kingdom
United Kingdom
Sanford Research
•
• P.O. Box 6291
• Spartanburg SC 29304
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
•
•
• Sanford Research
•
## Molecular Genetics
SYNE1 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SYNE1 Deficiency (
See
Two isoforms of the proteins are specifically expressed in the central nervous system when compared with other isoforms and with the related Nesprin2 protein: Nes1g is particularly expressed in CNS tissues along with its KLNes1g, which is abundantly expressed in the cerebellum [
Pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [
All
## Molecular Pathogenesis
See
Two isoforms of the proteins are specifically expressed in the central nervous system when compared with other isoforms and with the related Nesprin2 protein: Nes1g is particularly expressed in CNS tissues along with its KLNes1g, which is abundantly expressed in the cerebellum [
Pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [
All
## References
## Literature Cited
## Chapter Notes
Marie Beaudin, MD (2018-present)Jean-Pierre Bouchard, MD; Laval University (2007-2018)Nicolas Dupré, MD, MSc (2007-present)Pierre-Luc Gamache, MD, PhD (2018-present)François Gros-Louis, PhD (2007-present)Anne Noreau, MD, PhD; University of Montreal (2011-2018)Guy A Rouleau, MD, PhD; University of Montreal (2007-2018)
6 December 2018 (bp) Comprehensive update posted live
13 October 2011 (cd) Revision: cognitive changes associated with this disorder as reported by
18 August 2011 (cd) Revision: mutation scanning of select exons and prenatal testing clinically available
14 July 2011 (me) Comprehensive update posted live
15 September 2009 (cd) Revision: sequence analysis and targeted mutation analysis available clinically
23 February 2007 (me) Review posted live
6 February 2007 (nd) Original submission
• 6 December 2018 (bp) Comprehensive update posted live
• 13 October 2011 (cd) Revision: cognitive changes associated with this disorder as reported by
• 18 August 2011 (cd) Revision: mutation scanning of select exons and prenatal testing clinically available
• 14 July 2011 (me) Comprehensive update posted live
• 15 September 2009 (cd) Revision: sequence analysis and targeted mutation analysis available clinically
• 23 February 2007 (me) Review posted live
• 6 February 2007 (nd) Original submission
## Author History
Marie Beaudin, MD (2018-present)Jean-Pierre Bouchard, MD; Laval University (2007-2018)Nicolas Dupré, MD, MSc (2007-present)Pierre-Luc Gamache, MD, PhD (2018-present)François Gros-Louis, PhD (2007-present)Anne Noreau, MD, PhD; University of Montreal (2011-2018)Guy A Rouleau, MD, PhD; University of Montreal (2007-2018)
## Revision History
6 December 2018 (bp) Comprehensive update posted live
13 October 2011 (cd) Revision: cognitive changes associated with this disorder as reported by
18 August 2011 (cd) Revision: mutation scanning of select exons and prenatal testing clinically available
14 July 2011 (me) Comprehensive update posted live
15 September 2009 (cd) Revision: sequence analysis and targeted mutation analysis available clinically
23 February 2007 (me) Review posted live
6 February 2007 (nd) Original submission
• 6 December 2018 (bp) Comprehensive update posted live
• 13 October 2011 (cd) Revision: cognitive changes associated with this disorder as reported by
• 18 August 2011 (cd) Revision: mutation scanning of select exons and prenatal testing clinically available
• 14 July 2011 (me) Comprehensive update posted live
• 15 September 2009 (cd) Revision: sequence analysis and targeted mutation analysis available clinically
• 23 February 2007 (me) Review posted live
• 6 February 2007 (nd) Original submission
MRI of a female age 29 years with
|
[
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"K Bürk, DA Sival. Scales for the clinical evaluation of cerebellar disorders.. Handb Clin Neurol. 2018;154:329-39",
"Z Chen, Z Ren, W Mei, Q Ma, Y Shi, Y Zhang, S Li, L Xiang, J. Zhang. A novel SYNE1 gene mutation in a Chinese family of Emery-Dreifuss muscular dystrophy-like.. BMC Med Genet. 2017;18:63",
"M Coutelier, MB Hammer, G Stevanin, ML Monin, CS Davoine, F Mochel, P Labauge, C Ewenczyk, J Ding, JR Gibbs, D Hannequin, J Melki, A Toutain, V Laugel, S Forlani, P Charles, E Broussolle, S Thobois, A Afenjar, M Anheim, P Calvas, G Castelnovo, T de Broucker, M Vidailhet, A Moulignier, RT Ghnassia, C Tallaksen, C Mignot, C Goizet, I Le Ber, E Ollagnon-Roman, J Pouget, A Brice, A Singleton, A Durr. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes.. JAMA Neurol. 2018;75:591-9",
"NT Duong, GE Morris, LT Lam, Q Zhang, CA Sewry, CM Shanahan, I Holt. Nesprins: tissue-specific expression of epsilon and other short isoforms.. PLoS One. 2014;9",
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"P Gimpel, YL Lee, RM Sobota, A Calvi, V Koullourou, R Patel, K Mamchaoui, F Nédélec, S Shackleton, J Schmoranzer, B Burke, B Cadot, ER Gomes. Nesprin-1alpha-dependent microtubule nucleation from the nuclear envelope via Akap450 is necessary for nuclear positioning in muscle cells.. Curr Biol. 2017;27:2999-3009 e9",
"F Gros-Louis, N Dupré, P Dion, MA Fox, S Laurent, S Verreault, JR Sanes, JP Bouchard, GA Rouleau. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia.. Nat Genet. 2007;39:80-5",
"G Haliloglu, H Topaloglu. Arthrogryposis and fetal hypomobility syndrome.. Handb Clin Neurol. 2013;113:1311-9",
"F Hoche, X Guell, MG Vangel, JC Sherman, JD Schmahmann. The cerebellar cognitive affective/Schmahmann syndrome scale.. Brain. 2018;141:248-70",
"Y Izumi, R Miyamoto, H Morino, A Yoshizawa, K Nishinaka, F Udaka, M Kameyama, H Maruyama, H. Kawakami. Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease.. Neurology. 2013;80:600-1",
"R Laforce, JP Buteau, JP Bouchard, GA Rouleau, RW Bouchard, N Dupré. Cognitive impairment in ARCA-1, a newly discovered pure cerebellar ataxia syndrome.. Cerebellum. 2010;9:443-53",
"I Mademan, F Harmuth, I Giordano, D Timmann, S Magri, T Deconinck, J Claaßen, D Jokisch, G Genc, D Di Bella, S Romito, R Schüle, S Züchner, F Taroni, T Klockgether, L Schöls, P De Jonghe, P Bauer, E Consortium, J Baets, M. Synofzik. Multisystemic SYNE1 ataxia: confirming the high frequency and extending the mutational and phenotypic spectrum.. Brain. 2016;139",
"L Martineau, A Noreau, N. Dupré. Therapies for ataxias.. Curr Treat Options Neurol. 2014;16:300",
"C Potter, D Razafsky, D Wozniak, M Casey, S Penrose, X Ge, MR Mahjoub, D Hodzic. The KASH-containing isoform of Nesprin1 giant associates with ciliary rootlets of ependymal cells.. Neurobiol Dis. 2018;115:82-91",
"C Potter, W Zhu, D Razafsky, P Ruzycki, AV Kolesnikov, T Doggett, VJ Kefalov, E Betleja, MR Mahjoub, D Hodzic. Multiple isoforms of Nesprin1 are integral components of ciliary rootlets.. Curr Biol. 2017;27:2014-22 e6",
"D Rajgor, JA Mellad, F Autore, Q Zhang, CM Shanahan. Multiple novel nesprin-1 and nesprin-2 variants act as versatile tissue-specific intracellular scaffolds.. PLoS One. 2012;7",
"D Razafsky, D. Hodzic. A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I.. Neurobiol Dis. 2015;78:57-67",
"M Rossi, M Anheim, A Durr, C Klein, M Koenig, M Synofzik, C Marras, BP van de Warrenburg. The genetic nomenclature of recessive cerebellar ataxias.. Mov Disord. 2018;33:1056-76",
"N Ruffieux, F Colombo, E Gentaz, JM Annoni, L Chouiter, S Roulin Hefti, A Ruffieux, T Bihl. Successful neuropsychological rehabilitation in a patient with cerebellar cognitive affective syndrome.. Appl Neuropsychol Child. 2017;6:180-8",
"BA Sosa, A Rothballer, U Kutay, TU Schwartz. LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric SUN proteins.. Cell. 2012;149:1035-47",
"MJ Stroud, W Feng, J Zhang, J Veevers, X Fang, L Gerace, J Chen. Nesprin 1alpha2 is essential for mouse postnatal viability and nuclear positioning in skeletal muscle.. J Cell Biol. 2017;216:1915-24",
"M Sun, AK Johnson, V Nelakuditi, L Guidugli, D Fischer, K Arndt, L Ma, E Sandford, V Shakkottai, K Boycott, JW Chardon, Z Li, D Del Gaudio, M Burmeister, CM Gomez, DJ Waggoner, S Das. Targeted exome analysis identifies the genetic basis of disease in over 50% of patients with a wide range of ataxia-related phenotypes.. Genet Med. 2019;21:195-206",
"M Synofzik, R Schüle. Overcoming the divide between ataxias and spastic paraplegias: shared phenotypes, genes, and pathways.. Mov Disord. 2017;32:332-45",
"M Synofzik, K Smets, M Mallaret, D Di Bella, C Gallenmuller, J Baets, M Schulze, S Magri, E Sarto, M Mustafa, T Deconinck, T Haack, S Züchner, M Gonzalez, D Timmann, C Stendel, T Klopstock, A Durr, C Tranchant, M Sturm, W Hamza, L Nanetti, C Mariotti, M Koenig, L Schöls, R Schüle, P de Jonghe, M Anheim, F Taroni, P. Bauer. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study.. Brain. 2016;139:1378-93",
"BP van de Warrenburg, J van Gaalen, S Boesch, JM Burgunder, A Durr, P Giunti, T Klockgether, C Mariotti, M Pandolfo, O Riess. EFNS/ENS consensus on the diagnosis and management of chronic ataxias in adulthood.. Eur J Neurol. 2014;21:552-62",
"T Yoshinaga, K Nakamura, M Ishikawa, T Yamaguchi, K Takano, K Wakui, T Kosho, K Yoshida, Y Fukushima, Y. Sekijima. A novel frameshift mutation of SYNE1 in a Japanese family with autosomal recessive cerebellar ataxia type 8.. Hum Genome Var. 2017;4:17052",
"E Yucesan, SA Ugur Iseri, B Bilgic, Z Gormez, B Bakir Gungor, A Sarac, O Ozdemir, M Sagiroglu, H Gurvit, H Hanagasi, U Ozbek. SYNE1 related cerebellar ataxia presents with variable phenotypes in a consanguineous family from Turkey.. Neurol Sci. 2017;38:2203-7",
"TA Zesiewicz, G Wilmot, SH Kuo, S Perlman, PE Greenstein, SH Ying, T Ashizawa, SH Subramony, JD Schmahmann, KP Figueroa, H Mizusawa, L Schöls, JD Shaw, RM Dubinsky, MJ Armstrong, GS Gronseth, KL Sullivan. Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.. Neurology. 2018;90:464-71",
"Q Zhang, C Bethmann, NF Worth, JD Davies, C Wasner, A Feuer, CD Ragnauth, Q Yi, JA Mellad, DT Warren, MA Wheeler, JA Ellis, JN Skepper, M Vorgerd, B Schlotter-Weigel, PL Weissberg, RG Roberts, M Wehnert, CM Shanahan. Nesprin-1 and -2 are involved in the pathogenesis of Emery Dreifuss muscular dystrophy and are critical for nuclear envelope integrity.. Hum Mol Genet. 2007;16:2816-33"
] |
23/2/2007
|
6/12/2018
|
13/10/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
syngap1-id
|
syngap1-id
|
[
"SYNGAP1-Related Developmental and Epileptic Encephalopathy",
"SYNGAP1-Related Developmental and Epileptic Encephalopathy",
"Ras/Rap GTPase-activating protein SynGAP",
"SYNGAP1",
"SYNGAP1-Related Intellectual Disability"
] |
J Lloyd Holder, Fadi F Hamdan, Jacques L Michaud
|
Summary The diagnosis of
|
## Diagnosis
No formal diagnostic criteria have been published for
Generalized epilepsy;
and/or
Autism spectrum disorder (ASD).
The diagnosis of
A heterozygous pathogenic (or likely pathogenic) variant in
or
A deletion of 6p21.3 (~11%).
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 [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
Based on a review of published series and case reports
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 methods will detect deletions of a single exon up to a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. If a whole-gene deletion is detected by a gene-targeted deletion/duplication assay, CMA is needed to determine the size of the deletion.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 6p21.3 region; however, some 6p21.3 deletions may not have been detectable by older oligonucleotide or BAC platforms.
• Generalized epilepsy;
• and/or
• Autism spectrum disorder (ASD).
• A heterozygous pathogenic (or likely pathogenic) variant in
• or
• A deletion of 6p21.3 (~11%).
## Suggestive Findings
Generalized epilepsy;
and/or
Autism spectrum disorder (ASD).
• Generalized epilepsy;
• and/or
• Autism spectrum disorder (ASD).
## Establishing the Diagnosis
The diagnosis of
A heterozygous pathogenic (or likely pathogenic) variant in
or
A deletion of 6p21.3 (~11%).
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 [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
Based on a review of published series and case reports
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 methods will detect deletions of a single exon up to a whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined. If a whole-gene deletion is detected by a gene-targeted deletion/duplication assay, CMA is needed to determine the size of the deletion.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 6p21.3 region; however, some 6p21.3 deletions may not have been detectable by older oligonucleotide or BAC platforms.
• A heterozygous pathogenic (or likely pathogenic) variant in
• or
• A deletion of 6p21.3 (~11%).
## Clinical Characteristics
Since the original description of
Early motor development is characterized by hypotonia. The average age at walking was 26 months (range: 10.5 months to 5 years). A subset of these children had an ataxic gait that remained stable or improved over time.
Language is generally impaired; a third of individuals age five years or more remain nonverbal. In those who are verbal, language development ranges from use of single words only to four-to-five-word sentences.
While the epilepsy responds to a single anti-seizure medication in approximately half of affected individuals, it is pharmacoresistant in the remainder. Children with refractory seizures may be diagnosed with epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity).
No definitive phenotype-genotype correlation between the type of
Penetrance is 100%. All individuals with germline pathogenic variants in
The prevalence of
1% in a series of 500 individuals with epileptic encephalopathy [
0.75% in a large series of 931 unrelated children with intellectual disability [
• 1% in a series of 500 individuals with epileptic encephalopathy [
• 0.75% in a large series of 931 unrelated children with intellectual disability [
## Clinical Description
Since the original description of
Early motor development is characterized by hypotonia. The average age at walking was 26 months (range: 10.5 months to 5 years). A subset of these children had an ataxic gait that remained stable or improved over time.
Language is generally impaired; a third of individuals age five years or more remain nonverbal. In those who are verbal, language development ranges from use of single words only to four-to-five-word sentences.
While the epilepsy responds to a single anti-seizure medication in approximately half of affected individuals, it is pharmacoresistant in the remainder. Children with refractory seizures may be diagnosed with epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with frequent ongoing epileptiform activity).
## Genotype-Phenotype Correlations
No definitive phenotype-genotype correlation between the type of
## Penetrance
Penetrance is 100%. All individuals with germline pathogenic variants in
## Prevalence
The prevalence of
1% in a series of 500 individuals with epileptic encephalopathy [
0.75% in a large series of 931 unrelated children with intellectual disability [
• 1% in a series of 500 individuals with epileptic encephalopathy [
• 0.75% in a large series of 931 unrelated children with intellectual disability [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotype associated with
Most genes known to be associated with ID (see
## 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
Treatment of Manifestations in Individuals with
To date, no guidelines on choice of specific ASMs
Anecdotal reports of improved seizure control w/ketogenic diet in some persons
ASMs = anti-seizure medications
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
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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment 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 when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Monitor those with seizures as clinically indicated.
Assess as needed for anxiety, attention, and aggressive or self-injurious behavior.
Monitor developmental progress and educational needs.
See
Search
Search CURE ID (an FDA website) for information on novel uses of existing drugs for this condition (
• To date, no guidelines on choice of specific ASMs
• Anecdotal reports of improved seizure control w/ketogenic diet in some persons
• 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## 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
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
To date, no guidelines on choice of specific ASMs
Anecdotal reports of improved seizure control w/ketogenic diet in some persons
ASMs = anti-seizure medications
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
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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment 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 when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• To date, no guidelines on choice of specific ASMs
• Anecdotal reports of improved seizure control w/ketogenic diet in some persons
• 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment 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.
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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment 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 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 when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Monitor those with seizures as clinically indicated.
Assess as needed for anxiety, attention, and aggressive or self-injurious behavior.
Monitor developmental progress and educational needs.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
Search CURE ID (an FDA website) for information on novel uses of existing drugs for this condition (
## Genetic Counseling
Almost all probands with
Vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family to date [
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, the proband most likely has a
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have both somatic and germline mosaicism for the variant and may be mildly affected [
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
Most affected individuals reported to date have had 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 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.
• Almost all probands with
• Vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family to date [
• 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, the proband most likely has a
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have both somatic and germline mosaicism for the variant and may be mildly affected [
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• Most affected individuals reported to date have had 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 parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Almost all probands with
Vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family to date [
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, the proband most likely has a
Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have both somatic and germline mosaicism for the variant and may be mildly affected [
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
Most affected individuals reported to date have had a
• Almost all probands with
• Vertical transmission (from a mildly affected, mosaic parent to the proband) has been reported in one family to date [
• 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, the proband most likely has a
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have both somatic and germline mosaicism for the variant and may be mildly affected [
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• Most affected individuals reported to date have had 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 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
Speaking out for People with Intellectual and Developmental Disabilities
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
## Molecular Genetics
SYNGAP1-Related Intellectual Disability: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SYNGAP1-Related Intellectual Disability (
Molecular genetic testing for
By comparing human and rodent
## Chapter Notes
14 August 2025 (ma) Revision: additions to
21 February 2019 (bp) Review posted live
23 October 2017 (jm) Original submission
• 14 August 2025 (ma) Revision: additions to
• 21 February 2019 (bp) Review posted live
• 23 October 2017 (jm) Original submission
## Revision History
14 August 2025 (ma) Revision: additions to
21 February 2019 (bp) Review posted live
23 October 2017 (jm) Original submission
• 14 August 2025 (ma) Revision: additions to
• 21 February 2019 (bp) Review posted live
• 23 October 2017 (jm) Original submission
## References
## Literature Cited
|
[] |
21/2/2019
|
14/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sys-h
|
sys-h
|
[
"Inherited Systemic Hyalinosis",
"ANTXR2-Related Hyaline Fibromatosis Syndrome",
"Inherited Systemic Hyalinosis",
"ANTXR2-Related Hyaline Fibromatosis Syndrome",
"Anthrax toxin receptor 2",
"ANTXR2",
"Hyaline Fibromatosis Syndrome"
] |
Hyaline Fibromatosis Syndrome
|
Joseph TC Shieh, H Eugene Hoyme, Laura T Arbour
|
Summary Hyaline fibromatosis syndrome (HFS) is characterized by hyaline deposits in the papillary dermis and other tissues. It can present at birth or in infancy with severe pain with movement, progressive joint contractures, and often with severe motor disability, thickened skin, and hyperpigmented macules/patches over bony prominences of the joints. Gingival hypertrophy, skin nodules, pearly papules of the face and neck, and perianal masses are common. Complications of protein-losing enteropathy and failure to thrive can be life threatening. Cognitive development is normal. Many children with the severe form (previously called infantile systemic hyalinosis) have a significant risk of morbidity or mortality in early childhood; some with a milder phenotype (previously called juvenile hyaline fibromatosis) survive into adulthood. The diagnosis of HFS is established in a proband with characteristic clinical features and/or biallelic pathogenic (or likely pathogenic) variants in HFS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
Hyaline fibromatosis syndrome (HFS)
Serum albumin may be low.
Normal or slightly elevated ESR, anemia, and/or thrombocytosis
Immunoglobulin levels may be low and cellular immune responses depressed.
CD3 and CD4 lymphocyte subsets and ANA are unremarkable.
Note: This finding may not be evident in the early stages of the disease [
Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus.
Skeletal radiographs. Generalized osteopenia, periosteal reaction, and lucent lesions are nonspecific findings that may affect long bones as well as the axial skeleton.
Upper-gastrointestinal imaging studies may show rapid transit time.
Brain MRI is unremarkable.
The diagnosis of HFS
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
For an introduction to multigene panels click
When the diagnosis of HFS is not immediately recognized,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hyaline Fibromatosis 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.
•
• Serum albumin may be low.
• Normal or slightly elevated ESR, anemia, and/or thrombocytosis
• Immunoglobulin levels may be low and cellular immune responses depressed.
• CD3 and CD4 lymphocyte subsets and ANA are unremarkable.
• Note: This finding may not be evident in the early stages of the disease [
• Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus.
• Skeletal radiographs. Generalized osteopenia, periosteal reaction, and lucent lesions are nonspecific findings that may affect long bones as well as the axial skeleton.
• Upper-gastrointestinal imaging studies may show rapid transit time.
• Brain MRI is unremarkable.
## Suggestive Findings
Hyaline fibromatosis syndrome (HFS)
Serum albumin may be low.
Normal or slightly elevated ESR, anemia, and/or thrombocytosis
Immunoglobulin levels may be low and cellular immune responses depressed.
CD3 and CD4 lymphocyte subsets and ANA are unremarkable.
Note: This finding may not be evident in the early stages of the disease [
Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus.
Skeletal radiographs. Generalized osteopenia, periosteal reaction, and lucent lesions are nonspecific findings that may affect long bones as well as the axial skeleton.
Upper-gastrointestinal imaging studies may show rapid transit time.
Brain MRI is unremarkable.
•
• Serum albumin may be low.
• Normal or slightly elevated ESR, anemia, and/or thrombocytosis
• Immunoglobulin levels may be low and cellular immune responses depressed.
• CD3 and CD4 lymphocyte subsets and ANA are unremarkable.
• Note: This finding may not be evident in the early stages of the disease [
• Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus.
• Skeletal radiographs. Generalized osteopenia, periosteal reaction, and lucent lesions are nonspecific findings that may affect long bones as well as the axial skeleton.
• Upper-gastrointestinal imaging studies may show rapid transit time.
• Brain MRI is unremarkable.
## Establishing the Diagnosis
The diagnosis of HFS
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
For an introduction to multigene panels click
When the diagnosis of HFS is not immediately recognized,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hyaline Fibromatosis 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.
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of HFS is not immediately recognized,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hyaline Fibromatosis 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.
## Clinical Characteristics
Hyaline fibromatosis syndrome (HFS), named for the characteristic hyaline deposits in the papillary dermis and other tissues including the gastrointestinal tract of affected individuals, exhibits a broad spectrum of clinical severity [
To date, at least 93 individuals have been identified with a pathogenic variant in
Features of Hyaline Fibromatosis Syndrome
Presence of findings may be age dependent.
Cognitive function is preserved; however, individuals with delayed development have been reported [
Hepatomegaly may be present.
Susceptibility to fractures may be increased.
Recurrent infections may develop due to impaired cellular immune responses and reduced immunoglobulin levels [
At least two clinically diagnosed individuals developed squamous cell carcinoma [
Cardiovascular involvement is largely unknown. One instance of atrial thrombus has been reported.
Individuals with severe disease can succumb to infection or complications of protein-losing enteropathy.
Some individuals demonstrate a milder phenotype, which may be of later onset with potential survival into adulthood.
A clinical grading system for HFS has been proposed [
Those with at least one insertion/deletion in
In-frame and missense variants in the cytoplasmic domain were associated with a milder phenotype, with survival to adulthood without recurrent infections, diarrhea, or multiorgan failure. Skeletal manifestations, however, were variably present.
A review of
Before the molecular basis of HFS was understood, severe and milder forms of the disorder were described as separate conditions (infantile systemic hyalinosis and juvenile hyaline fibromatosis, respectively). It is now known that both severe and mild forms of HFS are caused by pathogenic variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
HFS is rare, but it has been recognized in families of various ethnic backgrounds on multiple continents.
• Cognitive function is preserved; however, individuals with delayed development have been reported [
• Hepatomegaly may be present.
• Susceptibility to fractures may be increased.
• Recurrent infections may develop due to impaired cellular immune responses and reduced immunoglobulin levels [
• At least two clinically diagnosed individuals developed squamous cell carcinoma [
• Cardiovascular involvement is largely unknown. One instance of atrial thrombus has been reported.
• Individuals with severe disease can succumb to infection or complications of protein-losing enteropathy.
• Some individuals demonstrate a milder phenotype, which may be of later onset with potential survival into adulthood.
• A clinical grading system for HFS has been proposed [
• Those with at least one insertion/deletion in
• In-frame and missense variants in the cytoplasmic domain were associated with a milder phenotype, with survival to adulthood without recurrent infections, diarrhea, or multiorgan failure. Skeletal manifestations, however, were variably present.
## Clinical Description
Hyaline fibromatosis syndrome (HFS), named for the characteristic hyaline deposits in the papillary dermis and other tissues including the gastrointestinal tract of affected individuals, exhibits a broad spectrum of clinical severity [
To date, at least 93 individuals have been identified with a pathogenic variant in
Features of Hyaline Fibromatosis Syndrome
Presence of findings may be age dependent.
Cognitive function is preserved; however, individuals with delayed development have been reported [
Hepatomegaly may be present.
Susceptibility to fractures may be increased.
Recurrent infections may develop due to impaired cellular immune responses and reduced immunoglobulin levels [
At least two clinically diagnosed individuals developed squamous cell carcinoma [
Cardiovascular involvement is largely unknown. One instance of atrial thrombus has been reported.
Individuals with severe disease can succumb to infection or complications of protein-losing enteropathy.
Some individuals demonstrate a milder phenotype, which may be of later onset with potential survival into adulthood.
A clinical grading system for HFS has been proposed [
• Cognitive function is preserved; however, individuals with delayed development have been reported [
• Hepatomegaly may be present.
• Susceptibility to fractures may be increased.
• Recurrent infections may develop due to impaired cellular immune responses and reduced immunoglobulin levels [
• At least two clinically diagnosed individuals developed squamous cell carcinoma [
• Cardiovascular involvement is largely unknown. One instance of atrial thrombus has been reported.
• Individuals with severe disease can succumb to infection or complications of protein-losing enteropathy.
• Some individuals demonstrate a milder phenotype, which may be of later onset with potential survival into adulthood.
• A clinical grading system for HFS has been proposed [
## Genotype-Phenotype Correlations
Those with at least one insertion/deletion in
In-frame and missense variants in the cytoplasmic domain were associated with a milder phenotype, with survival to adulthood without recurrent infections, diarrhea, or multiorgan failure. Skeletal manifestations, however, were variably present.
A review of
• Those with at least one insertion/deletion in
• In-frame and missense variants in the cytoplasmic domain were associated with a milder phenotype, with survival to adulthood without recurrent infections, diarrhea, or multiorgan failure. Skeletal manifestations, however, were variably present.
## Nomenclature
Before the molecular basis of HFS was understood, severe and milder forms of the disorder were described as separate conditions (infantile systemic hyalinosis and juvenile hyaline fibromatosis, respectively). It is now known that both severe and mild forms of HFS are caused by pathogenic variants in
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
HFS is rare, but it has been recognized in families of various ethnic backgrounds on multiple continents.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The conditions summarized in
Other Genes and Conditions of Interest in the Differential Diagnosis of Hyaline Fibromatosis Syndrome
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; HFS = hyaline fibromatosis syndrome; MOI = mode of inheritance
In addition to multicentric osteolysis nodulosis and arthropathy (MONA), this phenotype has been reported in the literature as Torg syndrome, Winchester-Torg (or Torg-Winchester) syndrome, and nodulosis-arthropathy-osteolysis (NAO) syndrome. All of these conditions have been shown to be caused by biallelic pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with hyaline fibromatosis syndrome (HFS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hyaline Fibromatosis Syndrome
GI = gastrointestinal; HFS = hyaline fibromatosis syndrome; MOI= mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Hyaline Fibromatosis Syndrome
Early consideration of nasogastric tube or gastrostomy tube feeding or parenteral nutrition
Nutrition should be tailored for possibility of malabsorption or lymphangiectasia.
A nutritionist should follow affected persons.
Gentle handling may ↓ pain that is worsened w/movement.
Splinting of affected joints may provide comfort.
Consultation w/a pain mgmt specialist may be helpful.
Palliative care consultation may be an option in severe cases.
Surgical excision is an option.
Anesthesiologists should be aware of difficulty of endotracheal intubation & mgmt in some affected persons [
Lesions may recur after excision.
Significant complication w/anesthesia has been reported [
Dermatology eval
Plastic surgery eval
Treatment of infection based on site & causative agent
Consider humoral & cellular immune workup.
PT = physical therapy
Recommended Surveillance for Individuals with Hyaline Fibromatosis Syndrome
Assessment of antibody levels, albumin
Assessment for GI malabsorption
Nutrition assessment
GI = gastrointestinal
See
Search
• Early consideration of nasogastric tube or gastrostomy tube feeding or parenteral nutrition
• Nutrition should be tailored for possibility of malabsorption or lymphangiectasia.
• Gentle handling may ↓ pain that is worsened w/movement.
• Splinting of affected joints may provide comfort.
• Consultation w/a pain mgmt specialist may be helpful.
• Palliative care consultation may be an option in severe cases.
• Surgical excision is an option.
• Anesthesiologists should be aware of difficulty of endotracheal intubation & mgmt in some affected persons [
• Lesions may recur after excision.
• Significant complication w/anesthesia has been reported [
• Dermatology eval
• Plastic surgery eval
• Treatment of infection based on site & causative agent
• Consider humoral & cellular immune workup.
• Assessment of antibody levels, albumin
• Assessment for GI malabsorption
• Nutrition assessment
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hyaline fibromatosis syndrome (HFS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Hyaline Fibromatosis Syndrome
GI = gastrointestinal; HFS = hyaline fibromatosis syndrome; MOI= mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Hyaline Fibromatosis Syndrome
Early consideration of nasogastric tube or gastrostomy tube feeding or parenteral nutrition
Nutrition should be tailored for possibility of malabsorption or lymphangiectasia.
A nutritionist should follow affected persons.
Gentle handling may ↓ pain that is worsened w/movement.
Splinting of affected joints may provide comfort.
Consultation w/a pain mgmt specialist may be helpful.
Palliative care consultation may be an option in severe cases.
Surgical excision is an option.
Anesthesiologists should be aware of difficulty of endotracheal intubation & mgmt in some affected persons [
Lesions may recur after excision.
Significant complication w/anesthesia has been reported [
Dermatology eval
Plastic surgery eval
Treatment of infection based on site & causative agent
Consider humoral & cellular immune workup.
PT = physical therapy
• Early consideration of nasogastric tube or gastrostomy tube feeding or parenteral nutrition
• Nutrition should be tailored for possibility of malabsorption or lymphangiectasia.
• Gentle handling may ↓ pain that is worsened w/movement.
• Splinting of affected joints may provide comfort.
• Consultation w/a pain mgmt specialist may be helpful.
• Palliative care consultation may be an option in severe cases.
• Surgical excision is an option.
• Anesthesiologists should be aware of difficulty of endotracheal intubation & mgmt in some affected persons [
• Lesions may recur after excision.
• Significant complication w/anesthesia has been reported [
• Dermatology eval
• Plastic surgery eval
• Treatment of infection based on site & causative agent
• Consider humoral & cellular immune workup.
## Surveillance
Recommended Surveillance for Individuals with Hyaline Fibromatosis Syndrome
Assessment of antibody levels, albumin
Assessment for GI malabsorption
Nutrition assessment
GI = gastrointestinal
• Assessment of antibody levels, albumin
• Assessment for GI malabsorption
• Nutrition assessment
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Hyaline fibromatosis syndrome (HFS) 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
Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
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.
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
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
• 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
Hyaline fibromatosis syndrome (HFS) 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
Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
If both parents are known to be heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
• 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
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
• If both parents are known to be heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing HFS.
## 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
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
The American Chronic Pain Association
•
• The American Chronic Pain Association
•
•
•
•
## Molecular Genetics
Hyaline Fibromatosis Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hyaline Fibromatosis Syndrome (
## Molecular Pathogenesis
## Chapter Notes
11 May 2023 (sw) Revision: "
23 July 2020 (sw) Comprehensive update posted live
11 April 2013 (me) Comprehensive update posted live
27 February 2008 (me) Review posted live
5 May 2004 (la) Original submission
• 11 May 2023 (sw) Revision: "
• 23 July 2020 (sw) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 27 February 2008 (me) Review posted live
• 5 May 2004 (la) Original submission
## Revision History
11 May 2023 (sw) Revision: "
23 July 2020 (sw) Comprehensive update posted live
11 April 2013 (me) Comprehensive update posted live
27 February 2008 (me) Review posted live
5 May 2004 (la) Original submission
• 11 May 2023 (sw) Revision: "
• 23 July 2020 (sw) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 27 February 2008 (me) Review posted live
• 5 May 2004 (la) Original submission
## References
## Literature Cited
|
[
"K Alreheili, A AlMehaidib, K Alsaleem, M Banemi, W Aldekhail, SM Al-Mayouf. Intestinal lymphangiectasia in a patient with infantile systemic hyalinosis syndrome: a rare cause of protein-losing enteropathy.. Ann Saudi Med. 2012;32:206-8",
"J Bürgi, B Kunz, L Abrami, J Deuquet, A Piersigilli, S Scholl-Bürgi, E Lausch, S Unger, A Superti-Furga, P Bonaldo, FG van der Goot. CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome.. Nat Commun. 2017;8:15861",
"D Casas-Alba, A Martínez-Monseny, RM Pino-Ramírez, L Alsina, E Castejón, S Navarro-Vilarrubí, B Pérez-Dueñas, M Serrano, F Palau, A García-Alix. Hyaline fibromatosis syndrome: Clinical update and phenotype-genotype correlations.. Hum Mutat. 2018;39:1752-63",
"C Cozma, M Hovakimyan, MI Iurașcu, N Makhseed, LA Selim, AM Alhashem, T Ben-Omran, IG Mahmoud, NM Al Menabawy, M Al-Mureikhi, M Martin, L Demuth, Z Yüksel, C Beetz, P Bauer, A Rolfs. Genetic, clinical and biochemical characterization of a large cohort of patients with hyaline fibromatosis syndrome.. Orphanet J Rare Dis. 2019;14:209",
"GR Criado, A González-Meneses, M Cañadas, E Rafel, F Yanes, IG De Terreros. Infantile systemic hyalinosis: a clinicopathological study.. Am J Med Genet A. 2004;129A:282-5",
"R Denadai, CE Raposo-Amaral, D Bertola, C Kim, N Alonso, T Hart, S Han, RF Stelini, CL Buzzo, CA Raposo-Amaral, PS Hart. Identification of 2 novel ANTXR2 mutations in patients with hyaline fibromatosis syndrome and proposal of a modified grading system.. Am J Med Genet A. 2012;158A:732-42",
"O Dowling, A Difeo, MC Ramirez, T Tukel, G Narla, L Bonafe, H Kayserili, M Yuksel-Apak, AS Paller, K Norton, AS Teebi, V Grum-Tokars, GS Martin, GE Davis, MJ Glucksman, JA Martignetti. Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis.. Am J Hum Genet 2003;73:957-66",
"GY El-Kamah, K Fong, M El-Ruby, HH Afifi, SE Clements, JE Lai-Cheong, K Amr, M El-Darouti, JA McGrath. Spectrum of mutations in the ANTXR2 (CMG2) gene in infantile systemic hyalinosis and juvenile hyaline fibromatosis.. Br J Dermatol. 2010;163:213-5",
"GY El-Kamah, MI Mostafa. Heterogeneity and atypical presentation in infantile systemic hyalinosis with severe labio-gingival enlargement: first Egyptian report.. Dermatol Online J. 2009;15:6",
"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",
"S Hanks, S Adams, J Douglas, L Arbour, DJ Atherton, S Balci, H Bode, ME Campbell, M Feingold, G Keser, W Kleijer, G Mancini, JA McGrath, F Muntoni, A Nanda, MD Teare, M Warman, FM Pope, A Superti-Furga, PA Futreal, N Rahman. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis.. Am J Hum Genet 2003;73:791-800",
"SA Hammoudah, LM El-Attar. Infantile systemic hyalinosis: Report of two severe cases from Saudi Arabia and review of the literature.. Intractable Rare Dis Res. 2016;5:124-8",
"B Härter, F Benedicenti, D Karall, E Lausch, G Schweigmann, F Stanzial, A Superti-Furga, S Scholl-Bürgi. Clinical aspects of hyaline fibromatosis syndrome and identification of a novel mutation.. Mol Genet Genomic Med. 2020;8",
"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",
"G Kawasaki, S Yanamoto, A Mizuno, S Fujita. Juvenile hyaline fibromatosis complicated with oral squamous cell carcinoma: a case report.. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:200-4",
"Y Klebanova, C. Schwindt. Infantile systemic hyalinosis: a case report of compromised cellular and humoral branches of the immune system leading to infections.. Pediatr Asthma Allergy Immunol. 2009;22:127-30",
"KC Nischal, D Sachdev, V Kharkar, S Mahajan. Juvenile hyaline fibromatosis.. J Postgrad Med 2004;50:125-6",
"M Pollard, EM Ollite, RW Walker. The anesthetic management of a child with infantile systemic hyalinosis.. Paediatr Anaesth. 2008;18:1123-4",
"F Qasem, A Abotaiban, H Ahmad. Airway management in a patient with infantile systemic hyalinosis.. J Anesth Clin Res 2012;3:263",
"CV Reeves, X Wang, PC Charles-Horvath, JY Vink, VY Borisenko, JA Young, JK Kitajewski. Anthrax toxin receptor 2 functions in ECM homeostasis of the murine reproductive tract and promotes MMP activity.. PLoS One. 2012;7",
"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 Schussler, RV Linkner, J Levitt, L Mehta, JA Martignetti, K Oishi. Protein-losing enteropathy and joint contractures caused by a novel homozygous ANTXR2 mutation.. Adv Genomics Genet. 2018;8:17-21",
"JTC Shieh, P Swidler, JA Martignetti, MC Ramirez, I Balboni, J Kaplan, J Kennedy, O Abdul-Rahman, GM Enns, C Sandborg, A Slavotinek, HE Hoyme. Systemic hyalinosis: a distinctive early childhood-onset disorder characterized by mutations in the anthrax toxin receptor 2 gene (ANTXR2).. Pediatrics 2006;118:e1485-92",
"K Shimizu, F Ogawa, Y Hamasaki, H Murota, I Katayama. A case of bullous pemphigoid arising in juvenile hyaline fibromatosis with oral squamous cell carcinoma.. J Dermatol 2005;32:650-3",
"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;191:1164-209",
"Z Zolkipli, C Longman, S Brown, N Rahman, SE Holder, F Muntoni. Skeletal muscle involvement in infantile systemic hyalinosis.. Eur J Paediatr Neurol 2003;7:401-6"
] |
27/2/2008
|
23/7/2020
|
11/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
taa
|
taa
|
[
"TGFBR1-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"TGFBR2-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"ACTA2-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"MYH11-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"FBN1-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"MYLK-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"SMAD3-Related Thoracic Aortic Aneurysms and Aortic Dissections",
"Actin, aortic smooth muscle",
"Biglycan",
"cGMP-dependent protein kinase 1",
"Collagen alpha-1(III) chain",
"Collagen alpha-5(IV) chain",
"Cystathionine beta-synthase",
"EGF-containing fibulin-like extracellular matrix protein 2",
"Elastin",
"Fibrillin-1",
"Fibrillin-2",
"Filamin-A",
"Forkhead box protein E3",
"Microfibrillar-associated protein 5",
"Mothers against decapentaplegic homolog 2",
"Mothers against decapentaplegic homolog 3",
"Mothers against decapentaplegic homolog 4",
"Myosin light chain kinase, smooth muscle",
"Myosin-11",
"Neurogenic locus notch homolog protein 1",
"Polycystin-1",
"Polycystin-2",
"Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4",
"Protein-lysine 6-oxidase",
"S-adenosylmethionine synthase isoform type-2",
"Ski oncogene",
"Solute carrier family 2, facilitated glucose transporter member 10",
"TGF-beta receptor type-1",
"TGF-beta receptor type-2",
"Transforming growth factor beta-2 proprotein",
"Transforming growth factor beta-3 proprotein",
"ACTA2",
"BGN",
"CBS",
"COL3A1",
"COL4A5",
"EFEMP2",
"ELN",
"FBN1",
"FBN2",
"FLNA",
"FOXE3",
"HCN4",
"LOX",
"MAT2A",
"MFAP5",
"MYH11",
"MYLK",
"NOTCH1",
"PKD1",
"PKD2",
"PRKG1",
"SKI",
"SLC2A10",
"SMAD2",
"SMAD3",
"SMAD4",
"TGFB2",
"TGFB3",
"TGFBR1",
"TGFBR2",
"Heritable Thoracic Aortic Disease (HTAD)",
"Overview"
] |
Heritable Thoracic Aortic Disease Overview
|
Dianna M Milewicz, Alana C Cecchi
|
Summary The purpose of this overview is to: Define the Review the Provide a strategy for Review Inform
|
## Clinical Characteristics of Thoracic Aortic Disease
A
To evaluate for a thoracic aortic aneurysm, the aortic diameter is measured (perpendicular to the axis of blood flow) by echocardiography, CT, or MRI at reproducible anatomic locations. Measurements of aortic diameters obtained from transthoracic echocardiography tend to be smaller than measurements obtained from CT or MRI [
Nomograms and z scores based on reference values for aortic root and ascending aortic diameters that account for biologic sex normalized to body surface area (aortic size index) are commonly used in the pediatric population to interpret clinically significant aortic dilatation in a growing child, but can also be applied to adults [
An
Aortic dissections are most commonly classified using Stanford and Debakey criteria. The Stanford system categorizes dissections based on the involvement of the ascending aorta. A newer classification system was proposed in 2020 to define aortic dissections in greater detail based on the location of entry tear and extent of dissection [
Thoracic aortic aneurysms of the aortic root and ascending aorta are usually asymptomatic and enlarge over time. When undiagnosed these aneurysms can lead to life-threatening acute type A aortic dissections.
The mortality rate for elective surgical repair of ascending aortic aneurysms at tertiary centers that routinely do these procedures is substantially lower than emergent surgery for a type A dissection [
Although aneurysms involving the ascending aorta often precede type A dissections, aortic dissection can occur in the absence of aortic enlargement. Data from the International Registry of Acute Aortic Dissection (IRAD) showed that up to 60% of individuals with acute type A dissections present with aortic diameters smaller than 5.5 cm [
Historically, the mortality rate associated with acute type A dissections was reported to be 1%-2% per hour, with the highest risk of sudden death in the first 48 hours after symptom onset [
Type B aortic dissections are associated with lower mortality rates compared with type A dissections, but still confer significant risk for short and long-term clinical complications [
• Thoracic aortic aneurysms of the aortic root and ascending aorta are usually asymptomatic and enlarge over time. When undiagnosed these aneurysms can lead to life-threatening acute type A aortic dissections.
• The mortality rate for elective surgical repair of ascending aortic aneurysms at tertiary centers that routinely do these procedures is substantially lower than emergent surgery for a type A dissection [
• Although aneurysms involving the ascending aorta often precede type A dissections, aortic dissection can occur in the absence of aortic enlargement. Data from the International Registry of Acute Aortic Dissection (IRAD) showed that up to 60% of individuals with acute type A dissections present with aortic diameters smaller than 5.5 cm [
• Historically, the mortality rate associated with acute type A dissections was reported to be 1%-2% per hour, with the highest risk of sudden death in the first 48 hours after symptom onset [
• Type B aortic dissections are associated with lower mortality rates compared with type A dissections, but still confer significant risk for short and long-term clinical complications [
## Causes of Heritable Thoracic Aortic Disease
A diagnosis of heritable thoracic aortic disease (HTAD) can be established in an individual with any of the following: (1) a highly penetrant pathogenic variant(s) in a known HTAD gene (see
A genetic cause of HTAD is identified in the majority of individuals with a clinical diagnosis of Marfan syndrome or Loeys-Dietz syndrome. However, a genetic cause of HTAD is identified in only approximately 20%-30% of individuals with a family history of thoracic aortic disease who do not have syndromic manifestations [
Genes Associated with Heritable Thoracic Aortic Disease
Nonsyndromic HTAD
Smooth muscle dysfunction syndrome (OMIM
Nonsyndromic HTAD
Nonsyndromic HTAD
Nonsyndromic HTAD
BAV = bicuspid aortic valve; HTAD = heritable thoracic aortic disease; PDA = patent ductus arteriosus
Genes are ordered first by strength of gene-disease validity classification and then alphabetically.
Other Genes in which Thoracic Aortic Disease Is Reported
Familial thoracic aortic aneurysm 12 (OMIM
Nonsyndromic HTAD
BAV = bicuspid aortic valve; HTAD = heritable thoracic aortic disease; PDA = patent ductus arteriosus
Genes are ordered first by validity classification and then alphabetically.
Gene classification regarding association with heritable thoracic aortic disease is primarily from
• Nonsyndromic HTAD
• Smooth muscle dysfunction syndrome (OMIM
• Nonsyndromic HTAD
• Nonsyndromic HTAD
• Nonsyndromic HTAD
• Familial thoracic aortic aneurysm 12 (OMIM
• Nonsyndromic HTAD
## Evaluation and Genetic Risk Assessment for Heritable Thoracic Aortic Disease in a Proband
Risk assessment for heritable thoracic aortic disease (HTAD) should incorporate data from the proband's medical history, physical examination, family history, and aortic and arterial imaging studies. Molecular genetic testing is recommended in all individuals with suspected HTAD.
Establishing a molecular genetic cause of HTAD is useful for tailoring management recommendations based on the causative gene, and to identify and counsel at-risk relatives. When an HTAD-related pathogenic variant(s) is not identified, clinical and family history information also inform risk of aortic dissection and can be used to guide medical and surgical management (see
The likelihood of identifying the genetic cause of HTAD in an individual with thoracic aortic disease varies based on clinical presentation and family history. Clinical and family history findings that increase the likelihood of identifying a pathogenic variant in an HTAD-related gene include:
Thoracic aortic aneurysm or dissection at age <60 years;
Family history of thoracic aortic disease, unexplained sudden death, or aneurysms/dissections in other arteries;
Syndromic features associated with
Aneurysms and dissections/ruptures of other arteries in an individual with thoracic aortic disease.
Note: Although these clinical and family history findings are useful for identifying individuals most likely to have a molecular cause identified, individuals without these findings can still benefit from molecular genetic testing and risk assessment [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Thoracic aortic aneurysm or dissection at age <60 years;
• Family history of thoracic aortic disease, unexplained sudden death, or aneurysms/dissections in other arteries;
• Syndromic features associated with
• Aneurysms and dissections/ruptures of other arteries in an individual with thoracic aortic disease.
## Molecular Genetic Testing
Establishing a molecular genetic cause of HTAD is useful for tailoring management recommendations based on the causative gene, and to identify and counsel at-risk relatives. When an HTAD-related pathogenic variant(s) is not identified, clinical and family history information also inform risk of aortic dissection and can be used to guide medical and surgical management (see
The likelihood of identifying the genetic cause of HTAD in an individual with thoracic aortic disease varies based on clinical presentation and family history. Clinical and family history findings that increase the likelihood of identifying a pathogenic variant in an HTAD-related gene include:
Thoracic aortic aneurysm or dissection at age <60 years;
Family history of thoracic aortic disease, unexplained sudden death, or aneurysms/dissections in other arteries;
Syndromic features associated with
Aneurysms and dissections/ruptures of other arteries in an individual with thoracic aortic disease.
Note: Although these clinical and family history findings are useful for identifying individuals most likely to have a molecular cause identified, individuals without these findings can still benefit from molecular genetic testing and risk assessment [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• Thoracic aortic aneurysm or dissection at age <60 years;
• Family history of thoracic aortic disease, unexplained sudden death, or aneurysms/dissections in other arteries;
• Syndromic features associated with
• Aneurysms and dissections/ruptures of other arteries in an individual with thoracic aortic disease.
## Management
This section provides information regarding recommendations for imaging surveillance, medical management, and surgical management in individuals with heritable thoracic aortic disease (HTAD) and imaging recommendations for family members of individuals with thoracic aortic disease of unknown genetic cause. Management should be based on the genetic cause (when possible) or based on the clinical and family history when a molecular genetic diagnosis cannot be established [
A baseline echocardiogram should be performed to assess aortic diameters (i.e., the aortic root and ascending aorta) and evaluate aortic valve anatomy and function. If the entire ascending aorta cannot be visualized on echocardiogram, CT or MRI may be indicated. Note that echocardiography may be needed to visualize the aortic root and cardiac valve structure and function unless a gated CT/MRI is performed.
Individuals diagnosed with a
If the aortic diameter is stable on repeat imaging, continue imaging surveillance every six to 24 months based on aortic diameter and other dissection risk factors.
If the rate of increase in aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered. The frequency of imaging may be modified based on the individual's age and family history [
The risk of aneurysms in arteries other than the aorta and/or other cardiovascular disease is variable and depends on the underlying cause of HTAD.
Imaging to assess for aneurysms in other arteries, moyamoya-like cerebrovascular disease, coronary artery disease, and other cardiovascular manifestations should be guided by family history and molecular genetic cause of HTAD, if established.
When the genetic cause of HTAD in a family is unknown, thoracic aortic imaging is recommended for first-degree relatives (i.e., parents, sibs, offspring) of all individuals with thoracic aortic disease. This recommendation applies to all at-risk relatives regardless of the proband's age of thoracic aortic disease diagnosis and presentation.
Screening via echocardiogram is recommended if the aortic root and ascending aorta are adequately visualized; otherwise, a CT or MRI may be indicated.
Additional head and neck imaging may be indicated if there is also a family history of aneurysms/dissections in the intracranial and cervical arteries.
Note: Family members with HTAD-related pathogenic variant(s) have, by definition, HTAD, and implementation of gene-based management is recommended.
Beta-adrenergic blocking agents (beta-blockers) have been shown to slow the rate of aortic root growth in individuals with
Studies investigating the use of celiprolol, a beta-blocker with vasodilatory properties, in individuals with
The efficacy of beta-blockers and angiotensin receptor blockers on slowing progressive aortic dilation has not been investigated in other known molecular causes of HTAD, but expert consensus generally supports the use of beta-blockers in individuals with other molecular causes of HTAD or no known molecular cause of HTAD [
Although pharmacotherapy and risk factor modification can slow progressive dilation of the aortic root and/or ascending aorta, the primary treatment to prevent premature death due to type A dissection is prophylactic surgical repair/replacement.
2022 AHA treatment guidelines proposed thresholds for prophylactic aortic root and ascending aortic repairs based on the causative HTAD gene. It is important to note that the presence of additional risk factors and family history should be considered when determining the timing of surgical repair; these are detailed in the AHA treatment guidelines [
Aneurysms in individuals with a pathogenic variant in certain genes (
Surgical Thresholds for Prophylactic Replacement of the Aortic Root and Ascending Aorta by HTAD Gene
Depending on presence of other risk factors and surgical expertise
Timing of prophylactic surgical repair should be based on aortic diameter at the time of dissection or age at aneurysm repair in affected family members.
If aortic diameters are not known for affected family members and the affected individual does not have other dissection risk factors, prophylactic repair is recommended when the maximal aortic diameter reaches ≥5.0 cm.
In individuals with other dissection risk factors, prophylactic repair is reasonable when the maximal aortic diameter reaches ≥4.5 cm if performed by an experienced surgeon who is part of a multidisciplinary aortic team.
The risk of peripartum aortic dissection and other pregnancy-related complications in individuals with HTAD varies based on the cause of HTAD, medical history, and family history. The majority of peripartum dissections occur in the third trimester and up to 12 weeks postpartum.
In the preconception period, individuals with HTAD should be counseled on recurrence risk (see
Pregnant individuals with HTAD and those at risk for HTAD should be managed by a multidisciplinary team including a cardiologist and maternal-fetal medicine specialist [
In some instances, cesarean delivery may be recommended over vaginal delivery, but studies investigating indications and outcomes are limited. Factors that influence the method of delivery include aortic diameter and prior history of aortic dissection (e.g., chronic dissection or portion of aorta with residual dissection). In general, vaginal delivery is acceptable for individuals with HTAD who have an aortic diameter <4.0 cm. Cesarean delivery can be considered for individuals with aortic diameters between 4.0 cm and 4.5 cm and is recommended when the aortic diameter reaches 4.5 cm. Cesarean delivery is recommended when there is a history of aortic dissection (residually dissected aorta).
After delivery, aortic imaging by echocardiogram and/or MRI/CT is recommended.
See
• Individuals diagnosed with a
• If the aortic diameter is stable on repeat imaging, continue imaging surveillance every six to 24 months based on aortic diameter and other dissection risk factors.
• If the rate of increase in aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered. The frequency of imaging may be modified based on the individual's age and family history [
• Screening via echocardiogram is recommended if the aortic root and ascending aorta are adequately visualized; otherwise, a CT or MRI may be indicated.
• Additional head and neck imaging may be indicated if there is also a family history of aneurysms/dissections in the intracranial and cervical arteries.
• Timing of prophylactic surgical repair should be based on aortic diameter at the time of dissection or age at aneurysm repair in affected family members.
• If aortic diameters are not known for affected family members and the affected individual does not have other dissection risk factors, prophylactic repair is recommended when the maximal aortic diameter reaches ≥5.0 cm.
• In individuals with other dissection risk factors, prophylactic repair is reasonable when the maximal aortic diameter reaches ≥4.5 cm if performed by an experienced surgeon who is part of a multidisciplinary aortic team.
## Imaging Surveillance
A baseline echocardiogram should be performed to assess aortic diameters (i.e., the aortic root and ascending aorta) and evaluate aortic valve anatomy and function. If the entire ascending aorta cannot be visualized on echocardiogram, CT or MRI may be indicated. Note that echocardiography may be needed to visualize the aortic root and cardiac valve structure and function unless a gated CT/MRI is performed.
Individuals diagnosed with a
If the aortic diameter is stable on repeat imaging, continue imaging surveillance every six to 24 months based on aortic diameter and other dissection risk factors.
If the rate of increase in aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered. The frequency of imaging may be modified based on the individual's age and family history [
The risk of aneurysms in arteries other than the aorta and/or other cardiovascular disease is variable and depends on the underlying cause of HTAD.
Imaging to assess for aneurysms in other arteries, moyamoya-like cerebrovascular disease, coronary artery disease, and other cardiovascular manifestations should be guided by family history and molecular genetic cause of HTAD, if established.
When the genetic cause of HTAD in a family is unknown, thoracic aortic imaging is recommended for first-degree relatives (i.e., parents, sibs, offspring) of all individuals with thoracic aortic disease. This recommendation applies to all at-risk relatives regardless of the proband's age of thoracic aortic disease diagnosis and presentation.
Screening via echocardiogram is recommended if the aortic root and ascending aorta are adequately visualized; otherwise, a CT or MRI may be indicated.
Additional head and neck imaging may be indicated if there is also a family history of aneurysms/dissections in the intracranial and cervical arteries.
Note: Family members with HTAD-related pathogenic variant(s) have, by definition, HTAD, and implementation of gene-based management is recommended.
• Individuals diagnosed with a
• If the aortic diameter is stable on repeat imaging, continue imaging surveillance every six to 24 months based on aortic diameter and other dissection risk factors.
• If the rate of increase in aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered. The frequency of imaging may be modified based on the individual's age and family history [
• Screening via echocardiogram is recommended if the aortic root and ascending aorta are adequately visualized; otherwise, a CT or MRI may be indicated.
• Additional head and neck imaging may be indicated if there is also a family history of aneurysms/dissections in the intracranial and cervical arteries.
## Thoracic Aortic Imaging Recommended for Individuals with HTAD
A baseline echocardiogram should be performed to assess aortic diameters (i.e., the aortic root and ascending aorta) and evaluate aortic valve anatomy and function. If the entire ascending aorta cannot be visualized on echocardiogram, CT or MRI may be indicated. Note that echocardiography may be needed to visualize the aortic root and cardiac valve structure and function unless a gated CT/MRI is performed.
Individuals diagnosed with a
If the aortic diameter is stable on repeat imaging, continue imaging surveillance every six to 24 months based on aortic diameter and other dissection risk factors.
If the rate of increase in aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered. The frequency of imaging may be modified based on the individual's age and family history [
• Individuals diagnosed with a
• If the aortic diameter is stable on repeat imaging, continue imaging surveillance every six to 24 months based on aortic diameter and other dissection risk factors.
• If the rate of increase in aortic diameter exceeds 0.5 cm per year, more frequent imaging should be considered. The frequency of imaging may be modified based on the individual's age and family history [
## Imaging of Other Arteries in Individuals with HTAD
The risk of aneurysms in arteries other than the aorta and/or other cardiovascular disease is variable and depends on the underlying cause of HTAD.
Imaging to assess for aneurysms in other arteries, moyamoya-like cerebrovascular disease, coronary artery disease, and other cardiovascular manifestations should be guided by family history and molecular genetic cause of HTAD, if established.
## Imaging Recommendations for Family Members of Individuals with HTAD of Unknown Genetic Cause
When the genetic cause of HTAD in a family is unknown, thoracic aortic imaging is recommended for first-degree relatives (i.e., parents, sibs, offspring) of all individuals with thoracic aortic disease. This recommendation applies to all at-risk relatives regardless of the proband's age of thoracic aortic disease diagnosis and presentation.
Screening via echocardiogram is recommended if the aortic root and ascending aorta are adequately visualized; otherwise, a CT or MRI may be indicated.
Additional head and neck imaging may be indicated if there is also a family history of aneurysms/dissections in the intracranial and cervical arteries.
Note: Family members with HTAD-related pathogenic variant(s) have, by definition, HTAD, and implementation of gene-based management is recommended.
• Screening via echocardiogram is recommended if the aortic root and ascending aorta are adequately visualized; otherwise, a CT or MRI may be indicated.
• Additional head and neck imaging may be indicated if there is also a family history of aneurysms/dissections in the intracranial and cervical arteries.
## Pharmacotherapy
Beta-adrenergic blocking agents (beta-blockers) have been shown to slow the rate of aortic root growth in individuals with
Studies investigating the use of celiprolol, a beta-blocker with vasodilatory properties, in individuals with
The efficacy of beta-blockers and angiotensin receptor blockers on slowing progressive aortic dilation has not been investigated in other known molecular causes of HTAD, but expert consensus generally supports the use of beta-blockers in individuals with other molecular causes of HTAD or no known molecular cause of HTAD [
## Risk Factor Modification
## Surgical Management of Aneurysms of the Aortic Root and Ascending Aorta
Although pharmacotherapy and risk factor modification can slow progressive dilation of the aortic root and/or ascending aorta, the primary treatment to prevent premature death due to type A dissection is prophylactic surgical repair/replacement.
2022 AHA treatment guidelines proposed thresholds for prophylactic aortic root and ascending aortic repairs based on the causative HTAD gene. It is important to note that the presence of additional risk factors and family history should be considered when determining the timing of surgical repair; these are detailed in the AHA treatment guidelines [
Aneurysms in individuals with a pathogenic variant in certain genes (
Surgical Thresholds for Prophylactic Replacement of the Aortic Root and Ascending Aorta by HTAD Gene
Depending on presence of other risk factors and surgical expertise
Timing of prophylactic surgical repair should be based on aortic diameter at the time of dissection or age at aneurysm repair in affected family members.
If aortic diameters are not known for affected family members and the affected individual does not have other dissection risk factors, prophylactic repair is recommended when the maximal aortic diameter reaches ≥5.0 cm.
In individuals with other dissection risk factors, prophylactic repair is reasonable when the maximal aortic diameter reaches ≥4.5 cm if performed by an experienced surgeon who is part of a multidisciplinary aortic team.
• Timing of prophylactic surgical repair should be based on aortic diameter at the time of dissection or age at aneurysm repair in affected family members.
• If aortic diameters are not known for affected family members and the affected individual does not have other dissection risk factors, prophylactic repair is recommended when the maximal aortic diameter reaches ≥5.0 cm.
• In individuals with other dissection risk factors, prophylactic repair is reasonable when the maximal aortic diameter reaches ≥4.5 cm if performed by an experienced surgeon who is part of a multidisciplinary aortic team.
## Pregnancy Management
The risk of peripartum aortic dissection and other pregnancy-related complications in individuals with HTAD varies based on the cause of HTAD, medical history, and family history. The majority of peripartum dissections occur in the third trimester and up to 12 weeks postpartum.
In the preconception period, individuals with HTAD should be counseled on recurrence risk (see
Pregnant individuals with HTAD and those at risk for HTAD should be managed by a multidisciplinary team including a cardiologist and maternal-fetal medicine specialist [
In some instances, cesarean delivery may be recommended over vaginal delivery, but studies investigating indications and outcomes are limited. Factors that influence the method of delivery include aortic diameter and prior history of aortic dissection (e.g., chronic dissection or portion of aorta with residual dissection). In general, vaginal delivery is acceptable for individuals with HTAD who have an aortic diameter <4.0 cm. Cesarean delivery can be considered for individuals with aortic diameters between 4.0 cm and 4.5 cm and is recommended when the aortic diameter reaches 4.5 cm. Cesarean delivery is recommended when there is a history of aortic dissection (residually dissected aorta).
After delivery, aortic imaging by echocardiogram and/or MRI/CT is recommended.
See
## Genetic Risk Assessment and Cascade Testing in Family Members of a Proband
Genetic counseling regarding risk to family members of a proband with heritable thoracic aortic disease (HTAD) depends on accurate molecular diagnosis (i.e., identification of the HTAD-causing pathogenic variant[s] in an affected family member) and confirmation of the mode of inheritance in each family. When a molecular diagnosis is established in a proband, genetic counseling should be tailored to the molecular diagnosis and family history.
HTAD is typically inherited in an autosomal dominant manner. Less commonly, HTAD is inherited in an X-linked (e.g.,
Note: A basic view of autosomal dominant nonsyndromic HTAD recurrence risk assessment is presented in this section; genetic counseling issues that may be specific to a given family or genetic cause of nonsyndromic HTAD and issues related to syndromic HTAD are not addressed.
Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of an HTAD-related pathogenic variant inherited from a parent. Because the penetrance of HTAD is reduced, the transmitting parent may or may not have a history of thoracic aortic or other associated vascular disease.
Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of a
Molecular genetic testing for the HTAD-related pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and – if the HTAD-related pathogenic variant is identified in a parent – implement gene-based management recommendations for the heterozygous parent.
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 a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Sibs who inherit a pathogenic variant should be counseled and managed based on the causative HTAD gene, family history, and other clinical or lifestyle risk factors (see
If the HTAD-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 theoretic possibility of parental germline mosaicism [
If a molecular genetic diagnosis has been established in the proband but the genetic status of the parents is unknown (e.g., the parents have not been tested for the familial HTAD-related pathogenic variant), genetic testing should be offered to all sibs regardless of their clinical history due to the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
Implementation of gene-based management recommendations should be initiated in family members with HTAD-related pathogenic variant(s) (see
Family members who did not inherit the familial HTAD-related pathogenic variant(s) (confirmed by genetic testing) can be discharged from the aortic/arterial surveillance protocol indicated for those who have an HTAD-related pathogenic variant(s).
• Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of an HTAD-related pathogenic variant inherited from a parent. Because the penetrance of HTAD is reduced, the transmitting parent may or may not have a history of thoracic aortic or other associated vascular disease.
• Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of a
• Molecular genetic testing for the HTAD-related pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and – if the HTAD-related pathogenic variant is identified in a parent – implement gene-based management recommendations for the heterozygous parent.
• 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 a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Sibs who inherit a pathogenic variant should be counseled and managed based on the causative HTAD gene, family history, and other clinical or lifestyle risk factors (see
• If the HTAD-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 theoretic possibility of parental germline mosaicism [
• If a molecular genetic diagnosis has been established in the proband but the genetic status of the parents is unknown (e.g., the parents have not been tested for the familial HTAD-related pathogenic variant), genetic testing should be offered to all sibs regardless of their clinical history due to the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Implementation of gene-based management recommendations should be initiated in family members with HTAD-related pathogenic variant(s) (see
• Family members who did not inherit the familial HTAD-related pathogenic variant(s) (confirmed by genetic testing) can be discharged from the aortic/arterial surveillance protocol indicated for those who have an HTAD-related pathogenic variant(s).
## Risk to Family Members of a Proband with a Pathogenic Variant in an Autosomal Dominant HTAD-Related Gene
Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of an HTAD-related pathogenic variant inherited from a parent. Because the penetrance of HTAD is reduced, the transmitting parent may or may not have a history of thoracic aortic or other associated vascular disease.
Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of a
Molecular genetic testing for the HTAD-related pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and – if the HTAD-related pathogenic variant is identified in a parent – implement gene-based management recommendations for the heterozygous parent.
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 a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
Sibs who inherit a pathogenic variant should be counseled and managed based on the causative HTAD gene, family history, and other clinical or lifestyle risk factors (see
If the HTAD-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 theoretic possibility of parental germline mosaicism [
If a molecular genetic diagnosis has been established in the proband but the genetic status of the parents is unknown (e.g., the parents have not been tested for the familial HTAD-related pathogenic variant), genetic testing should be offered to all sibs regardless of their clinical history due to the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of an HTAD-related pathogenic variant inherited from a parent. Because the penetrance of HTAD is reduced, the transmitting parent may or may not have a history of thoracic aortic or other associated vascular disease.
• Some individuals diagnosed with autosomal dominant HTAD have the disorder as the result of a
• Molecular genetic testing for the HTAD-related pathogenic variant identified in the proband is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and – if the HTAD-related pathogenic variant is identified in a parent – implement gene-based management recommendations for the heterozygous parent.
• 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 a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Sibs who inherit a pathogenic variant should be counseled and managed based on the causative HTAD gene, family history, and other clinical or lifestyle risk factors (see
• If the HTAD-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 theoretic possibility of parental germline mosaicism [
• If a molecular genetic diagnosis has been established in the proband but the genetic status of the parents is unknown (e.g., the parents have not been tested for the familial HTAD-related pathogenic variant), genetic testing should be offered to all sibs regardless of their clinical history due to the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
## Cascade Testing of Relatives at Risk
Implementation of gene-based management recommendations should be initiated in family members with HTAD-related pathogenic variant(s) (see
Family members who did not inherit the familial HTAD-related pathogenic variant(s) (confirmed by genetic testing) can be discharged from the aortic/arterial surveillance protocol indicated for those who have an HTAD-related pathogenic variant(s).
• Implementation of gene-based management recommendations should be initiated in family members with HTAD-related pathogenic variant(s) (see
• Family members who did not inherit the familial HTAD-related pathogenic variant(s) (confirmed by genetic testing) can be discharged from the aortic/arterial surveillance protocol indicated for those who have an HTAD-related pathogenic variant(s).
## Resources
Canada
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• Canada
•
## Chapter Notes
McGovern Medical School Department of Internal Medicine,
The authors are grateful to the patients and families participating in the research studies supported by the National Institutes of Health (R01HL109942), American Heart Association Merit Award, John Ritter Foundation for Aortic Health, Remembrin' Benjamin Foundation, Olivia Petrera-Cohen Research Fund, Family Fund, Genetic Aortic Disorders Association Canada (GADA Canada), and the Temerty Foundation.
Alana C Cecchi, MS, CGC (2023-present)Dianna M Milewicz, MD, PhD (2003-present)Ellen Regalado, MS, CGC; University of Texas Medical School (2011-2023)Van Tran-Fadulu, MS, CGC; University of Texas Medical School (2003-2011)
4 May 2023 (sw) Comprehensive update posted live
1 December 2016 (bp) Comprehensive update posted live; scope changed to overview
11 January 2011 (me) Comprehensive update posted live
10 May 2006 (me) Comprehensive update posted live
28 April 2005 (me) Comprehensive update posted live
13 February 2003 (me) Review posted live
11 July 2002 (dm) Original submission
• 4 May 2023 (sw) Comprehensive update posted live
• 1 December 2016 (bp) Comprehensive update posted live; scope changed to overview
• 11 January 2011 (me) Comprehensive update posted live
• 10 May 2006 (me) Comprehensive update posted live
• 28 April 2005 (me) Comprehensive update posted live
• 13 February 2003 (me) Review posted live
• 11 July 2002 (dm) Original submission
## Author Notes
McGovern Medical School Department of Internal Medicine,
## Acknowledgments
The authors are grateful to the patients and families participating in the research studies supported by the National Institutes of Health (R01HL109942), American Heart Association Merit Award, John Ritter Foundation for Aortic Health, Remembrin' Benjamin Foundation, Olivia Petrera-Cohen Research Fund, Family Fund, Genetic Aortic Disorders Association Canada (GADA Canada), and the Temerty Foundation.
## Author History
Alana C Cecchi, MS, CGC (2023-present)Dianna M Milewicz, MD, PhD (2003-present)Ellen Regalado, MS, CGC; University of Texas Medical School (2011-2023)Van Tran-Fadulu, MS, CGC; University of Texas Medical School (2003-2011)
## Revision History
4 May 2023 (sw) Comprehensive update posted live
1 December 2016 (bp) Comprehensive update posted live; scope changed to overview
11 January 2011 (me) Comprehensive update posted live
10 May 2006 (me) Comprehensive update posted live
28 April 2005 (me) Comprehensive update posted live
13 February 2003 (me) Review posted live
11 July 2002 (dm) Original submission
• 4 May 2023 (sw) Comprehensive update posted live
• 1 December 2016 (bp) Comprehensive update posted live; scope changed to overview
• 11 January 2011 (me) Comprehensive update posted live
• 10 May 2006 (me) Comprehensive update posted live
• 28 April 2005 (me) Comprehensive update posted live
• 13 February 2003 (me) Review posted live
• 11 July 2002 (dm) Original submission
## References
## Literature Cited
Thoracic aortic aneurysms involving the aortic root (a) and the ascending aorta (b)
Printed with permission from Baylor College of Medicine, Copyright 2016
Thoracic aortic dissections: Type A (a and b) and Type B (c)
Printed with permission from Baylor College of Medicine, Copyright 2016
|
[] |
13/2/2003
|
4/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tangier
|
tangier
|
[
"Analphalipoproteinemia",
"Familial High-Density Lipoprotein Deficiency 1",
"Primary Hypoalphalipoproteinemia 1",
"Primary Hypoalphalipoproteinemia 1",
"Familial High-Density Lipoprotein Deficiency 1",
"Analphalipoproteinemia",
"Phospholipid-transporting ATPase ABCA1",
"ABCA1",
"Tangier Disease"
] |
Tangier Disease
|
John R Burnett, Amanda J Hooper, Sally PA McCormick, Robert A Hegele
|
Summary Tangier disease is characterized by severe deficiency or absence of high-density lipoprotein (HDL) in the circulation resulting in tissue accumulation of cholesteryl esters throughout the body, particularly in the reticuloendothelial system. The major clinical signs of Tangier disease include hyperplastic yellow-orange tonsils, hepatosplenomegaly, and peripheral neuropathy, which may be either relapsing-remitting or chronic progressive in nature. Rarer complications may include corneal opacities that typically do not affect vision, premature atherosclerotic coronary artery disease occurring in the sixth and seventh decades of life (not usually before age 40 years), and mild hematologic manifestations, such as mild thrombocytopenia, reticulocytosis, stomatocytosis, or hemolytic anemia. The clinical expression of Tangier disease is variable, with some affected individuals only showing biochemical perturbations. The diagnosis of Tangier disease is established in a proband with absent or extremely low HDL-cholesterol and apo A-I levels and biallelic pathogenic variants in Tangier disease is inherited in an autosomal recessive manner. Most parents are heterozygous for a pathogenic variant. At conception each sib has a 25% chance of being unaffected, a 50% chance of being a carrier (with no overt clinical manifestations, but with plasma HDL-cholesterol concentrations that are ~50% of normal), 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 pathogenic variants in the family are known.
|
## Diagnosis
Formal clinical diagnostic criteria for Tangier disease have not been published.
Tangier disease
Enlarged tonsils that are yellow and/or orange in children and young adults
Peripheral neuropathy
Hepatomegaly and/or splenomegaly
Corneal opacities
Coronary artery disease
Lymphadenopathy
Blood disorders (especially thrombocytopenia)
Major findings:
Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
Small or absent alpha band on lipoprotein electrophoresis
Other laboratory findings:
Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
Decreased LDL-cholesterol concentration
Small beta or broad pre-beta band on lipoprotein electrophoresis
The diagnosis of Tangier disease
Note: If clinical molecular genetic testing cannot be performed, the presence of accumulation of cholesterol esters in tissue biopsies in an individual with typical clinical features of Tangier disease can be considered.
When the phenotypic and laboratory findings suggest the diagnosis of Tangier disease, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Tangier Disease
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.
• Enlarged tonsils that are yellow and/or orange in children and young adults
• Peripheral neuropathy
• Hepatomegaly and/or splenomegaly
• Corneal opacities
• Coronary artery disease
• Lymphadenopathy
• Blood disorders (especially thrombocytopenia)
• Major findings:
• Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
• Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
• Small or absent alpha band on lipoprotein electrophoresis
• Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
• Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
• Small or absent alpha band on lipoprotein electrophoresis
• Other laboratory findings:
• Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
• Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
• Decreased LDL-cholesterol concentration
• Small beta or broad pre-beta band on lipoprotein electrophoresis
• Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
• Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
• Decreased LDL-cholesterol concentration
• Small beta or broad pre-beta band on lipoprotein electrophoresis
• Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
• Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
• Small or absent alpha band on lipoprotein electrophoresis
• Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
• Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
• Decreased LDL-cholesterol concentration
• Small beta or broad pre-beta band on lipoprotein electrophoresis
• For an introduction to multigene panels click
## Suggestive Findings
Tangier disease
Enlarged tonsils that are yellow and/or orange in children and young adults
Peripheral neuropathy
Hepatomegaly and/or splenomegaly
Corneal opacities
Coronary artery disease
Lymphadenopathy
Blood disorders (especially thrombocytopenia)
Major findings:
Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
Small or absent alpha band on lipoprotein electrophoresis
Other laboratory findings:
Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
Decreased LDL-cholesterol concentration
Small beta or broad pre-beta band on lipoprotein electrophoresis
• Enlarged tonsils that are yellow and/or orange in children and young adults
• Peripheral neuropathy
• Hepatomegaly and/or splenomegaly
• Corneal opacities
• Coronary artery disease
• Lymphadenopathy
• Blood disorders (especially thrombocytopenia)
• Major findings:
• Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
• Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
• Small or absent alpha band on lipoprotein electrophoresis
• Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
• Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
• Small or absent alpha band on lipoprotein electrophoresis
• Other laboratory findings:
• Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
• Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
• Decreased LDL-cholesterol concentration
• Small beta or broad pre-beta band on lipoprotein electrophoresis
• Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
• Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
• Decreased LDL-cholesterol concentration
• Small beta or broad pre-beta band on lipoprotein electrophoresis
• Very low plasma HDL-cholesterol concentration, typically <5 mg/dL (0.125 mmol/L), rarely 5-10 mg/dL
• Very low or absent apo A-I concentration, usually <30 mg/dL (typically <5 mg/dL)
• Small or absent alpha band on lipoprotein electrophoresis
• Low plasma total cholesterol concentration, typically <150 mg/dL (4 mmol/L)
• Mild-to-moderate hypertriglyceridemia, up to 400 mg/dL (4.5 mmol/L)
• Decreased LDL-cholesterol concentration
• Small beta or broad pre-beta band on lipoprotein electrophoresis
## Establishing the Diagnosis
The diagnosis of Tangier disease
Note: If clinical molecular genetic testing cannot be performed, the presence of accumulation of cholesterol esters in tissue biopsies in an individual with typical clinical features of Tangier disease can be considered.
When the phenotypic and laboratory findings suggest the diagnosis of Tangier disease, molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Tangier Disease
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.
• For an introduction to multigene panels click
## Clinical Characteristics
Tangier disease is characterized by severe deficiency or absence of high-density lipoprotein (HDL) in the circulation resulting in tissue accumulation of cholesteryl esters throughout the body, particularly in the reticuloendothelial system [
Hyperplastic yellow-orange palatine and pharyngeal tonsils are typically first noted in late childhood or adolescence. This finding does not usually cause any symptoms; however, it may occasionally cause difficulty breathing or swallowing, recurrent ear or sinus infections, or obstructive sleep apnea.
Hepatomegaly and/or splenomegaly presents more commonly in adulthood.
Orange-brown focal deposits of the intestinal and rectal mucosa may be seen on colonoscopy, but typically do not cause any symptoms.
Lymphadenopathy may be found in the thoracic, axillary, and cervical regions of the body.
Multifocal mono- or polyneuropathy (monophasic or relapsing-remitting pattern)
Syringomyelia-like neuropathy (slowly progressive weakness, muscle wasting, and loss of pain and temperature sensation mainly affecting the upper extremities)
Subclinical or distal symmetric polyneuropathy (rare)
Mild thrombocytopenia
Reticulocytosis
Stomatocytosis
Hemolytic anemia
Given the small number of individuals with Tangier disease reported in the literature, reliable data on genotype-phenotype correlations are lacking.
With the exception of small founder populations (e.g., Tangier Island, Virginia, after which the disorder is named), Tangier disease is rare; fewer than 100 cases have been published.
• Hyperplastic yellow-orange palatine and pharyngeal tonsils are typically first noted in late childhood or adolescence. This finding does not usually cause any symptoms; however, it may occasionally cause difficulty breathing or swallowing, recurrent ear or sinus infections, or obstructive sleep apnea.
• Hepatomegaly and/or splenomegaly presents more commonly in adulthood.
• Orange-brown focal deposits of the intestinal and rectal mucosa may be seen on colonoscopy, but typically do not cause any symptoms.
• Lymphadenopathy may be found in the thoracic, axillary, and cervical regions of the body.
• Multifocal mono- or polyneuropathy (monophasic or relapsing-remitting pattern)
• Syringomyelia-like neuropathy (slowly progressive weakness, muscle wasting, and loss of pain and temperature sensation mainly affecting the upper extremities)
• Subclinical or distal symmetric polyneuropathy (rare)
• Mild thrombocytopenia
• Reticulocytosis
• Stomatocytosis
• Hemolytic anemia
## Clinical Description
Tangier disease is characterized by severe deficiency or absence of high-density lipoprotein (HDL) in the circulation resulting in tissue accumulation of cholesteryl esters throughout the body, particularly in the reticuloendothelial system [
Hyperplastic yellow-orange palatine and pharyngeal tonsils are typically first noted in late childhood or adolescence. This finding does not usually cause any symptoms; however, it may occasionally cause difficulty breathing or swallowing, recurrent ear or sinus infections, or obstructive sleep apnea.
Hepatomegaly and/or splenomegaly presents more commonly in adulthood.
Orange-brown focal deposits of the intestinal and rectal mucosa may be seen on colonoscopy, but typically do not cause any symptoms.
Lymphadenopathy may be found in the thoracic, axillary, and cervical regions of the body.
Multifocal mono- or polyneuropathy (monophasic or relapsing-remitting pattern)
Syringomyelia-like neuropathy (slowly progressive weakness, muscle wasting, and loss of pain and temperature sensation mainly affecting the upper extremities)
Subclinical or distal symmetric polyneuropathy (rare)
Mild thrombocytopenia
Reticulocytosis
Stomatocytosis
Hemolytic anemia
• Hyperplastic yellow-orange palatine and pharyngeal tonsils are typically first noted in late childhood or adolescence. This finding does not usually cause any symptoms; however, it may occasionally cause difficulty breathing or swallowing, recurrent ear or sinus infections, or obstructive sleep apnea.
• Hepatomegaly and/or splenomegaly presents more commonly in adulthood.
• Orange-brown focal deposits of the intestinal and rectal mucosa may be seen on colonoscopy, but typically do not cause any symptoms.
• Lymphadenopathy may be found in the thoracic, axillary, and cervical regions of the body.
• Multifocal mono- or polyneuropathy (monophasic or relapsing-remitting pattern)
• Syringomyelia-like neuropathy (slowly progressive weakness, muscle wasting, and loss of pain and temperature sensation mainly affecting the upper extremities)
• Subclinical or distal symmetric polyneuropathy (rare)
• Mild thrombocytopenia
• Reticulocytosis
• Stomatocytosis
• Hemolytic anemia
## Genotype-Phenotype Correlations
Given the small number of individuals with Tangier disease reported in the literature, reliable data on genotype-phenotype correlations are lacking.
## Prevalence
With the exception of small founder populations (e.g., Tangier Island, Virginia, after which the disorder is named), Tangier disease is rare; fewer than 100 cases have been published.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with Severe HDL Deficiency to Consider in the Differential Diagnosis of Tangier Disease
Apo A-I = apolipoprotein A-I; AR = autosomal recessive; LCAT = lecithin cholesterol acyltransferase; MOI = mode of inheritance
Only the biochemical perturbation is expressed in individuals who are heterozygous for an
## Management
To establish the extent of disease and needs in an individual diagnosed with Tangier disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Tangier Disease
A cardiac calcium score involves a noninvasive CT scan of the heart that is able to measure the amount of calcified plaque in the coronary arteries. This score is used to estimate the risk an affected individual has of developing coronary artery disease.
Treatment of Manifestations in Individuals with Tangier Disease
Mitigation of cardiovascular risk factors (including LDL-cholesterol concentrations using statin therapy and a low-fat diet) is indicated.
Recommended Surveillance for Individuals with Tangier Disease
Duplex coronary ultrasonography (See
The following should be avoided:
Obesity, because it makes walking more difficult
Medications that are toxic or potentially toxic to persons who are predisposed to the development of peripheral neuropathy, such as vincristine or taxols (paclitaxel)
Contact sports, in those with hepatosplenomegaly
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 preventive measures. Evaluations can include:
A lipid profile (including total cholesterol, HDL-cholesterol, triglyceride, and calculated LDL-cholesterol) and apo A-I concentration;
Molecular genetic testing if the pathogenic variants in the family are known.
See
See
Search
• Obesity, because it makes walking more difficult
• Medications that are toxic or potentially toxic to persons who are predisposed to the development of peripheral neuropathy, such as vincristine or taxols (paclitaxel)
• Contact sports, in those with hepatosplenomegaly
• A lipid profile (including total cholesterol, HDL-cholesterol, triglyceride, and calculated LDL-cholesterol) and apo A-I concentration;
• Molecular genetic testing if the pathogenic variants in the family are known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Tangier disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Tangier Disease
A cardiac calcium score involves a noninvasive CT scan of the heart that is able to measure the amount of calcified plaque in the coronary arteries. This score is used to estimate the risk an affected individual has of developing coronary artery disease.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Tangier Disease
## Prevention of Primary Manifestations
Mitigation of cardiovascular risk factors (including LDL-cholesterol concentrations using statin therapy and a low-fat diet) is indicated.
## Surveillance
Recommended Surveillance for Individuals with Tangier Disease
Duplex coronary ultrasonography (See
## Agents/Circumstances to Avoid
The following should be avoided:
Obesity, because it makes walking more difficult
Medications that are toxic or potentially toxic to persons who are predisposed to the development of peripheral neuropathy, such as vincristine or taxols (paclitaxel)
Contact sports, in those with hepatosplenomegaly
• Obesity, because it makes walking more difficult
• Medications that are toxic or potentially toxic to persons who are predisposed to the development of peripheral neuropathy, such as vincristine or taxols (paclitaxel)
• Contact sports, in those with hepatosplenomegaly
## 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 preventive measures. Evaluations can include:
A lipid profile (including total cholesterol, HDL-cholesterol, triglyceride, and calculated LDL-cholesterol) and apo A-I concentration;
Molecular genetic testing if the pathogenic variants in the family are known.
See
• A lipid profile (including total cholesterol, HDL-cholesterol, triglyceride, and calculated LDL-cholesterol) and apo A-I concentration;
• Molecular genetic testing if the pathogenic variants in the family are known.
## Pregnancy Management
See
## Therapies Under Investigation
Search
## Genetic Counseling
Tangier disease is inherited in an autosomal recessive manner. Heterozygous carriers of an
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and have no clinical manifestations, but they may have plasma HDL-cholesterol concentrations that are approximately one half of normal.
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 have no clinical manifestations, but often have plasma HDL-cholesterol concentrations that are approximately 50% of normal.
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 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 have no clinical manifestations, but they may have plasma HDL-cholesterol concentrations that are approximately one half of normal.
• 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 have no clinical manifestations, but often have plasma HDL-cholesterol concentrations that are approximately 50% of normal.
• 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
Tangier disease is inherited in an autosomal recessive manner. Heterozygous carriers of an
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and have no clinical manifestations, but they may have plasma HDL-cholesterol concentrations that are approximately one half of normal.
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 have no clinical manifestations, but often have plasma HDL-cholesterol concentrations that are approximately 50% of normal.
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and have no clinical manifestations, but they may have plasma HDL-cholesterol concentrations that are approximately one half of normal.
• 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 have no clinical manifestations, but often have plasma HDL-cholesterol concentrations that are approximately 50% of normal.
## Carrier (Heterozygote) 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 most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
Tangier Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tangier Disease (
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.
## References
## Literature Cited
## Chapter Notes
Robert A Hegele directs a tertiary referral lipid speciality clinic and a genomics core facility (
Robert A Hegele is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes of Health Research (Foundation Grant) and the Heart and Stroke Foundation of Ontario (G-18-0022147).
21 November 2019 (ma) Review posted live
18 April 2019 (jb) Original submission
• 21 November 2019 (ma) Review posted live
• 18 April 2019 (jb) Original submission
## Author Notes
Robert A Hegele directs a tertiary referral lipid speciality clinic and a genomics core facility (
## Acknowledgments
Robert A Hegele is supported by the Jacob J Wolfe Distinguished Medical Research Chair, the Edith Schulich Vinet Canada Research Chair in Human Genetics, the Martha G Blackburn Chair in Cardiovascular Research, and operating grants from the Canadian Institutes of Health Research (Foundation Grant) and the Heart and Stroke Foundation of Ontario (G-18-0022147).
## Revision History
21 November 2019 (ma) Review posted live
18 April 2019 (jb) Original submission
• 21 November 2019 (ma) Review posted live
• 18 April 2019 (jb) Original submission
|
[
"M Bodzioch, E Orsó, J Klucken, T Langmann, A Böttcher, W Diederich, W Drobnik, S Barlage, C Büchler, M Porsch-Ozcürümez, WE Kaminski, HW Hahmann, K Oette, G Rothe, C Aslanidis, KJ Lackner, G Schmitz. The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease.. Nat Genet. 1999;22:347-51",
"JR Burnett, AJJ Law, ML Yeong, MJ Crooke, AK Sharma. Severe aortic stenosis and atherosclerosis in a young man with Tangier disease.. Am J Cardiol 1994;73:923-5",
"JS Dron, J Wang, AJ Berberich, MA Iacocca, H Cao, P Yang, J Knoll, K Tremblay, D Brisson, C Netzer, I Gouni-Berthold, D Gaudet, RA Hegele. Large-scale deletions of the ABCA1 gene in patients with hypoalphalipoproteinemia.. J Lipid Res 2018;59:1529-35",
"AS Geller, EY Polisecki, MR Diffenderfer, BF Asztalos, SK Karathanasis, RA Hegele, EJ Schaefer. Genetic and secondary causes of severe HDL deficiency and cardiovascular disease.. J Lipid Res 2018;59:2421-35",
"M Liu, S Chung, GS Shelness, JS Parks. Hepatic ABCA1 and VLDL triglyceride production.. Biochim Biophys Acta 2012;1821:770-7",
"M Mercan, V Yayla, S Altinay, S. Seyhan. Peripheral neuropathy in Tangier disease: a literature review and assessment.. J Peripher Nerv Syst 2018;23:88-98",
"F Oldoni, RJ Sinke, JA Kuivenhoven. Mendelian disorders of high-density lipoprotein metabolism.. Circ Res 2014;114:124-42",
"H Qian, X Zhao, P Cao, J Lei, N Yan, X Gong. Structure of the human lipid exporter ABCA1.. Cell 2017;169:1228-1239.e10",
"F Quazi, RS Molday. Lipid transport by mammalian ABC proteins.. Essays Biochem 2011;50:265-90",
"DJ Rader, EM deGoma. Approach to the patient with extremely low HDL-cholesterol.. J Clin Endocrinol Metab 2012;97:3399-407",
"S Rust, M Rosier, H Funke, J Real, Z Amoura, JC Piette, JF Deleuze, HB Brewer, N Duverger, P Denèfle, G Assmann. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.. Nat Genet. 1999;22:352-5",
"EJ Schaefer, P Anthanont, MR Diffenderfer, E Polisecki, BF Asztalos. Diagnosis and treatment of high density lipoprotein deficiency.. Prog Cardiovasc Dis 2016;59:97-106",
"EJ Schaefer, RD Santos, BF Asztalos. Marked HDL deficiency and premature coronary heart disease.. Curr Opin Lipidol 2010;21:289-97"
] |
21/11/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tango2-mea
|
tango2-mea
|
[
"TANGO2 Deficiency Disorder",
"TANGO2-Related Metabolic Encephalopathy and Arrhythmias",
"TANGO2 Deficiency Disorder",
"TANGO2-Related Metabolic Encephalopathy and Arrhythmias",
"Transport and Golgi organization protein 2 homolog",
"TANGO2",
"TANGO2 Deficiency"
] |
TANGO2 Deficiency
|
Christina Y Miyake, Lindsay Burrage, Kevin Glinton, Kimberly Houck, Alfonso Hoyos-Martinez, Brett Graham, Yaping Yang, Brandy Rawls-Castillo, Fernando Scaglia, Claudia Soler-Alfonso, Seema R Lalani
|
Summary TANGO2 deficiency is characterized by developmental delay, intellectual disability, gait incoordination, speech difficulties, seizures, and hypothyroidism. Most individuals have TANGO2 spells, non-life-threatening paroxysmal worsening of baseline symptoms, including sudden onset of hypotonia, ataxia with loss of balance, head and body tilt, increased dysarthria, drooling, lethargy, and disorientation. In addition, life-threatening acute metabolic crises can occur, including rhabdomyolysis with elevated creatine phosphokinase and liver transaminases, hypoglycemia, prolonged QTc on EKG, ventricular arrhythmias, and/or cardiomyopathy. The diagnosis of TANGO2 deficiency is established in a proband with biallelic pathogenic variants in Treatment of non-acute presentation: developmental and educational support; anti-seizure medication for seizures; levothyroxine for hypothyroidism; feeding therapy and/or gastrostomy tube feeding as needed; standard treatments for constipation. TANGO2 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
TANGO2 deficiency should be suspected in a proband with the following clinical, laboratory, EKG, imaging, and family history findings.
Developmental delay (including motor and speech delays)
Spasticity
Poor coordination and unsteady gait
Speech difficulties (dysarthria, slurred or nasal speech)
Intellectual disability
Paroxysmal neurologic episodes (TANGO2 spells). Sudden onset of clumsy gait, falling, head tilt, body tilt, dystonia, abnormal posturing with hypertonicity, dysarthria, drooling, extreme fatigue, and disorientation
Acute metabolic crises. Rhabdomyolysis with muscle weakness, pain, or dark urine; ataxia, disorientation or coma, and developmental regression
Seizures
Exotropia
Constipation
TANGO2 spells or acute metabolic crisis in an individual with
During acute metabolic crises, elevated creatine phosphokinase, alanine transaminase, and aspartate transaminase, hypoglycemia, mild lactic acidosis, and mild hyperammonemia
Hypothyroidism with elevated thyroid-stimulating hormone and low thyroxine
The diagnosis of TANGO2 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 is likely involved, whereas genomic testing does not. Individuals with the distinctive findings of rhabdomyolysis, cardiac arrhythmias, and/or TANGO2 spells in the setting of neurodevelopmental delay are likely to be diagnosed using gene-targeted testing (see
Note: Targeted analysis for pathogenic variants can be performed first in selected populations if resources are limited.
In individuals of Hispanic ethnicity from Latin America, targeted analysis for pathogenic variant c.460G>A (p.Gly154Arg) and the ~34-kb deletion encompassing exons 3-9 can be performed.
In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9 can be performed.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TANGO2 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
Detection rate varies with the ethnicity of the individual being tested.
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 (including motor and speech delays)
• Spasticity
• Poor coordination and unsteady gait
• Speech difficulties (dysarthria, slurred or nasal speech)
• Intellectual disability
• Paroxysmal neurologic episodes (TANGO2 spells). Sudden onset of clumsy gait, falling, head tilt, body tilt, dystonia, abnormal posturing with hypertonicity, dysarthria, drooling, extreme fatigue, and disorientation
• Acute metabolic crises. Rhabdomyolysis with muscle weakness, pain, or dark urine; ataxia, disorientation or coma, and developmental regression
• Seizures
• Exotropia
• Constipation
• TANGO2 spells or acute metabolic crisis in an individual with
• During acute metabolic crises, elevated creatine phosphokinase, alanine transaminase, and aspartate transaminase, hypoglycemia, mild lactic acidosis, and mild hyperammonemia
• Hypothyroidism with elevated thyroid-stimulating hormone and low thyroxine
• In individuals of Hispanic ethnicity from Latin America, targeted analysis for pathogenic variant c.460G>A (p.Gly154Arg) and the ~34-kb deletion encompassing exons 3-9 can be performed.
• In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9 can be performed.
## Suggestive Findings
TANGO2 deficiency should be suspected in a proband with the following clinical, laboratory, EKG, imaging, and family history findings.
Developmental delay (including motor and speech delays)
Spasticity
Poor coordination and unsteady gait
Speech difficulties (dysarthria, slurred or nasal speech)
Intellectual disability
Paroxysmal neurologic episodes (TANGO2 spells). Sudden onset of clumsy gait, falling, head tilt, body tilt, dystonia, abnormal posturing with hypertonicity, dysarthria, drooling, extreme fatigue, and disorientation
Acute metabolic crises. Rhabdomyolysis with muscle weakness, pain, or dark urine; ataxia, disorientation or coma, and developmental regression
Seizures
Exotropia
Constipation
TANGO2 spells or acute metabolic crisis in an individual with
During acute metabolic crises, elevated creatine phosphokinase, alanine transaminase, and aspartate transaminase, hypoglycemia, mild lactic acidosis, and mild hyperammonemia
Hypothyroidism with elevated thyroid-stimulating hormone and low thyroxine
• Developmental delay (including motor and speech delays)
• Spasticity
• Poor coordination and unsteady gait
• Speech difficulties (dysarthria, slurred or nasal speech)
• Intellectual disability
• Paroxysmal neurologic episodes (TANGO2 spells). Sudden onset of clumsy gait, falling, head tilt, body tilt, dystonia, abnormal posturing with hypertonicity, dysarthria, drooling, extreme fatigue, and disorientation
• Acute metabolic crises. Rhabdomyolysis with muscle weakness, pain, or dark urine; ataxia, disorientation or coma, and developmental regression
• Seizures
• Exotropia
• Constipation
• TANGO2 spells or acute metabolic crisis in an individual with
• During acute metabolic crises, elevated creatine phosphokinase, alanine transaminase, and aspartate transaminase, hypoglycemia, mild lactic acidosis, and mild hyperammonemia
• Hypothyroidism with elevated thyroid-stimulating hormone and low thyroxine
## Establishing the Diagnosis
The diagnosis of TANGO2 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 is likely involved, whereas genomic testing does not. Individuals with the distinctive findings of rhabdomyolysis, cardiac arrhythmias, and/or TANGO2 spells in the setting of neurodevelopmental delay are likely to be diagnosed using gene-targeted testing (see
Note: Targeted analysis for pathogenic variants can be performed first in selected populations if resources are limited.
In individuals of Hispanic ethnicity from Latin America, targeted analysis for pathogenic variant c.460G>A (p.Gly154Arg) and the ~34-kb deletion encompassing exons 3-9 can be performed.
In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9 can be performed.
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TANGO2 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
Detection rate varies with the ethnicity of the individual being tested.
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.
• In individuals of Hispanic ethnicity from Latin America, targeted analysis for pathogenic variant c.460G>A (p.Gly154Arg) and the ~34-kb deletion encompassing exons 3-9 can be performed.
• In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9 can be performed.
## Option 1
Note: Targeted analysis for pathogenic variants can be performed first in selected populations if resources are limited.
In individuals of Hispanic ethnicity from Latin America, targeted analysis for pathogenic variant c.460G>A (p.Gly154Arg) and the ~34-kb deletion encompassing exons 3-9 can be performed.
In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9 can be performed.
For an introduction to multigene panels click
• In individuals of Hispanic ethnicity from Latin America, targeted analysis for pathogenic variant c.460G>A (p.Gly154Arg) and the ~34-kb deletion encompassing exons 3-9 can be performed.
• In individuals of European ancestry, targeted deletion analysis for the ~34-kb deletion encompassing exons 3-9 can be performed.
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TANGO2 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
Detection rate varies with the ethnicity of the individual being tested.
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
TANGO2 deficiency is characterized by developmental delay, intellectual disability, TANGO2 spells, acute metabolic crises, and risk of cardiac crisis. Additional features can include seizures, hypothyroidism, exotropia, and constipation. To date, more than 100 individuals have been identified with biallelic pathogenic variants in
TANGO2 Deficiency Disorder: Frequency of Select Features
Spasticity of lower extremities, hyperreflexia, and clonus are also frequently seen. Poor coordination, progressively unsteady gait, and clumsiness are frequently reported in ambulatory individuals, even prior to the first episode of rhabdomyolysis [
Almost all individuals with TANGO2 deficiency have speech difficulties, including dysarthria and slurred or nasal speech.
Individuals present with rhabdomyolysis with elevated CK, ALT, and AST and may have dark urine due to myoglobinuria. Complications from rhabdomyolysis are not common, even though CK levels can be significantly elevated in some individuals (>200,000 U/L). Severe hypoglycemia can be present in addition to mild hyperammonemia, elevated aldolase, elevated troponin, elevated lactate, and evidence of ketoacidosis and lactic acidosis on urine organic acids. Although an acylcarnitine profile during an acute metabolic crisis may show elevated C14:1, C14:2, and C16:1, no consistent acylcarnitine abnormalities have been identified in large studies [
While cardiac workup including EKG is normal at baseline, during an acute metabolic crisis, EKG changes are noted. The most common EKG finding is prolonged QTc that is often markedly prolonged (>500 msec). Transient type 1 Brugada pattern can also be seen in 33% of individuals.
B-complex vitamins or multivitamins may prevent metabolic crises in individuals with TANGO2 deficiency [
During cardiac crisis, life-threatening recalcitrant ventricular tachycardia (VT) or torsade de pointes can occur, leading to hemodynamic instability and cardiac arrest. These events can occur when an individual is acutely ill but also in those who appear stable with improving CK levels. The presence of marked QTc prolongation, type I Brugada pattern, and ventricular ectopy are concerning, as they precede VT (QTc >500 msec is associated with an increased risk of torsade de pointes). VT is difficult to control, often unresponsive to typical anti-arrhythmic therapy, and once VT occurs it may result in cardiac arrest and death. Cardiac arrest has been reported in almost 75% of individuals in cardiac crisis.
Ventricular arrhythmias and unexplained cardiovascular collapse during crises are the leading causes of mortality. Unexplained sudden death during sleep not associated with metabolic crisis has also been reported [
Affected individuals can also demonstrate echocardiographic changes during metabolic crisis, including ventricular dilatation and heart failure (systolic dysfunction). About 70% of those in cardiac crisis can develop heart failure. Systolic dysfunction can develop rapidly, and systolic function should be monitored closely during crisis. Both arrhythmias and cardiomyopathy are reversible, and full recovery is possible if the crisis resolves [
Supraventricular tachycardias and heart block have also been rarely reported.
To date, no clear genotype-phenotype correlations have been reported.
TANGO2 deficiency is also referred to as "metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration" (MECRCN) in OMIM.
The worldwide prevalence of TANGO2 deficiency is estimated to be 1:1,000,000, likely affecting more than 8,000 individuals.
## Clinical Description
TANGO2 deficiency is characterized by developmental delay, intellectual disability, TANGO2 spells, acute metabolic crises, and risk of cardiac crisis. Additional features can include seizures, hypothyroidism, exotropia, and constipation. To date, more than 100 individuals have been identified with biallelic pathogenic variants in
TANGO2 Deficiency Disorder: Frequency of Select Features
Spasticity of lower extremities, hyperreflexia, and clonus are also frequently seen. Poor coordination, progressively unsteady gait, and clumsiness are frequently reported in ambulatory individuals, even prior to the first episode of rhabdomyolysis [
Almost all individuals with TANGO2 deficiency have speech difficulties, including dysarthria and slurred or nasal speech.
Individuals present with rhabdomyolysis with elevated CK, ALT, and AST and may have dark urine due to myoglobinuria. Complications from rhabdomyolysis are not common, even though CK levels can be significantly elevated in some individuals (>200,000 U/L). Severe hypoglycemia can be present in addition to mild hyperammonemia, elevated aldolase, elevated troponin, elevated lactate, and evidence of ketoacidosis and lactic acidosis on urine organic acids. Although an acylcarnitine profile during an acute metabolic crisis may show elevated C14:1, C14:2, and C16:1, no consistent acylcarnitine abnormalities have been identified in large studies [
While cardiac workup including EKG is normal at baseline, during an acute metabolic crisis, EKG changes are noted. The most common EKG finding is prolonged QTc that is often markedly prolonged (>500 msec). Transient type 1 Brugada pattern can also be seen in 33% of individuals.
B-complex vitamins or multivitamins may prevent metabolic crises in individuals with TANGO2 deficiency [
During cardiac crisis, life-threatening recalcitrant ventricular tachycardia (VT) or torsade de pointes can occur, leading to hemodynamic instability and cardiac arrest. These events can occur when an individual is acutely ill but also in those who appear stable with improving CK levels. The presence of marked QTc prolongation, type I Brugada pattern, and ventricular ectopy are concerning, as they precede VT (QTc >500 msec is associated with an increased risk of torsade de pointes). VT is difficult to control, often unresponsive to typical anti-arrhythmic therapy, and once VT occurs it may result in cardiac arrest and death. Cardiac arrest has been reported in almost 75% of individuals in cardiac crisis.
Ventricular arrhythmias and unexplained cardiovascular collapse during crises are the leading causes of mortality. Unexplained sudden death during sleep not associated with metabolic crisis has also been reported [
Affected individuals can also demonstrate echocardiographic changes during metabolic crisis, including ventricular dilatation and heart failure (systolic dysfunction). About 70% of those in cardiac crisis can develop heart failure. Systolic dysfunction can develop rapidly, and systolic function should be monitored closely during crisis. Both arrhythmias and cardiomyopathy are reversible, and full recovery is possible if the crisis resolves [
Supraventricular tachycardias and heart block have also been rarely reported.
## Genotype-Phenotype Correlations
To date, no clear genotype-phenotype correlations have been reported.
## Nomenclature
TANGO2 deficiency is also referred to as "metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration" (MECRCN) in OMIM.
## Prevalence
The worldwide prevalence of TANGO2 deficiency is estimated to be 1:1,000,000, likely affecting more than 8,000 individuals.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Disorders to Consider in the Differential Diagnosis of TANGO2 Deficiency
AR = autosomal recessive; CK = creatine phosphokinase; MOI = mode of inheritance; QTc = corrected QT
## Management
No clinical practice guidelines for TANGO2 deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with TANGO2 deficiency in
To establish the extent of disease and needs in all other individuals diagnosed with TANGO2 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with TANGO2 Deficiency in Acute Metabolic Crisis
Blood glucose, CK, ALT, AST
Chemistry panel incl serum Mg
Plasma lactate & troponin
Global MAPS™ if feasible
Continuous bedside rhythm monitoring should be initiated immediately & continued throughout hospitalization to assess for ventricular ectopy & life-threatening ventricular arrhythmias until crisis resolves.
Obtain EKG to measure QTc & assess for Brugada pattern
Echocardiogram to assess ventricular function
ALT = alanine transaminase; AST = aspartate transaminase; CK = creatine phosphokinase; Global MAPS™ = Global Metabolomic Assisted Pathway Screen; ICU = intensive care unit; IV = intravenous; Mg = magnesium; NGT = nasogastric tube; QTc = corrected QT; T4 = thyroxine; TPN = total parenteral nutrition; TSH = thyroid-stimulating hormone
Recommended Evaluations Following Initial Diagnosis in Individuals with TANGO2 Deficiency
Developmental assessment
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Referral to neurologist if seizures are suspected or spasticity is present
EEG if seizures are suspected
Referral to cardiac electrophysiologist or cardiologist (if electrophysiologist is not available)
EKG & Holter
Echocardiogram
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; T4 = thyroxine; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for TANGO2 deficiency.
Daily supplementation with a multivitamin including all eight B vitamins or a B-complex vitamin at the minimum recommended daily allowance for age (see
B-complex vitamins include thiamine (B
The exact dose of B vitamin supplementation required to prevent crises is not known.
B vitamins are water soluble with no known side effects, with the exception of high doses of vitamin B
Minimum Recommended Daily Allowance for B Vitamins by Age and Sex
Adapted from
Early management during acute metabolic crises is paramount to prevent the development of a cardiac crisis. A plan for emergency treatment should be in place for families and physicians to initiate appropriate steps to suppress acute catabolism and promote hydration to minimize the risk of life-threatening rhabdomyolysis and cardiac tachyarrhythmias (see
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
Treatment for Acute Metabolic Crises in Individuals with TANGO2 Deficiency
Well appearing;
Eating regular diet;
Normal glucose levels on admission;
EKG QTc <480 msec.
New diagnosis;
Ill appearing or obtunded;
Not tolerating oral diet;
Hypoglycemia;
EKG QTc ≥480 msec.
IV fluids w/dextrose
Echocardiogram to assess cardiac function
Adjust IV fluid rate to avoid pulmonary edema; if normal cardiac function, IV fluids at 1.5-2x maintenance rate
Treat as necessary to maintain normal potassium.
Maintain serum Mg >2.2 mg/dL w/oral or IV Mg supplements.
Vitamin supplementation is critical, especially folate (vitamin B
Administer vitamins via NGT, IV, or TPN if not tolerating PO.
IV fluids w/dextrose alone will not reverse rhabdomyolysis; nutritional support has been shown to ↓ CK levels.
Acute kidney injury & complications from rhabdomyolysis are rare.
Obtain EKG to assess QTc & presence of Brugada pattern. Daily EKG to monitor QTc & assess for presence of Brugada pattern. Continue daily EKG until steady downward trend in serum CK; if QTc becomes >480 msec, transfer to ICU.
IV Mg supplementation to maintain serum Mg >2.2 mg/dL. If QTc is 2.2 mg/dL using oral or intermittent IV supplements. If QTc is >480 msec, then replace Mg using continuous IV.
Continuous rhythm monitoring to assess for PVCs & arrhythmias, particularly VT. Transfer to ICU if any premature ventricular contractions are noted.
Obtain echocardiogram to assess function & adjust IVF rate based on cardiac function. Repeat echocardiogram every 3 days; echocardiogram less frequently after downward trend in serum CK; echocardiogram prior to discharge.
Multivitamin supplementation upon admission incl all 8 B vitamins (minimum RDA for age); can be given in IV fluids until oral assessment completed.
Monitor oral intake. Nutritional support (oral, NGT, or TPN) can prevent evolving cardiac crisis; most sick persons do not consume enough by oral diet.
Ensure access to ICU w/ECMO in case of recalcitrant arrhythmia.
Use of continuous monitoring leads in the high precordial placement can be helpful to visualize the intermittent development of a type I Brugada pattern.
Avoid QT-prolonging drugs.
Immediate transfer to ICU
Continuous IV Mg to maintain serum Mg >2.2 mg/dL
Keep isoproterenol bolus (0.03-0.05 µg/kg) at bedside.
Consider isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy.
IV multivitamin supplement incl all 8 B vitamins
PVCs are harbingers of VT, which can develop rapidly once PVCs are noted.
Beta-adrenergic blockers have not been shown to be consistently effective. VT tends to occur at lower heart rates, & hence avoiding beta-adrenergic blockers should be strongly considered.
Avoid QT-prolonging drugs during crisis.
Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone)
Continuous bedside rhythm monitoring
Direct current cardioversion is acutely effective, but VT/VF is often recurrent & recalcitrant.
Administer isoproterenol bolus (0.03-0.05 µg/kg) & repeat if necessary.
Continuous isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy. VT tends to occur more frequently at lower heart rates.
IV multivitamin supplement incl all 8 B vitamins.
Consider 1 g IV folate (B
In those w/ICD w/atrial lead, use atrial pacing at rates faster than sinus. Be cautious of development of tachycardia-induced cardiomyopathy.
If TdPs continues despite first-line approaches, consider pacing using temporary esophageal pacing lead or ventricular lead.
If VT/TdPs is recalcitrant, have ECMO treatment available.
Temporary or surgical sympathetic denervation can be considered for recalcitrant VT.
Consider IV calcium channel blocker.
Consider avoiding beta-adrenergic blockers.
Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone).
VT is extremely difficult to manage in persons w/TANGO2 deficiency. VT is often unresponsive to standard therapies; in addition, standard therapies can make VT worse.
Continue monitoring.
Continue nutritional support & vitamin supplementation.
Maintain Mg >2.2 mg/dL.
Consider inotropic support that ↑ heart rate (see treatments for
Isoproterenol can be given, but use w/caution for extended periods & monitor cardiac function closely.
Atrial pacing can be used as an alternative to isoproterenol.
If inotropic support is required, one that ↑ heart rate such as epinephrine should be considered, as this may help minimize VT/TdPs
Atrial pacing is preferred over ventricular pacing.
A transesophageal lead can be used in an emergency or for short-term pacing until a temporary wire can be placed.
Consider inotropic support that ↑ heart rate (epinephrine), which may potentially prevent arrhythmias. Be careful w/fluid resuscitation to avoid pulmonary edema.
Consider ECMO, since full recovery has been shown when metabolic crisis resolves.
Systolic dysfunction can develop rapidly.
Pulseless electrical activity & cardiac shock leading to death have occurred despite treatment.
Continue Mg as first-line treatment.
Consider inotropic support that ↑ heart rate (epinephrine).
CK = creatine phosphokinase; ECMO = extracorporeal membrane oxygenation; GI = gastrointestinal; ICD = implantable cardioverter defibrillator; ICU = intensive care unit; IV = intravenous; Mg = magnesium; NGT = nasogastric tube; PO = per os (by mouth); PVC = premature ventricular contraction; RDA = recommended daily allowance; TdPs = torsade de pointes; TPN = total parenteral nutrition; VF = ventricular fibrillation; VT = ventricular tachycardia
Cardiac rhythmic disturbances that occur in individuals with TANGO2 deficiency are predominantly ventricular tachyarrhythmias.
This can be done with a temporary pacing wire for longer-term pacing.
Routine (Non-Acute) Treatment in Individuals with TANGO2 Deficiency
Consider referral to neurologist.
Avoid ketogenic diet; acute metabolic crises after initiation of ketogenic diet have been reported.
Valproate has been safely & successfully used.
Feeding therapy as needed
Gastrostomy tube feeding as needed
Standard treatments for constipation
Consider gastrostomy tube in persons w/issues maintaining adequate nutritional intake to ensure adequate nutrition & vitamin intake during times of illness.
No restriction in diet is required. Frequent snacking is typically reported.
Avoid fasting.
ASM = anti-seizure medication; ICD = implantable cardioverter defibrillator
Questions regarding definitive treatment remain.
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. In individuals with TANGO2 deficiency, receptive language skills are generally better than expressive language skills, and this should be taken into account during assessments.
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 complications.
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, consider involving appropriate specialists to aid in management of baclofen, Botox
Recommended Surveillance for Individuals with TANGO2 Deficiency
Physical medicine, OT/PT assessment of mobility, spasticity, self-help skills
Monitor developmental progress & educational needs.
EKG & Holter
Echocardiogram
EKG (baseline)
Echocardiogram (baseline)
OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone
Avoid triggers for TANGO2 spells and acute metabolic crisis (e.g., fasting, dehydration, overexertion, exposure to excessive heat, ketogenic diet, infections).
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing for the familial
See
Search
Vitamin dosing and which specific vitamins help alleviate manifestations of TANGO2 deficiency are still under investigation.
• Blood glucose, CK, ALT, AST
• Chemistry panel incl serum Mg
• Plasma lactate & troponin
• Global MAPS™ if feasible
• Continuous bedside rhythm monitoring should be initiated immediately & continued throughout hospitalization to assess for ventricular ectopy & life-threatening ventricular arrhythmias until crisis resolves.
• Obtain EKG to measure QTc & assess for Brugada pattern
• Echocardiogram to assess ventricular function
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Referral to neurologist if seizures are suspected or spasticity is present
• EEG if seizures are suspected
• Referral to cardiac electrophysiologist or cardiologist (if electrophysiologist is not available)
• EKG & Holter
• Echocardiogram
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• B-complex vitamins include thiamine (B
• The exact dose of B vitamin supplementation required to prevent crises is not known.
• B vitamins are water soluble with no known side effects, with the exception of high doses of vitamin B
• Well appearing;
• Eating regular diet;
• Normal glucose levels on admission;
• EKG QTc <480 msec.
• New diagnosis;
• Ill appearing or obtunded;
• Not tolerating oral diet;
• Hypoglycemia;
• EKG QTc ≥480 msec.
• IV fluids w/dextrose
• Echocardiogram to assess cardiac function
• Adjust IV fluid rate to avoid pulmonary edema; if normal cardiac function, IV fluids at 1.5-2x maintenance rate
• Treat as necessary to maintain normal potassium.
• Maintain serum Mg >2.2 mg/dL w/oral or IV Mg supplements.
• Vitamin supplementation is critical, especially folate (vitamin B
• Administer vitamins via NGT, IV, or TPN if not tolerating PO.
• IV fluids w/dextrose alone will not reverse rhabdomyolysis; nutritional support has been shown to ↓ CK levels.
• Acute kidney injury & complications from rhabdomyolysis are rare.
• Obtain EKG to assess QTc & presence of Brugada pattern. Daily EKG to monitor QTc & assess for presence of Brugada pattern. Continue daily EKG until steady downward trend in serum CK; if QTc becomes >480 msec, transfer to ICU.
• IV Mg supplementation to maintain serum Mg >2.2 mg/dL. If QTc is 2.2 mg/dL using oral or intermittent IV supplements. If QTc is >480 msec, then replace Mg using continuous IV.
• Continuous rhythm monitoring to assess for PVCs & arrhythmias, particularly VT. Transfer to ICU if any premature ventricular contractions are noted.
• Obtain echocardiogram to assess function & adjust IVF rate based on cardiac function. Repeat echocardiogram every 3 days; echocardiogram less frequently after downward trend in serum CK; echocardiogram prior to discharge.
• Multivitamin supplementation upon admission incl all 8 B vitamins (minimum RDA for age); can be given in IV fluids until oral assessment completed.
• Monitor oral intake. Nutritional support (oral, NGT, or TPN) can prevent evolving cardiac crisis; most sick persons do not consume enough by oral diet.
• Ensure access to ICU w/ECMO in case of recalcitrant arrhythmia.
• Use of continuous monitoring leads in the high precordial placement can be helpful to visualize the intermittent development of a type I Brugada pattern.
• Avoid QT-prolonging drugs.
• Immediate transfer to ICU
• Continuous IV Mg to maintain serum Mg >2.2 mg/dL
• Keep isoproterenol bolus (0.03-0.05 µg/kg) at bedside.
• Consider isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy.
• IV multivitamin supplement incl all 8 B vitamins
• PVCs are harbingers of VT, which can develop rapidly once PVCs are noted.
• Beta-adrenergic blockers have not been shown to be consistently effective. VT tends to occur at lower heart rates, & hence avoiding beta-adrenergic blockers should be strongly considered.
• Avoid QT-prolonging drugs during crisis.
• Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone)
• Continuous bedside rhythm monitoring
• Direct current cardioversion is acutely effective, but VT/VF is often recurrent & recalcitrant.
• Administer isoproterenol bolus (0.03-0.05 µg/kg) & repeat if necessary.
• Continuous isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy. VT tends to occur more frequently at lower heart rates.
• IV multivitamin supplement incl all 8 B vitamins.
• Consider 1 g IV folate (B
• In those w/ICD w/atrial lead, use atrial pacing at rates faster than sinus. Be cautious of development of tachycardia-induced cardiomyopathy.
• If TdPs continues despite first-line approaches, consider pacing using temporary esophageal pacing lead or ventricular lead.
• If VT/TdPs is recalcitrant, have ECMO treatment available.
• Temporary or surgical sympathetic denervation can be considered for recalcitrant VT.
• Consider IV calcium channel blocker.
• Consider avoiding beta-adrenergic blockers.
• Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone).
• VT is extremely difficult to manage in persons w/TANGO2 deficiency. VT is often unresponsive to standard therapies; in addition, standard therapies can make VT worse.
• Continue monitoring.
• Continue nutritional support & vitamin supplementation.
• Maintain Mg >2.2 mg/dL.
• Consider inotropic support that ↑ heart rate (see treatments for
• Isoproterenol can be given, but use w/caution for extended periods & monitor cardiac function closely.
• Atrial pacing can be used as an alternative to isoproterenol.
• If inotropic support is required, one that ↑ heart rate such as epinephrine should be considered, as this may help minimize VT/TdPs
• Atrial pacing is preferred over ventricular pacing.
• A transesophageal lead can be used in an emergency or for short-term pacing until a temporary wire can be placed.
• Consider inotropic support that ↑ heart rate (epinephrine), which may potentially prevent arrhythmias. Be careful w/fluid resuscitation to avoid pulmonary edema.
• Consider ECMO, since full recovery has been shown when metabolic crisis resolves.
• Systolic dysfunction can develop rapidly.
• Pulseless electrical activity & cardiac shock leading to death have occurred despite treatment.
• Continue Mg as first-line treatment.
• Consider inotropic support that ↑ heart rate (epinephrine).
• Consider referral to neurologist.
• Avoid ketogenic diet; acute metabolic crises after initiation of ketogenic diet have been reported.
• Valproate has been safely & successfully used.
• Feeding therapy as needed
• Gastrostomy tube feeding as needed
• Standard treatments for constipation
• Consider gastrostomy tube in persons w/issues maintaining adequate nutritional intake to ensure adequate nutrition & vitamin intake during times of illness.
• No restriction in diet is required. Frequent snacking is typically reported.
• Avoid fasting.
• 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 complications.
• 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, consider involving appropriate specialists to aid in management of baclofen, Botox
• Physical medicine, OT/PT assessment of mobility, spasticity, self-help skills
• Monitor developmental progress & educational needs.
• EKG & Holter
• Echocardiogram
• EKG (baseline)
• Echocardiogram (baseline)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TANGO2 deficiency in
To establish the extent of disease and needs in all other individuals diagnosed with TANGO2 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with TANGO2 Deficiency in Acute Metabolic Crisis
Blood glucose, CK, ALT, AST
Chemistry panel incl serum Mg
Plasma lactate & troponin
Global MAPS™ if feasible
Continuous bedside rhythm monitoring should be initiated immediately & continued throughout hospitalization to assess for ventricular ectopy & life-threatening ventricular arrhythmias until crisis resolves.
Obtain EKG to measure QTc & assess for Brugada pattern
Echocardiogram to assess ventricular function
ALT = alanine transaminase; AST = aspartate transaminase; CK = creatine phosphokinase; Global MAPS™ = Global Metabolomic Assisted Pathway Screen; ICU = intensive care unit; IV = intravenous; Mg = magnesium; NGT = nasogastric tube; QTc = corrected QT; T4 = thyroxine; TPN = total parenteral nutrition; TSH = thyroid-stimulating hormone
Recommended Evaluations Following Initial Diagnosis in Individuals with TANGO2 Deficiency
Developmental assessment
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Referral to neurologist if seizures are suspected or spasticity is present
EEG if seizures are suspected
Referral to cardiac electrophysiologist or cardiologist (if electrophysiologist is not available)
EKG & Holter
Echocardiogram
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; T4 = thyroxine; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Blood glucose, CK, ALT, AST
• Chemistry panel incl serum Mg
• Plasma lactate & troponin
• Global MAPS™ if feasible
• Continuous bedside rhythm monitoring should be initiated immediately & continued throughout hospitalization to assess for ventricular ectopy & life-threatening ventricular arrhythmias until crisis resolves.
• Obtain EKG to measure QTc & assess for Brugada pattern
• Echocardiogram to assess ventricular function
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Referral to neurologist if seizures are suspected or spasticity is present
• EEG if seizures are suspected
• Referral to cardiac electrophysiologist or cardiologist (if electrophysiologist is not available)
• EKG & Holter
• Echocardiogram
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for TANGO2 deficiency.
Daily supplementation with a multivitamin including all eight B vitamins or a B-complex vitamin at the minimum recommended daily allowance for age (see
B-complex vitamins include thiamine (B
The exact dose of B vitamin supplementation required to prevent crises is not known.
B vitamins are water soluble with no known side effects, with the exception of high doses of vitamin B
Minimum Recommended Daily Allowance for B Vitamins by Age and Sex
Adapted from
Early management during acute metabolic crises is paramount to prevent the development of a cardiac crisis. A plan for emergency treatment should be in place for families and physicians to initiate appropriate steps to suppress acute catabolism and promote hydration to minimize the risk of life-threatening rhabdomyolysis and cardiac tachyarrhythmias (see
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
Treatment for Acute Metabolic Crises in Individuals with TANGO2 Deficiency
Well appearing;
Eating regular diet;
Normal glucose levels on admission;
EKG QTc <480 msec.
New diagnosis;
Ill appearing or obtunded;
Not tolerating oral diet;
Hypoglycemia;
EKG QTc ≥480 msec.
IV fluids w/dextrose
Echocardiogram to assess cardiac function
Adjust IV fluid rate to avoid pulmonary edema; if normal cardiac function, IV fluids at 1.5-2x maintenance rate
Treat as necessary to maintain normal potassium.
Maintain serum Mg >2.2 mg/dL w/oral or IV Mg supplements.
Vitamin supplementation is critical, especially folate (vitamin B
Administer vitamins via NGT, IV, or TPN if not tolerating PO.
IV fluids w/dextrose alone will not reverse rhabdomyolysis; nutritional support has been shown to ↓ CK levels.
Acute kidney injury & complications from rhabdomyolysis are rare.
Obtain EKG to assess QTc & presence of Brugada pattern. Daily EKG to monitor QTc & assess for presence of Brugada pattern. Continue daily EKG until steady downward trend in serum CK; if QTc becomes >480 msec, transfer to ICU.
IV Mg supplementation to maintain serum Mg >2.2 mg/dL. If QTc is 2.2 mg/dL using oral or intermittent IV supplements. If QTc is >480 msec, then replace Mg using continuous IV.
Continuous rhythm monitoring to assess for PVCs & arrhythmias, particularly VT. Transfer to ICU if any premature ventricular contractions are noted.
Obtain echocardiogram to assess function & adjust IVF rate based on cardiac function. Repeat echocardiogram every 3 days; echocardiogram less frequently after downward trend in serum CK; echocardiogram prior to discharge.
Multivitamin supplementation upon admission incl all 8 B vitamins (minimum RDA for age); can be given in IV fluids until oral assessment completed.
Monitor oral intake. Nutritional support (oral, NGT, or TPN) can prevent evolving cardiac crisis; most sick persons do not consume enough by oral diet.
Ensure access to ICU w/ECMO in case of recalcitrant arrhythmia.
Use of continuous monitoring leads in the high precordial placement can be helpful to visualize the intermittent development of a type I Brugada pattern.
Avoid QT-prolonging drugs.
Immediate transfer to ICU
Continuous IV Mg to maintain serum Mg >2.2 mg/dL
Keep isoproterenol bolus (0.03-0.05 µg/kg) at bedside.
Consider isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy.
IV multivitamin supplement incl all 8 B vitamins
PVCs are harbingers of VT, which can develop rapidly once PVCs are noted.
Beta-adrenergic blockers have not been shown to be consistently effective. VT tends to occur at lower heart rates, & hence avoiding beta-adrenergic blockers should be strongly considered.
Avoid QT-prolonging drugs during crisis.
Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone)
Continuous bedside rhythm monitoring
Direct current cardioversion is acutely effective, but VT/VF is often recurrent & recalcitrant.
Administer isoproterenol bolus (0.03-0.05 µg/kg) & repeat if necessary.
Continuous isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy. VT tends to occur more frequently at lower heart rates.
IV multivitamin supplement incl all 8 B vitamins.
Consider 1 g IV folate (B
In those w/ICD w/atrial lead, use atrial pacing at rates faster than sinus. Be cautious of development of tachycardia-induced cardiomyopathy.
If TdPs continues despite first-line approaches, consider pacing using temporary esophageal pacing lead or ventricular lead.
If VT/TdPs is recalcitrant, have ECMO treatment available.
Temporary or surgical sympathetic denervation can be considered for recalcitrant VT.
Consider IV calcium channel blocker.
Consider avoiding beta-adrenergic blockers.
Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone).
VT is extremely difficult to manage in persons w/TANGO2 deficiency. VT is often unresponsive to standard therapies; in addition, standard therapies can make VT worse.
Continue monitoring.
Continue nutritional support & vitamin supplementation.
Maintain Mg >2.2 mg/dL.
Consider inotropic support that ↑ heart rate (see treatments for
Isoproterenol can be given, but use w/caution for extended periods & monitor cardiac function closely.
Atrial pacing can be used as an alternative to isoproterenol.
If inotropic support is required, one that ↑ heart rate such as epinephrine should be considered, as this may help minimize VT/TdPs
Atrial pacing is preferred over ventricular pacing.
A transesophageal lead can be used in an emergency or for short-term pacing until a temporary wire can be placed.
Consider inotropic support that ↑ heart rate (epinephrine), which may potentially prevent arrhythmias. Be careful w/fluid resuscitation to avoid pulmonary edema.
Consider ECMO, since full recovery has been shown when metabolic crisis resolves.
Systolic dysfunction can develop rapidly.
Pulseless electrical activity & cardiac shock leading to death have occurred despite treatment.
Continue Mg as first-line treatment.
Consider inotropic support that ↑ heart rate (epinephrine).
CK = creatine phosphokinase; ECMO = extracorporeal membrane oxygenation; GI = gastrointestinal; ICD = implantable cardioverter defibrillator; ICU = intensive care unit; IV = intravenous; Mg = magnesium; NGT = nasogastric tube; PO = per os (by mouth); PVC = premature ventricular contraction; RDA = recommended daily allowance; TdPs = torsade de pointes; TPN = total parenteral nutrition; VF = ventricular fibrillation; VT = ventricular tachycardia
Cardiac rhythmic disturbances that occur in individuals with TANGO2 deficiency are predominantly ventricular tachyarrhythmias.
This can be done with a temporary pacing wire for longer-term pacing.
Routine (Non-Acute) Treatment in Individuals with TANGO2 Deficiency
Consider referral to neurologist.
Avoid ketogenic diet; acute metabolic crises after initiation of ketogenic diet have been reported.
Valproate has been safely & successfully used.
Feeding therapy as needed
Gastrostomy tube feeding as needed
Standard treatments for constipation
Consider gastrostomy tube in persons w/issues maintaining adequate nutritional intake to ensure adequate nutrition & vitamin intake during times of illness.
No restriction in diet is required. Frequent snacking is typically reported.
Avoid fasting.
ASM = anti-seizure medication; ICD = implantable cardioverter defibrillator
Questions regarding definitive treatment remain.
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. In individuals with TANGO2 deficiency, receptive language skills are generally better than expressive language skills, and this should be taken into account during assessments.
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 complications.
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, consider involving appropriate specialists to aid in management of baclofen, Botox
• B-complex vitamins include thiamine (B
• The exact dose of B vitamin supplementation required to prevent crises is not known.
• B vitamins are water soluble with no known side effects, with the exception of high doses of vitamin B
• Well appearing;
• Eating regular diet;
• Normal glucose levels on admission;
• EKG QTc <480 msec.
• New diagnosis;
• Ill appearing or obtunded;
• Not tolerating oral diet;
• Hypoglycemia;
• EKG QTc ≥480 msec.
• IV fluids w/dextrose
• Echocardiogram to assess cardiac function
• Adjust IV fluid rate to avoid pulmonary edema; if normal cardiac function, IV fluids at 1.5-2x maintenance rate
• Treat as necessary to maintain normal potassium.
• Maintain serum Mg >2.2 mg/dL w/oral or IV Mg supplements.
• Vitamin supplementation is critical, especially folate (vitamin B
• Administer vitamins via NGT, IV, or TPN if not tolerating PO.
• IV fluids w/dextrose alone will not reverse rhabdomyolysis; nutritional support has been shown to ↓ CK levels.
• Acute kidney injury & complications from rhabdomyolysis are rare.
• Obtain EKG to assess QTc & presence of Brugada pattern. Daily EKG to monitor QTc & assess for presence of Brugada pattern. Continue daily EKG until steady downward trend in serum CK; if QTc becomes >480 msec, transfer to ICU.
• IV Mg supplementation to maintain serum Mg >2.2 mg/dL. If QTc is 2.2 mg/dL using oral or intermittent IV supplements. If QTc is >480 msec, then replace Mg using continuous IV.
• Continuous rhythm monitoring to assess for PVCs & arrhythmias, particularly VT. Transfer to ICU if any premature ventricular contractions are noted.
• Obtain echocardiogram to assess function & adjust IVF rate based on cardiac function. Repeat echocardiogram every 3 days; echocardiogram less frequently after downward trend in serum CK; echocardiogram prior to discharge.
• Multivitamin supplementation upon admission incl all 8 B vitamins (minimum RDA for age); can be given in IV fluids until oral assessment completed.
• Monitor oral intake. Nutritional support (oral, NGT, or TPN) can prevent evolving cardiac crisis; most sick persons do not consume enough by oral diet.
• Ensure access to ICU w/ECMO in case of recalcitrant arrhythmia.
• Use of continuous monitoring leads in the high precordial placement can be helpful to visualize the intermittent development of a type I Brugada pattern.
• Avoid QT-prolonging drugs.
• Immediate transfer to ICU
• Continuous IV Mg to maintain serum Mg >2.2 mg/dL
• Keep isoproterenol bolus (0.03-0.05 µg/kg) at bedside.
• Consider isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy.
• IV multivitamin supplement incl all 8 B vitamins
• PVCs are harbingers of VT, which can develop rapidly once PVCs are noted.
• Beta-adrenergic blockers have not been shown to be consistently effective. VT tends to occur at lower heart rates, & hence avoiding beta-adrenergic blockers should be strongly considered.
• Avoid QT-prolonging drugs during crisis.
• Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone)
• Continuous bedside rhythm monitoring
• Direct current cardioversion is acutely effective, but VT/VF is often recurrent & recalcitrant.
• Administer isoproterenol bolus (0.03-0.05 µg/kg) & repeat if necessary.
• Continuous isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy. VT tends to occur more frequently at lower heart rates.
• IV multivitamin supplement incl all 8 B vitamins.
• Consider 1 g IV folate (B
• In those w/ICD w/atrial lead, use atrial pacing at rates faster than sinus. Be cautious of development of tachycardia-induced cardiomyopathy.
• If TdPs continues despite first-line approaches, consider pacing using temporary esophageal pacing lead or ventricular lead.
• If VT/TdPs is recalcitrant, have ECMO treatment available.
• Temporary or surgical sympathetic denervation can be considered for recalcitrant VT.
• Consider IV calcium channel blocker.
• Consider avoiding beta-adrenergic blockers.
• Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone).
• VT is extremely difficult to manage in persons w/TANGO2 deficiency. VT is often unresponsive to standard therapies; in addition, standard therapies can make VT worse.
• Continue monitoring.
• Continue nutritional support & vitamin supplementation.
• Maintain Mg >2.2 mg/dL.
• Consider inotropic support that ↑ heart rate (see treatments for
• Isoproterenol can be given, but use w/caution for extended periods & monitor cardiac function closely.
• Atrial pacing can be used as an alternative to isoproterenol.
• If inotropic support is required, one that ↑ heart rate such as epinephrine should be considered, as this may help minimize VT/TdPs
• Atrial pacing is preferred over ventricular pacing.
• A transesophageal lead can be used in an emergency or for short-term pacing until a temporary wire can be placed.
• Consider inotropic support that ↑ heart rate (epinephrine), which may potentially prevent arrhythmias. Be careful w/fluid resuscitation to avoid pulmonary edema.
• Consider ECMO, since full recovery has been shown when metabolic crisis resolves.
• Systolic dysfunction can develop rapidly.
• Pulseless electrical activity & cardiac shock leading to death have occurred despite treatment.
• Continue Mg as first-line treatment.
• Consider inotropic support that ↑ heart rate (epinephrine).
• Consider referral to neurologist.
• Avoid ketogenic diet; acute metabolic crises after initiation of ketogenic diet have been reported.
• Valproate has been safely & successfully used.
• Feeding therapy as needed
• Gastrostomy tube feeding as needed
• Standard treatments for constipation
• Consider gastrostomy tube in persons w/issues maintaining adequate nutritional intake to ensure adequate nutrition & vitamin intake during times of illness.
• No restriction in diet is required. Frequent snacking is typically reported.
• Avoid fasting.
• 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 complications.
• 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, consider involving appropriate specialists to aid in management of baclofen, Botox
## Targeted Therapy
Daily supplementation with a multivitamin including all eight B vitamins or a B-complex vitamin at the minimum recommended daily allowance for age (see
B-complex vitamins include thiamine (B
The exact dose of B vitamin supplementation required to prevent crises is not known.
B vitamins are water soluble with no known side effects, with the exception of high doses of vitamin B
Minimum Recommended Daily Allowance for B Vitamins by Age and Sex
Adapted from
• B-complex vitamins include thiamine (B
• The exact dose of B vitamin supplementation required to prevent crises is not known.
• B vitamins are water soluble with no known side effects, with the exception of high doses of vitamin B
## Supportive Care
Early management during acute metabolic crises is paramount to prevent the development of a cardiac crisis. A plan for emergency treatment should be in place for families and physicians to initiate appropriate steps to suppress acute catabolism and promote hydration to minimize the risk of life-threatening rhabdomyolysis and cardiac tachyarrhythmias (see
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
Treatment for Acute Metabolic Crises in Individuals with TANGO2 Deficiency
Well appearing;
Eating regular diet;
Normal glucose levels on admission;
EKG QTc <480 msec.
New diagnosis;
Ill appearing or obtunded;
Not tolerating oral diet;
Hypoglycemia;
EKG QTc ≥480 msec.
IV fluids w/dextrose
Echocardiogram to assess cardiac function
Adjust IV fluid rate to avoid pulmonary edema; if normal cardiac function, IV fluids at 1.5-2x maintenance rate
Treat as necessary to maintain normal potassium.
Maintain serum Mg >2.2 mg/dL w/oral or IV Mg supplements.
Vitamin supplementation is critical, especially folate (vitamin B
Administer vitamins via NGT, IV, or TPN if not tolerating PO.
IV fluids w/dextrose alone will not reverse rhabdomyolysis; nutritional support has been shown to ↓ CK levels.
Acute kidney injury & complications from rhabdomyolysis are rare.
Obtain EKG to assess QTc & presence of Brugada pattern. Daily EKG to monitor QTc & assess for presence of Brugada pattern. Continue daily EKG until steady downward trend in serum CK; if QTc becomes >480 msec, transfer to ICU.
IV Mg supplementation to maintain serum Mg >2.2 mg/dL. If QTc is 2.2 mg/dL using oral or intermittent IV supplements. If QTc is >480 msec, then replace Mg using continuous IV.
Continuous rhythm monitoring to assess for PVCs & arrhythmias, particularly VT. Transfer to ICU if any premature ventricular contractions are noted.
Obtain echocardiogram to assess function & adjust IVF rate based on cardiac function. Repeat echocardiogram every 3 days; echocardiogram less frequently after downward trend in serum CK; echocardiogram prior to discharge.
Multivitamin supplementation upon admission incl all 8 B vitamins (minimum RDA for age); can be given in IV fluids until oral assessment completed.
Monitor oral intake. Nutritional support (oral, NGT, or TPN) can prevent evolving cardiac crisis; most sick persons do not consume enough by oral diet.
Ensure access to ICU w/ECMO in case of recalcitrant arrhythmia.
Use of continuous monitoring leads in the high precordial placement can be helpful to visualize the intermittent development of a type I Brugada pattern.
Avoid QT-prolonging drugs.
Immediate transfer to ICU
Continuous IV Mg to maintain serum Mg >2.2 mg/dL
Keep isoproterenol bolus (0.03-0.05 µg/kg) at bedside.
Consider isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy.
IV multivitamin supplement incl all 8 B vitamins
PVCs are harbingers of VT, which can develop rapidly once PVCs are noted.
Beta-adrenergic blockers have not been shown to be consistently effective. VT tends to occur at lower heart rates, & hence avoiding beta-adrenergic blockers should be strongly considered.
Avoid QT-prolonging drugs during crisis.
Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone)
Continuous bedside rhythm monitoring
Direct current cardioversion is acutely effective, but VT/VF is often recurrent & recalcitrant.
Administer isoproterenol bolus (0.03-0.05 µg/kg) & repeat if necessary.
Continuous isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy. VT tends to occur more frequently at lower heart rates.
IV multivitamin supplement incl all 8 B vitamins.
Consider 1 g IV folate (B
In those w/ICD w/atrial lead, use atrial pacing at rates faster than sinus. Be cautious of development of tachycardia-induced cardiomyopathy.
If TdPs continues despite first-line approaches, consider pacing using temporary esophageal pacing lead or ventricular lead.
If VT/TdPs is recalcitrant, have ECMO treatment available.
Temporary or surgical sympathetic denervation can be considered for recalcitrant VT.
Consider IV calcium channel blocker.
Consider avoiding beta-adrenergic blockers.
Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone).
VT is extremely difficult to manage in persons w/TANGO2 deficiency. VT is often unresponsive to standard therapies; in addition, standard therapies can make VT worse.
Continue monitoring.
Continue nutritional support & vitamin supplementation.
Maintain Mg >2.2 mg/dL.
Consider inotropic support that ↑ heart rate (see treatments for
Isoproterenol can be given, but use w/caution for extended periods & monitor cardiac function closely.
Atrial pacing can be used as an alternative to isoproterenol.
If inotropic support is required, one that ↑ heart rate such as epinephrine should be considered, as this may help minimize VT/TdPs
Atrial pacing is preferred over ventricular pacing.
A transesophageal lead can be used in an emergency or for short-term pacing until a temporary wire can be placed.
Consider inotropic support that ↑ heart rate (epinephrine), which may potentially prevent arrhythmias. Be careful w/fluid resuscitation to avoid pulmonary edema.
Consider ECMO, since full recovery has been shown when metabolic crisis resolves.
Systolic dysfunction can develop rapidly.
Pulseless electrical activity & cardiac shock leading to death have occurred despite treatment.
Continue Mg as first-line treatment.
Consider inotropic support that ↑ heart rate (epinephrine).
CK = creatine phosphokinase; ECMO = extracorporeal membrane oxygenation; GI = gastrointestinal; ICD = implantable cardioverter defibrillator; ICU = intensive care unit; IV = intravenous; Mg = magnesium; NGT = nasogastric tube; PO = per os (by mouth); PVC = premature ventricular contraction; RDA = recommended daily allowance; TdPs = torsade de pointes; TPN = total parenteral nutrition; VF = ventricular fibrillation; VT = ventricular tachycardia
Cardiac rhythmic disturbances that occur in individuals with TANGO2 deficiency are predominantly ventricular tachyarrhythmias.
This can be done with a temporary pacing wire for longer-term pacing.
Routine (Non-Acute) Treatment in Individuals with TANGO2 Deficiency
Consider referral to neurologist.
Avoid ketogenic diet; acute metabolic crises after initiation of ketogenic diet have been reported.
Valproate has been safely & successfully used.
Feeding therapy as needed
Gastrostomy tube feeding as needed
Standard treatments for constipation
Consider gastrostomy tube in persons w/issues maintaining adequate nutritional intake to ensure adequate nutrition & vitamin intake during times of illness.
No restriction in diet is required. Frequent snacking is typically reported.
Avoid fasting.
ASM = anti-seizure medication; ICD = implantable cardioverter defibrillator
Questions regarding definitive treatment remain.
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. In individuals with TANGO2 deficiency, receptive language skills are generally better than expressive language skills, and this should be taken into account during assessments.
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 complications.
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, consider involving appropriate specialists to aid in management of baclofen, Botox
• Well appearing;
• Eating regular diet;
• Normal glucose levels on admission;
• EKG QTc <480 msec.
• New diagnosis;
• Ill appearing or obtunded;
• Not tolerating oral diet;
• Hypoglycemia;
• EKG QTc ≥480 msec.
• IV fluids w/dextrose
• Echocardiogram to assess cardiac function
• Adjust IV fluid rate to avoid pulmonary edema; if normal cardiac function, IV fluids at 1.5-2x maintenance rate
• Treat as necessary to maintain normal potassium.
• Maintain serum Mg >2.2 mg/dL w/oral or IV Mg supplements.
• Vitamin supplementation is critical, especially folate (vitamin B
• Administer vitamins via NGT, IV, or TPN if not tolerating PO.
• IV fluids w/dextrose alone will not reverse rhabdomyolysis; nutritional support has been shown to ↓ CK levels.
• Acute kidney injury & complications from rhabdomyolysis are rare.
• Obtain EKG to assess QTc & presence of Brugada pattern. Daily EKG to monitor QTc & assess for presence of Brugada pattern. Continue daily EKG until steady downward trend in serum CK; if QTc becomes >480 msec, transfer to ICU.
• IV Mg supplementation to maintain serum Mg >2.2 mg/dL. If QTc is 2.2 mg/dL using oral or intermittent IV supplements. If QTc is >480 msec, then replace Mg using continuous IV.
• Continuous rhythm monitoring to assess for PVCs & arrhythmias, particularly VT. Transfer to ICU if any premature ventricular contractions are noted.
• Obtain echocardiogram to assess function & adjust IVF rate based on cardiac function. Repeat echocardiogram every 3 days; echocardiogram less frequently after downward trend in serum CK; echocardiogram prior to discharge.
• Multivitamin supplementation upon admission incl all 8 B vitamins (minimum RDA for age); can be given in IV fluids until oral assessment completed.
• Monitor oral intake. Nutritional support (oral, NGT, or TPN) can prevent evolving cardiac crisis; most sick persons do not consume enough by oral diet.
• Ensure access to ICU w/ECMO in case of recalcitrant arrhythmia.
• Use of continuous monitoring leads in the high precordial placement can be helpful to visualize the intermittent development of a type I Brugada pattern.
• Avoid QT-prolonging drugs.
• Immediate transfer to ICU
• Continuous IV Mg to maintain serum Mg >2.2 mg/dL
• Keep isoproterenol bolus (0.03-0.05 µg/kg) at bedside.
• Consider isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy.
• IV multivitamin supplement incl all 8 B vitamins
• PVCs are harbingers of VT, which can develop rapidly once PVCs are noted.
• Beta-adrenergic blockers have not been shown to be consistently effective. VT tends to occur at lower heart rates, & hence avoiding beta-adrenergic blockers should be strongly considered.
• Avoid QT-prolonging drugs during crisis.
• Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone)
• Continuous bedside rhythm monitoring
• Direct current cardioversion is acutely effective, but VT/VF is often recurrent & recalcitrant.
• Administer isoproterenol bolus (0.03-0.05 µg/kg) & repeat if necessary.
• Continuous isoproterenol infusion at 0.01-1 µg/kg/min. Titrate to maintain heart rates that suppress ectopy. VT tends to occur more frequently at lower heart rates.
• IV multivitamin supplement incl all 8 B vitamins.
• Consider 1 g IV folate (B
• In those w/ICD w/atrial lead, use atrial pacing at rates faster than sinus. Be cautious of development of tachycardia-induced cardiomyopathy.
• If TdPs continues despite first-line approaches, consider pacing using temporary esophageal pacing lead or ventricular lead.
• If VT/TdPs is recalcitrant, have ECMO treatment available.
• Temporary or surgical sympathetic denervation can be considered for recalcitrant VT.
• Consider IV calcium channel blocker.
• Consider avoiding beta-adrenergic blockers.
• Avoid sodium channel blockers (e.g., lidocaine, procainamide, amiodarone).
• VT is extremely difficult to manage in persons w/TANGO2 deficiency. VT is often unresponsive to standard therapies; in addition, standard therapies can make VT worse.
• Continue monitoring.
• Continue nutritional support & vitamin supplementation.
• Maintain Mg >2.2 mg/dL.
• Consider inotropic support that ↑ heart rate (see treatments for
• Isoproterenol can be given, but use w/caution for extended periods & monitor cardiac function closely.
• Atrial pacing can be used as an alternative to isoproterenol.
• If inotropic support is required, one that ↑ heart rate such as epinephrine should be considered, as this may help minimize VT/TdPs
• Atrial pacing is preferred over ventricular pacing.
• A transesophageal lead can be used in an emergency or for short-term pacing until a temporary wire can be placed.
• Consider inotropic support that ↑ heart rate (epinephrine), which may potentially prevent arrhythmias. Be careful w/fluid resuscitation to avoid pulmonary edema.
• Consider ECMO, since full recovery has been shown when metabolic crisis resolves.
• Systolic dysfunction can develop rapidly.
• Pulseless electrical activity & cardiac shock leading to death have occurred despite treatment.
• Continue Mg as first-line treatment.
• Consider inotropic support that ↑ heart rate (epinephrine).
• Consider referral to neurologist.
• Avoid ketogenic diet; acute metabolic crises after initiation of ketogenic diet have been reported.
• Valproate has been safely & successfully used.
• Feeding therapy as needed
• Gastrostomy tube feeding as needed
• Standard treatments for constipation
• Consider gastrostomy tube in persons w/issues maintaining adequate nutritional intake to ensure adequate nutrition & vitamin intake during times of illness.
• No restriction in diet is required. Frequent snacking is typically reported.
• Avoid fasting.
• 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 complications.
• 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, consider involving appropriate specialists to aid in management of baclofen, Botox
##
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. In individuals with TANGO2 deficiency, receptive language skills are generally better than expressive language skills, and this should be taken into account during assessments.
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 complications.
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, consider involving appropriate specialists to aid in management of baclofen, Botox
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset complications.
• 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, consider involving appropriate specialists to aid in management of baclofen, Botox
## Surveillance
Recommended Surveillance for Individuals with TANGO2 Deficiency
Physical medicine, OT/PT assessment of mobility, spasticity, self-help skills
Monitor developmental progress & educational needs.
EKG & Holter
Echocardiogram
EKG (baseline)
Echocardiogram (baseline)
OT = occupational therapy; PT = physical therapy; T4 = thyroxine; TSH = thyroid-stimulating hormone
• Physical medicine, OT/PT assessment of mobility, spasticity, self-help skills
• Monitor developmental progress & educational needs.
• EKG & Holter
• Echocardiogram
• EKG (baseline)
• Echocardiogram (baseline)
## Agents/Circumstances to Avoid
Avoid triggers for TANGO2 spells and acute metabolic crisis (e.g., fasting, dehydration, overexertion, exposure to excessive heat, ketogenic diet, infections).
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing for the familial
See
## Therapies Under Investigation
Search
Vitamin dosing and which specific vitamins help alleviate manifestations of TANGO2 deficiency are still under investigation.
## Genetic Counseling
TANGO2 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. (This is frequently observed in TANGO2 deficiency.)
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 to date, are not known to be at risk of developing the disorder.
If both parents are known to be heterozygous for a
Significant differences in clinical manifestations have been observed among sibs with the same biallelic
Heterozygotes (carriers) are asymptomatic and to date, are not known to be 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 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. (This is frequently observed in TANGO2 deficiency.)
• 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. (This is frequently observed in TANGO2 deficiency.)
• 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 to date, are not known to be 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. (This is frequently observed in TANGO2 deficiency.)
• 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 differences in clinical manifestations have been observed among sibs with the same biallelic
• Heterozygotes (carriers) are asymptomatic and to date, are not known to be 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
TANGO2 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. (This is frequently observed in TANGO2 deficiency.)
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 to date, are not known to be at risk of developing the disorder.
If both parents are known to be heterozygous for a
Significant differences in clinical manifestations have been observed among sibs with the same biallelic
Heterozygotes (carriers) are asymptomatic and to date, are not known to be at risk of developing the disorder.
• 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. (This is frequently observed in TANGO2 deficiency.)
• 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. (This is frequently observed in TANGO2 deficiency.)
• 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 to date, are not known to be 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. (This is frequently observed in TANGO2 deficiency.)
• 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 differences in clinical manifestations have been observed among sibs with the same biallelic
• Heterozygotes (carriers) are asymptomatic and to date, are not known to be 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 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
300 Plaza Middlesex
Middletown CT 06457
•
• 300 Plaza Middlesex
• Middletown CT 06457
•
## Molecular Genetics
TANGO2 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TANGO2 Deficiency (
Notable TANGO2 Pathogenic Variants
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Notable TANGO2 Pathogenic Variants
Variants listed in the table have been provided by the authors.
## Chapter Notes
We thank the TANGO2 Research Foundation for their continued support.
Lindsay Burrage, MD, PhD (2018-present)Kevin Glinton, MD, PhD (2023-present)Brett Graham, MD, PhD (2018-present)Kimberly Houck, MD (2023-present)Alfonso Hoyos-Martinez, MD (2023-present)Seema R Lalani, MD (2018-present)Yi-Chen Lai, MD; Baylor College of Medicine (2018-2023)Christina Y Miyake, MD, MS (2018-present)Brandy Rawls-Castillo, MS, RD, LD (2023-present)Fernando Scaglia, MD (2018-present)Claudia Soler-Alfonso, MD (2018-present)Yaping Yang, PhD (2018-present)
9 March 2023 (sw) Comprehensive update posted live
20 December 2018 (ma) Comprehensive update posted live
25 January 2018 (sw) Review posted live
23 September 2017 (srl) Original submission
•
•
•
•
•
•
•
•
•
•
• 9 March 2023 (sw) Comprehensive update posted live
• 20 December 2018 (ma) Comprehensive update posted live
• 25 January 2018 (sw) Review posted live
• 23 September 2017 (srl) Original submission
## Author Notes
•
•
•
•
•
•
•
•
•
•
## Acknowledgments
We thank the TANGO2 Research Foundation for their continued support.
## Author History
Lindsay Burrage, MD, PhD (2018-present)Kevin Glinton, MD, PhD (2023-present)Brett Graham, MD, PhD (2018-present)Kimberly Houck, MD (2023-present)Alfonso Hoyos-Martinez, MD (2023-present)Seema R Lalani, MD (2018-present)Yi-Chen Lai, MD; Baylor College of Medicine (2018-2023)Christina Y Miyake, MD, MS (2018-present)Brandy Rawls-Castillo, MS, RD, LD (2023-present)Fernando Scaglia, MD (2018-present)Claudia Soler-Alfonso, MD (2018-present)Yaping Yang, PhD (2018-present)
## Revision History
9 March 2023 (sw) Comprehensive update posted live
20 December 2018 (ma) Comprehensive update posted live
25 January 2018 (sw) Review posted live
23 September 2017 (srl) Original submission
• 9 March 2023 (sw) Comprehensive update posted live
• 20 December 2018 (ma) Comprehensive update posted live
• 25 January 2018 (sw) Review posted live
• 23 September 2017 (srl) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
25/1/2018
|
9/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tar
|
tar
|
[
"TAR Syndrome",
"TAR Syndrome",
"RNA-binding protein 8A",
"RBM8A",
"Thrombocytopenia Absent Radius Syndrome"
] |
Thrombocytopenia Absent Radius Syndrome
|
Florence Petit, Simon Boussion
|
Summary Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur. The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region including TAR syndrome is caused by compound heterozygosity for a null allele and an If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an If one parent is known to be heterozygous for a null allele and the other parent has biallelic If one parent is known to be heterozygous for an Individuals who are heterozygotes (carriers) for one TAR syndrome-related pathogenic variant (either an
|
## Diagnosis
Thrombocytopenia absent radius (TAR) syndrome
Bilateral absence of the radii with the presence of both thumbs
Thrombocytopenia, usually <50 platelets/nL (normal range: 150-400 platelets/nL)
The diagnosis of TAR syndrome
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 Thrombocytopenia Absent Radius Syndrome
CMA = chromosomal microarray; CNV = copy number variant
See
See
Copy number variation analysis detects the 1q21.1 deletion containing
Both a 200-kb and a more common 500-kb TAR syndrome-associated deletion have been described. Because the deletion often extends beyond the 200-kb minimally deleted region [
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
Sequence analysis requires inclusion of the 5' UTR, 3' UTR, and intronic regions. A heterozygous
• Bilateral absence of the radii with the presence of both thumbs
• Thrombocytopenia, usually <50 platelets/nL (normal range: 150-400 platelets/nL)
## Suggestive Findings
Thrombocytopenia absent radius (TAR) syndrome
Bilateral absence of the radii with the presence of both thumbs
Thrombocytopenia, usually <50 platelets/nL (normal range: 150-400 platelets/nL)
• Bilateral absence of the radii with the presence of both thumbs
• Thrombocytopenia, usually <50 platelets/nL (normal range: 150-400 platelets/nL)
## Establishing the Diagnosis
The diagnosis of TAR syndrome
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 Thrombocytopenia Absent Radius Syndrome
CMA = chromosomal microarray; CNV = copy number variant
See
See
Copy number variation analysis detects the 1q21.1 deletion containing
Both a 200-kb and a more common 500-kb TAR syndrome-associated deletion have been described. Because the deletion often extends beyond the 200-kb minimally deleted region [
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
Sequence analysis requires inclusion of the 5' UTR, 3' UTR, and intronic regions. A heterozygous
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Thrombocytopenia Absent Radius Syndrome
CMA = chromosomal microarray; CNV = copy number variant
See
See
Copy number variation analysis detects the 1q21.1 deletion containing
Both a 200-kb and a more common 500-kb TAR syndrome-associated deletion have been described. Because the deletion often extends beyond the 200-kb minimally deleted region [
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
Sequence analysis requires inclusion of the 5' UTR, 3' UTR, and intronic regions. A heterozygous
## Clinical Characteristics
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia that is generally transient. Additional manifestations can include cow's milk allergy and anomalies of the lower limbs, ribs, vertebrae, heart, and genitourinary system. To date, more than 150 individuals have been reported with a TAR-related
Thrombocytopenia Absent Radius Syndrome: Frequency of Select Features
The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth-finger clinodactyly is common.
Lower limbs are affected in almost half of indiviuals with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
Cow's milk allergy is common, and can be associated with exacerbation of thrombocytopenia, either by direct immunoglobulin E (IgE) immune-mediated mechanism or secondary to increased gastrointestinal bleeding caused by loss of coagulation proteins [
Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm
Individuals with TAR syndrome have one null allele and a hypomorphic allele on opposite homologous chromosomes. The hypomorphic allele is usually located in the 5' UTR, intron 1, or 3' UTR.
Only limited genotype-phenotype correlations have been described:
The
Individuals with intronic hypomorphic allele
Penetrance appears to be complete in individuals who have biallelic
The prevalence of TAR syndrome is estimated at 1:100,000 to 1:200,000, but it is likely more frequent in populations of African descent, due to a recurrent
• The
• Individuals with intronic hypomorphic allele
## Clinical Description
Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia that is generally transient. Additional manifestations can include cow's milk allergy and anomalies of the lower limbs, ribs, vertebrae, heart, and genitourinary system. To date, more than 150 individuals have been reported with a TAR-related
Thrombocytopenia Absent Radius Syndrome: Frequency of Select Features
The upper limbs may also have hypoplasia or absence of the ulnae, humeri, and shoulder girdles. Fingers may show syndactyly, and fifth-finger clinodactyly is common.
Lower limbs are affected in almost half of indiviuals with TAR syndrome; hip dislocation, coxa valga, femoral and/or tibial torsion, genu varum, and absence of the patella are common findings. The most severe limb involvement is tetraphocomelia.
Cow's milk allergy is common, and can be associated with exacerbation of thrombocytopenia, either by direct immunoglobulin E (IgE) immune-mediated mechanism or secondary to increased gastrointestinal bleeding caused by loss of coagulation proteins [
Leukemoid reactions have been reported in some individuals with TAR syndrome, with white blood cell counts exceeding 35,000 cells/mm
## Genotype-Phenotype Correlations
Individuals with TAR syndrome have one null allele and a hypomorphic allele on opposite homologous chromosomes. The hypomorphic allele is usually located in the 5' UTR, intron 1, or 3' UTR.
Only limited genotype-phenotype correlations have been described:
The
Individuals with intronic hypomorphic allele
• The
• Individuals with intronic hypomorphic allele
## Penetrance
Penetrance appears to be complete in individuals who have biallelic
## Prevalence
The prevalence of TAR syndrome is estimated at 1:100,000 to 1:200,000, but it is likely more frequent in populations of African descent, due to a recurrent
## Genetically Related Disorders
No phenotypes other than those discussed in this
No phenotypes other than those discussed in this
## Differential Diagnosis
Hereditary disorders of known genetic cause that include radial aplasia as a component manifestation and can show some overlap with thrombocytopenia absent radius (TAR) syndrome are summarized in
Genetic Disorders Associated with Radial Aplasia in the Differential Diagnosis of Thrombocytopenia Absent Radius Syndrome
AD = autosomal dominant; AR = autosomal recessive; BMF = bone marrow failure; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (
## Management
Clinical practice guidelines for anesthesia and dental care in thrombocytopenia absent radius (TAR) syndrome have been published [
To establish the extent of disease and needs in an individual diagnosed with TAR syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Thrombocytopenia Absent Radius Syndrome
Clinical assessment for upper- & lower-extremity anomalies
X-rays if needed by orthopedist
Bone marrow biopsies to confirm hypomegakaryocytic bone marrow are typically no longer performed.
Platelet function is somewhat impaired, suggesting that drugs such as NSAIDS (incl aspirin) should be avoided or monitored carefully.
Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
Assess for episodes of severe gastroenteritis.
Cow's milk allergy or intolerance is frequent; consider non-cow's milk formula.
Cow's milk allergy & gastroenteritis may precipitate thrombocytopenia.
Renal ultrasound exam
Assess renal function w/serum electrolyte concentrations, BUN, & creatinine in those w/renal malformation.
Pelvic ultrasound exam in females
Community or
Social work involvement for parental support;
Home nursing referral.
BUN = blood urea nitrogen; MOI = mode of inheritance; NSAIDs = nonsteroidal anti-inflammatory drugs; TAR = thrombocytopenia absent radius
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Thrombocytopenia Absent Radius Syndrome
In newborns, platelet transfusion threshold is unknown.
In older persons, platelet transfusion threshold is <10 platelets/nL.
Frequent platelet transfusion can lead to alloimmunization & ↑ risk of infection.
Bone marrow transplantation is generally not indicated, given transient nature of thrombocytopenia in TAR syndrome.
TAR = thrombocytopenia absent radius
Recommended Surveillance for Individuals with Thrombocytopenia Absent Radius Syndrome
Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
Assess for episodes of severe gastroenteritis.
BUN = blood urea nitrogen
Avoid cow's milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children).
Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs including aspirin should be avoided or used with caution.
See
Fewer than ten pregnancies have been reported in women with TAR syndrome [
Other considerations during pregnancy include potential difficulties with administration of regional anesthetics (given potential difficulties with vascular access) and difficulties accessing the airway for general anesthesia [
Search
• Clinical assessment for upper- & lower-extremity anomalies
• X-rays if needed by orthopedist
• Bone marrow biopsies to confirm hypomegakaryocytic bone marrow are typically no longer performed.
• Platelet function is somewhat impaired, suggesting that drugs such as NSAIDS (incl aspirin) should be avoided or monitored carefully.
• Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
• Assess for episodes of severe gastroenteritis.
• Cow's milk allergy or intolerance is frequent; consider non-cow's milk formula.
• Cow's milk allergy & gastroenteritis may precipitate thrombocytopenia.
• Renal ultrasound exam
• Assess renal function w/serum electrolyte concentrations, BUN, & creatinine in those w/renal malformation.
• Pelvic ultrasound exam in females
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• In newborns, platelet transfusion threshold is unknown.
• In older persons, platelet transfusion threshold is <10 platelets/nL.
• Frequent platelet transfusion can lead to alloimmunization & ↑ risk of infection.
• Bone marrow transplantation is generally not indicated, given transient nature of thrombocytopenia in TAR syndrome.
• Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
• Assess for episodes of severe gastroenteritis.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TAR syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Thrombocytopenia Absent Radius Syndrome
Clinical assessment for upper- & lower-extremity anomalies
X-rays if needed by orthopedist
Bone marrow biopsies to confirm hypomegakaryocytic bone marrow are typically no longer performed.
Platelet function is somewhat impaired, suggesting that drugs such as NSAIDS (incl aspirin) should be avoided or monitored carefully.
Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
Assess for episodes of severe gastroenteritis.
Cow's milk allergy or intolerance is frequent; consider non-cow's milk formula.
Cow's milk allergy & gastroenteritis may precipitate thrombocytopenia.
Renal ultrasound exam
Assess renal function w/serum electrolyte concentrations, BUN, & creatinine in those w/renal malformation.
Pelvic ultrasound exam in females
Community or
Social work involvement for parental support;
Home nursing referral.
BUN = blood urea nitrogen; MOI = mode of inheritance; NSAIDs = nonsteroidal anti-inflammatory drugs; TAR = thrombocytopenia absent radius
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Clinical assessment for upper- & lower-extremity anomalies
• X-rays if needed by orthopedist
• Bone marrow biopsies to confirm hypomegakaryocytic bone marrow are typically no longer performed.
• Platelet function is somewhat impaired, suggesting that drugs such as NSAIDS (incl aspirin) should be avoided or monitored carefully.
• Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
• Assess for episodes of severe gastroenteritis.
• Cow's milk allergy or intolerance is frequent; consider non-cow's milk formula.
• Cow's milk allergy & gastroenteritis may precipitate thrombocytopenia.
• Renal ultrasound exam
• Assess renal function w/serum electrolyte concentrations, BUN, & creatinine in those w/renal malformation.
• Pelvic ultrasound exam in females
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Thrombocytopenia Absent Radius Syndrome
In newborns, platelet transfusion threshold is unknown.
In older persons, platelet transfusion threshold is <10 platelets/nL.
Frequent platelet transfusion can lead to alloimmunization & ↑ risk of infection.
Bone marrow transplantation is generally not indicated, given transient nature of thrombocytopenia in TAR syndrome.
TAR = thrombocytopenia absent radius
• In newborns, platelet transfusion threshold is unknown.
• In older persons, platelet transfusion threshold is <10 platelets/nL.
• Frequent platelet transfusion can lead to alloimmunization & ↑ risk of infection.
• Bone marrow transplantation is generally not indicated, given transient nature of thrombocytopenia in TAR syndrome.
## Surveillance
Recommended Surveillance for Individuals with Thrombocytopenia Absent Radius Syndrome
Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
Assess for episodes of severe gastroenteritis.
BUN = blood urea nitrogen
• Assess for poor weight gain, failure to thrive, vomiting, or diarrhea.
• Assess for episodes of severe gastroenteritis.
## Agents/Circumstances to Avoid
Avoid cow's milk to reduce the severity of gastroenteritis and associated thrombocytopenia (in older children).
Platelet function is somewhat impaired, suggesting that drugs such as nonsteroidal anti-inflammatory drugs including aspirin should be avoided or used with caution.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Fewer than ten pregnancies have been reported in women with TAR syndrome [
Other considerations during pregnancy include potential difficulties with administration of regional anesthetics (given potential difficulties with vascular access) and difficulties accessing the airway for general anesthesia [
## Therapies Under Investigation
Search
## Genetic Counseling
Thrombocytopenia absent radius (TAR) syndrome is caused by compound heterozygosity for a null allele (most often a 500-kb deletion or 200-kb deletion including
The parents of an individual with TAR syndrome are typically unaffected. One parent is presumed to be a carrier of an
Rarely, one parent of an individual with TAR syndrome is a carrier of an
Approximately 50%-75% of individuals with TAR syndrome inherited the 200-kb minimally deleted region at 1q21.1 from an unaffected parent. The deletion occurs
Molecular genetic testing for the TAR syndrome-related pathogenic variants identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk assessment.
Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an
If one parent is known to be heterozygous for a null allele and the other parent has biallelic
If one parent is known to be heterozygous for an
Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
An individual with TAR syndrome will transmit either a null allele or an
If the reproductive partner of an individual with TAR syndrome is a carrier of a heterozygous
If the reproductive partner of an individual with TAR syndrome has biallelic (homozygous or compound heterozygous)
Carrier testing for at-risk relatives requires prior identification of the TAR syndrome-related pathogenic variants in the family.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 of a TAR syndrome-related pathogenic variant, or are at risk of being carriers.
Once the causative null allele and
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 TAR syndrome are typically unaffected. One parent is presumed to be a carrier of an
• Rarely, one parent of an individual with TAR syndrome is a carrier of an
• Approximately 50%-75% of individuals with TAR syndrome inherited the 200-kb minimally deleted region at 1q21.1 from an unaffected parent. The deletion occurs
• Molecular genetic testing for the TAR syndrome-related pathogenic variants identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk assessment.
• Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
• If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an
• If one parent is known to be heterozygous for a null allele and the other parent has biallelic
• If one parent is known to be heterozygous for an
• Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
• An individual with TAR syndrome will transmit either a null allele or an
• If the reproductive partner of an individual with TAR syndrome is a carrier of a heterozygous
• If the reproductive partner of an individual with TAR syndrome has biallelic (homozygous or compound 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 carriers of a TAR syndrome-related pathogenic variant, or are at risk of being carriers.
## Mode of Inheritance
Thrombocytopenia absent radius (TAR) syndrome is caused by compound heterozygosity for a null allele (most often a 500-kb deletion or 200-kb deletion including
## Risk to Family Members
The parents of an individual with TAR syndrome are typically unaffected. One parent is presumed to be a carrier of an
Rarely, one parent of an individual with TAR syndrome is a carrier of an
Approximately 50%-75% of individuals with TAR syndrome inherited the 200-kb minimally deleted region at 1q21.1 from an unaffected parent. The deletion occurs
Molecular genetic testing for the TAR syndrome-related pathogenic variants identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk assessment.
Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an
If one parent is known to be heterozygous for a null allele and the other parent has biallelic
If one parent is known to be heterozygous for an
Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
An individual with TAR syndrome will transmit either a null allele or an
If the reproductive partner of an individual with TAR syndrome is a carrier of a heterozygous
If the reproductive partner of an individual with TAR syndrome has biallelic (homozygous or compound heterozygous)
• The parents of an individual with TAR syndrome are typically unaffected. One parent is presumed to be a carrier of an
• Rarely, one parent of an individual with TAR syndrome is a carrier of an
• Approximately 50%-75% of individuals with TAR syndrome inherited the 200-kb minimally deleted region at 1q21.1 from an unaffected parent. The deletion occurs
• Molecular genetic testing for the TAR syndrome-related pathogenic variants identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk assessment.
• Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
• If one parent is known to be heterozygous for a null allele and the other parent is heterozygous for an
• If one parent is known to be heterozygous for a null allele and the other parent has biallelic
• If one parent is known to be heterozygous for an
• Individuals who are heterozygotes (carriers) for one TAR-syndrome related pathogenic variant (either an
• An individual with TAR syndrome will transmit either a null allele or an
• If the reproductive partner of an individual with TAR syndrome is a carrier of a heterozygous
• If the reproductive partner of an individual with TAR syndrome has biallelic (homozygous or compound heterozygous)
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the TAR syndrome-related pathogenic variants in the family.
## 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 of a TAR syndrome-related pathogenic variant, 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 of a TAR syndrome-related pathogenic variant, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the causative null allele and
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
Thrombocytopenia Absent Radius Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Thrombocytopenia Absent Radius Syndrome (
Thrombocytopenia absent radius (TAR) syndrome is the result of loss of function of RBM8A, reducing the expression of RBM8A below a critical threshold [
The consequences of insufficiency on the functioning of the EJC and its repercussions on cellular metabolism are not fully understood. Although the EJC appears to act ubiquitously, the reason why some tissues are consistently and severely affected by downregulation of RBM8A while other organs are spared is unknown. It has been shown, for example, that hypomorphic alleles lead to a loss of expression in osteoblastic and megakaryocytic cells in vitro, but not in human vascular cells [
Several authors have studied the mechanism of thrombocytopenia in TAR syndrome by studying the thrombopoietin receptor (TPO) signaling pathway. In TAR syndrome, thrombocytopenia is characterized by a very low rate of megakaryocytic precursors within the bone marrow. While the TPO signaling pathway plays a major role in the control of megakaryocyte differentiation, to date no association between it and TAR syndrome has been demonstrated [
Notable
Variants listed in the table have been provided by the authors.
Note that individuals homozygous for these hypomorphic alleles do not have features of TAR syndrome.
## Molecular Pathogenesis
Thrombocytopenia absent radius (TAR) syndrome is the result of loss of function of RBM8A, reducing the expression of RBM8A below a critical threshold [
The consequences of insufficiency on the functioning of the EJC and its repercussions on cellular metabolism are not fully understood. Although the EJC appears to act ubiquitously, the reason why some tissues are consistently and severely affected by downregulation of RBM8A while other organs are spared is unknown. It has been shown, for example, that hypomorphic alleles lead to a loss of expression in osteoblastic and megakaryocytic cells in vitro, but not in human vascular cells [
Several authors have studied the mechanism of thrombocytopenia in TAR syndrome by studying the thrombopoietin receptor (TPO) signaling pathway. In TAR syndrome, thrombocytopenia is characterized by a very low rate of megakaryocytic precursors within the bone marrow. While the TPO signaling pathway plays a major role in the control of megakaryocyte differentiation, to date no association between it and TAR syndrome has been demonstrated [
Notable
Variants listed in the table have been provided by the authors.
Note that individuals homozygous for these hypomorphic alleles do not have features of TAR syndrome.
## Chapter Notes
Prof Florence Petit (
Prof Petit is also interested in hearing from clinicians treating families affected by TAR syndrome in whom no causative variants have been identified through molecular genetic testing.
Contact Prof Petit to inquire about review of
We acknowledge all clinicians and researchers, patients, and families who contributed to a better description and understanding of TAR syndrome.
Simon Boussion, MD (2022-present)Florence Petit, MD, PhD (2022-present)Helga V Toriello, PhD; Michigan State University (2009-2022)
2 November 2023 (aa) Revision: clarification of disease mechanism (loss of function) in
25 August 2022 (sw) Comprehensive update posted live
8 December 2016 (sw) Comprehensive update posted live
29 May 2014 (me) Comprehensive update posted live
2 February 2012 (me) Comprehensive update posted live
8 December 2009 (me) Review posted live
26 August 2009 (hvt) Original submission
• 2 November 2023 (aa) Revision: clarification of disease mechanism (loss of function) in
• 25 August 2022 (sw) Comprehensive update posted live
• 8 December 2016 (sw) Comprehensive update posted live
• 29 May 2014 (me) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 8 December 2009 (me) Review posted live
• 26 August 2009 (hvt) Original submission
## Author Notes
Prof Florence Petit (
Prof Petit is also interested in hearing from clinicians treating families affected by TAR syndrome in whom no causative variants have been identified through molecular genetic testing.
Contact Prof Petit to inquire about review of
## Acknowledgments
We acknowledge all clinicians and researchers, patients, and families who contributed to a better description and understanding of TAR syndrome.
## Author History
Simon Boussion, MD (2022-present)Florence Petit, MD, PhD (2022-present)Helga V Toriello, PhD; Michigan State University (2009-2022)
## Revision History
2 November 2023 (aa) Revision: clarification of disease mechanism (loss of function) in
25 August 2022 (sw) Comprehensive update posted live
8 December 2016 (sw) Comprehensive update posted live
29 May 2014 (me) Comprehensive update posted live
2 February 2012 (me) Comprehensive update posted live
8 December 2009 (me) Review posted live
26 August 2009 (hvt) Original submission
• 2 November 2023 (aa) Revision: clarification of disease mechanism (loss of function) in
• 25 August 2022 (sw) Comprehensive update posted live
• 8 December 2016 (sw) Comprehensive update posted live
• 29 May 2014 (me) Comprehensive update posted live
• 2 February 2012 (me) Comprehensive update posted live
• 8 December 2009 (me) Review posted live
• 26 August 2009 (hvt) Original submission
## References
## Literature Cited
|
[] |
8/12/2009
|
25/8/2022
|
2/11/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
tardbp-als
|
tardbp-als
|
[
"TARDBP-ALS-FTD",
"TDP-43 Proteinopathy",
"TDP-43-Linked ALS-FTD",
"TARDBP-ALS-FTD",
"TDP-43 Proteinopathy",
"TDP-43-Linked ALS-FTD",
"TAR DNA-binding protein 43",
"TARDBP",
"TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia"
] |
Vaishnavi Manohar, Leon Crowley, Jemeen Sreedharan
|
Summary In this The diagnosis of
|
With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that heterozygous
A phenotypic spectrum encompassing pure (i.e., without other neurologic findings) amyotrophic lateral sclerosis (ALS; most common), pure (i.e., without other neurologic findings) frontotemporal dementia (FTD; rare), a combination of ALS and FTD, and atypical neurologic phenotypes;
Variable expressivity such that individuals with the same
Because
• A phenotypic spectrum encompassing pure (i.e., without other neurologic findings) amyotrophic lateral sclerosis (ALS; most common), pure (i.e., without other neurologic findings) frontotemporal dementia (FTD; rare), a combination of ALS and FTD, and atypical neurologic phenotypes;
• Variable expressivity such that individuals with the same
## Diagnosis
In this
No consensus clinical diagnostic criteria for
Note: Simplex cases (i.e., a single occurrence of the disorder in a family) are sometimes referred to as "sporadic cases"; however, because the term "sporadic" can imply a non-recurring (non-genetic) cause, the term "simplex" is preferred.
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 [
Because
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 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 the proposed mechanism that leads to
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Note: Simplex cases (i.e., a single occurrence of the disorder in a family) are sometimes referred to as "sporadic cases"; however, because the term "sporadic" can imply a non-recurring (non-genetic) cause, the term "simplex" is preferred.
## 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 [
Because
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 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 the proposed mechanism that leads to
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Most individuals with
Of note, the clinical presentation of
Features are ranked as common if present >33%, if frequency was mentioned.
For
Since most
However, of note:
Three
Phenotypic manifestations of
In a Sardinian population with FTD caused by
While there is intra- and interfamilial variability in the age of onset and clinical presentation, the pathogenicity of missense variants shows high penetrance and males and females are similarly affected [
Dedicated online databases provide detailed information on geographic prevalence of
• Three
• Phenotypic manifestations of
• In a Sardinian population with FTD caused by
## Clinical Description
Most individuals with
Of note, the clinical presentation of
Features are ranked as common if present >33%, if frequency was mentioned.
For
## Genotype-Phenotype Correlations
Since most
However, of note:
Three
Phenotypic manifestations of
In a Sardinian population with FTD caused by
• Three
• Phenotypic manifestations of
• In a Sardinian population with FTD caused by
## Penetrance
While there is intra- and interfamilial variability in the age of onset and clinical presentation, the pathogenicity of missense variants shows high penetrance and males and females are similarly affected [
## Prevalence
Dedicated online databases provide detailed information on geographic prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
A rare ALS/FTD variant of
• A rare ALS/FTD variant of
## Management
No clinical practice guidelines specifically for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
UMN involvement: assess spasticity, Babinski signs, hyperreflexia
LMN involvement: assess weakness, amyotrophy, fasciculations; perform EMG
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
Physical therapy needs
Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
Fine motor function (e.g., hands, feet, face, fingers, & toes)
Home adaptations for ADL & safety
Attention to possible alcohol or drug abuse
Referral for psychiatric eval as needed
Community or online
Social work involvement for parental support;
Home nursing referral.
Early discussion of advanced care planning
The affected person's perspective & burden must be taken into account for clinical decision making.
The presence of cognitive impairment may raise ethical concerns.
ADL = activities of daily living; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Individuals with
Treatment of Manifestations in Individuals with
When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs
Often a temporizing measure until individuals become more apathetic.
Risk of iatrogenic extrapyramidal syndrome
ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor; UMN = upper motor neuron
Based on
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, see
Recommended Surveillance for Individuals with
ADL = activities of daily living; NA = not applicable; OT = occupational therapy; PT = physical therapy
Based on
See
Incidences of ALS complicating pregnancy are rare, since the disease shows a low prevalence in women of reproductive age. Pregnancy of women with ALS is largely complicated by impaired respiratory function due to underlying weakness of the diaphragm and costal muscles and the increased respiratory and weight-bearing demands of pregnancy [
Maternal ALS is not particularly associated with poorer neonatal outcomes and does not appear to cause obstetric complications. However, the method and timing of delivery may be influenced by the severity of the disease. Although natural delivery is possible because ALS does not affect the motor and sensory nerves of the uterus [
Riluzole can safely be used during pregnancy, although its effects on fetal growth remain unclear. Low birth weight has previously been reported when used during pregnancy [
See
Unlike
Search
• UMN involvement: assess spasticity, Babinski signs, hyperreflexia
• LMN involvement: assess weakness, amyotrophy, fasciculations; perform EMG
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• Physical therapy needs
• Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
• Fine motor function (e.g., hands, feet, face, fingers, & toes)
• Home adaptations for ADL & safety
• Attention to possible alcohol or drug abuse
• Referral for psychiatric eval as needed
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
• Early discussion of advanced care planning
• The affected person's perspective & burden must be taken into account for clinical decision making.
• The presence of cognitive impairment may raise ethical concerns.
• When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs
• Often a temporizing measure until individuals become more apathetic.
• Risk of iatrogenic extrapyramidal syndrome
## 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
UMN involvement: assess spasticity, Babinski signs, hyperreflexia
LMN involvement: assess weakness, amyotrophy, fasciculations; perform EMG
Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
Physical therapy needs
Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
Fine motor function (e.g., hands, feet, face, fingers, & toes)
Home adaptations for ADL & safety
Attention to possible alcohol or drug abuse
Referral for psychiatric eval as needed
Community or online
Social work involvement for parental support;
Home nursing referral.
Early discussion of advanced care planning
The affected person's perspective & burden must be taken into account for clinical decision making.
The presence of cognitive impairment may raise ethical concerns.
ADL = activities of daily living; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• UMN involvement: assess spasticity, Babinski signs, hyperreflexia
• LMN involvement: assess weakness, amyotrophy, fasciculations; perform EMG
• Muscle tone; joint range of motion; posture; mobility; strength, coordination, & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• Physical therapy needs
• Need for assistive walking devices (e.g., cane, walker, walker w/wheels, walker w/seat, wheelchair)
• Fine motor function (e.g., hands, feet, face, fingers, & toes)
• Home adaptations for ADL & safety
• Attention to possible alcohol or drug abuse
• Referral for psychiatric eval as needed
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
• Early discussion of advanced care planning
• The affected person's perspective & burden must be taken into account for clinical decision making.
• The presence of cognitive impairment may raise ethical concerns.
## Treatment of Manifestations
There is no cure for
Individuals with
Treatment of Manifestations in Individuals with
When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs
Often a temporizing measure until individuals become more apathetic.
Risk of iatrogenic extrapyramidal syndrome
ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor; UMN = upper motor neuron
Based on
• When severe manifestations (agitation, aggressiveness, psychosis) are refractory to SSRIs
• Often a temporizing measure until individuals become more apathetic.
• Risk of iatrogenic extrapyramidal syndrome
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, see
Recommended Surveillance for Individuals with
ADL = activities of daily living; NA = not applicable; OT = occupational therapy; PT = physical therapy
Based on
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Incidences of ALS complicating pregnancy are rare, since the disease shows a low prevalence in women of reproductive age. Pregnancy of women with ALS is largely complicated by impaired respiratory function due to underlying weakness of the diaphragm and costal muscles and the increased respiratory and weight-bearing demands of pregnancy [
Maternal ALS is not particularly associated with poorer neonatal outcomes and does not appear to cause obstetric complications. However, the method and timing of delivery may be influenced by the severity of the disease. Although natural delivery is possible because ALS does not affect the motor and sensory nerves of the uterus [
Riluzole can safely be used during pregnancy, although its effects on fetal growth remain unclear. Low birth weight has previously been reported when used during pregnancy [
See
## Therapies Under Investigation
Unlike
Search
## Genetic Counseling
Note: Rarely, homozygous pathogenic (or likely pathogenic) variants in
About half of individuals diagnosed with
About half 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The clinical presentation of
If the
If both parents are clinically unaffected but their genetic status is unknown, sibs are still 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.
Predictive testing may facilitate recruitment into future gene-specific clinical trials (see
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
• About half of individuals diagnosed with
• About half 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The clinical presentation of
• If the
• If both parents are clinically unaffected but their genetic status is unknown, sibs are still 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.
• Predictive testing may facilitate recruitment into future gene-specific clinical trials (see
• 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
Note: Rarely, homozygous pathogenic (or likely pathogenic) variants in
## Risk to Family Members (Autosomal Dominant Inheritance)
About half of individuals diagnosed with
About half 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
The clinical presentation of
If the
If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for
• About half of individuals diagnosed with
• About half 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The clinical presentation of
• If the
• If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for
## 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.
Predictive testing may facilitate recruitment into future gene-specific clinical trials (see
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.
• Predictive testing may facilitate recruitment into future gene-specific clinical trials (see
• 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
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## Molecular Genetics
TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia (
Most pathogenic variants are found in exon 6, which encodes for the glycine-rich C-terminal region of TDP-43 [
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Most pathogenic variants are found in exon 6, which encodes for the glycine-rich C-terminal region of TDP-43 [
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Robert H Baloh, MD, PhD; Washington University School of Medicine (2009–2022)Leon Crowley, MSc (2022–present)Matthew M Harms, MD; Washington University School of Medicine (2009–2022)Vaishnavi Manohar, MTech (2022–present)Timothy M Miller, MD, PhD; Washington University School of Medicine (2009–2022)Jemeen Sreedharan, BSc, MBBS, MRCP, PhD (2022–present)
5 January 2023 (bp) Comprehensive update posted live
12 March 2015 (me) Comprehensive update posted live
28 May 2009 (cd) Revision: prenatal testing available
23 April 2009 (et) Review posted live
14 November 2008 (rhb) Original submission
• 5 January 2023 (bp) Comprehensive update posted live
• 12 March 2015 (me) Comprehensive update posted live
• 28 May 2009 (cd) Revision: prenatal testing available
• 23 April 2009 (et) Review posted live
• 14 November 2008 (rhb) Original submission
## Author History
Robert H Baloh, MD, PhD; Washington University School of Medicine (2009–2022)Leon Crowley, MSc (2022–present)Matthew M Harms, MD; Washington University School of Medicine (2009–2022)Vaishnavi Manohar, MTech (2022–present)Timothy M Miller, MD, PhD; Washington University School of Medicine (2009–2022)Jemeen Sreedharan, BSc, MBBS, MRCP, PhD (2022–present)
## Revision History
5 January 2023 (bp) Comprehensive update posted live
12 March 2015 (me) Comprehensive update posted live
28 May 2009 (cd) Revision: prenatal testing available
23 April 2009 (et) Review posted live
14 November 2008 (rhb) Original submission
• 5 January 2023 (bp) Comprehensive update posted live
• 12 March 2015 (me) Comprehensive update posted live
• 28 May 2009 (cd) Revision: prenatal testing available
• 23 April 2009 (et) Review posted live
• 14 November 2008 (rhb) Original submission
## References
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"S Lattante, GA Rouleau, E Kabashi. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update.. Hum Mutat. 2013;34:812-26",
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"M Neumann, DM Sampathu, LK Kwong, AC Truax, MC Micsenyi, TT Chou, J Bruce, T Schuck, M Grossman, CM Clark, LF McCluskey, BL Miller, E Masliah, IR Mackenzie, H Feldman, W Feiden, HA Kretzschmar, JQ Trojanowski, VM Lee. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.. Science. 2006;314:130-3",
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"S Pinto, K Vlahoviček, E. Buratti. PRO-MINE: A bioinformatics repository and analytical tool for TARDBP mutations.. Hum Mutat. 2011;32:E1948-58",
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"A Yokoseki, A Shiga, CF Tan, A Tagawa, H Kaneko, A Koyama, H Eguchi, A Tsujino, T Ikeuchi, A Kakita, K Okamoto, M Nishizawa, H Takahashi, O Onodera. TDP-43 mutation in familial amyotrophic lateral sclerosis.. Ann Neurol. 2008;63:538-42"
] |
23/4/2009
|
5/1/2023
|
28/5/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tay-sachs
|
tay-sachs
|
[
"Beta-Hexosaminidase A Deficiency",
"GM2 Gangliosidosis, Type I",
"Tay-Sachs Disease",
"Beta-Hexosaminidase A Deficiency",
"GM2 Gangliosidosis, Type I",
"Tay-Sachs Disease",
"Subacute Juvenile Tay-Sachs Disease",
"Acute Infantile Tay-Sachs Disease",
"Late-Onset Tay-Sachs Disease",
"Beta-hexosaminidase subunit alpha",
"HEXA",
"HEXA Disorders"
] |
Camilo Toro, Leila Shirvan, Cynthia Tifft
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Summary The classic clinical phenotype is known as Tay-Sachs disease (TSD), characterized by progressive weakness, loss of motor skills beginning between ages three and six months, decreased visual attentiveness, and increased or exaggerated startle response with a cherry-red spot observable on the retina followed by developmental plateau and loss of skills after eight to ten months. Seizures are common by 12 months with further deterioration in the second year of life and death occurring between ages two and three years with some survival to five to seven years. Subacute juvenile TSD is associated with normal developmental milestones until age two years, when the emergence of abnormal gait or dysarthria is noted followed by loss of previously acquired skills and cognitive decline. Spasticity, dysphagia, and seizures are present by the end of the first decade of life, with death within the second decade of life, usually by aspiration. Late-onset TSD presents in older teens or young adults with a slowly progressive spectrum of neurologic symptoms including lower-extremity weakness with muscle atrophy, dysarthria, incoordination, tremor, mild spasticity and/or dystonia, and psychiatric manifestations including acute psychosis. Clinical variability even among affected members of the same family is observed in both the subacute juvenile and the late-onset TSD phenotypes. The diagnosis of a Acute infantile Tay-Sachs disease (TSD), subacute juvenile TSD, and late-onset TSD (comprising the clinical spectrum of
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Acute infantile Tay-Sachs disease
Subacute juvenile Tay-Sachs disease
Late-onset Tay-Sachs disease
For synonyms and outdated names see
Beta-hexosaminidase A (HEX A; often referred to in the shortened form, "hexosaminidase A") is a heterodimer comprising a single alpha chain and a single beta chain. The alpha chain is encoded by
• Acute infantile Tay-Sachs disease
• Subacute juvenile Tay-Sachs disease
• Late-onset Tay-Sachs disease
## Diagnosis
Progressive weakness and loss of motor skills beginning between ages three and six months
Decreased attentiveness
An increased or exaggerated startle response
A cherry-red spot of the fovea centralis of the macula of the retina
A normal-sized liver and spleen
Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia
Onset of seizures beginning around age 12 months
Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months
A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
Progressive spasticity resulting in loss of independent ambulation
Progressive dysarthria, drooling, and eventually absent speech
Normal-sized liver and spleen
Onset of seizures
Progressive global brain atrophy on neuroimaging [
Onset of symptoms in teens or adulthood
Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls
Dysarthria, tremor, and incoordination
Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease)
Isolated cerebellar atrophy on neuroimaging
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 [
Individuals with acute infantile TSD have no or extremely low HEX A enzymatic activity.
Individuals with subacute juvenile or late-onset TSD have some minimal residual HEX A enzymatic activity.
Note: The enzyme HEX A is a heterodimer of one alpha subunit and one beta subunit (encoded by the genes
Note: Pseudodeficiency refers to an in vitro phenomenon caused by specific
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of a
Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by a slowly progressive neurodegeneration,
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
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.
• Progressive weakness and loss of motor skills beginning between ages three and six months
• Decreased attentiveness
• An increased or exaggerated startle response
• A cherry-red spot of the fovea centralis of the macula of the retina
• A normal-sized liver and spleen
• Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia
• Onset of seizures beginning around age 12 months
• Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months
• A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
• Progressive spasticity resulting in loss of independent ambulation
• Progressive dysarthria, drooling, and eventually absent speech
• Normal-sized liver and spleen
• Onset of seizures
• Progressive global brain atrophy on neuroimaging [
• Onset of symptoms in teens or adulthood
• Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls
• Dysarthria, tremor, and incoordination
• Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease)
• Isolated cerebellar atrophy on neuroimaging
• Individuals with acute infantile TSD have no or extremely low HEX A enzymatic activity.
• Individuals with subacute juvenile or late-onset TSD have some minimal residual HEX A enzymatic activity.
• Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
• For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
• For an introduction to multigene panels click
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
## Suggestive Findings
Progressive weakness and loss of motor skills beginning between ages three and six months
Decreased attentiveness
An increased or exaggerated startle response
A cherry-red spot of the fovea centralis of the macula of the retina
A normal-sized liver and spleen
Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia
Onset of seizures beginning around age 12 months
Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months
A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
Progressive spasticity resulting in loss of independent ambulation
Progressive dysarthria, drooling, and eventually absent speech
Normal-sized liver and spleen
Onset of seizures
Progressive global brain atrophy on neuroimaging [
Onset of symptoms in teens or adulthood
Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls
Dysarthria, tremor, and incoordination
Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease)
Isolated cerebellar atrophy on neuroimaging
• Progressive weakness and loss of motor skills beginning between ages three and six months
• Decreased attentiveness
• An increased or exaggerated startle response
• A cherry-red spot of the fovea centralis of the macula of the retina
• A normal-sized liver and spleen
• Generalized muscular hypotonia with sustained ankle clonus and hyperreflexia
• Onset of seizures beginning around age 12 months
• Progressive macrocephaly with proportionate ventricular enlargement on neuroimaging beginning at age 18 months
• A period of normal development until ages two to five years followed by a plateauing of skills and then loss of previously acquired developmental skills
• Progressive spasticity resulting in loss of independent ambulation
• Progressive dysarthria, drooling, and eventually absent speech
• Normal-sized liver and spleen
• Onset of seizures
• Progressive global brain atrophy on neuroimaging [
• Onset of symptoms in teens or adulthood
• Progressive neurogenic weakness of antigravity muscles in the lower extremities and frequent falls
• Dysarthria, tremor, and incoordination
• Acute psychiatric manifestations including psychosis (which can be the initial manifestation of disease)
• Isolated cerebellar atrophy on neuroimaging
## 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 [
Individuals with acute infantile TSD have no or extremely low HEX A enzymatic activity.
Individuals with subacute juvenile or late-onset TSD have some minimal residual HEX A enzymatic activity.
Note: The enzyme HEX A is a heterodimer of one alpha subunit and one beta subunit (encoded by the genes
Note: Pseudodeficiency refers to an in vitro phenomenon caused by specific
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of
When the phenotypic and laboratory findings suggest the diagnosis of a
Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by a slowly progressive neurodegeneration,
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
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.
• Individuals with acute infantile TSD have no or extremely low HEX A enzymatic activity.
• Individuals with subacute juvenile or late-onset TSD have some minimal residual HEX A enzymatic activity.
• Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
• For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
• For an introduction to multigene panels click
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of a
Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
For an introduction to multigene panels click
• Targeted analysis for pathogenic variants can be performed first in individuals of specific ethnicity:
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
• For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see
• For an introduction to multigene panels click
• Note: (1) The presence of one pseudodeficiency allele reduces the in vitro HEX A enzymatic activity toward synthetic substrates but does not reduce enzymatic activity with the natural substrate, GM2 ganglioside. All enzymatic assays use the artificial substrate because the naturally occurring GM2 ganglioside is not a stable reagent and is not available. Thus, a problem emerges in interpreting enzymatic deficiency. Molecular genetic testing provides the basis to differentiate a pathogenic allele from a pseudodeficiency allele. (2) About 35% of non-Jewish individuals identified as heterozygotes by HEX A enzyme-based testing are carriers of a pseudodeficiency allele. (3) About 2% of Ashkenazi Jewish individuals identified as heterozygotes by HEX A enzyme-based testing in carrier screening programs are actually heterozygous for a pseudodeficiency allele (see
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by a slowly progressive neurodegeneration,
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
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
The clinical phenotype of
While case reports of individuals abound, there is a paucity of prospective natural history studies for Tay-Sachs disease delineating the progression of disease subtypes over time.
Subtypes of
Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.
After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence seizures typically become more frequent and severe.
Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [
Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of individuals with acute infantile Tay-Sachs disease to between five and seven years [
A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.
Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, individuals may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [
Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.
Children with the acute infantile form of TSD have excessive and ubiquitous neuronal glycolipid storage (≤12% of the brain dry weight), of which the enormous predominance is the specific glycolipid GM2 ganglioside. Individuals with the adult-onset forms have less accumulation of glycolipid; it may even be restricted to specific brain regions. For example, in LOTS the neocortex may be spared, while the hippocampus, brain stem nuclei, and the spinal cord are markedly affected [
In general, individuals with two null (nonexpressing) alleles have the infantile form, individuals with one null allele and one missense allele have the subacute juvenile-onset phenotype, and individuals with two missense alleles have the milder late-onset phenotype. This reflects the inverse correlation of the level of the residual activity of the HEX A enzyme with the severity of the disease: the lower the level of the enzymatic activity, the more severe the phenotype is likely to be.
Tay-Sachs disease was originally described as "infantile amaurotic idiocy" and "amaurotic familial infantile idiocy" by Tay and Sachs, respectively.
When GM2 ganglioside was identified as the major accumulating substrate, the nomenclature included the terms "infantile ganglioside lipidosis," "type 1 GM2 gangliosidosis," and "acute infantile GM2 gangliosidosis."
When deficient HEX A enzymatic activity was identified, the disease was then referred to as "hexosaminidase A deficiency," "HEX A deficiency," or "type 1 hexosaminidase A deficiency."
When the subacute juvenile and late-onset phenotypes were identified, they were referred to as the "B1 variant of GM2 gangliosidoses" or "juvenile (subacute) hexosaminidase deficiency" and "chronic or adult-onset hexosaminidase A deficiency," respectively.
Before the advent of population-based carrier screening, education, and counseling programs for the prevention of TSD in Jewish communities, the incidence of TSD was estimated at 1:3,600 Ashkenazi Jewish births. At that birth rate, the carrier rate for TSD is approximately 1:30 among Jewish Americans of Ashkenazi extraction (i.e., from Central and Eastern Europe).
Carrier screening studies have indicated that the frequency of the Ashkenazi Jewish founder variants in individuals whose parents and respective grandparents were of Ashkenazi Jewish descent is 1:27.4 [
As the result of extensive genetic counseling of carriers identified through carrier screening programs and monitoring of at-risk pregnancies, the incidence of TSD in the Ashkenazi Jewish population of North America has been reduced by greater than 90% [
Among Sephardic Jews and all non-Jews, the disease incidence has been observed to be about 100 times lower, corresponding to a tenfold lower carrier frequency (between 1:250 and 1:300).
TSD has been reported in children in virtually all population groups studied.
Other genetically isolated populations have been found to carry founder
French Canadians of the eastern St Lawrence Valley, Quebec;
Cajuns from Louisiana.
• Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
• Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.
• After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence seizures typically become more frequent and severe.
• Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [
• Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of individuals with acute infantile Tay-Sachs disease to between five and seven years [
• A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
• A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.
• Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
• Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
• Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
• Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, individuals may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
• Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [
• Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
• Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.
• French Canadians of the eastern St Lawrence Valley, Quebec;
• Cajuns from Louisiana.
## Clinical Description
The clinical phenotype of
While case reports of individuals abound, there is a paucity of prospective natural history studies for Tay-Sachs disease delineating the progression of disease subtypes over time.
Subtypes of
Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.
After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence seizures typically become more frequent and severe.
Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [
Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of individuals with acute infantile Tay-Sachs disease to between five and seven years [
A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.
Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, individuals may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [
Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.
• Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
• Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.
• After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence seizures typically become more frequent and severe.
• Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [
• Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of individuals with acute infantile Tay-Sachs disease to between five and seven years [
• A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
• A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.
• Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
• Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
• Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
• Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, individuals may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
• Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [
• Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
• Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.
## Acute Infantile Tay-Sachs Disease
Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.
After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence seizures typically become more frequent and severe.
Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [
Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of individuals with acute infantile Tay-Sachs disease to between five and seven years [
• Progressive weakness begins between ages three and six months, along with myoclonic jerks and an exaggerated startle reaction to sudden stimuli.
• Decreasing visual attentiveness and unusual eye movements at age three to six months may be the first sign prompting parents to seek medical attention, where subsequent ophthalmologic evaluation reveals the characteristic cherry-red macula seen in virtually all children with infantile disease.
• After age eight to ten months, progression of the disease is rapid. Spontaneous or purposeful voluntary movements diminish, and the infant becomes progressively less responsive. Vision deteriorates rapidly. Seizures are common by age 12 months. Subtle partial complex seizures or absence seizures typically become more frequent and severe.
• Progressive enlargement of the head typically begins by age 18 months resulting from reactive cerebral gliosis but eventually followed by ventriculomegaly [
• Further deterioration in the second year of life results in decerebrate posturing, difficulties in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three years, although the use of a gastrostomy tube to minimize aspiration events and improved pulmonary hygiene with the use of vibrating vests has extended the life span of individuals with acute infantile Tay-Sachs disease to between five and seven years [
## Subacute Juvenile Tay-Sachs Disease
A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.
• A decrease in visual acuity occurs much later in subacute juvenile Tay-Sachs disease than in the acute infantile form of the disease and the cherry-red spot is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the course of the disease.
• A vegetative state with decerebrate posturing begins to appear in many individuals by age ten to 15 years, followed within a few years by death, usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary toilet may extend life span. In some individuals, the disease pursues a particularly aggressive course, culminating in death within two to four years of symptom onset.
## Late-Onset Tay-Sachs Disease (LOTS)
Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, individuals may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [
Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.
• Most, if not all, individuals with LOTS develop progressive neurogenic muscle weakness and wasting.
• Early in the disease course, weakness involves the lower extremities, particularly the knee extensors and hip flexors. Atrophy, cramps, and fasciculations are common. Affected individuals relate progressive difficulty in climbing steps or bleachers, eventually requiring the aid of handrails. As knee extensor muscle weakness progresses, individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain knees locked results in collapse and injury.
• Upper-extremity strength may become affected years later with a predilection for elbow extension (triceps) weakness. Long tract findings including spasticity, upgoing toes, and brisk reflexes can be present but may be obscured by lower motor neuron weakness.
• Dysarthria is common; the speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. The poor articulation emerges primarily from cerebellar dysfunction; however, individuals may demonstrate associated features of focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Despite prominent dysarthria, dysphagia and aspiration events are not common early in LOTS.
• Decreased balance requiring a wide base of support, decreased dexterity, and tremor are frequent findings in LOTS. These – along with the presence of saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination – are attributed at least in part to cerebellar dysfunction [
• Psychiatric manifestations including comorbid anxiety and depression are common. Acute psychosis and mania can occur, representing the initial manifestation of disease in some individuals.
• Deficits in executive function and memory are reported in some individuals and can be associated with progressive brain volume loss. Contrary to the acute infantile and subacute juvenile phenotypes, however, declines in higher cortical functioning develop slowly, often over decades after the onset of disease symptoms.
## Neuropathology
Children with the acute infantile form of TSD have excessive and ubiquitous neuronal glycolipid storage (≤12% of the brain dry weight), of which the enormous predominance is the specific glycolipid GM2 ganglioside. Individuals with the adult-onset forms have less accumulation of glycolipid; it may even be restricted to specific brain regions. For example, in LOTS the neocortex may be spared, while the hippocampus, brain stem nuclei, and the spinal cord are markedly affected [
## Genotype-Phenotype Correlations
In general, individuals with two null (nonexpressing) alleles have the infantile form, individuals with one null allele and one missense allele have the subacute juvenile-onset phenotype, and individuals with two missense alleles have the milder late-onset phenotype. This reflects the inverse correlation of the level of the residual activity of the HEX A enzyme with the severity of the disease: the lower the level of the enzymatic activity, the more severe the phenotype is likely to be.
## Nomenclature
Tay-Sachs disease was originally described as "infantile amaurotic idiocy" and "amaurotic familial infantile idiocy" by Tay and Sachs, respectively.
When GM2 ganglioside was identified as the major accumulating substrate, the nomenclature included the terms "infantile ganglioside lipidosis," "type 1 GM2 gangliosidosis," and "acute infantile GM2 gangliosidosis."
When deficient HEX A enzymatic activity was identified, the disease was then referred to as "hexosaminidase A deficiency," "HEX A deficiency," or "type 1 hexosaminidase A deficiency."
When the subacute juvenile and late-onset phenotypes were identified, they were referred to as the "B1 variant of GM2 gangliosidoses" or "juvenile (subacute) hexosaminidase deficiency" and "chronic or adult-onset hexosaminidase A deficiency," respectively.
## Prevalence
Before the advent of population-based carrier screening, education, and counseling programs for the prevention of TSD in Jewish communities, the incidence of TSD was estimated at 1:3,600 Ashkenazi Jewish births. At that birth rate, the carrier rate for TSD is approximately 1:30 among Jewish Americans of Ashkenazi extraction (i.e., from Central and Eastern Europe).
Carrier screening studies have indicated that the frequency of the Ashkenazi Jewish founder variants in individuals whose parents and respective grandparents were of Ashkenazi Jewish descent is 1:27.4 [
As the result of extensive genetic counseling of carriers identified through carrier screening programs and monitoring of at-risk pregnancies, the incidence of TSD in the Ashkenazi Jewish population of North America has been reduced by greater than 90% [
Among Sephardic Jews and all non-Jews, the disease incidence has been observed to be about 100 times lower, corresponding to a tenfold lower carrier frequency (between 1:250 and 1:300).
TSD has been reported in children in virtually all population groups studied.
Other genetically isolated populations have been found to carry founder
French Canadians of the eastern St Lawrence Valley, Quebec;
Cajuns from Louisiana.
• French Canadians of the eastern St Lawrence Valley, Quebec;
• Cajuns from Louisiana.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The neurologic symptoms that develop in the course of
Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile Tay-Sachs Disease
The disorders included in
CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease
In activator-deficient TSD, enzymatic activity of both HEX A and HEX B is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside.
Progressive weakness and loss of motor skills between ages six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
Genetic Disorders of Interest in the Differential Diagnosis of Subacute Juvenile Tay-Sachs disease
The disorders included in
CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease
Genetic Disorders in the Differential Diagnosis of Late-Onset Tay-Sachs Disease
AD = autosomal dominant; AR = autosomal recessive; CPK = creatine phosphokinase; EKG = electrocardiogram; LOTS = late-onset Tay-Sachs disease; MOI = mode of inheritance; XL = X-linked
Lead and other heavy metal poisoning, infectious and postinfectious meningoencephalitis, subacute sclerosing panencephalitis, hydrocephalus, and neurologic manifestations of other systemic diseases may mimic the neurologic findings associated with
## Hereditary Disorders
Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile Tay-Sachs Disease
The disorders included in
CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease
In activator-deficient TSD, enzymatic activity of both HEX A and HEX B is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside.
Progressive weakness and loss of motor skills between ages six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
Genetic Disorders of Interest in the Differential Diagnosis of Subacute Juvenile Tay-Sachs disease
The disorders included in
CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease
Genetic Disorders in the Differential Diagnosis of Late-Onset Tay-Sachs Disease
AD = autosomal dominant; AR = autosomal recessive; CPK = creatine phosphokinase; EKG = electrocardiogram; LOTS = late-onset Tay-Sachs disease; MOI = mode of inheritance; XL = X-linked
## Infantile Onset
Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile Tay-Sachs Disease
The disorders included in
CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease
In activator-deficient TSD, enzymatic activity of both HEX A and HEX B is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside.
Progressive weakness and loss of motor skills between ages six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen
In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.
## Subacute Juvenile Onset
Genetic Disorders of Interest in the Differential Diagnosis of Subacute Juvenile Tay-Sachs disease
The disorders included in
CSF = cerebrospinal fluid; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = hexosaminidase B; TSD = Tay-Sachs disease
## Late Onset
Genetic Disorders in the Differential Diagnosis of Late-Onset Tay-Sachs Disease
AD = autosomal dominant; AR = autosomal recessive; CPK = creatine phosphokinase; EKG = electrocardiogram; LOTS = late-onset Tay-Sachs disease; MOI = mode of inheritance; XL = X-linked
## Acquired Disorders
Lead and other heavy metal poisoning, infectious and postinfectious meningoencephalitis, subacute sclerosing panencephalitis, hydrocephalus, and neurologic manifestations of other systemic diseases may mimic the neurologic findings associated with
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile Tay-Sachs Disease
To incl brain MRI
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Need for adaptive devices
Need for PT (to prevent deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
EEG = electroencephalogram; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Subacute Juvenile Tay-Sachs Disease
To incl brain MRI
Consider EEG if seizures are a concern.
Evaluate for spasticity.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for IEP
Gross motor & fine motor skills
Mobility, independence in ADL, & need for adaptive devices
Need for PT (to prevent fixed deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support.
ADL = activities of daily living; EEG = electroencephalogram; IEP = individualized education program; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Late-Onset Tay-Sachs Disease
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
Community or online
Social work involvement for support.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
For the most part, treatment for acute infantile Tay-Sachs disease (TSD) is supportive and directed to providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures. The treatment for the subacute juvenile and late-onset TSD phenotypes is directed to providing the services of a physiatrist and team of physical, occupational, and speech therapists for maximizing function and providing aids for activities of daily living.
Treatment of Manifestations in Individuals with Acute Infantile Tay-Sachs Disease
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
Education of parents/caregivers
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
Treatment of Manifestations in Individuals with Subacute Juvenile Tay-Sachs Disease
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
Education of parents/caregivers
ASM = anti-seizure medication; IEP = individualized education program
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
Treatment of Manifestations in Individuals with Late-Onset Tay-Sachs Disease
Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
Cognitive behavioral therapy ↑ coping skills.
Electroconvulsive therapy reported beneficial in some cases
OT = occupational therapy; PT = physical therapy
There are no formal guidelines for surveillance for those affected with
Neurology evaluations should commence at the time of diagnosis for all subtypes of TSD if not previously established, and follow up should be dictated by emergent clinical concerns.
For individuals with
Positioning that increases aspiration risk during feedings;
Seizure medication dosages that result in excessive sedation.
For individuals with
Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
Circumstances that exacerbate the risk of falls.
For individuals with
Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
Psychiatric medications that have been associated with disease worsening (e.g., haloperidol, risperidone, and chlorpromazine) [
See
Current studies include:
A
A
A
A
Search
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Need for adaptive devices
• Need for PT (to prevent deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Evaluate for spasticity.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for IEP
• Gross motor & fine motor skills
• Mobility, independence in ADL, & need for adaptive devices
• Need for PT (to prevent fixed deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support.
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
• Community or online
• Social work involvement for support.
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
• Education of parents/caregivers
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
• Education of parents/caregivers
• Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
• Cognitive behavioral therapy ↑ coping skills.
• Electroconvulsive therapy reported beneficial in some cases
• Positioning that increases aspiration risk during feedings;
• Seizure medication dosages that result in excessive sedation.
• Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
• Circumstances that exacerbate the risk of falls.
• Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
• Psychiatric medications that have been associated with disease worsening (e.g., haloperidol, risperidone, and chlorpromazine) [
• A
• A
• A
• A
## 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 Acute Infantile Tay-Sachs Disease
To incl brain MRI
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Need for adaptive devices
Need for PT (to prevent deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support;
Home nursing referral.
EEG = electroencephalogram; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Subacute Juvenile Tay-Sachs Disease
To incl brain MRI
Consider EEG if seizures are a concern.
Evaluate for spasticity.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for IEP
Gross motor & fine motor skills
Mobility, independence in ADL, & need for adaptive devices
Need for PT (to prevent fixed deformities)
To incl swallow study for eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for constipation.
Community or
Social work involvement for parental support.
ADL = activities of daily living; EEG = electroencephalogram; IEP = individualized education program; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis in Individuals with Late-Onset Tay-Sachs Disease
Gross motor & fine motor skills
Mobility, ADL, & need for adaptive devices
Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
Community or online
Social work involvement for support.
ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Need for adaptive devices
• Need for PT (to prevent deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Evaluate for spasticity.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for IEP
• Gross motor & fine motor skills
• Mobility, independence in ADL, & need for adaptive devices
• Need for PT (to prevent fixed deformities)
• To incl swallow study for eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Community or
• Social work involvement for parental support.
• Gross motor & fine motor skills
• Mobility, ADL, & need for adaptive devices
• Need for PT (to prevent falls & pressure wounds) &/or OT to maximize independence in ADL
• Community or online
• Social work involvement for support.
## Treatment of Manifestations
For the most part, treatment for acute infantile Tay-Sachs disease (TSD) is supportive and directed to providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures. The treatment for the subacute juvenile and late-onset TSD phenotypes is directed to providing the services of a physiatrist and team of physical, occupational, and speech therapists for maximizing function and providing aids for activities of daily living.
Treatment of Manifestations in Individuals with Acute Infantile Tay-Sachs Disease
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
Education of parents/caregivers
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
Treatment of Manifestations in Individuals with Subacute Juvenile Tay-Sachs Disease
Seizures are often progressive & refractory.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
Education of parents/caregivers
ASM = anti-seizure medication; IEP = individualized education program
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
Treatment of Manifestations in Individuals with Late-Onset Tay-Sachs Disease
Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
Cognitive behavioral therapy ↑ coping skills.
Electroconvulsive therapy reported beneficial in some cases
OT = occupational therapy; PT = physical therapy
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
• Education of parents/caregivers
• Seizures are often progressive & refractory.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Complete seizure control is seldom achieved & requires balancing w/sedative side effects of ASM.
• Education of parents/caregivers
• Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
• Cognitive behavioral therapy ↑ coping skills.
• Electroconvulsive therapy reported beneficial in some cases
## Surveillance
There are no formal guidelines for surveillance for those affected with
Neurology evaluations should commence at the time of diagnosis for all subtypes of TSD if not previously established, and follow up should be dictated by emergent clinical concerns.
## Agents/Circumstances to Avoid
For individuals with
Positioning that increases aspiration risk during feedings;
Seizure medication dosages that result in excessive sedation.
For individuals with
Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
Circumstances that exacerbate the risk of falls.
For individuals with
Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
Psychiatric medications that have been associated with disease worsening (e.g., haloperidol, risperidone, and chlorpromazine) [
• Positioning that increases aspiration risk during feedings;
• Seizure medication dosages that result in excessive sedation.
• Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
• Circumstances that exacerbate the risk of falls.
• Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
• Psychiatric medications that have been associated with disease worsening (e.g., haloperidol, risperidone, and chlorpromazine) [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Current studies include:
A
A
A
A
Search
• A
• A
• A
• A
## Genetic Counseling
Acute infantile Tay-Sachs disease (TSD), subacute juvenile TSD, and late-onset TSD (comprising the clinical spectrum of
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
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing recommendations for the reproductive partners of known carriers (or the reproductive partners of individuals with late-onset TSD) who do not have a family history of TSD are addressed in
Population Screening for
Does not detect some noncoding pathogenic variants.
Detection of VUS
Limited sensitivity
As marriage outside of the ethnic group becomes more common, ethnicity-based targeted screening loses predictive value.
Serum enzyme assay results may be w/in "inconclusive" range.
False positives resulting from pseudodeficiency alleles
False negatives resulting from B1 variant allele
Follow-up molecular testing required if a carrier couple wants to pursue prenatal testing / PGT
Leukocyte testing (rather than serum testing) should be ordered in women who are pregnant or using oral contraception.
HEX A = beta-hexosaminidase A; NGS = next-generation sequencing; PGT = preimplantation genetic testing; VUS = variants of uncertain significance
Based on the
See
More than 150
In individuals with an inconclusive result on serum enzyme assay (as well as pregnant women and women taking oral contraceptives), white blood cells rather than serum must be assayed.
Alleles that code for an enzyme that does not metabolize the synthetic substrate for GM2 ganglioside in vitro, but does metabolize GM2 ganglioside in vivo
The protein encoded by the B1 allele metabolizes the synthetic substrate for GM2 ganglioside in vitro but does not metabolize GM2 ganglioside in vivo.
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.
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
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Does not detect some noncoding pathogenic variants.
• Detection of VUS
• Limited sensitivity
• As marriage outside of the ethnic group becomes more common, ethnicity-based targeted screening loses predictive value.
• Serum enzyme assay results may be w/in "inconclusive" range.
• False positives resulting from pseudodeficiency alleles
• False negatives resulting from B1 variant allele
• Follow-up molecular testing required if a carrier couple wants to pursue prenatal testing / PGT
• Leukocyte testing (rather than serum testing) should be ordered in women who are pregnant or using oral contraception.
• 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
Acute infantile Tay-Sachs disease (TSD), subacute juvenile TSD, and late-onset TSD (comprising the clinical spectrum of
## 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
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
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing recommendations for the reproductive partners of known carriers (or the reproductive partners of individuals with late-onset TSD) who do not have a family history of TSD are addressed in
## Related Genetic Counseling Issues
Population Screening for
Does not detect some noncoding pathogenic variants.
Detection of VUS
Limited sensitivity
As marriage outside of the ethnic group becomes more common, ethnicity-based targeted screening loses predictive value.
Serum enzyme assay results may be w/in "inconclusive" range.
False positives resulting from pseudodeficiency alleles
False negatives resulting from B1 variant allele
Follow-up molecular testing required if a carrier couple wants to pursue prenatal testing / PGT
Leukocyte testing (rather than serum testing) should be ordered in women who are pregnant or using oral contraception.
HEX A = beta-hexosaminidase A; NGS = next-generation sequencing; PGT = preimplantation genetic testing; VUS = variants of uncertain significance
Based on the
See
More than 150
In individuals with an inconclusive result on serum enzyme assay (as well as pregnant women and women taking oral contraceptives), white blood cells rather than serum must be assayed.
Alleles that code for an enzyme that does not metabolize the synthetic substrate for GM2 ganglioside in vitro, but does metabolize GM2 ganglioside in vivo
The protein encoded by the B1 allele metabolizes the synthetic substrate for GM2 ganglioside in vitro but does not metabolize GM2 ganglioside in vivo.
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.
• Does not detect some noncoding pathogenic variants.
• Detection of VUS
• Limited sensitivity
• As marriage outside of the ethnic group becomes more common, ethnicity-based targeted screening loses predictive value.
• Serum enzyme assay results may be w/in "inconclusive" range.
• False positives resulting from pseudodeficiency alleles
• False negatives resulting from B1 variant allele
• Follow-up molecular testing required if a carrier couple wants to pursue prenatal testing / PGT
• Leukocyte testing (rather than serum testing) should be ordered in women who are pregnant or using oral contraception.
• 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
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
HEXA Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for HEXA Disorders (
Biallelic pathogenic variants in
In contrast, the so-called B1 variant allele results in a β-hexosaminidase A enzyme that is able to degrade the artificial substrate, but not the natural GM2 ganglioside, which leads to false negative enzyme testing results.
Notable
LOTS = late-onset Tay Sachs
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Biallelic pathogenic variants in
In contrast, the so-called B1 variant allele results in a β-hexosaminidase A enzyme that is able to degrade the artificial substrate, but not the natural GM2 ganglioside, which leads to false negative enzyme testing results.
Notable
LOTS = late-onset Tay Sachs
Variants listed in the table have been provided by the authors.
## Chapter Notes
Authors' websites:
This work was supported by funds from the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
The authors wish to acknowledge all participants in the Neurodegeneration in Glycosphingolipid Storage Disorders' Natural History Study at the NIH (ClinicalTrials.gov Identifier:
Robert J Desnick, PhD, MD, FACMG; Icahn School of Medicine at Mount Sinai (1999-2020)Michael M Kaback, MD, FACMG; University of California, San Diego (1999-2020)Leila Shirvan, BA (2020-present)Cynthia Tifft, MD, PhD (2020-present)Camilo Toro, MD (2020-present)
1 October 2020 (ha) Comprehensive update posted live
11 August 2011 (me) Comprehensive update posted live
19 May 2006 (me) Comprehensive update posted live
9 January 2004 (me) Comprehensive update posted live
30 October 2001 (me) Comprehensive update posted live
11 March 1999 (me) Review posted live
April 1998 (mk) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 1 October 2020 (ha) Comprehensive update posted live
• 11 August 2011 (me) Comprehensive update posted live
• 19 May 2006 (me) Comprehensive update posted live
• 9 January 2004 (me) Comprehensive update posted live
• 30 October 2001 (me) Comprehensive update posted live
• 11 March 1999 (me) Review posted live
• April 1998 (mk) Original submission
## Author Notes
Authors' websites:
## Acknowledgments
This work was supported by funds from the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
The authors wish to acknowledge all participants in the Neurodegeneration in Glycosphingolipid Storage Disorders' Natural History Study at the NIH (ClinicalTrials.gov Identifier:
## Author History
Robert J Desnick, PhD, MD, FACMG; Icahn School of Medicine at Mount Sinai (1999-2020)Michael M Kaback, MD, FACMG; University of California, San Diego (1999-2020)Leila Shirvan, BA (2020-present)Cynthia Tifft, MD, PhD (2020-present)Camilo Toro, MD (2020-present)
## Revision History
1 October 2020 (ha) Comprehensive update posted live
11 August 2011 (me) Comprehensive update posted live
19 May 2006 (me) Comprehensive update posted live
9 January 2004 (me) Comprehensive update posted live
30 October 2001 (me) Comprehensive update posted live
11 March 1999 (me) Review posted live
April 1998 (mk) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 1 October 2020 (ha) Comprehensive update posted live
• 11 August 2011 (me) Comprehensive update posted live
• 19 May 2006 (me) Comprehensive update posted live
• 9 January 2004 (me) Comprehensive update posted live
• 30 October 2001 (me) Comprehensive update posted live
• 11 March 1999 (me) Review posted live
• April 1998 (mk) Original submission
## References
NTSAD. Position Statement 2019 Update – "Standards for Tay-Sachs Carrier Screening." Available
• NTSAD. Position Statement 2019 Update – "Standards for Tay-Sachs Carrier Screening." Available
## Published Guidelines / Consensus Statements
NTSAD. Position Statement 2019 Update – "Standards for Tay-Sachs Carrier Screening." Available
• NTSAD. Position Statement 2019 Update – "Standards for Tay-Sachs Carrier Screening." Available
## Literature Cited
|
[] |
11/3/1999
|
1/10/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tbc1d24-dis
|
tbc1d24-dis
|
[
"DOORS Syndrome (Deafness, Onychodystrophy, Osteodystrophy, Mental Retardation, and Seizures)",
"TBC1D24-Related Familial Infantile Myoclonic Epilepsy (FIME)",
"TBC1D24-Related Progressive Myoclonus Epilepsy (PME)",
"TBC1D24-Related Developmental and Epileptic Encephalopathy (DEE)",
"TBC1D24-Related Autosomal Dominant Nonsyndromic Hearing Loss (DFNA)",
"TBC1D24-Related Autosomal Recessive Nonsyndromic Hearing Loss (DFNB)",
"TBC1D24-Related Epilepsy of Infancy with Migrating Focal Seizures",
"TBC1D24-Related Rolandic Epilepsy with Paroxysmal Exercise-Induced Dystonia and Writer's Cramp (EPRPDC)",
"TBC1 domain family member 24",
"TBC1D24",
"TBC1D24-Related Disorders"
] |
Simona Balestrini, Philippe M Campeau, Davide Mei, Renzo Guerrini, Sanjay Sisodiya
|
Summary The diagnosis of a Most Once the
|
DOORS syndrome (
Familial infantile myoclonic epilepsy (FIME)
Progressive myoclonic epilepsy (PME)
Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC)
Developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS)
Autosomal recessive nonsyndromic hearing loss (DFNB)
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• DOORS syndrome (
• Familial infantile myoclonic epilepsy (FIME)
• Progressive myoclonic epilepsy (PME)
• Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC)
• Developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS)
• Autosomal recessive nonsyndromic hearing loss (DFNB)
## Diagnosis
DOORS syndrome (
Familial infantile myoclonic epilepsy (FIME)
Progressive myoclonic epilepsy (PME)
Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC)
Developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS)
Autosomal recessive nonsyndromic hearing loss (DFNB)
Autosomal dominant nonsyndromic hearing loss (DFNA)
A
Deafness, including profound sensorineural hearing loss
Seizures
Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
Variable EEG findings including centrotemporal sharp waves and spikes
Other neurologic features including:
Ataxia
Exercise-induced dystonia
Writer's cramp, difficulties with fine motor skills
Neurodevelopmental features, including intellectual disability / developmental delays; can vary in severity from mild to severe delays with progressive neurologic decline
Nail and digital features including:
Onychodystrophy (short/absent nails)
Osteodystrophy (short phalanges)
The diagnosis of a
Biallelic
A heterozygous
Notes: (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
Note: (1) The molecular diagnostic yield appears to be highest in individuals who have all five typical features of DOORS syndrome [
For an introduction to multigene panels click
For an introduction to CMA click
When the diagnosis of a
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.
A contiguous gene deletion syndrome involving
• DOORS syndrome (
• Familial infantile myoclonic epilepsy (FIME)
• Progressive myoclonic epilepsy (PME)
• Rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp (EPRPDC)
• Developmental and epileptic encephalopathy (DEE), including epilepsy of infancy with migrating focal seizures (EIMFS)
• Autosomal recessive nonsyndromic hearing loss (DFNB)
• Autosomal dominant nonsyndromic hearing loss (DFNA)
• Deafness, including profound sensorineural hearing loss
• Seizures
• Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
• Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
• Variable EEG findings including centrotemporal sharp waves and spikes
• Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
• Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
• Variable EEG findings including centrotemporal sharp waves and spikes
• Other neurologic features including:
• Ataxia
• Exercise-induced dystonia
• Writer's cramp, difficulties with fine motor skills
• Ataxia
• Exercise-induced dystonia
• Writer's cramp, difficulties with fine motor skills
• Neurodevelopmental features, including intellectual disability / developmental delays; can vary in severity from mild to severe delays with progressive neurologic decline
• Nail and digital features including:
• Onychodystrophy (short/absent nails)
• Osteodystrophy (short phalanges)
• Onychodystrophy (short/absent nails)
• Osteodystrophy (short phalanges)
• Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
• Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
• Variable EEG findings including centrotemporal sharp waves and spikes
• Ataxia
• Exercise-induced dystonia
• Writer's cramp, difficulties with fine motor skills
• Onychodystrophy (short/absent nails)
• Osteodystrophy (short phalanges)
• Biallelic
• A heterozygous
## Suggestive Findings
A
Deafness, including profound sensorineural hearing loss
Seizures
Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
Variable EEG findings including centrotemporal sharp waves and spikes
Other neurologic features including:
Ataxia
Exercise-induced dystonia
Writer's cramp, difficulties with fine motor skills
Neurodevelopmental features, including intellectual disability / developmental delays; can vary in severity from mild to severe delays with progressive neurologic decline
Nail and digital features including:
Onychodystrophy (short/absent nails)
Osteodystrophy (short phalanges)
• Deafness, including profound sensorineural hearing loss
• Seizures
• Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
• Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
• Variable EEG findings including centrotemporal sharp waves and spikes
• Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
• Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
• Variable EEG findings including centrotemporal sharp waves and spikes
• Other neurologic features including:
• Ataxia
• Exercise-induced dystonia
• Writer's cramp, difficulties with fine motor skills
• Ataxia
• Exercise-induced dystonia
• Writer's cramp, difficulties with fine motor skills
• Neurodevelopmental features, including intellectual disability / developmental delays; can vary in severity from mild to severe delays with progressive neurologic decline
• Nail and digital features including:
• Onychodystrophy (short/absent nails)
• Osteodystrophy (short phalanges)
• Onychodystrophy (short/absent nails)
• Osteodystrophy (short phalanges)
• Variable in severity; can be mild to severe, including early-onset and intractable epilepsy
• Different seizure types including myoclonic, generalized tonic-clonic, focal including hemifacial, with or without autonomic changes
• Variable EEG findings including centrotemporal sharp waves and spikes
• Ataxia
• Exercise-induced dystonia
• Writer's cramp, difficulties with fine motor skills
• Onychodystrophy (short/absent nails)
• Osteodystrophy (short phalanges)
## Establishing the Diagnosis
The diagnosis of a
Biallelic
A heterozygous
Notes: (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
Note: (1) The molecular diagnostic yield appears to be highest in individuals who have all five typical features of DOORS syndrome [
For an introduction to multigene panels click
For an introduction to CMA click
When the diagnosis of a
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.
A contiguous gene deletion syndrome involving
• Biallelic
• A heterozygous
## Option 1
Note: (1) The molecular diagnostic yield appears to be highest in individuals who have all five typical features of DOORS syndrome [
For an introduction to multigene panels click
For an introduction to CMA click
## Option 2
When the diagnosis of a
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.
A contiguous gene deletion syndrome involving
## Clinical Characteristics
Pathogenic variants in
The contribution of
Epilepsy/Deafness Phenotypes in
Although a significant proportion of individuals with this phenotype have a genetic etiology,
Five families reported [
One family and three unrelated individuals [
Two families and five sporadic cases reported [
Six families [
One family and 11 unrelated individuals reported [
Autosomal recessive deafness; seven families [
Autosomal dominant deafness; eight families [
To date, at least 200 individuals have been identified with pathogenic variant(s) in
Sensorineural hearing loss is often profound and prelingual. Some individuals have benefited from cochlear implants.
Onychoosteodystrophy affects the hands and feet equally. Small or absent nails (onychodystrophy) and hypoplastic terminal phalanges (osteodystrophy) are noted in most individuals. A triphalangeal thumb is present in one third of affected individuals.
Intellectual disability can vary significantly in degree but is often severe [
Seizures, present in most individuals with DOORS syndrome, usually start in the first year of life. The seizures are more often generalized tonic-clonic, but myoclonic, partial, and absence seizures also occur. Occasionally their frequency or severity increases. In several instances, seizures have been difficult to control even with multiple anti-seizure medications and have led to status epilepticus and death.
On brain MRI, hyperintense T
Microcephaly (estimated to occur in one third of individuals)
Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
Skeletal anomalies (e.g., calcaneal deformities)
Hypothyroidism
Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [
Visual impairment [
Peripheral neuropathy (in 1 individual with confirmed
Hypochromic microcytic anemia (reported in at least 1 individual with confirmed
Intellect may be normal; all seven members of an Italian family with FIME and biallelic
Adult individuals can still exhibit mild nystagmus and postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug. Treatment with carbidopa/levodopa, lamotrigine, and benzodiazepines can be effective for treatment of dystonic attacks or seizures. Acetazolamide, flunarizine, valproate, and levetiracetam have been reported as ineffective. Treatment with ubidecarenone was tentatively started at age 30 years in one individual who reported no overall benefits and ceased medication after two months, as seizures had long been under remission and exercise-induced dystonia episodes were rare at the time [
Brain MRI is typically normal including in adulthood in most individuals [
Clinical manifestations in individuals with
Clinical findings in individuals with
Additional compound heterozygous pathogenic variants have been reported in three Moroccan families [
Clinical findings in individuals with
Other phenotypes seen in individuals with biallelic
Several clinical features have been observed in individuals who have heterozygous pathogenic
Two unrelated individuals with generalized tonic-clonic seizures and biallelic pathogenic
In a family with autosomal recessive hearing loss, an individual with a heterozygous
A family history of seizures was also reported in two families with DOORS syndrome, including a mother who was heterozygous for the
In a family with an atypical neurologic phenotype in the proband, the affected individual's mother and her brother had seizures in childhood and adolescence, respectively. Both were confirmed to have a heterozygous pathogenic
In general, loss-of-function (LOF) variants (frameshift, nonsense, or splice site variants) are associated with more severe epilepsy phenotypes with resistance to anti-seizure medications (ASM) and early death, except when the LOF variant is in the last exon.
TBC1D24 (TBC1 domain family member 24; protein encoded by
To date, all known pathogenic variants of
The
The
The
The
Penetrance of
The acronym "DOOR syndrome" was coined in 1975 [
Developmental and epileptic encephalopathies (DEE) are defined by the International League Against Epilepsy (ILAE) as conditions in which epileptiform EEG abnormalities themselves are believed to contribute to progressive disturbance in cerebral function [
Epilepsy of infancy with migrating focal seizures (EIMFS) – a type of DEE – was initially referred to as migrating partial seizures of infancy (MMPSI) [
The prevalence of
• Microcephaly (estimated to occur in one third of individuals)
• Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
• Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
• Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
• Skeletal anomalies (e.g., calcaneal deformities)
• Hypothyroidism
• Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
• Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [
• Visual impairment [
• Peripheral neuropathy (in 1 individual with confirmed
• Hypochromic microcytic anemia (reported in at least 1 individual with confirmed
• In general, loss-of-function (LOF) variants (frameshift, nonsense, or splice site variants) are associated with more severe epilepsy phenotypes with resistance to anti-seizure medications (ASM) and early death, except when the LOF variant is in the last exon.
• TBC1D24 (TBC1 domain family member 24; protein encoded by
• To date, all known pathogenic variants of
• The
• The
• The
• The
## Clinical Description
Pathogenic variants in
The contribution of
Epilepsy/Deafness Phenotypes in
Although a significant proportion of individuals with this phenotype have a genetic etiology,
Five families reported [
One family and three unrelated individuals [
Two families and five sporadic cases reported [
Six families [
One family and 11 unrelated individuals reported [
Autosomal recessive deafness; seven families [
Autosomal dominant deafness; eight families [
To date, at least 200 individuals have been identified with pathogenic variant(s) in
Sensorineural hearing loss is often profound and prelingual. Some individuals have benefited from cochlear implants.
Onychoosteodystrophy affects the hands and feet equally. Small or absent nails (onychodystrophy) and hypoplastic terminal phalanges (osteodystrophy) are noted in most individuals. A triphalangeal thumb is present in one third of affected individuals.
Intellectual disability can vary significantly in degree but is often severe [
Seizures, present in most individuals with DOORS syndrome, usually start in the first year of life. The seizures are more often generalized tonic-clonic, but myoclonic, partial, and absence seizures also occur. Occasionally their frequency or severity increases. In several instances, seizures have been difficult to control even with multiple anti-seizure medications and have led to status epilepticus and death.
On brain MRI, hyperintense T
Microcephaly (estimated to occur in one third of individuals)
Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
Skeletal anomalies (e.g., calcaneal deformities)
Hypothyroidism
Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [
Visual impairment [
Peripheral neuropathy (in 1 individual with confirmed
Hypochromic microcytic anemia (reported in at least 1 individual with confirmed
Intellect may be normal; all seven members of an Italian family with FIME and biallelic
Adult individuals can still exhibit mild nystagmus and postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug. Treatment with carbidopa/levodopa, lamotrigine, and benzodiazepines can be effective for treatment of dystonic attacks or seizures. Acetazolamide, flunarizine, valproate, and levetiracetam have been reported as ineffective. Treatment with ubidecarenone was tentatively started at age 30 years in one individual who reported no overall benefits and ceased medication after two months, as seizures had long been under remission and exercise-induced dystonia episodes were rare at the time [
Brain MRI is typically normal including in adulthood in most individuals [
Clinical manifestations in individuals with
Clinical findings in individuals with
Additional compound heterozygous pathogenic variants have been reported in three Moroccan families [
Clinical findings in individuals with
Other phenotypes seen in individuals with biallelic
Several clinical features have been observed in individuals who have heterozygous pathogenic
Two unrelated individuals with generalized tonic-clonic seizures and biallelic pathogenic
In a family with autosomal recessive hearing loss, an individual with a heterozygous
A family history of seizures was also reported in two families with DOORS syndrome, including a mother who was heterozygous for the
In a family with an atypical neurologic phenotype in the proband, the affected individual's mother and her brother had seizures in childhood and adolescence, respectively. Both were confirmed to have a heterozygous pathogenic
• Microcephaly (estimated to occur in one third of individuals)
• Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
• Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
• Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
• Skeletal anomalies (e.g., calcaneal deformities)
• Hypothyroidism
• Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
• Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [
• Visual impairment [
• Peripheral neuropathy (in 1 individual with confirmed
• Hypochromic microcytic anemia (reported in at least 1 individual with confirmed
## DOORS Syndrome
Sensorineural hearing loss is often profound and prelingual. Some individuals have benefited from cochlear implants.
Onychoosteodystrophy affects the hands and feet equally. Small or absent nails (onychodystrophy) and hypoplastic terminal phalanges (osteodystrophy) are noted in most individuals. A triphalangeal thumb is present in one third of affected individuals.
Intellectual disability can vary significantly in degree but is often severe [
Seizures, present in most individuals with DOORS syndrome, usually start in the first year of life. The seizures are more often generalized tonic-clonic, but myoclonic, partial, and absence seizures also occur. Occasionally their frequency or severity increases. In several instances, seizures have been difficult to control even with multiple anti-seizure medications and have led to status epilepticus and death.
On brain MRI, hyperintense T
Microcephaly (estimated to occur in one third of individuals)
Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
Skeletal anomalies (e.g., calcaneal deformities)
Hypothyroidism
Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [
Visual impairment [
Peripheral neuropathy (in 1 individual with confirmed
Hypochromic microcytic anemia (reported in at least 1 individual with confirmed
• Microcephaly (estimated to occur in one third of individuals)
• Other cranial anomalies (sagittal craniosynostosis, frontal bossing, trigonocephaly, or brachycephaly in several other affected individuals)
• Dental anomalies (delayed eruption, wide spacing, and abnormal shape, size, and number)
• Congenital heart defects (e.g., double outlet right ventricle, atrial septal defect, third-degree atrioventricular block)
• Skeletal anomalies (e.g., calcaneal deformities)
• Hypothyroidism
• Renal and urinary tract anomalies (e.g., hydronephrosis, nephrocalcinosis)
• Elevated levels of urinary 2-oxoglutaric acid, which can fluctuate between normal and elevated over time [
• Visual impairment [
• Peripheral neuropathy (in 1 individual with confirmed
• Hypochromic microcytic anemia (reported in at least 1 individual with confirmed
## Familial Infantile Myoclonic Epilepsy (FIME)
Intellect may be normal; all seven members of an Italian family with FIME and biallelic
## Progressive Myoclonic Epilepsy (PME)
## Rolandic Epilepsy with Paroxysmal Exercise-Induced Dystonia and Writer's Cramp (EPRPDC)
Adult individuals can still exhibit mild nystagmus and postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug. Treatment with carbidopa/levodopa, lamotrigine, and benzodiazepines can be effective for treatment of dystonic attacks or seizures. Acetazolamide, flunarizine, valproate, and levetiracetam have been reported as ineffective. Treatment with ubidecarenone was tentatively started at age 30 years in one individual who reported no overall benefits and ceased medication after two months, as seizures had long been under remission and exercise-induced dystonia episodes were rare at the time [
Brain MRI is typically normal including in adulthood in most individuals [
## Developmental and Epileptic Encephalopathy (DEE)
Clinical manifestations in individuals with
## Autosomal Recessive Nonsyndromic Hearing Loss (DFNB)
Clinical findings in individuals with
Additional compound heterozygous pathogenic variants have been reported in three Moroccan families [
## Autosomal Dominant Nonsyndromic Hearing Loss (DFNA)
Clinical findings in individuals with
## Other Phenotypes
Other phenotypes seen in individuals with biallelic
## Heterozygotes
Several clinical features have been observed in individuals who have heterozygous pathogenic
Two unrelated individuals with generalized tonic-clonic seizures and biallelic pathogenic
In a family with autosomal recessive hearing loss, an individual with a heterozygous
A family history of seizures was also reported in two families with DOORS syndrome, including a mother who was heterozygous for the
In a family with an atypical neurologic phenotype in the proband, the affected individual's mother and her brother had seizures in childhood and adolescence, respectively. Both were confirmed to have a heterozygous pathogenic
## Genotype-Phenotype Correlations
In general, loss-of-function (LOF) variants (frameshift, nonsense, or splice site variants) are associated with more severe epilepsy phenotypes with resistance to anti-seizure medications (ASM) and early death, except when the LOF variant is in the last exon.
TBC1D24 (TBC1 domain family member 24; protein encoded by
To date, all known pathogenic variants of
The
The
The
The
• In general, loss-of-function (LOF) variants (frameshift, nonsense, or splice site variants) are associated with more severe epilepsy phenotypes with resistance to anti-seizure medications (ASM) and early death, except when the LOF variant is in the last exon.
• TBC1D24 (TBC1 domain family member 24; protein encoded by
• To date, all known pathogenic variants of
• The
• The
• The
• The
## Penetrance
Penetrance of
## Nomenclature
The acronym "DOOR syndrome" was coined in 1975 [
Developmental and epileptic encephalopathies (DEE) are defined by the International League Against Epilepsy (ILAE) as conditions in which epileptiform EEG abnormalities themselves are believed to contribute to progressive disturbance in cerebral function [
Epilepsy of infancy with migrating focal seizures (EIMFS) – a type of DEE – was initially referred to as migrating partial seizures of infancy (MMPSI) [
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
A
## Differential Diagnosis
Genetic Disorders in the Differential Diagnosis of DOORS Syndrome
Absence of 2-oxoglutaric aciduria
Variably seen: coarse face, generalized hypertrichosis, scoliosis (some), gingival overgrowth (some), & 5th finger hypoplasia
Variable ID/DD, seizures in
Seizures have been suspected in 1 person w/
Absence of 2-oxoglutaric aciduria
Coarse face, hypertrichosis, gingival overgrowth, scoliosis
No seizures in persons w/
Absence of 2-oxoglutaric aciduria
Dental anomalies (conical, hypoplastic teeth) (some)
Absence of ID/DD & seizures
Absence of 2-oxoglutaric aciduria
Broad & proximally implanted thumbs, long great toes
2-oxoglutaric aciduria in 1 individual
ID/DD, seizures
Urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine
Metabolic decompensation
↑ 2-oxoglutaric acid
ID/DD, movement disorder
Absence of 2-oxoglutaric aciduria
Hyperphosphatasia
Absence of deafness
↑ 2-oxoglutaric acid
Severe DD, seizures
↑ D-2- & L-2-hydroxyglutaric acid
Severe neonatal encephalopathy w/early death
No skeletal manifestations
Absence of 2-oxoglutaric aciduria
Coarse face, prominent finger joints & broad distal phalanges, scoliosis (some)
Absence of 2-oxoglutaric aciduria
Blepharophimosis
Hypoplastic/absent terminal phalanges rarely seen
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
Pathogenic variants are typically
Disorders to Consider in the Differential Diagnosis of FIME and PME
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance
Neuronal ceroid-lipofuscinosis (NCL) is inherited in an autosomal recessive manner with the exception of
DEE is genetically heterogeneous. More than 100 genes are known to be associated with DEE. See
See
• Absence of 2-oxoglutaric aciduria
• Variably seen: coarse face, generalized hypertrichosis, scoliosis (some), gingival overgrowth (some), & 5th finger hypoplasia
• Variable ID/DD, seizures in
• Seizures have been suspected in 1 person w/
• Absence of 2-oxoglutaric aciduria
• Coarse face, hypertrichosis, gingival overgrowth, scoliosis
• No seizures in persons w/
• Absence of 2-oxoglutaric aciduria
• Dental anomalies (conical, hypoplastic teeth) (some)
• Absence of ID/DD & seizures
• Absence of 2-oxoglutaric aciduria
• Broad & proximally implanted thumbs, long great toes
• 2-oxoglutaric aciduria in 1 individual
• ID/DD, seizures
• Urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine
• Metabolic decompensation
• ↑ 2-oxoglutaric acid
• ID/DD, movement disorder
• Absence of 2-oxoglutaric aciduria
• Hyperphosphatasia
• Absence of deafness
• ↑ 2-oxoglutaric acid
• Severe DD, seizures
• ↑ D-2- & L-2-hydroxyglutaric acid
• Severe neonatal encephalopathy w/early death
• No skeletal manifestations
• Absence of 2-oxoglutaric aciduria
• Coarse face, prominent finger joints & broad distal phalanges, scoliosis (some)
• Absence of 2-oxoglutaric aciduria
• Blepharophimosis
• Hypoplastic/absent terminal phalanges rarely seen
## DOORS Syndrome
Genetic Disorders in the Differential Diagnosis of DOORS Syndrome
Absence of 2-oxoglutaric aciduria
Variably seen: coarse face, generalized hypertrichosis, scoliosis (some), gingival overgrowth (some), & 5th finger hypoplasia
Variable ID/DD, seizures in
Seizures have been suspected in 1 person w/
Absence of 2-oxoglutaric aciduria
Coarse face, hypertrichosis, gingival overgrowth, scoliosis
No seizures in persons w/
Absence of 2-oxoglutaric aciduria
Dental anomalies (conical, hypoplastic teeth) (some)
Absence of ID/DD & seizures
Absence of 2-oxoglutaric aciduria
Broad & proximally implanted thumbs, long great toes
2-oxoglutaric aciduria in 1 individual
ID/DD, seizures
Urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine
Metabolic decompensation
↑ 2-oxoglutaric acid
ID/DD, movement disorder
Absence of 2-oxoglutaric aciduria
Hyperphosphatasia
Absence of deafness
↑ 2-oxoglutaric acid
Severe DD, seizures
↑ D-2- & L-2-hydroxyglutaric acid
Severe neonatal encephalopathy w/early death
No skeletal manifestations
Absence of 2-oxoglutaric aciduria
Coarse face, prominent finger joints & broad distal phalanges, scoliosis (some)
Absence of 2-oxoglutaric aciduria
Blepharophimosis
Hypoplastic/absent terminal phalanges rarely seen
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
Pathogenic variants are typically
• Absence of 2-oxoglutaric aciduria
• Variably seen: coarse face, generalized hypertrichosis, scoliosis (some), gingival overgrowth (some), & 5th finger hypoplasia
• Variable ID/DD, seizures in
• Seizures have been suspected in 1 person w/
• Absence of 2-oxoglutaric aciduria
• Coarse face, hypertrichosis, gingival overgrowth, scoliosis
• No seizures in persons w/
• Absence of 2-oxoglutaric aciduria
• Dental anomalies (conical, hypoplastic teeth) (some)
• Absence of ID/DD & seizures
• Absence of 2-oxoglutaric aciduria
• Broad & proximally implanted thumbs, long great toes
• 2-oxoglutaric aciduria in 1 individual
• ID/DD, seizures
• Urinary excretion of 3-hydroxyisovalerate & 3-methylcrotonylglycine
• Metabolic decompensation
• ↑ 2-oxoglutaric acid
• ID/DD, movement disorder
• Absence of 2-oxoglutaric aciduria
• Hyperphosphatasia
• Absence of deafness
• ↑ 2-oxoglutaric acid
• Severe DD, seizures
• ↑ D-2- & L-2-hydroxyglutaric acid
• Severe neonatal encephalopathy w/early death
• No skeletal manifestations
• Absence of 2-oxoglutaric aciduria
• Coarse face, prominent finger joints & broad distal phalanges, scoliosis (some)
• Absence of 2-oxoglutaric aciduria
• Blepharophimosis
• Hypoplastic/absent terminal phalanges rarely seen
## Familial Infantile Myoclonic Epilepsy (FIME) and Progressive Myoclonus Epilepsy (PME)
Disorders to Consider in the Differential Diagnosis of FIME and PME
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance
Neuronal ceroid-lipofuscinosis (NCL) is inherited in an autosomal recessive manner with the exception of
## Developmental and Epileptic Encephalopathy (DEE)
DEE is genetically heterogeneous. More than 100 genes are known to be associated with DEE. See
## Hereditary Hearing Loss and Deafness
See
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
EEG to assess overall degree & types of seizures
Baseline brain MRI
Neurologic exam to assess if a movement disorder or other neurologic involvement (e.g., dysarthria nystagmus, peripheral neuropathy) is present
Head circumference to establish presence of microcephaly & assess whether other cranial abnormalities are present
Community or
Social work involvement for parental support
Home nursing referral
ID = intellectual disability; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Many ASMs may be effective; none have been demonstrated to be effective specifically for this disorder.
Education of parents/caregivers
Adults can still exhibit mild nystagmus & postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug.
Treatment w/carbidopa/levodopa, lamotrigine, & benzodiazepines can be effective for treatment of dystonic attacks or seizures.
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; EPRPDC = rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp
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).
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor those w/seizures as clinically indicated, w/repeat EEGs as indicated depending on seizure frequency &/or progression.
Assess for new manifestations such as seizures or any other neurologic features.
At each visit
Persons w/epilepsy, irrespective of cause, should have periodic EEGs.
Consider repeat neuroimaging in case of new symptoms or clinical deterioration.
Individuals with a heterozygous
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss.
See
In general, no information on specific prenatal presentations is available.
Polyhydramnios is often noted when a fetus has DOORS syndrome [
Search
• EEG to assess overall degree & types of seizures
• Baseline brain MRI
• Neurologic exam to assess if a movement disorder or other neurologic involvement (e.g., dysarthria nystagmus, peripheral neuropathy) is present
• Head circumference to establish presence of microcephaly & assess whether other cranial abnormalities are present
• Community or
• Social work involvement for parental support
• Home nursing referral
• Many ASMs may be effective; none have been demonstrated to be effective specifically for this disorder.
• Education of parents/caregivers
• Adults can still exhibit mild nystagmus & postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug.
• Treatment w/carbidopa/levodopa, lamotrigine, & benzodiazepines can be effective for treatment of dystonic attacks or seizures.
• 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).
• Monitor those w/seizures as clinically indicated, w/repeat EEGs as indicated depending on seizure frequency &/or progression.
• Assess for new manifestations such as seizures or any other neurologic features.
• At each visit
• Persons w/epilepsy, irrespective of cause, should have periodic EEGs.
• Consider repeat neuroimaging in case of new symptoms or clinical deterioration.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
EEG to assess overall degree & types of seizures
Baseline brain MRI
Neurologic exam to assess if a movement disorder or other neurologic involvement (e.g., dysarthria nystagmus, peripheral neuropathy) is present
Head circumference to establish presence of microcephaly & assess whether other cranial abnormalities are present
Community or
Social work involvement for parental support
Home nursing referral
ID = intellectual disability; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• EEG to assess overall degree & types of seizures
• Baseline brain MRI
• Neurologic exam to assess if a movement disorder or other neurologic involvement (e.g., dysarthria nystagmus, peripheral neuropathy) is present
• Head circumference to establish presence of microcephaly & assess whether other cranial abnormalities are present
• 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 have been demonstrated to be effective specifically for this disorder.
Education of parents/caregivers
Adults can still exhibit mild nystagmus & postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug.
Treatment w/carbidopa/levodopa, lamotrigine, & benzodiazepines can be effective for treatment of dystonic attacks or seizures.
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; EPRPDC = rolandic epilepsy with paroxysmal exercise-induced dystonia and writer's cramp
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).
• Many ASMs may be effective; none have been demonstrated to be effective specifically for this disorder.
• Education of parents/caregivers
• Adults can still exhibit mild nystagmus & postural tremor of the hands. Trihexyphenidyl can be effective as an anti-tremor drug.
• Treatment w/carbidopa/levodopa, lamotrigine, & benzodiazepines can be effective for treatment of dystonic attacks or seizures.
• 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).
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor those w/seizures as clinically indicated, w/repeat EEGs as indicated depending on seizure frequency &/or progression.
Assess for new manifestations such as seizures or any other neurologic features.
At each visit
Persons w/epilepsy, irrespective of cause, should have periodic EEGs.
Consider repeat neuroimaging in case of new symptoms or clinical deterioration.
• Monitor those w/seizures as clinically indicated, w/repeat EEGs as indicated depending on seizure frequency &/or progression.
• Assess for new manifestations such as seizures or any other neurologic features.
• At each visit
• Persons w/epilepsy, irrespective of cause, should have periodic EEGs.
• Consider repeat neuroimaging in case of new symptoms or clinical deterioration.
## Agents/Circumstances to Avoid
Individuals with a heterozygous
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from early treatment of seizures and/or hearing loss.
See
## Pregnancy Management
In general, no information on specific prenatal presentations is available.
Polyhydramnios is often noted when a fetus has DOORS syndrome [
## Therapies Under Investigation
Search
## Genetic Counseling
Most
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 typically asymptomatic. It is possible that certain
If both parents are known to be heterozygous for a
Sibs who inherit biallelic pathogenic variants are likely to have clinical manifestations similar to those in the proband.
Heterozygotes (carriers) are typically asymptomatic. It is possible that certain
To date, individuals with DOORS syndrome,
The offspring of an individual with
See Management,
Clear communication between individuals with hearing loss, families, and health care providers is key. D/deaf and hard of hearing (DHH) persons may use a variety of communication methods including spoken language, sign language, lip reading, and written notes. For DHH individuals and families who use sign language, a certified sign language interpreter must be used. Communication aids such as visual aids and verbal cues when changing topics can be helpful.
It is important to ascertain and address the questions and concerns of the family/individual. DHH persons may be interested in obtaining information about the cause of their hearing loss, including information on medical, educational, and social services. Others may seek information about the chance of having children with hearing loss and information for family planning decisions.
The use of neutral or balanced terminology can enhance the provision of services; for example: use of the term "chance" instead of "risk"; "deaf" or "hearing" instead of "affected" or "unaffected"; and "deaf" or "hard of hearing" instead of "hearing impaired." Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." Terms such as "handicap" should be avoided.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 typically asymptomatic. It is possible that certain
• 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
• Sibs who inherit biallelic pathogenic variants are likely to have clinical manifestations similar to those in the proband.
• Heterozygotes (carriers) are typically asymptomatic. It is possible that certain
• To date, individuals with DOORS syndrome,
• The offspring of an individual with
• Clear communication between individuals with hearing loss, families, and health care providers is key. D/deaf and hard of hearing (DHH) persons may use a variety of communication methods including spoken language, sign language, lip reading, and written notes. For DHH individuals and families who use sign language, a certified sign language interpreter must be used. Communication aids such as visual aids and verbal cues when changing topics can be helpful.
• It is important to ascertain and address the questions and concerns of the family/individual. DHH persons may be interested in obtaining information about the cause of their hearing loss, including information on medical, educational, and social services. Others may seek information about the chance of having children with hearing loss and information for family planning decisions.
• The use of neutral or balanced terminology can enhance the provision of services; for example: use of the term "chance" instead of "risk"; "deaf" or "hearing" instead of "affected" or "unaffected"; and "deaf" or "hard of hearing" instead of "hearing impaired." Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." Terms such as "handicap" should be avoided.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Most
## Risk to Family Members (Autosomal Recessive Inheritance)
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 typically asymptomatic. It is possible that certain
If both parents are known to be heterozygous for a
Sibs who inherit biallelic pathogenic variants are likely to have clinical manifestations similar to those in the proband.
Heterozygotes (carriers) are typically asymptomatic. It is possible that certain
To date, individuals with DOORS syndrome,
The offspring of an individual with
• 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 typically asymptomatic. It is possible that certain
• 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
• Sibs who inherit biallelic pathogenic variants are likely to have clinical manifestations similar to those in the proband.
• Heterozygotes (carriers) are typically asymptomatic. It is possible that certain
• To date, individuals with DOORS syndrome,
• The offspring of an individual with
## Related Genetic Counseling Issues
See Management,
Clear communication between individuals with hearing loss, families, and health care providers is key. D/deaf and hard of hearing (DHH) persons may use a variety of communication methods including spoken language, sign language, lip reading, and written notes. For DHH individuals and families who use sign language, a certified sign language interpreter must be used. Communication aids such as visual aids and verbal cues when changing topics can be helpful.
It is important to ascertain and address the questions and concerns of the family/individual. DHH persons may be interested in obtaining information about the cause of their hearing loss, including information on medical, educational, and social services. Others may seek information about the chance of having children with hearing loss and information for family planning decisions.
The use of neutral or balanced terminology can enhance the provision of services; for example: use of the term "chance" instead of "risk"; "deaf" or "hearing" instead of "affected" or "unaffected"; and "deaf" or "hard of hearing" instead of "hearing impaired." Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." Terms such as "handicap" should be avoided.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• Clear communication between individuals with hearing loss, families, and health care providers is key. D/deaf and hard of hearing (DHH) persons may use a variety of communication methods including spoken language, sign language, lip reading, and written notes. For DHH individuals and families who use sign language, a certified sign language interpreter must be used. Communication aids such as visual aids and verbal cues when changing topics can be helpful.
• It is important to ascertain and address the questions and concerns of the family/individual. DHH persons may be interested in obtaining information about the cause of their hearing loss, including information on medical, educational, and social services. Others may seek information about the chance of having children with hearing loss and information for family planning decisions.
• The use of neutral or balanced terminology can enhance the provision of services; for example: use of the term "chance" instead of "risk"; "deaf" or "hearing" instead of "affected" or "unaffected"; and "deaf" or "hard of hearing" instead of "hearing impaired." Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented." Terms such as "handicap" should be avoided.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Canada
•
•
•
•
•
• Canada
•
•
•
•
•
•
•
## Molecular Genetics
TBC1D24-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TBC1D24-Related Disorders (
Cellular studies have revealed that disease-causing variants that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. Genetic disruption of
Autosomal recessive disorders (DOORS syndrome, FIME, EIMFS, PME, EPRPDC, DEE, and DFNB): loss of function
Autosomal dominant disorders (DFNA): unknown
EIMFS = epilepsy of infancy with migrating focal seizures; NCSE = non-convulsive status epilepticus
Variants listed in the table have been provided by the authors.
• Autosomal recessive disorders (DOORS syndrome, FIME, EIMFS, PME, EPRPDC, DEE, and DFNB): loss of function
• Autosomal dominant disorders (DFNA): unknown
## Molecular Pathogenesis
Cellular studies have revealed that disease-causing variants that disrupt either of the conserved protein domains in TBC1D24 are implicated in neuronal development and survival and are likely acting as loss-of-function alleles. Genetic disruption of
Autosomal recessive disorders (DOORS syndrome, FIME, EIMFS, PME, EPRPDC, DEE, and DFNB): loss of function
Autosomal dominant disorders (DFNA): unknown
EIMFS = epilepsy of infancy with migrating focal seizures; NCSE = non-convulsive status epilepticus
Variants listed in the table have been provided by the authors.
• Autosomal recessive disorders (DOORS syndrome, FIME, EIMFS, PME, EPRPDC, DEE, and DFNB): loss of function
• Autosomal dominant disorders (DFNA): unknown
## Chapter Notes
The authors would like to thank the patients and family members who take part in the TBC1D24 Foundation and have contributed hugely to our understanding of this disorder.
This work was supported by Current Research 2023 of the Italian Ministry of Health (to RG, SB), Ministry of University and Research (MIUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) (to RG, SB), Brain Optical Mapping by Fondazione CARIFI (to RG), and DECODEE, Call Health 2018 of the Tuscany Region (to RG).
Simona Balestrini, MD, PhD (2024-present)Philippe M Campeau, MD (2015-present)Renzo Guerrini, MD, FRCP (2024-present)Raoul CM Hennekam, MD, PhD; University of Amsterdam (2015-2024)Davide Mei, MSc (2024-present)Bettina E Mucha, MD; Sainte-Justine Hospital (2015-2024)Sanjay Sisodiya, MD, PhD (2015-present)
24 October 2024 (gm) Comprehensive update posted live
7 December 2017 (ma) Comprehensive update posted live
26 February 2015 (me) Review posted live
31 July 2014 (pmc) Original submission
• 24 October 2024 (gm) Comprehensive update posted live
• 7 December 2017 (ma) Comprehensive update posted live
• 26 February 2015 (me) Review posted live
• 31 July 2014 (pmc) Original submission
## Author Notes
The authors would like to thank the patients and family members who take part in the TBC1D24 Foundation and have contributed hugely to our understanding of this disorder.
## Acknowledgments
This work was supported by Current Research 2023 of the Italian Ministry of Health (to RG, SB), Ministry of University and Research (MIUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) (to RG, SB), Brain Optical Mapping by Fondazione CARIFI (to RG), and DECODEE, Call Health 2018 of the Tuscany Region (to RG).
## Author History
Simona Balestrini, MD, PhD (2024-present)Philippe M Campeau, MD (2015-present)Renzo Guerrini, MD, FRCP (2024-present)Raoul CM Hennekam, MD, PhD; University of Amsterdam (2015-2024)Davide Mei, MSc (2024-present)Bettina E Mucha, MD; Sainte-Justine Hospital (2015-2024)Sanjay Sisodiya, MD, PhD (2015-present)
## Revision History
24 October 2024 (gm) Comprehensive update posted live
7 December 2017 (ma) Comprehensive update posted live
26 February 2015 (me) Review posted live
31 July 2014 (pmc) Original submission
• 24 October 2024 (gm) Comprehensive update posted live
• 7 December 2017 (ma) Comprehensive update posted live
• 26 February 2015 (me) Review posted live
• 31 July 2014 (pmc) Original submission
## References
## Literature Cited
|
[] |
26/2/2015
|
24/10/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tbck-ndd
|
tbck-ndd
|
[
"Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies-3 (IHPRF3)",
"TBCK Encephaloneuronopathy",
"TBCK Syndrome",
"Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies-3 (IHPRF3)",
"TBCK Encephaloneuronopathy",
"TBCK Syndrome",
"TBC domain-containing protein kinase-like protein",
"TBCK",
"TBCK-Related Neurodevelopmental Disorder"
] |
Xilma Ortiz-Gonzalez, Holly Dubbs, Kierstin Keller, Emily Durham
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Severe-to-profound developmental delay (DD) and/or intellectual disability (ID)
Severe hypotonia, typically congenital
Infantile feeding difficulties
Neuromuscular weakness, often progressive, with progressive spasticity and distal muscle wasting
Respiratory insufficiency or failure (not always congenital but often progressive due to neuromuscular weakness)
Epilepsy
Short stature, specifically brachymelia
Ophthalmologic involvement, including nystagmus and cortical visual impairment
Coarse facial features with further dysmorphic features (See
White matter changes, including periventricular lesions
Cerebellar hypoplasia
Diffuse brain atrophy
Thin corpus callosum
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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A founder variant, c.376C>T (p.Arg126Ter), has been reported in individuals of Puerto Rican ancestry [
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.
• Severe-to-profound developmental delay (DD) and/or intellectual disability (ID)
• Severe hypotonia, typically congenital
• Infantile feeding difficulties
• Neuromuscular weakness, often progressive, with progressive spasticity and distal muscle wasting
• Respiratory insufficiency or failure (not always congenital but often progressive due to neuromuscular weakness)
• Epilepsy
• Short stature, specifically brachymelia
• Ophthalmologic involvement, including nystagmus and cortical visual impairment
• Coarse facial features with further dysmorphic features (See
• White matter changes, including periventricular lesions
• Cerebellar hypoplasia
• Diffuse brain atrophy
• Thin corpus callosum
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Severe-to-profound developmental delay (DD) and/or intellectual disability (ID)
Severe hypotonia, typically congenital
Infantile feeding difficulties
Neuromuscular weakness, often progressive, with progressive spasticity and distal muscle wasting
Respiratory insufficiency or failure (not always congenital but often progressive due to neuromuscular weakness)
Epilepsy
Short stature, specifically brachymelia
Ophthalmologic involvement, including nystagmus and cortical visual impairment
Coarse facial features with further dysmorphic features (See
White matter changes, including periventricular lesions
Cerebellar hypoplasia
Diffuse brain atrophy
Thin corpus callosum
• Severe-to-profound developmental delay (DD) and/or intellectual disability (ID)
• Severe hypotonia, typically congenital
• Infantile feeding difficulties
• Neuromuscular weakness, often progressive, with progressive spasticity and distal muscle wasting
• Respiratory insufficiency or failure (not always congenital but often progressive due to neuromuscular weakness)
• Epilepsy
• Short stature, specifically brachymelia
• Ophthalmologic involvement, including nystagmus and cortical visual impairment
• Coarse facial features with further dysmorphic features (See
• White matter changes, including periventricular lesions
• Cerebellar hypoplasia
• Diffuse brain atrophy
• Thin corpus callosum
## 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A founder variant, c.376C>T (p.Arg126Ter), has been reported in individuals of Puerto Rican ancestry [
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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, at least 117 individuals have been identified [E Durham, personal observation] and 73 individuals have been reported in the literature with biallelic pathogenic variants in
Dyslipidemia typically involves hypercholesterolemia &/or hypertriglyceridemia
There are a few reports of congenital cardiac structural defects (<10 affected persons reported)
Based on
Seizures provoked by fever during infancy are common.
Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
Reports of head size have been variable in the literature, with some affected individuals demonstrating microcephaly and some macrocephaly, but most are normocephalic.
Head asymmetry, brachycephaly, plagiocephaly, and turricephaly have all been reported [
By age five years, noninvasive nocturnal respiratory support is often required.
About 75% of affected teenagers require tracheotomy support.
Left ventricular hypertrophy may develop in late adolescence / early adulthood.
There are fewer than ten reports of various congenital cardiac anomalies in affected individuals; it is unclear if structural heart defects are a rare finding in affected individuals or if this represents a rare co-occurrence of two unrelated diagnoses [
The
Prevalence may be as high as 1:1,000,000 worldwide but is about four times higher in Admixed American populations, including the Boricua
• Dyslipidemia typically involves hypercholesterolemia &/or hypertriglyceridemia
• There are a few reports of congenital cardiac structural defects (<10 affected persons reported)
• Seizures provoked by fever during infancy are common.
• Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
• Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Seizures provoked by fever during infancy are common.
• Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
• Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Seizures provoked by fever during infancy are common.
• Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
• Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Reports of head size have been variable in the literature, with some affected individuals demonstrating microcephaly and some macrocephaly, but most are normocephalic.
• Head asymmetry, brachycephaly, plagiocephaly, and turricephaly have all been reported [
• By age five years, noninvasive nocturnal respiratory support is often required.
• About 75% of affected teenagers require tracheotomy support.
• Left ventricular hypertrophy may develop in late adolescence / early adulthood.
• There are fewer than ten reports of various congenital cardiac anomalies in affected individuals; it is unclear if structural heart defects are a rare finding in affected individuals or if this represents a rare co-occurrence of two unrelated diagnoses [
## Clinical Description
To date, at least 117 individuals have been identified [E Durham, personal observation] and 73 individuals have been reported in the literature with biallelic pathogenic variants in
Dyslipidemia typically involves hypercholesterolemia &/or hypertriglyceridemia
There are a few reports of congenital cardiac structural defects (<10 affected persons reported)
Based on
Seizures provoked by fever during infancy are common.
Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
Reports of head size have been variable in the literature, with some affected individuals demonstrating microcephaly and some macrocephaly, but most are normocephalic.
Head asymmetry, brachycephaly, plagiocephaly, and turricephaly have all been reported [
By age five years, noninvasive nocturnal respiratory support is often required.
About 75% of affected teenagers require tracheotomy support.
Left ventricular hypertrophy may develop in late adolescence / early adulthood.
There are fewer than ten reports of various congenital cardiac anomalies in affected individuals; it is unclear if structural heart defects are a rare finding in affected individuals or if this represents a rare co-occurrence of two unrelated diagnoses [
• Dyslipidemia typically involves hypercholesterolemia &/or hypertriglyceridemia
• There are a few reports of congenital cardiac structural defects (<10 affected persons reported)
• Seizures provoked by fever during infancy are common.
• Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
• Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Seizures provoked by fever during infancy are common.
• Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
• Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Seizures provoked by fever during infancy are common.
• Later in childhood, seizures progress most commonly to symptomatic multifocal epilepsy, although epilepsy syndromes including infantile spasms and Lennox-Gastaut syndrome have been reported. Published data is insufficient to determine frequency of these less common epilepsy syndromes in affected individuals.
• Some affected individuals experience progression to medication-refractory epilepsy with mixed focal and generalized features in adolescence/adulthood [X Ortiz-Gonzalez, personal observation].
• Reports of head size have been variable in the literature, with some affected individuals demonstrating microcephaly and some macrocephaly, but most are normocephalic.
• Head asymmetry, brachycephaly, plagiocephaly, and turricephaly have all been reported [
• By age five years, noninvasive nocturnal respiratory support is often required.
• About 75% of affected teenagers require tracheotomy support.
• Left ventricular hypertrophy may develop in late adolescence / early adulthood.
• There are fewer than ten reports of various congenital cardiac anomalies in affected individuals; it is unclear if structural heart defects are a rare finding in affected individuals or if this represents a rare co-occurrence of two unrelated diagnoses [
## Genotype-Phenotype Correlations
The
## Prevalence
Prevalence may be as high as 1:1,000,000 worldwide but is about four times higher in Admixed American populations, including the Boricua
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic disorders of interest in the differential diagnosis of
Genes of Interest in the Differential Diagnosis of
Hypotonia
Severe DD/ID
Seizures
Peripheral motor neuropathy
Congenital contractures/arthrogryposis
Distinct dysmorphic features
Hypotonia
Severe DD/ID
Coarse dysmorphic features incl macroglossia
Note: Phenotype is very similar to
Congenital hypotonia
Seizures
Peripheral neuropathy
Auditory neuropathy
Not assoc with facial features characteristic of
AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NDD = neurodevelopmental disorder;
• Hypotonia
• Severe DD/ID
• Seizures
• Peripheral motor neuropathy
• Congenital contractures/arthrogryposis
• Distinct dysmorphic features
• Hypotonia
• Severe DD/ID
• Coarse dysmorphic features incl macroglossia
• Note: Phenotype is very similar to
• Congenital hypotonia
• Seizures
• Peripheral neuropathy
• Auditory neuropathy
• Not assoc with facial features characteristic of
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
To incl brain MRI
Consider EEG if seizures are a concern.
If clinically suspected due to hyporeflexia, EMG/NCS may be considered.
If evidence of profound neuromuscular weakness, consider eval for nocturnal hypoventilation.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider eval for alternative communication device.
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
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.
If fever/illness of unknown source, consider eval for UTI & hyponatremia.
Consider renal ultrasound in those w/history of UTI.
Consider referral to nephrologist.
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; DXA = dual-energy x-ray absorptiometry; EMG = electromyography; MOI = mode of inheritance; NCS = nerve conduction study; 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
Caution is advised w/use of valproic acid & ketogenic diet due to evidence for secondary mitochondrial dysfunction.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizure action plan; consider rescue at 3 minutes, as there is high risk of status epilepticus.
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: 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
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 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).
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
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & weakness.
Physical medicine & OT/PT assessment of mobility & self-help skills
Assessment for progressive contractures & bony fractures
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
To include total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides
Anecdotally, some affected individuals have had adverse effects to bisphosphonate infusions for management of osteoporosis. The frequency and mechanism of this observation in the
See
Search
• To incl brain MRI
• Consider EEG if seizures are a concern.
• If clinically suspected due to hyporeflexia, EMG/NCS may be considered.
• If evidence of profound neuromuscular weakness, consider eval for nocturnal hypoventilation.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider eval for alternative communication device.
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• 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.
• If fever/illness of unknown source, consider eval for UTI & hyponatremia.
• Consider renal ultrasound in those w/history of UTI.
• Consider referral to nephrologist.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Caution is advised w/use of valproic acid & ketogenic diet due to evidence for secondary mitochondrial dysfunction.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizure action plan; consider rescue at 3 minutes, as there is high risk of status epilepticus.
• 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: 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 children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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).
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & weakness.
• Physical medicine & OT/PT assessment of mobility & self-help skills
• Assessment for progressive contractures & bony fractures
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
To incl brain MRI
Consider EEG if seizures are a concern.
If clinically suspected due to hyporeflexia, EMG/NCS may be considered.
If evidence of profound neuromuscular weakness, consider eval for nocturnal hypoventilation.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider eval for alternative communication device.
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
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.
If fever/illness of unknown source, consider eval for UTI & hyponatremia.
Consider renal ultrasound in those w/history of UTI.
Consider referral to nephrologist.
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; DXA = dual-energy x-ray absorptiometry; EMG = electromyography; MOI = mode of inheritance; NCS = nerve conduction study; 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 brain MRI
• Consider EEG if seizures are a concern.
• If clinically suspected due to hyporeflexia, EMG/NCS may be considered.
• If evidence of profound neuromuscular weakness, consider eval for nocturnal hypoventilation.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider eval for alternative communication device.
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• 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.
• If fever/illness of unknown source, consider eval for UTI & hyponatremia.
• Consider renal ultrasound in those w/history of UTI.
• Consider referral to nephrologist.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Caution is advised w/use of valproic acid & ketogenic diet due to evidence for secondary mitochondrial dysfunction.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizure action plan; consider rescue at 3 minutes, as there is high risk of status epilepticus.
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: 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
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 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).
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.
• Caution is advised w/use of valproic acid & ketogenic diet due to evidence for secondary mitochondrial dysfunction.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizure action plan; consider rescue at 3 minutes, as there is high risk of status epilepticus.
• 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: 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 children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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
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
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & weakness.
Physical medicine & OT/PT assessment of mobility & self-help skills
Assessment for progressive contractures & bony fractures
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
To include total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & weakness.
• Physical medicine & OT/PT assessment of mobility & self-help skills
• Assessment for progressive contractures & bony fractures
## Agents/Circumstances to Avoid
Anecdotally, some affected individuals have had adverse effects to bisphosphonate infusions for management of osteoporosis. The frequency and mechanism of this observation in the
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
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.
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.
Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in individuals of Puerto Rican ancestry (see
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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in individuals of Puerto Rican ancestry (see
## Mode of Inheritance
## 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 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.
## 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.
Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry. A founder variant has been identified in individuals of Puerto Rican ancestry (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 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. A founder variant has been identified in individuals of Puerto Rican ancestry (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 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
TBCK Syndrome Data Collection Program
•
•
•
•
•
• TBCK Syndrome Data Collection Program
•
## Molecular Genetics
TBCK-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TBCK-Related Neurodevelopmental Disorder (
TBCK was recently found to be a component of a novel mRNA transport complex called the five-subunit endosomal Rab5 and RNA/ribosome intermediary (FERRY) complex. Intriguingly, of the five proteins proposed to form the FERRY complex (TBCK, PP1R21, C12orf4, CRYZL1, and GATD1) [
Variants listed in the table have been provided by the authors.
See also
## Molecular Pathogenesis
TBCK was recently found to be a component of a novel mRNA transport complex called the five-subunit endosomal Rab5 and RNA/ribosome intermediary (FERRY) complex. Intriguingly, of the five proteins proposed to form the FERRY complex (TBCK, PP1R21, C12orf4, CRYZL1, and GATD1) [
Variants listed in the table have been provided by the authors.
See also
## Chapter Notes
Children's Hospital of Philadelphia
We are thankful to the TBCK foundation for their ongoing support and advocacy.
12 June 2025 (ma) Review posted live
31 October 2024 (xog) Original submission
• 12 June 2025 (ma) Review posted live
• 31 October 2024 (xog) Original submission
## Author Notes
Children's Hospital of Philadelphia
## Acknowledgments
We are thankful to the TBCK foundation for their ongoing support and advocacy.
## Revision History
12 June 2025 (ma) Review posted live
31 October 2024 (xog) Original submission
• 12 June 2025 (ma) Review posted live
• 31 October 2024 (xog) Original submission
## References
## Literature Cited
|
[] |
12/6/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
tbrs
|
tbrs
|
[
"DNMT3A Overgrowth Syndrome",
"DNMT3A Overgrowth Syndrome",
"TBRS",
"DNA (cytosine-5)-methyltransferase 3A",
"DNMT3A",
"Tatton-Brown-Rahman Syndrome"
] |
Tatton-Brown-Rahman Syndrome
|
Philip J Ostrowski, Katrina Tatton-Brown
|
Summary Tatton-Brown-Rahman syndrome (TBRS) is an overgrowth / intellectual disability syndrome characterized by length/height and/or head circumference ≥2 standard deviations above the mean for age and sex, obesity / increased weight, intellectual disability that ranges from mild to severe, joint hypermobility, hypotonia, behavioral/psychiatric issues, kyphoscoliosis, and seizures. Individuals with TBRS have subtle dysmorphic features, including a round face with coarse features, thick horizontal low-set eyebrows, narrow (as measured vertically) palpebral fissures, and prominent upper central incisors. The facial gestalt is most easily recognizable in the teenage years. TBRS may be associated with an increased risk of developing acute myeloid leukemia. There are less clear associations with aortic root dilatation and increased risk of other hematologic and solid tumors. The diagnosis of TBRS is established in a proband with suggestive findings and a heterozygous pathogenic variant in TBRS is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for Tatton-Brown-Rahman syndrome (TBRS) have been published.
TBRS
Generalized overgrowth (length/height and/or head circumference ≥2 standard deviations above the mean for age and sex) [
Mild-to-severe developmental delay (DD) or intellectual disability (ID)
AND
Any of the following features presenting in infancy or childhood/adolescence:
Dysmorphic facial features (See
Joint hypermobility
Hypotonia
Kyphoscoliosis
Seizures, including variable afebrile seizure types
Cryptorchidism
Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
Acute myeloid leukemia and possibly other hematologic malignancies
The diagnosis of TBRS
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 TBRS, 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 intellectual disability or the clinician is unfamiliar with the TBRS phenotype, then
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Tatton-Brown-Rahman Syndrome
See
See
One additional individual with a contiguous gene deletion (not included in these calculations) has 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
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.
• Generalized overgrowth (length/height and/or head circumference ≥2 standard deviations above the mean for age and sex) [
• Mild-to-severe developmental delay (DD) or intellectual disability (ID)
• Any of the following features presenting in infancy or childhood/adolescence:
• Dysmorphic facial features (See
• Joint hypermobility
• Hypotonia
• Kyphoscoliosis
• Seizures, including variable afebrile seizure types
• Cryptorchidism
• Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
• Acute myeloid leukemia and possibly other hematologic malignancies
• Dysmorphic facial features (See
• Joint hypermobility
• Hypotonia
• Kyphoscoliosis
• Seizures, including variable afebrile seizure types
• Cryptorchidism
• Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
• Acute myeloid leukemia and possibly other hematologic malignancies
• Dysmorphic facial features (See
• Joint hypermobility
• Hypotonia
• Kyphoscoliosis
• Seizures, including variable afebrile seizure types
• Cryptorchidism
• Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
• Acute myeloid leukemia and possibly other hematologic malignancies
• For an introduction to multigene panels click
## Suggestive Findings
TBRS
Generalized overgrowth (length/height and/or head circumference ≥2 standard deviations above the mean for age and sex) [
Mild-to-severe developmental delay (DD) or intellectual disability (ID)
AND
Any of the following features presenting in infancy or childhood/adolescence:
Dysmorphic facial features (See
Joint hypermobility
Hypotonia
Kyphoscoliosis
Seizures, including variable afebrile seizure types
Cryptorchidism
Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
Acute myeloid leukemia and possibly other hematologic malignancies
• Generalized overgrowth (length/height and/or head circumference ≥2 standard deviations above the mean for age and sex) [
• Mild-to-severe developmental delay (DD) or intellectual disability (ID)
• Any of the following features presenting in infancy or childhood/adolescence:
• Dysmorphic facial features (See
• Joint hypermobility
• Hypotonia
• Kyphoscoliosis
• Seizures, including variable afebrile seizure types
• Cryptorchidism
• Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
• Acute myeloid leukemia and possibly other hematologic malignancies
• Dysmorphic facial features (See
• Joint hypermobility
• Hypotonia
• Kyphoscoliosis
• Seizures, including variable afebrile seizure types
• Cryptorchidism
• Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
• Acute myeloid leukemia and possibly other hematologic malignancies
• Dysmorphic facial features (See
• Joint hypermobility
• Hypotonia
• Kyphoscoliosis
• Seizures, including variable afebrile seizure types
• Cryptorchidism
• Behavior problems, most commonly autism spectrum disorder, although a variety of behavioral issues have been described (See
• Acute myeloid leukemia and possibly other hematologic malignancies
## Establishing the Diagnosis
The diagnosis of TBRS
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 TBRS, 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 intellectual disability or the clinician is unfamiliar with the TBRS phenotype, then
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Tatton-Brown-Rahman Syndrome
See
See
One additional individual with a contiguous gene deletion (not included in these calculations) has 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
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.
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings suggest the diagnosis of TBRS, 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 intellectual disability or the clinician is unfamiliar with the TBRS phenotype, then
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Tatton-Brown-Rahman Syndrome
See
See
One additional individual with a contiguous gene deletion (not included in these calculations) has 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
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
The cardinal features of Tatton-Brown-Rahman syndrome (TBRS) are overgrowth and mild-to-severe intellectual disability. Other common features include joint hypermobility, obesity / increased weight, hypotonia, behavioral/psychiatric problems, kyphoscoliosis, and seizures. To date, more than 90 individuals with a pathogenic variant in
Select Features of Tatton-Brown-Rahman Syndrome
Tall stature (height ≥2 SD above mean) in ~70%
Macrocephaly (head circumference ≥2 SD above mean) in ~50%
SD = standard deviation(s)
Defined as length/height and/or head circumference ≥2 SD above the mean for age and sex
Defined as weight ≥2 SD above the mean for age and sex
This figure is an estimate based on cases reported to date; the precise risk remains unknown.
Tall stature (height ≥2 standard deviations [SD] above the mean for age and sex) is present in about 70% of individuals. Height ranges from 0.3 SD below to 6 SD above the mean.
Macrocephaly (head circumference ≥2 SD above the mean for age and sex) is present in around 50% of affected individuals. Head circumference ranges from 1.2 SD below to 8.0 SD above the mean.
About 65% of affected individuals are overweight or obese (weight ≥2 SD above the mean for age and sex). Weight ranges from 1.1 SD below to 4.5 SD above the mean.
There is relatively little information about birth measurements, although overgrowth typically is present from early childhood. In those for whom measurements were available, mean birth weight was 1.3 SD above the mean (range: 1.1 SD below to 4.0 SD above mean), mean birth head circumference was 2.3 SD above the mean (range: 0.6 to 6.5 SD above mean), and mean birth length was 1.6 SD above the mean (range: 0.0 to 4.4 SD above mean) [
A subsequent publication reported more detailed cognitive and behavioral profiles of a smaller cohort (n=18, age 7-33 years) [
In a series of 18 individuals with a confirmed molecular diagnosis, autistic traits were present in the majority, and eight (44%) fulfilled the ADOS-2 criteria for a formal diagnosis of autism [
The prevalence of autistic traits was lower in older individuals, suggesting that symptoms may improve with age, but this is based on cross-sectional assessment of a relatively small cohort rather than long-term observation.
Other behavior problems reported in a smaller proportion of affected individuals include [
Anxiety
Aggression
Psychotic disorders
Bipolar disorder
Obsessive behaviors
Compulsive eating
The most common malignancy is acute myeloid leukemia (AML; 4/8 individuals); cases of lymphoid malignancy and myelodysplastic syndrome have also been reported.
The median age at diagnosis is 9.6 years (range: age 2.5-12 years), with the cases of AML diagnosed between ages nine and 20 years.
Limited information exists regarding lifetime cancer risk in individuals with TBRS, as the majority of individuals identified to date who have developed cancer are children or young adults.
Single case reports of a specific cancer in an individual with TBRS have been published; however, in the absence of further known cases, it is not clear whether these tumors are specifically associated with TBRS or are rare co-occurrences. The tumors are as follows:
Neuroblastoma [
Medulloblastoma [
Benign glioma [
Acromegaly as a result of a pituitary adenoma [
Ganglioneuroblastoma and T-cell lymphoblastic lymphoma [
A round face with coarse features (describing some loss of definition of the nose, lips, mouth, and chin because of rounded and heavy features)
Thick horizontal low-set (i.e., closer than anticipated to the orbit) eyebrows
Narrow (as measured vertically) palpebral fissures
Prominent upper central incisors
Mitral valve prolapse
Dilated cardiomyopathy
Arrhythmia
The prevalence of TBRS is unknown. More than 90 cases have been reported in the literature to date [
• Tall stature (height ≥2 SD above mean) in ~70%
• Macrocephaly (head circumference ≥2 SD above mean) in ~50%
• Tall stature (height ≥2 standard deviations [SD] above the mean for age and sex) is present in about 70% of individuals. Height ranges from 0.3 SD below to 6 SD above the mean.
• Macrocephaly (head circumference ≥2 SD above the mean for age and sex) is present in around 50% of affected individuals. Head circumference ranges from 1.2 SD below to 8.0 SD above the mean.
• About 65% of affected individuals are overweight or obese (weight ≥2 SD above the mean for age and sex). Weight ranges from 1.1 SD below to 4.5 SD above the mean.
• In a series of 18 individuals with a confirmed molecular diagnosis, autistic traits were present in the majority, and eight (44%) fulfilled the ADOS-2 criteria for a formal diagnosis of autism [
• The prevalence of autistic traits was lower in older individuals, suggesting that symptoms may improve with age, but this is based on cross-sectional assessment of a relatively small cohort rather than long-term observation.
• Anxiety
• Aggression
• Psychotic disorders
• Bipolar disorder
• Obsessive behaviors
• Compulsive eating
• The most common malignancy is acute myeloid leukemia (AML; 4/8 individuals); cases of lymphoid malignancy and myelodysplastic syndrome have also been reported.
• The median age at diagnosis is 9.6 years (range: age 2.5-12 years), with the cases of AML diagnosed between ages nine and 20 years.
• Limited information exists regarding lifetime cancer risk in individuals with TBRS, as the majority of individuals identified to date who have developed cancer are children or young adults.
• Neuroblastoma [
• Medulloblastoma [
• Benign glioma [
• Acromegaly as a result of a pituitary adenoma [
• Ganglioneuroblastoma and T-cell lymphoblastic lymphoma [
• A round face with coarse features (describing some loss of definition of the nose, lips, mouth, and chin because of rounded and heavy features)
• Thick horizontal low-set (i.e., closer than anticipated to the orbit) eyebrows
• Narrow (as measured vertically) palpebral fissures
• Prominent upper central incisors
• Mitral valve prolapse
• Dilated cardiomyopathy
• Arrhythmia
• Mitral valve prolapse
• Dilated cardiomyopathy
• Arrhythmia
• Mitral valve prolapse
• Dilated cardiomyopathy
• Arrhythmia
## Clinical Description
The cardinal features of Tatton-Brown-Rahman syndrome (TBRS) are overgrowth and mild-to-severe intellectual disability. Other common features include joint hypermobility, obesity / increased weight, hypotonia, behavioral/psychiatric problems, kyphoscoliosis, and seizures. To date, more than 90 individuals with a pathogenic variant in
Select Features of Tatton-Brown-Rahman Syndrome
Tall stature (height ≥2 SD above mean) in ~70%
Macrocephaly (head circumference ≥2 SD above mean) in ~50%
SD = standard deviation(s)
Defined as length/height and/or head circumference ≥2 SD above the mean for age and sex
Defined as weight ≥2 SD above the mean for age and sex
This figure is an estimate based on cases reported to date; the precise risk remains unknown.
Tall stature (height ≥2 standard deviations [SD] above the mean for age and sex) is present in about 70% of individuals. Height ranges from 0.3 SD below to 6 SD above the mean.
Macrocephaly (head circumference ≥2 SD above the mean for age and sex) is present in around 50% of affected individuals. Head circumference ranges from 1.2 SD below to 8.0 SD above the mean.
About 65% of affected individuals are overweight or obese (weight ≥2 SD above the mean for age and sex). Weight ranges from 1.1 SD below to 4.5 SD above the mean.
There is relatively little information about birth measurements, although overgrowth typically is present from early childhood. In those for whom measurements were available, mean birth weight was 1.3 SD above the mean (range: 1.1 SD below to 4.0 SD above mean), mean birth head circumference was 2.3 SD above the mean (range: 0.6 to 6.5 SD above mean), and mean birth length was 1.6 SD above the mean (range: 0.0 to 4.4 SD above mean) [
A subsequent publication reported more detailed cognitive and behavioral profiles of a smaller cohort (n=18, age 7-33 years) [
In a series of 18 individuals with a confirmed molecular diagnosis, autistic traits were present in the majority, and eight (44%) fulfilled the ADOS-2 criteria for a formal diagnosis of autism [
The prevalence of autistic traits was lower in older individuals, suggesting that symptoms may improve with age, but this is based on cross-sectional assessment of a relatively small cohort rather than long-term observation.
Other behavior problems reported in a smaller proportion of affected individuals include [
Anxiety
Aggression
Psychotic disorders
Bipolar disorder
Obsessive behaviors
Compulsive eating
The most common malignancy is acute myeloid leukemia (AML; 4/8 individuals); cases of lymphoid malignancy and myelodysplastic syndrome have also been reported.
The median age at diagnosis is 9.6 years (range: age 2.5-12 years), with the cases of AML diagnosed between ages nine and 20 years.
Limited information exists regarding lifetime cancer risk in individuals with TBRS, as the majority of individuals identified to date who have developed cancer are children or young adults.
Single case reports of a specific cancer in an individual with TBRS have been published; however, in the absence of further known cases, it is not clear whether these tumors are specifically associated with TBRS or are rare co-occurrences. The tumors are as follows:
Neuroblastoma [
Medulloblastoma [
Benign glioma [
Acromegaly as a result of a pituitary adenoma [
Ganglioneuroblastoma and T-cell lymphoblastic lymphoma [
A round face with coarse features (describing some loss of definition of the nose, lips, mouth, and chin because of rounded and heavy features)
Thick horizontal low-set (i.e., closer than anticipated to the orbit) eyebrows
Narrow (as measured vertically) palpebral fissures
Prominent upper central incisors
Mitral valve prolapse
Dilated cardiomyopathy
Arrhythmia
• Tall stature (height ≥2 SD above mean) in ~70%
• Macrocephaly (head circumference ≥2 SD above mean) in ~50%
• Tall stature (height ≥2 standard deviations [SD] above the mean for age and sex) is present in about 70% of individuals. Height ranges from 0.3 SD below to 6 SD above the mean.
• Macrocephaly (head circumference ≥2 SD above the mean for age and sex) is present in around 50% of affected individuals. Head circumference ranges from 1.2 SD below to 8.0 SD above the mean.
• About 65% of affected individuals are overweight or obese (weight ≥2 SD above the mean for age and sex). Weight ranges from 1.1 SD below to 4.5 SD above the mean.
• In a series of 18 individuals with a confirmed molecular diagnosis, autistic traits were present in the majority, and eight (44%) fulfilled the ADOS-2 criteria for a formal diagnosis of autism [
• The prevalence of autistic traits was lower in older individuals, suggesting that symptoms may improve with age, but this is based on cross-sectional assessment of a relatively small cohort rather than long-term observation.
• Anxiety
• Aggression
• Psychotic disorders
• Bipolar disorder
• Obsessive behaviors
• Compulsive eating
• The most common malignancy is acute myeloid leukemia (AML; 4/8 individuals); cases of lymphoid malignancy and myelodysplastic syndrome have also been reported.
• The median age at diagnosis is 9.6 years (range: age 2.5-12 years), with the cases of AML diagnosed between ages nine and 20 years.
• Limited information exists regarding lifetime cancer risk in individuals with TBRS, as the majority of individuals identified to date who have developed cancer are children or young adults.
• Neuroblastoma [
• Medulloblastoma [
• Benign glioma [
• Acromegaly as a result of a pituitary adenoma [
• Ganglioneuroblastoma and T-cell lymphoblastic lymphoma [
• A round face with coarse features (describing some loss of definition of the nose, lips, mouth, and chin because of rounded and heavy features)
• Thick horizontal low-set (i.e., closer than anticipated to the orbit) eyebrows
• Narrow (as measured vertically) palpebral fissures
• Prominent upper central incisors
• Mitral valve prolapse
• Dilated cardiomyopathy
• Arrhythmia
• Mitral valve prolapse
• Dilated cardiomyopathy
• Arrhythmia
• Mitral valve prolapse
• Dilated cardiomyopathy
• Arrhythmia
## Genotype-Phenotype Correlations
## Prevalence
The prevalence of TBRS is unknown. More than 90 cases have been reported in the literature to date [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Disorders with Overgrowth and Intellectual Disability in the Differential Diagnosis of Tatton-Brown-Rahman Syndrome
Macrocephaly
Obesity
Mild-to-moderate ID
Tall chin, prognathism, broad forehead, prominent supraorbital ridge
Frontal bossing, downslanted palpebral fissures, high hairline
Tall stature
Macrocephaly
Variable ID
Hypotonia
Hypertelorism, round face, "stuck-on" chin
Tall stature
Macrocephaly
Scoliosis
Ligamentous laxity
Hypotonia at birth
Broad forehead, widely spaced eyes, almond-shaped palpebral fissures
Tall stature
Macrocephaly
Variable ID (some w/normal intellect)
Umbilical hernia
Camptodactyly, boutonniere deformity, talipes equinovarus
Advanced bone age
Macrocephaly
ID
Prominent jaw & forehead
Macrocephaly
Coarse facial features
Macrostomia, macroglossia, palatal abnormalities
Polydactyly
Supernumerary nipples
Diastasis recti
Pectus excavatum
Sotos syndrome-like condition
Tall stature
Variable ID
Ophthalmologic abnormalities are common.
Growth frequently normalizes in teenagers & young adults.
Broad/prominent forehead, dolichocephaly, bitemporal narrowing w/sparse frontotemporal hair, downslanted palpebral fissures, malar flushing (in children), long prominent chin
Pre- & postnatal overgrowth
Variable ID
Advanced bone age
Scoliosis
Joint hypermobility
Tall stature
Macrocephaly
Scoliosis
Joint hypermobility
Hypotonia
AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; OGID = overgrowth with intellectual disability; XL = X-linked
• Macrocephaly
• Obesity
• Mild-to-moderate ID
• Tall chin, prognathism, broad forehead, prominent supraorbital ridge
• Frontal bossing, downslanted palpebral fissures, high hairline
• Tall stature
• Macrocephaly
• Variable ID
• Hypotonia
• Hypertelorism, round face, "stuck-on" chin
• Tall stature
• Macrocephaly
• Scoliosis
• Ligamentous laxity
• Hypotonia at birth
• Broad forehead, widely spaced eyes, almond-shaped palpebral fissures
• Tall stature
• Macrocephaly
• Variable ID (some w/normal intellect)
• Umbilical hernia
• Camptodactyly, boutonniere deformity, talipes equinovarus
• Advanced bone age
• Macrocephaly
• ID
• Prominent jaw & forehead
• Macrocephaly
• Coarse facial features
• Macrostomia, macroglossia, palatal abnormalities
• Polydactyly
• Supernumerary nipples
• Diastasis recti
• Pectus excavatum
• Sotos syndrome-like condition
• Tall stature
• Variable ID
• Ophthalmologic abnormalities are common.
• Growth frequently normalizes in teenagers & young adults.
• Broad/prominent forehead, dolichocephaly, bitemporal narrowing w/sparse frontotemporal hair, downslanted palpebral fissures, malar flushing (in children), long prominent chin
• Pre- & postnatal overgrowth
• Variable ID
• Advanced bone age
• Scoliosis
• Joint hypermobility
• Tall stature
• Macrocephaly
• Scoliosis
• Joint hypermobility
• Hypotonia
## Management
No clinical practice guidelines for Tatton-Brown-Rahman syndrome (TBRS) have been published.
Since the majority of individuals with TBRS are in good general health, the authors recommend a pragmatic approach to management, consisting of a series of initial assessments at diagnosis, patient/family education about potential complications, and regular symptom review with treatment as required [
To establish the extent of disease and needs in an individual diagnosed with TBRS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Tatton-Brown-Rahman Syndrome
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI if indicated by clinical symptoms.
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Joint hypermobility &/or kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Inform patients/families of potential risk of hematologic malignancy, w/emphasis on symptom awareness.
There is no evidence-based screening regimen, but low threshold should be adopted for investigation for malignancy in case of symptoms.
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; CBC = complete blood count; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TBRS = Tatton-Brown-Rahman syndrome
Which may include renal ultrasound and/or voiding cystourethrogram (VCUG)
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Tatton-Brown-Rahman Syndrome
Many ASMs may be effective; none has been demonstrated effective specifically for TBRS.
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; 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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 Tatton-Brown-Rahman Syndrome
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures & changes in tone.
ADHD = attention-deficit/hyperactivity disorder; CBC = complete blood count; OT = occupational therapy; PT = physical therapy
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI if indicated by clinical symptoms.
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Joint hypermobility &/or kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Inform patients/families of potential risk of hematologic malignancy, w/emphasis on symptom awareness.
• There is no evidence-based screening regimen, but low threshold should be adopted for investigation for malignancy in case of symptoms.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Many ASMs may be effective; none has been demonstrated effective specifically for TBRS.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures & changes in tone.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TBRS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Tatton-Brown-Rahman Syndrome
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI if indicated by clinical symptoms.
Consider EEG if seizures are a concern.
Gross motor & fine motor skills
Joint hypermobility &/or kyphoscoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Inform patients/families of potential risk of hematologic malignancy, w/emphasis on symptom awareness.
There is no evidence-based screening regimen, but low threshold should be adopted for investigation for malignancy in case of symptoms.
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; CBC = complete blood count; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TBRS = Tatton-Brown-Rahman syndrome
Which may include renal ultrasound and/or voiding cystourethrogram (VCUG)
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI if indicated by clinical symptoms.
• Consider EEG if seizures are a concern.
• Gross motor & fine motor skills
• Joint hypermobility &/or kyphoscoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Inform patients/families of potential risk of hematologic malignancy, w/emphasis on symptom awareness.
• There is no evidence-based screening regimen, but low threshold should be adopted for investigation for malignancy in case of symptoms.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Tatton-Brown-Rahman Syndrome
Many ASMs may be effective; none has been demonstrated effective specifically for TBRS.
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; 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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 ASMs may be effective; none has been demonstrated effective specifically for TBRS.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
## 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, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with Tatton-Brown-Rahman Syndrome
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures & changes in tone.
ADHD = attention-deficit/hyperactivity disorder; CBC = complete blood count; OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures & changes in tone.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Tatton-Brown-Rahman syndrome (TBRS) is an autosomal dominant disorder typically caused by a
Nearly all probands reported to date with TBRS whose parents have undergone molecular genetic testing have the disorder as the result of a
Rarely, individuals diagnosed with TBRS have the disorder as the result of a
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 cells only.
* A parent with somatic and germline mosaicism for a
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 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.
• Nearly all probands reported to date with TBRS whose parents have undergone molecular genetic testing have the disorder as the result of a
• Rarely, individuals diagnosed with TBRS have the disorder as the result of a
• 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 cells only.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• 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
Tatton-Brown-Rahman syndrome (TBRS) is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Nearly all probands reported to date with TBRS whose parents have undergone molecular genetic testing have the disorder as the result of a
Rarely, individuals diagnosed with TBRS have the disorder as the result of a
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 cells only.
* A parent with somatic and germline mosaicism for a
If a parent of the proband is known to have the
If the
• Nearly all probands reported to date with TBRS whose parents have undergone molecular genetic testing have the disorder as the result of a
• Rarely, individuals diagnosed with TBRS have the disorder as the result of a
• 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 cells only.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• 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 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
Tatton-Brown-Rahman Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tatton-Brown-Rahman Syndrome (
Methylation studies in mouse models and humans have demonstrated that
Truncating variants, splice site variants, and whole-gene deletions are assumed to cause disease as a result of haploinsufficiency. The pathogenic missense variants reported to date are clustered within the three functional domains of DNMT3A (proline-tryptophan-tryptophan-proline [PWWP] domain, ATRX-DNMT3A-DNMT3L-type zinc finger [ADD] domain, and DNA methyltransferase domain), suggesting that they are likely to cause disease by affecting the function of these domains [
For individuals with TBRS who have psychiatric issues, it has been suggested that abnormal catalytic function of the methyltransferase domain could affect metabolic pathways in the brain [
Notable
AML = acute myeloid leukemia; TBRS = Tatton-Brown-Rahman syndrome
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Methylation studies in mouse models and humans have demonstrated that
Truncating variants, splice site variants, and whole-gene deletions are assumed to cause disease as a result of haploinsufficiency. The pathogenic missense variants reported to date are clustered within the three functional domains of DNMT3A (proline-tryptophan-tryptophan-proline [PWWP] domain, ATRX-DNMT3A-DNMT3L-type zinc finger [ADD] domain, and DNA methyltransferase domain), suggesting that they are likely to cause disease by affecting the function of these domains [
For individuals with TBRS who have psychiatric issues, it has been suggested that abnormal catalytic function of the methyltransferase domain could affect metabolic pathways in the brain [
Notable
AML = acute myeloid leukemia; TBRS = Tatton-Brown-Rahman syndrome
Variants listed in the table have been provided by the authors.
## Cancer and Benign Tumors
## Chapter Notes
Dr Philip Ostrowski is a clinical genetics registrar at St George's Hospital and Great Ormond Street Hospital in London. He has a special interest in cardiovascular genetics, and has published case series describing the overgrowth phenotypes associated with pathogenic variants in
The authors would like to thank the individuals with Tatton-Brown-Rahman syndrome and their families, who have taught us a lot about this syndrome. We would also like to thank the clinician collaborator teams of physicians, genetic counselors, nurses, therapists and allied professionals, and trainees who have generously cared for these patients and supported efforts to gather information to clarify features and optimize care for patients and families.
30 June 2022 (ma) Review posted live
31 January 2022 (ktb) Original submission
• 30 June 2022 (ma) Review posted live
• 31 January 2022 (ktb) Original submission
## Author Notes
Dr Philip Ostrowski is a clinical genetics registrar at St George's Hospital and Great Ormond Street Hospital in London. He has a special interest in cardiovascular genetics, and has published case series describing the overgrowth phenotypes associated with pathogenic variants in
## Acknowledgments
The authors would like to thank the individuals with Tatton-Brown-Rahman syndrome and their families, who have taught us a lot about this syndrome. We would also like to thank the clinician collaborator teams of physicians, genetic counselors, nurses, therapists and allied professionals, and trainees who have generously cared for these patients and supported efforts to gather information to clarify features and optimize care for patients and families.
## Revision History
30 June 2022 (ma) Review posted live
31 January 2022 (ktb) Original submission
• 30 June 2022 (ma) Review posted live
• 31 January 2022 (ktb) Original submission
## References
## Literature Cited
|
[] |
30/6/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tbs
|
tbs
|
[
"Sal-like protein 1",
"SALL1",
"SALL1-Related Townes-Brocks Syndrome"
] |
Claudio Graziano, Giulia Olivucci
|
Summary The diagnosis of
|
## Diagnosis
Imperforate anus or anal stenosis
Dysplastic ears (overfolded superior helices, preauricular tags, microtia)
Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius
Sensorineural and/or conductive hearing impairment
Foot malformations
Impaired kidney function with or without kidney malformations
Genitourinary malformations
Congenital heart disease
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 a combination of
When the 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
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 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.
• Imperforate anus or anal stenosis
• Dysplastic ears (overfolded superior helices, preauricular tags, microtia)
• Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius
• Sensorineural and/or conductive hearing impairment
• Foot malformations
• Impaired kidney function with or without kidney malformations
• Genitourinary malformations
• Congenital heart disease
• For an introduction to multigene panels click
## Suggestive Findings
Imperforate anus or anal stenosis
Dysplastic ears (overfolded superior helices, preauricular tags, microtia)
Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius
Sensorineural and/or conductive hearing impairment
Foot malformations
Impaired kidney function with or without kidney malformations
Genitourinary malformations
Congenital heart disease
• Imperforate anus or anal stenosis
• Dysplastic ears (overfolded superior helices, preauricular tags, microtia)
• Typical thumb malformations (preaxial polydactyly, triphalangeal thumbs, hypoplastic thumbs) without hypoplasia of the radius
• Sensorineural and/or conductive hearing impairment
• Foot malformations
• Impaired kidney function with or without kidney malformations
• Genitourinary malformations
• Congenital heart disease
## 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 a combination of
When the 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
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 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.
• For an introduction to multigene panels click
## Option 1
When the 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
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 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
Based on 165 affected individuals from 101 families with a confirmed
No clinically relevant genotype-phenotype correlations have been identified for the majority of pathogenic variants, most of which are private.
The most common pathogenic variant,
In general, pathogenic variants within the hot spot region that is toward the 5' end in exon 2 appear to be associated with a more severe outcome than pathogenic variants towards the 3' end in exon 2. In addition, the phenotype associated with deletions of
Penetrance is likely 100%, if individuals at the mild end of the phenotypic spectrum are included. Note: One
Townes-Brocks syndrome was previously referred to as REAR syndrome (for
Approximately 200 individuals with
## Clinical Description
Based on 165 affected individuals from 101 families with a confirmed
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified for the majority of pathogenic variants, most of which are private.
The most common pathogenic variant,
In general, pathogenic variants within the hot spot region that is toward the 5' end in exon 2 appear to be associated with a more severe outcome than pathogenic variants towards the 3' end in exon 2. In addition, the phenotype associated with deletions of
## Penetrance
Penetrance is likely 100%, if individuals at the mild end of the phenotypic spectrum are included. Note: One
## Nomenclature
Townes-Brocks syndrome was previously referred to as REAR syndrome (for
## Prevalence
Approximately 200 individuals with
## Genetically Related (Allelic) Disorders
An individual with homozygous
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
Toe syndactyly, telecanthus, anogenital & renal malformations similar to TBS
Likely lethal in males
In 2 families later determined to have
Note: No affected family members had the typical
Duane anomaly & radial ray defects
Less commonly, hearing loss & renal position anomalies
In persons w/features suggestive of
Molecular genetic testing of
Upper-limb defects involving carpal bone(s) &, variably, radial &/or thenar bones
Congenital heart malformation
Thumb anomalies can resemble those in
AD = autosomal dominant; CAKUT = congenital anomalies of kidney and urinary tract; MOI = mode of inheritance; TBS = Townes-Brocks Syndrome; XL = X-linked
Although
J Kohlhase, personal observations
• Toe syndactyly, telecanthus, anogenital & renal malformations similar to TBS
• Likely lethal in males
• In 2 families later determined to have
• Note: No affected family members had the typical
• Duane anomaly & radial ray defects
• Less commonly, hearing loss & renal position anomalies
• In persons w/features suggestive of
• Molecular genetic testing of
• Upper-limb defects involving carpal bone(s) &, variably, radial &/or thenar bones
• Congenital heart malformation
• Thumb anomalies can resemble those in
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Referral to surgeon for anal anomalies if present
Assessment for constipation &/or gastroesophageal reflux
Clinical assessment for upper- & lower-extremity anomalies
Radiographs as recommended by orthopedist
Renal ultrasound
Assessment of kidney function w/serum electrolyte concentrations, BUN, & creatinine
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
BUN = blood urea nitrogen; MOI = mode of inheritance;
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
Mgmt per orthopedist
Severe malformations of hands may require surgery (e.g., removal of additional thumbs).
Developmental & education support as needed
Neuropsychiatric referral & mgmt as needed for behavioral issues
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor developmental progress & educational needs.
Behavioral assessment
BUN = blood urea nitrogen
Medications that cause renal or otic toxicity should be avoided.
Molecular genetic testing for the
See
Consider prenatal cardiac evaluation in pregnant women with
Search
• Referral to surgeon for anal anomalies if present
• Assessment for constipation &/or gastroesophageal reflux
• Clinical assessment for upper- & lower-extremity anomalies
• Radiographs as recommended by orthopedist
• Renal ultrasound
• Assessment of kidney function w/serum electrolyte concentrations, BUN, & creatinine
• 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
• Mgmt per orthopedist
• Severe malformations of hands may require surgery (e.g., removal of additional thumbs).
• Developmental & education support as needed
• Neuropsychiatric referral & mgmt as needed for behavioral issues
• Monitor developmental progress & educational needs.
• Behavioral assessment
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Referral to surgeon for anal anomalies if present
Assessment for constipation &/or gastroesophageal reflux
Clinical assessment for upper- & lower-extremity anomalies
Radiographs as recommended by orthopedist
Renal ultrasound
Assessment of kidney function w/serum electrolyte concentrations, BUN, & creatinine
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
BUN = blood urea nitrogen; MOI = mode of inheritance;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Referral to surgeon for anal anomalies if present
• Assessment for constipation &/or gastroesophageal reflux
• Clinical assessment for upper- & lower-extremity anomalies
• Radiographs as recommended by orthopedist
• Renal ultrasound
• Assessment of kidney function w/serum electrolyte concentrations, BUN, & creatinine
• 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
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
Mgmt per orthopedist
Severe malformations of hands may require surgery (e.g., removal of additional thumbs).
Developmental & education support as needed
Neuropsychiatric referral & mgmt as needed for behavioral issues
• Mgmt per orthopedist
• Severe malformations of hands may require surgery (e.g., removal of additional thumbs).
• Developmental & education support as needed
• Neuropsychiatric referral & mgmt as needed for behavioral issues
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Monitor developmental progress & educational needs.
Behavioral assessment
BUN = blood urea nitrogen
• Monitor developmental progress & educational needs.
• Behavioral assessment
## Agents/Circumstances to Avoid
Medications that cause renal or otic toxicity should be avoided.
## Evaluation of Relatives at Risk
Molecular genetic testing for the
See
## Pregnancy Management
Consider prenatal cardiac evaluation in pregnant women with
## Therapies Under Investigation
Search
## Genetic Counseling
About 50% of individuals diagnosed with
About 50% 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
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
* A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a
The family history of some individuals diagnosed with
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%.
Although the penetrance of
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.
• About 50% of individuals diagnosed with
• About 50% 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
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
• * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
• * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
• * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic 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%.
• Although the penetrance of
• 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
About 50% of individuals diagnosed with
About 50% 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
The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
* A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a
The family history of some individuals diagnosed with
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%.
Although the penetrance of
If the parents have not been tested for the
• About 50% of individuals diagnosed with
• About 50% 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
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
• * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
• * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic mosaicism for a
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Four individuals with somatic and gonadal mosaicism have been reported [
• * A parent with somatic and gonadal mosaicism may be mildly/minimally affected. Clinical signs in parents with somatic 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%.
• Although the penetrance of
• 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
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
SALL1-Related Townes-Brocks Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SALL1-Related Townes-Brocks Syndrome (
Most
The critical point in pathogenesis appears to be the correct dosage of functional SALL1 protein at the heterochromatic foci. A deletion of one allele results in a 50% reduction of this dosage. A 5' truncating pathogenic variant possibly leads to a truncated protein, which does not localize to the physiologic site of action but binds other SAL proteins and moves them from the nucleus to the cytoplasm. Therefore, in most instances the more severe phenotype of the 5' truncating pathogenic variants may result from a greater than 50% reduction of the functional protein at the site of action. Furthermore, truncated SALL1 might impede the function of primary cilia, since primary fibroblasts derived from
Pathogenic variants further 3' in
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Most
The critical point in pathogenesis appears to be the correct dosage of functional SALL1 protein at the heterochromatic foci. A deletion of one allele results in a 50% reduction of this dosage. A 5' truncating pathogenic variant possibly leads to a truncated protein, which does not localize to the physiologic site of action but binds other SAL proteins and moves them from the nucleus to the cytoplasm. Therefore, in most instances the more severe phenotype of the 5' truncating pathogenic variants may result from a greater than 50% reduction of the functional protein at the site of action. Furthermore, truncated SALL1 might impede the function of primary cilia, since primary fibroblasts derived from
Pathogenic variants further 3' in
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Claudio Graziano, MD (2024-present)Jürgen Kohlhase, MD; Center for Human Genetics (2006-2024)Giulia Olivucci, MD (2024-present)
14 August 2025 (aa) Revision:
8 August 2024 (sw) Comprehensive update posted live
14 January 2016 (me) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
24 January 2007 (me) Review posted live
17 November 2006 (jk) Original submission
• 14 August 2025 (aa) Revision:
• 8 August 2024 (sw) Comprehensive update posted live
• 14 January 2016 (me) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 24 January 2007 (me) Review posted live
• 17 November 2006 (jk) Original submission
## Author History
Claudio Graziano, MD (2024-present)Jürgen Kohlhase, MD; Center for Human Genetics (2006-2024)Giulia Olivucci, MD (2024-present)
## Revision History
14 August 2025 (aa) Revision:
8 August 2024 (sw) Comprehensive update posted live
14 January 2016 (me) Comprehensive update posted live
3 May 2012 (me) Comprehensive update posted live
24 January 2007 (me) Review posted live
17 November 2006 (jk) Original submission
• 14 August 2025 (aa) Revision:
• 8 August 2024 (sw) Comprehensive update posted live
• 14 January 2016 (me) Comprehensive update posted live
• 3 May 2012 (me) Comprehensive update posted live
• 24 January 2007 (me) Review posted live
• 17 November 2006 (jk) Original submission
## References
## Literature Cited
|
[] |
24/1/2007
|
8/8/2024
|
14/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tcs
|
tcs
|
[
"Mandibulofacial Dysostosis",
"Treacher Collins-Franceschetti Syndrome",
"Mandibulofacial Dysostosis",
"Treacher Collins-Franceschetti Syndrome",
"DNA-directed RNA polymerase I subunit RPA2",
"DNA-directed RNA polymerases I and III subunit RPAC1",
"DNA-directed RNA polymerases I and III subunit RPAC2",
"Treacle protein",
"POLR1B",
"POLR1C",
"POLR1D",
"TCOF1",
"Treacher Collins Syndrome"
] |
Treacher Collins Syndrome
|
Mafalda Barbosa, Ethylin Wang Jabs, Sara Huston
|
Summary Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible. External ear anomalies include absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Significant respiratory and feeding difficulties can be present in infancy. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically, intellect is normal. The diagnosis of TCS is established in a proband with characteristic clinical features and/or a heterozygous pathogenic variant in TCS can be inherited in an autosomal dominant or autosomal recessive manner. Autosomal dominant inheritance accounts for most of TCS, most commonly heterozygous pathogenic variants in Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
No consensus clinical diagnostic criteria for Treacher Collins syndrome (TCS) have been published.
TCS
Lower eyelid abnormalities including coloboma (notching) of the lower eyelid and sparse, partially absent, or totally absent eyelashes and tear ducts
Malar hypoplasia due to hypoplasia of the zygomatic arch and lateral aspects of the orbits resulting in downward-slanted palpebral fissures, a bilaterally symmetric convex facial profile, and prominent nose
Mandibular hypoplasia with micro- or retrognathia
External ear abnormalities including absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals
Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones
Hypoplasia or aplasia (discontinuity) of the zygomatic arch, detected by occipitomental radiographs (Waters view) [
Mandibular retrognathia, detected by orthopantomogram [
The clinical diagnosis of TCS can be established in a proband with characteristic bilaterally symmetric abnormalities of the facial and mandibular structures, including downslanted palpebral fissures, hypoplasia of the zygomatic complex and mandible, and conductive hearing loss. Clinical features such as limb anomalies, microcephaly, and/or intellectual disability are rare in individuals with TCS and should prompt consideration of other disorders (see
The molecular diagnosis of TCS
A heterozygous pathogenic (or likely pathogenic) variant in
Biallelic pathogenic (or likely pathogenic) variants in
Heterozygous deletion of 5q32-q33.1 that includes
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 CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Treacher Collins Syndrome
AD = autosomal dominant; AR = autosomal recessive; CMA = chromosomal microarray; MOI = mode of inheritance; TCS = Treacher Collins syndrome
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. 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
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
The same homozygous variant,
Reported deletions range from single exon to whole gene [
• Lower eyelid abnormalities including coloboma (notching) of the lower eyelid and sparse, partially absent, or totally absent eyelashes and tear ducts
• Malar hypoplasia due to hypoplasia of the zygomatic arch and lateral aspects of the orbits resulting in downward-slanted palpebral fissures, a bilaterally symmetric convex facial profile, and prominent nose
• Mandibular hypoplasia with micro- or retrognathia
• External ear abnormalities including absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals
• Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones
• Hypoplasia or aplasia (discontinuity) of the zygomatic arch, detected by occipitomental radiographs (Waters view) [
• Mandibular retrognathia, detected by orthopantomogram [
• A heterozygous pathogenic (or likely pathogenic) variant in
• Biallelic pathogenic (or likely pathogenic) variants in
• Heterozygous deletion of 5q32-q33.1 that includes
## Suggestive Findings
TCS
Lower eyelid abnormalities including coloboma (notching) of the lower eyelid and sparse, partially absent, or totally absent eyelashes and tear ducts
Malar hypoplasia due to hypoplasia of the zygomatic arch and lateral aspects of the orbits resulting in downward-slanted palpebral fissures, a bilaterally symmetric convex facial profile, and prominent nose
Mandibular hypoplasia with micro- or retrognathia
External ear abnormalities including absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals
Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones
Hypoplasia or aplasia (discontinuity) of the zygomatic arch, detected by occipitomental radiographs (Waters view) [
Mandibular retrognathia, detected by orthopantomogram [
• Lower eyelid abnormalities including coloboma (notching) of the lower eyelid and sparse, partially absent, or totally absent eyelashes and tear ducts
• Malar hypoplasia due to hypoplasia of the zygomatic arch and lateral aspects of the orbits resulting in downward-slanted palpebral fissures, a bilaterally symmetric convex facial profile, and prominent nose
• Mandibular hypoplasia with micro- or retrognathia
• External ear abnormalities including absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals
• Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones
• Hypoplasia or aplasia (discontinuity) of the zygomatic arch, detected by occipitomental radiographs (Waters view) [
• Mandibular retrognathia, detected by orthopantomogram [
## Establishing the Diagnosis
The clinical diagnosis of TCS can be established in a proband with characteristic bilaterally symmetric abnormalities of the facial and mandibular structures, including downslanted palpebral fissures, hypoplasia of the zygomatic complex and mandible, and conductive hearing loss. Clinical features such as limb anomalies, microcephaly, and/or intellectual disability are rare in individuals with TCS and should prompt consideration of other disorders (see
The molecular diagnosis of TCS
A heterozygous pathogenic (or likely pathogenic) variant in
Biallelic pathogenic (or likely pathogenic) variants in
Heterozygous deletion of 5q32-q33.1 that includes
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 CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Treacher Collins Syndrome
AD = autosomal dominant; AR = autosomal recessive; CMA = chromosomal microarray; MOI = mode of inheritance; TCS = Treacher Collins syndrome
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. 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
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
The same homozygous variant,
Reported deletions range from single exon to whole gene [
• A heterozygous pathogenic (or likely pathogenic) variant in
• Biallelic pathogenic (or likely pathogenic) variants in
• Heterozygous deletion of 5q32-q33.1 that includes
## Clinical Diagnosis
The clinical diagnosis of TCS can be established in a proband with characteristic bilaterally symmetric abnormalities of the facial and mandibular structures, including downslanted palpebral fissures, hypoplasia of the zygomatic complex and mandible, and conductive hearing loss. Clinical features such as limb anomalies, microcephaly, and/or intellectual disability are rare in individuals with TCS and should prompt consideration of other disorders (see
## Molecular Diagnosis
The molecular diagnosis of TCS
A heterozygous pathogenic (or likely pathogenic) variant in
Biallelic pathogenic (or likely pathogenic) variants in
Heterozygous deletion of 5q32-q33.1 that includes
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 CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Treacher Collins Syndrome
AD = autosomal dominant; AR = autosomal recessive; CMA = chromosomal microarray; MOI = mode of inheritance; TCS = Treacher Collins syndrome
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. 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
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
The same homozygous variant,
Reported deletions range from single exon to whole gene [
• A heterozygous pathogenic (or likely pathogenic) variant in
• Biallelic pathogenic (or likely pathogenic) variants in
• Heterozygous deletion of 5q32-q33.1 that includes
##
For an introduction to multigene panels click
##
For an introduction to CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Treacher Collins Syndrome
AD = autosomal dominant; AR = autosomal recessive; CMA = chromosomal microarray; MOI = mode of inheritance; TCS = Treacher Collins syndrome
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. 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
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
The same homozygous variant,
Reported deletions range from single exon to whole gene [
## Clinical Characteristics
Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanted palpebral fissures, malar hypoplasia, and micro- or retrognathia. Hypoplasia of the zygomatic bones, maxilla, and mandible can cause significant respiratory and feeding difficulties. Ear abnormalities are associated with conductive hearing loss. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia.
Significant inter- and intrafamilial clinical variability is common. While some individuals may be so mildly affected as to go undiagnosed, others can have severe facial involvement and life-threatening airway compromise [
Treacher Collins Syndrome: Frequency of Select Features
Individuals with
Individuals with
The most common 5-bp deletion in exon 24 (
Individuals with pathogenic variants in exon 15 have a significantly lower frequency of microtia, conductive deafness, and atresia of the external ear canal [
While the penetrance of pathogenic variants associated with TCS is high, reduced penetrance in
Autosomal dominant TCS has variably been termed Fransceschetti-Zwahlen-Klein syndrome and zygoauromandibular dysplasia.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The prevalence of TCS is estimated at 1:80,000 [
• Individuals with
• The most common 5-bp deletion in exon 24 (
• Individuals with pathogenic variants in exon 15 have a significantly lower frequency of microtia, conductive deafness, and atresia of the external ear canal [
## Clinical Description
Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanted palpebral fissures, malar hypoplasia, and micro- or retrognathia. Hypoplasia of the zygomatic bones, maxilla, and mandible can cause significant respiratory and feeding difficulties. Ear abnormalities are associated with conductive hearing loss. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia.
Significant inter- and intrafamilial clinical variability is common. While some individuals may be so mildly affected as to go undiagnosed, others can have severe facial involvement and life-threatening airway compromise [
Treacher Collins Syndrome: Frequency of Select Features
## Phenotype Correlations by Gene
Individuals with
## Genotype-Phenotype Correlations
Individuals with
The most common 5-bp deletion in exon 24 (
Individuals with pathogenic variants in exon 15 have a significantly lower frequency of microtia, conductive deafness, and atresia of the external ear canal [
• Individuals with
• The most common 5-bp deletion in exon 24 (
• Individuals with pathogenic variants in exon 15 have a significantly lower frequency of microtia, conductive deafness, and atresia of the external ear canal [
## Penetrance
While the penetrance of pathogenic variants associated with TCS is high, reduced penetrance in
## Nomenclature
Autosomal dominant TCS has variably been termed Fransceschetti-Zwahlen-Klein syndrome and zygoauromandibular dysplasia.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The prevalence of TCS is estimated at 1:80,000 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Treacher Collins Syndrome
Mandibulofacial dysostosis
Eyelid coloboma
Micrognathia
Cleft lip/palate
Limb deformities
Postaxial abnormalities (e.g., small or absent 5th digit incl 5th metacarpal, ulnar hypoplasia, absent 5th toe)
Mandibulofacial hypoplasia
Malformed ears
Micrognathia
Prominent cheeks
Round face
Mandibulofacial dysostosis
Malformed ears
Eyelid coloboma
Alopecia
Intact palate
Mandibulofacial dysostosis
Microtia
Preauricular skin tags
Microcephaly is present in most affected persons.
Intellectual disability
Asymmetry of facial features
Esophageal atresia / tracheoesophageal fistula in ~34%
Thumb abnormalities in ~33%
Mandibulofacial dysostosis
Microtia
Preauricular skin tags
Cleft lip/palate
Asymmetric
Ocular epibulbar dermoid cyst
Vertebral anomalies, Klippel-Feil anomaly
Mandibulofacial dysostosis
Micrognathia
Eyelid coloboma
Cleft lip/palate
Microtia/anotia
Abnormal neurodevelopment in ~78% (e.g., abnormal muscle tone, developmental delay, epilepsy)
Congenital heart defects in ~44% (e.g., septal defects)
Limb defects in ~33% (e.g., bowed long bones)
Downslanted palpebral fissures
Micrognathia
Mandibulofacial dysostosis
Malformed ears
Downslanted palpebral fissures
Micrognathia
Mandibulofacial dysostosis
Limb deformities
Preaxial abnormalities (e.g., small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, radioulnar synostosis)
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; TCS = Treacher Collins syndrome; XL = X-linked
In a cohort of 670 individuals with craniofacial (hemifacial) microsomia,
Genetic alterations involving
Disorders of Unknown Genetic Cause with Mandibulofacial Dysostosis in the Differential Diagnosis of Treacher Collins Syndrome
Growth failure
Microcephaly
Agenesis of corpus callosum
Intellectual disability
Urogenital anomalies in affected males
Facial dysmorphisms (hypertelorism, flattened nasal bridge, anteverted nares)
Short neck
Microcephaly
Intellectual disability
High-arched palate
Webbed neck
Upslanted palpebral fissures
Hypoplastic tragus & ear lobes
Severe mandibular deficiencies (e.g., temporomandibular joint, ankylosis, aglossia/microglossia, rare craniofacial cleft)
Progressive micrognathia or retrognathia
TCS = Treacher Collins syndrome
Disruption of a long-range
In one study, 52 of 266 individuals with congenital mandibular hypoplasia had TCS [
• Mandibulofacial dysostosis
• Eyelid coloboma
• Micrognathia
• Cleft lip/palate
• Limb deformities
• Postaxial abnormalities (e.g., small or absent 5th digit incl 5th metacarpal, ulnar hypoplasia, absent 5th toe)
• Mandibulofacial hypoplasia
• Malformed ears
• Micrognathia
• Prominent cheeks
• Round face
• Mandibulofacial dysostosis
• Malformed ears
• Eyelid coloboma
• Alopecia
• Intact palate
• Mandibulofacial dysostosis
• Microtia
• Preauricular skin tags
• Microcephaly is present in most affected persons.
• Intellectual disability
• Asymmetry of facial features
• Esophageal atresia / tracheoesophageal fistula in ~34%
• Thumb abnormalities in ~33%
• Mandibulofacial dysostosis
• Microtia
• Preauricular skin tags
• Cleft lip/palate
• Asymmetric
• Ocular epibulbar dermoid cyst
• Vertebral anomalies, Klippel-Feil anomaly
• Mandibulofacial dysostosis
• Micrognathia
• Eyelid coloboma
• Cleft lip/palate
• Microtia/anotia
• Abnormal neurodevelopment in ~78% (e.g., abnormal muscle tone, developmental delay, epilepsy)
• Congenital heart defects in ~44% (e.g., septal defects)
• Limb defects in ~33% (e.g., bowed long bones)
• Downslanted palpebral fissures
• Micrognathia
• Mandibulofacial dysostosis
• Malformed ears
• Downslanted palpebral fissures
• Micrognathia
• Mandibulofacial dysostosis
• Limb deformities
• Preaxial abnormalities (e.g., small or absent thumbs, triphalangeal thumbs, radial hypoplasia or aplasia, radioulnar synostosis)
• Growth failure
• Microcephaly
• Agenesis of corpus callosum
• Intellectual disability
• Urogenital anomalies in affected males
• Facial dysmorphisms (hypertelorism, flattened nasal bridge, anteverted nares)
• Short neck
• Microcephaly
• Intellectual disability
• High-arched palate
• Webbed neck
• Upslanted palpebral fissures
• Hypoplastic tragus & ear lobes
• Severe mandibular deficiencies (e.g., temporomandibular joint, ankylosis, aglossia/microglossia, rare craniofacial cleft)
• Progressive micrognathia or retrognathia
## Management
No clinical practice guidelines for Treacher Collins syndrome (TCS) 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 TCS, the evaluations summarized in
Treacher Collins Syndrome: Recommended Evaluations Following Initial Diagnosis
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance; TCS = Treacher Collins syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team that typically comprises a clinical geneticist, plastic surgeon, head and neck surgeon, otolaryngologist, oral surgeon, orthodontist, audiologist, speech-language pathologist, and psychologist.
Major management issues can be stratified by three age groups and graded for severity [
Procedures for surgical intervention for the airway, if needed, are standard, primarily for improving respiratory function or restoring patency of the nostrils and distraction of the mandible. Intubation techniques other than direct laryngoscopy may be required during surgeries [
Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (approximately age five to seven years).
External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [
Eyelid reconstruction to correct downslanted palpebral fissures can use redundant upper eyelid skin [
Misaligned teeth often require orthodonture.
Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
Type IIB (moderate to severe) malformation at skeletal maturity (age ~16 years)
Type III (severe) malformation at age six to ten years
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with Treacher Collins Syndrome
See
Search
• Community or
• Social work involvement for parental support
• Home nursing referral
• Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (approximately age five to seven years).
• External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
• External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
• Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [
• Eyelid reconstruction to correct downslanted palpebral fissures can use redundant upper eyelid skin [
• Misaligned teeth often require orthodonture.
• Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
• Type IIB (moderate to severe) malformation at skeletal maturity (age ~16 years)
• Type III (severe) malformation at age six to ten years
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TCS, the evaluations summarized in
Treacher Collins Syndrome: Recommended Evaluations Following Initial Diagnosis
Community or
Social work involvement for parental support
Home nursing referral
MOI = mode of inheritance; TCS = Treacher Collins syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team that typically comprises a clinical geneticist, plastic surgeon, head and neck surgeon, otolaryngologist, oral surgeon, orthodontist, audiologist, speech-language pathologist, and psychologist.
Major management issues can be stratified by three age groups and graded for severity [
Procedures for surgical intervention for the airway, if needed, are standard, primarily for improving respiratory function or restoring patency of the nostrils and distraction of the mandible. Intubation techniques other than direct laryngoscopy may be required during surgeries [
Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (approximately age five to seven years).
External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [
Eyelid reconstruction to correct downslanted palpebral fissures can use redundant upper eyelid skin [
Misaligned teeth often require orthodonture.
Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
Type IIB (moderate to severe) malformation at skeletal maturity (age ~16 years)
Type III (severe) malformation at age six to ten years
• Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (approximately age five to seven years).
• External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
• External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
• Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [
• Eyelid reconstruction to correct downslanted palpebral fissures can use redundant upper eyelid skin [
• Misaligned teeth often require orthodonture.
• Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
• Type IIB (moderate to severe) malformation at skeletal maturity (age ~16 years)
• Type III (severe) malformation at age six to ten years
## Birth to Age Two Years
Procedures for surgical intervention for the airway, if needed, are standard, primarily for improving respiratory function or restoring patency of the nostrils and distraction of the mandible. Intubation techniques other than direct laryngoscopy may be required during surgeries [
## Age Three to 12 Years
Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (approximately age five to seven years).
External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [
Eyelid reconstruction to correct downslanted palpebral fissures can use redundant upper eyelid skin [
Misaligned teeth often require orthodonture.
• Zygomatic and orbital reconstruction can be undertaken once cranio-orbitozygomatic bony development is complete (approximately age five to seven years).
• External ear reconstruction should be performed after age six years and should precede reconstruction of the external auditory canal or middle ear.
• External auditory canal and middle ear reconstruction should be performed for individuals with bilateral microtia and/or narrow ear canals.
• Coloboma of the lower eyelid can be treated with botulinum toxin and subsequent surgery [
• Eyelid reconstruction to correct downslanted palpebral fissures can use redundant upper eyelid skin [
• Misaligned teeth often require orthodonture.
## Age 13 to 18 Years
Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
Type IIB (moderate to severe) malformation at skeletal maturity (age ~16 years)
Type III (severe) malformation at age six to ten years
• Type I (mild) and type IIA (moderate) malformation at age 13 to 16 years
• Type IIB (moderate to severe) malformation at skeletal maturity (age ~16 years)
• Type III (severe) malformation at age six to ten years
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with Treacher Collins Syndrome
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Treacher Collins syndrome (TCS) can be inherited in an autosomal dominant or autosomal recessive manner.
Autosomal dominant inheritance accounts for most of TCS, most commonly caused by heterozygous pathogenic variants in
Autosomal recessive inheritance accounts for a minority of TCS, caused by biallelic pathogenic variants in
About 55%-61% of probands with autosomal dominant TCS have the disorder as the result of a
About 40% of individuals diagnosed with autosomal dominant TCS have an affected parent.
If the proband appears to be the only affected family member (i.e., a simplex case), recommended evaluations for both parents of a proband include:
Molecular genetic testing if a molecular diagnosis has been established in the proband;
If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of 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.* Maternal and paternal somatic and germline mosaicism have been reported [
* 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 unaffected or mildly/minimally affected [
The family history of some individuals diagnosed with TCS may appear to be negative because of failure to recognize the mild expression of the disorder in family members or the rare occurrence of reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and molecular genetic testing if a molecular diagnosis has been established 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 specific malformations and their severity cannot be predicted in sibs who inherit a pathogenic variant because significant intrafamilial clinical variability is common in autosomal dominant forms of TCS [
If the proband has a known
If the parents have not been tested for the pathogenic variant identified in the proband but 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 TCS because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
The parents of a child with autosomal recessive TCS 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 TCS-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.
If both parents are known to be heterozygous for a TCS-causing pathogenic variant, each sib of an individual with autosomal recessive TCS 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.
The specific malformations and their severity cannot be predicted in offspring who inherit biallelic TCS-related pathogenic variants.
Heterozygotes (carriers) are 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.
Note: (1) The presence of a TCS
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.
• Autosomal dominant inheritance accounts for most of TCS, most commonly caused by heterozygous pathogenic variants in
• Autosomal recessive inheritance accounts for a minority of TCS, caused by biallelic pathogenic variants in
• About 55%-61% of probands with autosomal dominant TCS have the disorder as the result of a
• About 40% of individuals diagnosed with autosomal dominant TCS have an affected parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), recommended evaluations for both parents of a proband include:
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of 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.* Maternal and paternal somatic and germline mosaicism have been reported [
• * 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 unaffected or mildly/minimally affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal and paternal somatic and germline mosaicism have been reported [
• * 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 unaffected or mildly/minimally affected [
• The family history of some individuals diagnosed with TCS may appear to be negative because of failure to recognize the mild expression of the disorder in family members or the rare occurrence of reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and molecular genetic testing if a molecular diagnosis has been established in the proband.
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal and paternal somatic and germline mosaicism have been reported [
• * 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 unaffected or 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%. The specific malformations and their severity cannot be predicted in sibs who inherit a pathogenic variant because significant intrafamilial clinical variability is common in autosomal dominant forms of TCS [
• If the proband has a known
• If the parents have not been tested for the pathogenic variant identified in the proband but 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 TCS because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
• The parents of a child with autosomal recessive TCS 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 TCS-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.
• 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 TCS-causing pathogenic variant, each sib of an individual with autosomal recessive TCS 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.
• The specific malformations and their severity cannot be predicted in offspring who inherit biallelic TCS-related pathogenic variants.
• Heterozygotes (carriers) are 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
Treacher Collins syndrome (TCS) can be inherited in an autosomal dominant or autosomal recessive manner.
Autosomal dominant inheritance accounts for most of TCS, most commonly caused by heterozygous pathogenic variants in
Autosomal recessive inheritance accounts for a minority of TCS, caused by biallelic pathogenic variants in
• Autosomal dominant inheritance accounts for most of TCS, most commonly caused by heterozygous pathogenic variants in
• Autosomal recessive inheritance accounts for a minority of TCS, caused by biallelic pathogenic variants in
## Autosomal Dominant Inheritance – Risk to Family Members
About 55%-61% of probands with autosomal dominant TCS have the disorder as the result of a
About 40% of individuals diagnosed with autosomal dominant TCS have an affected parent.
If the proband appears to be the only affected family member (i.e., a simplex case), recommended evaluations for both parents of a proband include:
Molecular genetic testing if a molecular diagnosis has been established in the proband;
If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of 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.* Maternal and paternal somatic and germline mosaicism have been reported [
* 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 unaffected or mildly/minimally affected [
The family history of some individuals diagnosed with TCS may appear to be negative because of failure to recognize the mild expression of the disorder in family members or the rare occurrence of reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and molecular genetic testing if a molecular diagnosis has been established 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 specific malformations and their severity cannot be predicted in sibs who inherit a pathogenic variant because significant intrafamilial clinical variability is common in autosomal dominant forms of TCS [
If the proband has a known
If the parents have not been tested for the pathogenic variant identified in the proband but 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 TCS because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
• About 55%-61% of probands with autosomal dominant TCS have the disorder as the result of a
• About 40% of individuals diagnosed with autosomal dominant TCS have an affected parent.
• If the proband appears to be the only affected family member (i.e., a simplex case), recommended evaluations for both parents of a proband include:
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
• If a molecular diagnosis has been established in the proband, the pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of 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.* Maternal and paternal somatic and germline mosaicism have been reported [
• * 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 unaffected or mildly/minimally affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal and paternal somatic and germline mosaicism have been reported [
• * 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 unaffected or mildly/minimally affected [
• The family history of some individuals diagnosed with TCS may appear to be negative because of failure to recognize the mild expression of the disorder in family members or the rare occurrence of reduced penetrance in a heterozygous parent. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and molecular genetic testing if a molecular diagnosis has been established in the proband.
• Molecular genetic testing if a molecular diagnosis has been established in the proband;
• If a molecular diagnosis has not been established in the proband, audiologic evaluation and occipitomental radiographic examination (Waters view). Radiographic examination may reveal mild zygomatic arch hypoplasia or even aplasia [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal and paternal somatic and germline mosaicism have been reported [
• * 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 unaffected or 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%. The specific malformations and their severity cannot be predicted in sibs who inherit a pathogenic variant because significant intrafamilial clinical variability is common in autosomal dominant forms of TCS [
• If the proband has a known
• If the parents have not been tested for the pathogenic variant identified in the proband but 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 TCS because of the possibility of reduced penetrance in a parent or parental germline mosaicism.
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive TCS 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 TCS-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.
If both parents are known to be heterozygous for a TCS-causing pathogenic variant, each sib of an individual with autosomal recessive TCS 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.
The specific malformations and their severity cannot be predicted in offspring who inherit biallelic TCS-related pathogenic variants.
Heterozygotes (carriers) are asymptomatic.
• The parents of a child with autosomal recessive TCS 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 TCS-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.
• 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 TCS-causing pathogenic variant, each sib of an individual with autosomal recessive TCS 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.
• The specific malformations and their severity cannot be predicted in offspring who inherit biallelic TCS-related pathogenic variants.
• Heterozygotes (carriers) are asymptomatic.
## 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
Note: (1) The presence of a TCS
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
Treacher Collins Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Treacher Collins Syndrome (
Cartilage and bone making up the craniofacial complex is primarily derived from neural crest cells [
Pathogenic Variants Referenced in This
AR = autosomal recessive
Variants listed in the table have been provided by the authors.
Genes from
## Molecular Pathogenesis
Cartilage and bone making up the craniofacial complex is primarily derived from neural crest cells [
Pathogenic Variants Referenced in This
AR = autosomal recessive
Variants listed in the table have been provided by the authors.
Genes from
## Chapter Notes
We acknowledge Mac Hays for his background research.
Mafalda Barbosa, MD, PhD, FACMG (2024-present)Garry R Cutting, MD; Johns Hopkins University (2004-2011)Sara Huston, MS (2004-present)Ethylin Wang Jabs, MD (2011-present)
20 June 2024 (sw) Comprehensive update posted live
27 September 2018 (bp) Comprehensive update posted live
27 October 2011 (me) Comprehensive update posted live
27 October 2006 (me) Comprehensive update posted live
20 July 2004 (me) Review posted live
1 March 2004 (shk,gc) Original submission
• 20 June 2024 (sw) Comprehensive update posted live
• 27 September 2018 (bp) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 27 October 2006 (me) Comprehensive update posted live
• 20 July 2004 (me) Review posted live
• 1 March 2004 (shk,gc) Original submission
## Acknowledgments
We acknowledge Mac Hays for his background research.
## Author History
Mafalda Barbosa, MD, PhD, FACMG (2024-present)Garry R Cutting, MD; Johns Hopkins University (2004-2011)Sara Huston, MS (2004-present)Ethylin Wang Jabs, MD (2011-present)
## Revision History
20 June 2024 (sw) Comprehensive update posted live
27 September 2018 (bp) Comprehensive update posted live
27 October 2011 (me) Comprehensive update posted live
27 October 2006 (me) Comprehensive update posted live
20 July 2004 (me) Review posted live
1 March 2004 (shk,gc) Original submission
• 20 June 2024 (sw) Comprehensive update posted live
• 27 September 2018 (bp) Comprehensive update posted live
• 27 October 2011 (me) Comprehensive update posted live
• 27 October 2006 (me) Comprehensive update posted live
• 20 July 2004 (me) Review posted live
• 1 March 2004 (shk,gc) Original submission
## References
## Literature Cited
|
[] |
20/7/2004
|
20/6/2024
|
20/8/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
td
|
td
|
[
"Fibroblast growth factor receptor 3",
"FGFR3",
"Thanatophoric Dysplasia"
] |
Thanatophoric Dysplasia
|
Tegan French, Ravi Savarirayan
|
Summary Thanatophoric dysplasia (TD) is a short-limb skeletal dysplasia that is usually lethal in the perinatal period. TD is divided into subtypes: TD type 1 is characterized by micromelia with bowed femurs and, uncommonly, the presence of craniosynostosis of varying severity. TD type 2 is characterized by micromelia with straight femurs and uniform presence of moderate-to-severe craniosynostosis with cloverleaf skull deformity. Other features common to type 1 and type 2 include: short ribs, narrow thorax, relative macrocephaly, distinctive facial features, brachydactyly, hypotonia, and redundant skin folds along the limbs. Most affected infants die of respiratory insufficiency shortly after birth. Rare long-term survivors have been reported. The diagnosis of TD is established in a proband with characteristic clinical and/or radiologic features and/or a heterozygous pathogenic variant in TD is inherited in an autosomal dominant manner; the majority of probands have a
|
Thanatophoric dysplasia type 1 (
Thanatophoric dysplasia type 2 (
For synonyms and outdated names, see
• Thanatophoric dysplasia type 1 (
• Thanatophoric dysplasia type 2 (
## Diagnosis
Formal diagnostic criteria for thanatophoric dysplasia (TD) have not been established.
TD
First trimester
Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
Increased nuchal translucency
Second/third trimester
Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
Well-ossified spine and skull
Platyspondyly
Ventriculomegaly
Narrow chest cavity with short ribs
Polyhydramnios
Bowed femurs (TD type 1)
Brain anomalies
Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
Relative macrocephaly
Relative macrocephaly
Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
Large anterior fontanelle
Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis
Marked shortening of the limbs (micromelia)
Redundant skin folds
Narrow bell-shaped thorax with short ribs and protuberant abdomen
Relatively normal trunk length
Brachydactyly with trident hand
Bowed femurs (TD type 1)
Generalized hypotonia
Rhizomelic shortening of the long bones
Irregular metaphyses of the long bones
Platyspondyly
Small foramen magnum with brain stem compression
Bowed femurs (TD type 1)
Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [
The diagnosis of thanatophoric dysplasia
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 thanatophoric dysplasia is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of thanatophoric dysplasia, molecular genetic testing approaches can include
If TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the
If TD type 1 is suspected, sequence analysis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other lethal skeletal dysplasias,
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 Thanatophoric Dysplasia
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
TD due to two
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.
• First trimester
• Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
• Increased nuchal translucency
• Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
• Increased nuchal translucency
• Second/third trimester
• Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
• Well-ossified spine and skull
• Platyspondyly
• Ventriculomegaly
• Narrow chest cavity with short ribs
• Polyhydramnios
• Bowed femurs (TD type 1)
• Brain anomalies
• Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
• Relative macrocephaly
• Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
• Well-ossified spine and skull
• Platyspondyly
• Ventriculomegaly
• Narrow chest cavity with short ribs
• Polyhydramnios
• Bowed femurs (TD type 1)
• Brain anomalies
• Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
• Relative macrocephaly
• Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
• Increased nuchal translucency
• Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
• Well-ossified spine and skull
• Platyspondyly
• Ventriculomegaly
• Narrow chest cavity with short ribs
• Polyhydramnios
• Bowed femurs (TD type 1)
• Brain anomalies
• Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
• Relative macrocephaly
• Relative macrocephaly
• Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
• Large anterior fontanelle
• Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis
• Marked shortening of the limbs (micromelia)
• Redundant skin folds
• Narrow bell-shaped thorax with short ribs and protuberant abdomen
• Relatively normal trunk length
• Brachydactyly with trident hand
• Bowed femurs (TD type 1)
• Generalized hypotonia
• Rhizomelic shortening of the long bones
• Irregular metaphyses of the long bones
• Platyspondyly
• Small foramen magnum with brain stem compression
• Bowed femurs (TD type 1)
• Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
• CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [
• If TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the
• If TD type 1 is suspected, sequence analysis of
## Suggestive Findings
TD
First trimester
Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
Increased nuchal translucency
Second/third trimester
Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
Well-ossified spine and skull
Platyspondyly
Ventriculomegaly
Narrow chest cavity with short ribs
Polyhydramnios
Bowed femurs (TD type 1)
Brain anomalies
Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
Relative macrocephaly
Relative macrocephaly
Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
Large anterior fontanelle
Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis
Marked shortening of the limbs (micromelia)
Redundant skin folds
Narrow bell-shaped thorax with short ribs and protuberant abdomen
Relatively normal trunk length
Brachydactyly with trident hand
Bowed femurs (TD type 1)
Generalized hypotonia
Rhizomelic shortening of the long bones
Irregular metaphyses of the long bones
Platyspondyly
Small foramen magnum with brain stem compression
Bowed femurs (TD type 1)
Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [
• First trimester
• Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
• Increased nuchal translucency
• Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
• Increased nuchal translucency
• Second/third trimester
• Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
• Well-ossified spine and skull
• Platyspondyly
• Ventriculomegaly
• Narrow chest cavity with short ribs
• Polyhydramnios
• Bowed femurs (TD type 1)
• Brain anomalies
• Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
• Relative macrocephaly
• Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
• Well-ossified spine and skull
• Platyspondyly
• Ventriculomegaly
• Narrow chest cavity with short ribs
• Polyhydramnios
• Bowed femurs (TD type 1)
• Brain anomalies
• Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
• Relative macrocephaly
• Shortening of the long bones, possibly visible as early as 12 to 14 weeks' gestation
• Increased nuchal translucency
• Growth deficiency with limb length below fifth centile recognizable by 20 weeks' gestation
• Well-ossified spine and skull
• Platyspondyly
• Ventriculomegaly
• Narrow chest cavity with short ribs
• Polyhydramnios
• Bowed femurs (TD type 1)
• Brain anomalies
• Cloverleaf skull. Craniosynostosis involving coronal, lambdoid, and sagittal sutures, resulting in a trilobed skull shape (previously referred to as
• Relative macrocephaly
• Relative macrocephaly
• Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
• Large anterior fontanelle
• Frontal bossing, flat facies with a depressed nasal bridge, ocular proptosis
• Marked shortening of the limbs (micromelia)
• Redundant skin folds
• Narrow bell-shaped thorax with short ribs and protuberant abdomen
• Relatively normal trunk length
• Brachydactyly with trident hand
• Bowed femurs (TD type 1)
• Generalized hypotonia
• Rhizomelic shortening of the long bones
• Irregular metaphyses of the long bones
• Platyspondyly
• Small foramen magnum with brain stem compression
• Bowed femurs (TD type 1)
• Cloverleaf skull (always in TD type 2; sometimes in TD type 1)
• CNS abnormalities including temporal lobe malformations, hydrocephalus, brain stem hypoplasia, neuronal migration abnormalities [
## Establishing the Diagnosis
The diagnosis of thanatophoric dysplasia
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 thanatophoric dysplasia is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of thanatophoric dysplasia, molecular genetic testing approaches can include
If TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the
If TD type 1 is suspected, sequence analysis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other lethal skeletal dysplasias,
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 Thanatophoric Dysplasia
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
TD due to two
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 TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the
• If TD type 1 is suspected, sequence analysis of
## Option 1
When the phenotypic findings suggest the diagnosis of thanatophoric dysplasia, molecular genetic testing approaches can include
If TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the
If TD type 1 is suspected, sequence analysis of
For an introduction to multigene panels click
• If TD type 2 is suspected on the basis of straight femurs and cloverleaf skull, targeted testing for the
• If TD type 1 is suspected, sequence analysis of
## Option 2
When the phenotype is indistinguishable from many other lethal skeletal dysplasias,
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 Thanatophoric Dysplasia
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
TD due to two
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
The clinical and radiographic features of thanatophoric dysplasia (TD) types 1 and 2 are evident prenatally or in the immediate newborn period. Respiratory insufficiency typically results in early neonatal death, and is due to a small chest cavity and/or foramen magnum narrowing with brain stem compression. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications.
To date, more than 200 individuals with TD have been identified with a pathogenic variant in
Select Features of Thanatophoric Dysplasia
Birth length well < 3rd centile
Birth weight & head circumference may be normal, but growth restriction of these parameters occurs in infancy & childhood.
Five long-term survivors reported [
One infant reported at age 11 months required suboccipital decompression due to clonus and decreased limb movements secondary to a narrow foramen magnum [
Temporal lobe malformations and megalencephaly are likely universal [
Brain malformations are the most likely etiology of seizures in individuals with TD; however, additional complications such as hypoxia related to respiratory insufficiency may also play a role.
Severe developmental delay is reported, with a stall in developmental progress at a developmental age of 12-20 months (see
Less common neurologic findings include hypoplasia or agenesis of the corpus callosum. Encephalocele has been reported, likely as a secondary consequence of raised intracranial pressure and abnormal skull formation [
Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [
Renal abnormalities [
Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [
Thanatophoric Dysplasia: Clinical Features of Long-Term Survivors
Hydrocephalus requiring shunt
Suboccipital decompression
Seizures
Hydrocephalus requiring shunt
Suboccipital decompression
Seizures
Mild ventriculomegaly
Marked stenosis of skull base & upper cervical spine
Clinically suspected high cervical myelopathy but no surgery
Seizures
Significant hearing impairment
Cholesteatoma
Mixed hearing impairment
Bilateral hearing aids
Weight: 2.1 kg
Length: 37 cm
OFC: 35 cm
Weight: 3.26 kg
Length: 41 cm
OFC: 39.5 cm
Weight: 2.6 kg
Length: 37 cm
OFC: 37 cm
Weight: 8.82 kg
Length: 65 cm
OFC: 47.5 cm
Weight: 6.5 kg
Length: 55 cm
OFC: 49 cm
Weight: 4.7 kg
Length: 49 cm
OFC: 46.1 cm
Craniosynostosis
Renal calculi
Generalized joint hypermobility
Hip & knee flexion contractures
ND = not documented; OFC = occipitofrontal head circumference
Unpublished data are referenced describing a boy age 9 years with TD [
Further deterioration by third decade of life and no longer able to use limbs or lift head
Growth parameter estimates based on growth charts
Slow linear growth, -6 to -6.5 SD below the mean on the achondroplasia growth charts; OFC at +1 SD in infancy and at -1.7 SD at age 8.7 years
An
The penetrance is 100%.
Thanatophoric dysplasia was originally described as thanatophoric dwarfism, a term no longer in use. The descriptor "thanatophoric" is derived from the Greek for "death bearing," and refers to the very high incidence of perinatal death due to the multisystem complications of this condition. However, aggressive management has resulted in rare reports of long-term survivors, contradicting this initial description.
The lethal platyspondylic dysplasia (San Diego type) was previously considered a separate clinical entity, but is now recognized as the same condition as TD [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The incidence of TD is reported to be 1:20,000 [
• Birth length well < 3rd centile
• Birth weight & head circumference may be normal, but growth restriction of these parameters occurs in infancy & childhood.
• Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [
• Renal abnormalities [
• Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [
• Hydrocephalus requiring shunt
• Suboccipital decompression
• Seizures
• Hydrocephalus requiring shunt
• Suboccipital decompression
• Seizures
• Mild ventriculomegaly
• Marked stenosis of skull base & upper cervical spine
• Clinically suspected high cervical myelopathy but no surgery
• Seizures
• Significant hearing impairment
• Cholesteatoma
• Mixed hearing impairment
• Bilateral hearing aids
• Weight: 2.1 kg
• Length: 37 cm
• OFC: 35 cm
• Weight: 3.26 kg
• Length: 41 cm
• OFC: 39.5 cm
• Weight: 2.6 kg
• Length: 37 cm
• OFC: 37 cm
• Weight: 8.82 kg
• Length: 65 cm
• OFC: 47.5 cm
• Weight: 6.5 kg
• Length: 55 cm
• OFC: 49 cm
• Weight: 4.7 kg
• Length: 49 cm
• OFC: 46.1 cm
• Craniosynostosis
• Renal calculi
• Generalized joint hypermobility
• Hip & knee flexion contractures
• An
## Clinical Description
The clinical and radiographic features of thanatophoric dysplasia (TD) types 1 and 2 are evident prenatally or in the immediate newborn period. Respiratory insufficiency typically results in early neonatal death, and is due to a small chest cavity and/or foramen magnum narrowing with brain stem compression. However, long-term survivors have been reported, including rare reports of survival to adulthood with aggressive ventilatory support and surgical management of neurologic complications.
To date, more than 200 individuals with TD have been identified with a pathogenic variant in
Select Features of Thanatophoric Dysplasia
Birth length well < 3rd centile
Birth weight & head circumference may be normal, but growth restriction of these parameters occurs in infancy & childhood.
Five long-term survivors reported [
One infant reported at age 11 months required suboccipital decompression due to clonus and decreased limb movements secondary to a narrow foramen magnum [
Temporal lobe malformations and megalencephaly are likely universal [
Brain malformations are the most likely etiology of seizures in individuals with TD; however, additional complications such as hypoxia related to respiratory insufficiency may also play a role.
Severe developmental delay is reported, with a stall in developmental progress at a developmental age of 12-20 months (see
Less common neurologic findings include hypoplasia or agenesis of the corpus callosum. Encephalocele has been reported, likely as a secondary consequence of raised intracranial pressure and abnormal skull formation [
Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [
Renal abnormalities [
Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [
Thanatophoric Dysplasia: Clinical Features of Long-Term Survivors
Hydrocephalus requiring shunt
Suboccipital decompression
Seizures
Hydrocephalus requiring shunt
Suboccipital decompression
Seizures
Mild ventriculomegaly
Marked stenosis of skull base & upper cervical spine
Clinically suspected high cervical myelopathy but no surgery
Seizures
Significant hearing impairment
Cholesteatoma
Mixed hearing impairment
Bilateral hearing aids
Weight: 2.1 kg
Length: 37 cm
OFC: 35 cm
Weight: 3.26 kg
Length: 41 cm
OFC: 39.5 cm
Weight: 2.6 kg
Length: 37 cm
OFC: 37 cm
Weight: 8.82 kg
Length: 65 cm
OFC: 47.5 cm
Weight: 6.5 kg
Length: 55 cm
OFC: 49 cm
Weight: 4.7 kg
Length: 49 cm
OFC: 46.1 cm
Craniosynostosis
Renal calculi
Generalized joint hypermobility
Hip & knee flexion contractures
ND = not documented; OFC = occipitofrontal head circumference
Unpublished data are referenced describing a boy age 9 years with TD [
Further deterioration by third decade of life and no longer able to use limbs or lift head
Growth parameter estimates based on growth charts
Slow linear growth, -6 to -6.5 SD below the mean on the achondroplasia growth charts; OFC at +1 SD in infancy and at -1.7 SD at age 8.7 years
• Birth length well < 3rd centile
• Birth weight & head circumference may be normal, but growth restriction of these parameters occurs in infancy & childhood.
• Cardiac defects. Truncus arteriosus, ventricular septal defect, and patent foramen ovale have been reported [
• Renal abnormalities [
• Protein losing enteropathy with intestinal lymphangestasia, reported in one individual [
• Hydrocephalus requiring shunt
• Suboccipital decompression
• Seizures
• Hydrocephalus requiring shunt
• Suboccipital decompression
• Seizures
• Mild ventriculomegaly
• Marked stenosis of skull base & upper cervical spine
• Clinically suspected high cervical myelopathy but no surgery
• Seizures
• Significant hearing impairment
• Cholesteatoma
• Mixed hearing impairment
• Bilateral hearing aids
• Weight: 2.1 kg
• Length: 37 cm
• OFC: 35 cm
• Weight: 3.26 kg
• Length: 41 cm
• OFC: 39.5 cm
• Weight: 2.6 kg
• Length: 37 cm
• OFC: 37 cm
• Weight: 8.82 kg
• Length: 65 cm
• OFC: 47.5 cm
• Weight: 6.5 kg
• Length: 55 cm
• OFC: 49 cm
• Weight: 4.7 kg
• Length: 49 cm
• OFC: 46.1 cm
• Craniosynostosis
• Renal calculi
• Generalized joint hypermobility
• Hip & knee flexion contractures
## Genotype-Phenotype Correlations
An
• An
## Penetrance
The penetrance is 100%.
## Nomenclature
Thanatophoric dysplasia was originally described as thanatophoric dwarfism, a term no longer in use. The descriptor "thanatophoric" is derived from the Greek for "death bearing," and refers to the very high incidence of perinatal death due to the multisystem complications of this condition. However, aggressive management has resulted in rare reports of long-term survivors, contradicting this initial description.
The lethal platyspondylic dysplasia (San Diego type) was previously considered a separate clinical entity, but is now recognized as the same condition as TD [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The incidence of TD is reported to be 1:20,000 [
## Genetically Related (Allelic) Disorders
Typically lethal in perinatal period
Clinical presentation similar to TD, w/short limbs & foramen magnum stenosis
Family history of achondroplasia in both parents
These conditions can be impossible to distinguish on clinical & radiographic grounds.
Rare disorder characterized by extremely short stature, severe tibial bowing, seizures, foramen magnum stenosis, hydrocephalus, structural brain malformations, developmental delay, & acanthosis nigricans
Caused by
Tibial bowing
Clavicular bowing
Unlike TD, persons w/SADDAN dysplasia often survive beyond infancy w/o ventilatory support. However, respiratory support or ventilation may be required in neonatal period & neonatal death is reported.
AD = autosomal dominant
See
A dominant-negative mechanism is suspected to cause decreased
• Typically lethal in perinatal period
• Clinical presentation similar to TD, w/short limbs & foramen magnum stenosis
• Family history of achondroplasia in both parents
• These conditions can be impossible to distinguish on clinical & radiographic grounds.
• Rare disorder characterized by extremely short stature, severe tibial bowing, seizures, foramen magnum stenosis, hydrocephalus, structural brain malformations, developmental delay, & acanthosis nigricans
• Caused by
• Tibial bowing
• Clavicular bowing
• Unlike TD, persons w/SADDAN dysplasia often survive beyond infancy w/o ventilatory support. However, respiratory support or ventilation may be required in neonatal period & neonatal death is reported.
## Differential Diagnosis
Other Genes of Interest in the Differential Diagnosis of Thanatophoric Dysplasia
May be lethal in perinatal period or infancy
Narrow thorax & short ribs; short stature & short limbs noted in infancy (But survivors may manifest only mild-to-moderate short stature.)
Polydactyly & wide variety of multisystem features common; may involve cardiac, renal, liver, pancreatic, intestinal, genital, retinal, & ectodermal tissues
Improvement in respiratory status occurs in some survivors w/skeletal ciliopathies, & persons may manifest only mild-to-moderate short stature.
Typically lethal in perinatal period
Markedly shortened & bowed long bones; severe short stature
Absence of severe micromelia; craniosynostosis; small iliac bones, narrow sacroiliac notch, & platyspondyly; bowing more significant than in TD
Note: TD is not assoc w/undermineralization, fractures, wormian bones, dentinogenesis imperfecta, or dark blue sclera.
Typically lethal in perinatal period
Short stature w/micromelia, relative macrocephaly, short ribs, & brachydactyly
Minimal or absent ossification of vertebral bodies, iliac, & ischial bones in ACG
Rib fractures in type II ACG
Distinctive facial features, short neck w/excess soft tissue
Typically lethal in perinatal period
Short long bones w/ragged metaphyses, platyspondyly, & short ribs
Bowed radius/tibia may be present.
PLSD-T can be differentiated histologically by presence of dilated loops of endoplasmic reticulum in chondrocytes.
Typically lethal in perinatal period
Short long bones, metaphyseal abnormalities, cupped ribs, platyspondyly, brachydactyly
Cerebral ventriculomegaly, other CNS abnormalities
Irregular ("lacy") ossifications in iliac wings & calcaneus
Disproportionately long fibulae
Cardiac anomalies incl structural congenital heart disease
Typically lethal in perinatal period
Narrow thorax, short stature, bowed limbs
Spine anisospondyly is present.
Cleft palate & encephalocele may be present.
May be lethal in perinatal period
Short long bones, platyspondyly, relative macrocephaly, small chest
May be lethal in perinatal period
Short limbed short stature, narrow chest w/short ribs, narrowed cervical canal, platyspondyly
Frontal bossing, depressed nasal bridge
Developmental delay
Hearing impairment
Absence of epiphyseal ossification of the knees
Square iliac bones
Horizontal acetabulae w/medial & lateral spurs
Hypoplastic ischia
Most affected children do not survive 1st decade of life; a proportion die in the neonatal period.
Rhizomelia, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities, coronal cleft or notch of vertebral bodies
Brain malformations
Punctate epiphyseal dysplasia evident as stippled epiphyses on radiography; coronal vertebral clefts may be present.
Rhizomelia prominent (compared to micromelia in TD)
Birth weight, length, & head circumference often at lower range of normal
Cataracts usually present at birth or in 1st few mos of life
Typically lethal in perinatal period
Short-limbed short stature
Platyspondyly
Hypoplastic iliac bones w/characteristic appearance resembling a snail
Broad long bones
Precocious ossification of the tarsus
Hydrops
Typically lethal in perinatal period
Variable stature (short to normal), w/short limbs & narrow thorax
Profound hypoplasia of the body of the scapulae (compared to globally small scapulae in TD)
Tibial & femoral bowing (w/longer femurs compared to TD)
Tubular bones are poorly developed & show immature ossification, w/nonossification of thoracic pedicles.
Many have 11 pairs of ribs.
Skin dimples are often present.
≤75% of persons w/CD w/a 46,XY karyotype have either female external genitalia or ambiguous genitalia.
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; TD = thanatophoric dysplasia
Biallelic inheritance of pathogenic variants in
Clinically, osteogenesis imperfecta (OI) was classified into four types; the type most reminiscent of TD is OI type II (perinatally lethal OI).
The Luton type is considered to be a mild form of the Torrance type [
• May be lethal in perinatal period or infancy
• Narrow thorax & short ribs; short stature & short limbs noted in infancy (But survivors may manifest only mild-to-moderate short stature.)
• Polydactyly & wide variety of multisystem features common; may involve cardiac, renal, liver, pancreatic, intestinal, genital, retinal, & ectodermal tissues
• Improvement in respiratory status occurs in some survivors w/skeletal ciliopathies, & persons may manifest only mild-to-moderate short stature.
• Typically lethal in perinatal period
• Markedly shortened & bowed long bones; severe short stature
• Absence of severe micromelia; craniosynostosis; small iliac bones, narrow sacroiliac notch, & platyspondyly; bowing more significant than in TD
• Note: TD is not assoc w/undermineralization, fractures, wormian bones, dentinogenesis imperfecta, or dark blue sclera.
• Typically lethal in perinatal period
• Short stature w/micromelia, relative macrocephaly, short ribs, & brachydactyly
• Minimal or absent ossification of vertebral bodies, iliac, & ischial bones in ACG
• Rib fractures in type II ACG
• Distinctive facial features, short neck w/excess soft tissue
• Typically lethal in perinatal period
• Short long bones w/ragged metaphyses, platyspondyly, & short ribs
• Bowed radius/tibia may be present.
• PLSD-T can be differentiated histologically by presence of dilated loops of endoplasmic reticulum in chondrocytes.
• Typically lethal in perinatal period
• Short long bones, metaphyseal abnormalities, cupped ribs, platyspondyly, brachydactyly
• Cerebral ventriculomegaly, other CNS abnormalities
• Irregular ("lacy") ossifications in iliac wings & calcaneus
• Disproportionately long fibulae
• Cardiac anomalies incl structural congenital heart disease
• Typically lethal in perinatal period
• Narrow thorax, short stature, bowed limbs
• Spine anisospondyly is present.
• Cleft palate & encephalocele may be present.
• May be lethal in perinatal period
• Short long bones, platyspondyly, relative macrocephaly, small chest
• May be lethal in perinatal period
• Short limbed short stature, narrow chest w/short ribs, narrowed cervical canal, platyspondyly
• Frontal bossing, depressed nasal bridge
• Developmental delay
• Hearing impairment
• Absence of epiphyseal ossification of the knees
• Square iliac bones
• Horizontal acetabulae w/medial & lateral spurs
• Hypoplastic ischia
• Most affected children do not survive 1st decade of life; a proportion die in the neonatal period.
• Rhizomelia, punctate calcifications in cartilage w/epiphyseal & metaphyseal abnormalities, coronal cleft or notch of vertebral bodies
• Brain malformations
• Punctate epiphyseal dysplasia evident as stippled epiphyses on radiography; coronal vertebral clefts may be present.
• Rhizomelia prominent (compared to micromelia in TD)
• Birth weight, length, & head circumference often at lower range of normal
• Cataracts usually present at birth or in 1st few mos of life
• Typically lethal in perinatal period
• Short-limbed short stature
• Platyspondyly
• Hypoplastic iliac bones w/characteristic appearance resembling a snail
• Broad long bones
• Precocious ossification of the tarsus
• Hydrops
• Typically lethal in perinatal period
• Variable stature (short to normal), w/short limbs & narrow thorax
• Profound hypoplasia of the body of the scapulae (compared to globally small scapulae in TD)
• Tibial & femoral bowing (w/longer femurs compared to TD)
• Tubular bones are poorly developed & show immature ossification, w/nonossification of thoracic pedicles.
• Many have 11 pairs of ribs.
• Skin dimples are often present.
• ≤75% of persons w/CD w/a 46,XY karyotype have either female external genitalia or ambiguous genitalia.
## Management
Diagnosis of thanatophoric dysplasia (TD) most often occurs prenatally. When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see
Long-term survivors are rare and require aggressive intervention for complications of the condition. The family should be informed of prognosis on the basis of the reports of complications in long-term survivors.
Recommended Evaluations Following Initial Diagnosis in Individuals with Thanatophoric Dysplasia
Assessment of respiratory rate, skin color, & oxygen saturations
Arterial blood gases may be helpful in infants who survive immediate postnatal period.
Polysomnography
Assessment for foramen magnum stenosis
Brain stem compression may contribute to respiratory insufficiency.
Cervical myelopathy may → quadriplegia.
Community or
Social work involvement for parental support;
Home nursing referral.
CNS = central nervous system; MOI = mode of inheritance; TD = thanatophoric dysplasia
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Decisions about management should be made following consultation with parents and a discussion of the complications, clinical course, and prognosis of the condition. Considerations may include the parents' desire for extreme life-support measures or provision of comfort care for the newborn.
Treatment of Manifestations in Individuals with Thanatophoric Dysplasia
Assessment of pulmonary function
Assessment of previous spine imaging for "spine at risk" findings
Availability of ICU care
Availability of anesthesia staff w/experience in mgmt of skeletal dysplasias
Maintenance of cervical spine in a neutral position (may require intubation using specialized intubation equipment)
Consideration of spinal monitoring during the procedure to evaluate safety during intraoperative manipulations
Eval by neurosurgeon for suboccipital decompression
Standard mgmt of complications of spinal cord compression such as spasticity
Consensus perioperative management guidelines for individuals with skeletal dysplasia have been published [
Recommended Surveillance for Individuals with Thanatophoric Dysplasia
Assessment of respiratory status
Neuroimaging in event of respiratory deterioration to evaluate for compression of brain stem at craniocervical junction
Assessment of neurologic status
EEG in event of seizure activity
Neuroimaging if signs/symptoms of spinal cord compression
See
When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice. Potential pregnancy complications include prematurity, polyhydramnios, malpresentation, and cephalopelvic disproportion caused by macrocephaly from hydrocephalus or a flexed and rigid neck. Cephalocentesis and cesarean section may be considered to avoid maternal complications.
Management of an affected pregnancy is determined following discussion between the medical team and family regarding prognosis and the need for aggressive life-saving measures in survivors. This is often center-specific. Indicators of lethality on ultrasound can provide additional information.
Consensus guidelines on perinatal management of skeletal dysplasias have been published [
Over the past five years several new precision therapies have begun to emerge for achondroplasia (an allelic
Search
• Assessment of respiratory rate, skin color, & oxygen saturations
• Arterial blood gases may be helpful in infants who survive immediate postnatal period.
• Polysomnography
• Assessment for foramen magnum stenosis
• Brain stem compression may contribute to respiratory insufficiency.
• Cervical myelopathy may → quadriplegia.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Assessment of pulmonary function
• Assessment of previous spine imaging for "spine at risk" findings
• Availability of ICU care
• Availability of anesthesia staff w/experience in mgmt of skeletal dysplasias
• Maintenance of cervical spine in a neutral position (may require intubation using specialized intubation equipment)
• Consideration of spinal monitoring during the procedure to evaluate safety during intraoperative manipulations
• Eval by neurosurgeon for suboccipital decompression
• Standard mgmt of complications of spinal cord compression such as spasticity
• Assessment of respiratory status
• Neuroimaging in event of respiratory deterioration to evaluate for compression of brain stem at craniocervical junction
• Assessment of neurologic status
• EEG in event of seizure activity
• Neuroimaging if signs/symptoms of spinal cord compression
## Evaluations Following Initial Diagnosis
Diagnosis of thanatophoric dysplasia (TD) most often occurs prenatally. When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see
Long-term survivors are rare and require aggressive intervention for complications of the condition. The family should be informed of prognosis on the basis of the reports of complications in long-term survivors.
Recommended Evaluations Following Initial Diagnosis in Individuals with Thanatophoric Dysplasia
Assessment of respiratory rate, skin color, & oxygen saturations
Arterial blood gases may be helpful in infants who survive immediate postnatal period.
Polysomnography
Assessment for foramen magnum stenosis
Brain stem compression may contribute to respiratory insufficiency.
Cervical myelopathy may → quadriplegia.
Community or
Social work involvement for parental support;
Home nursing referral.
CNS = central nervous system; MOI = mode of inheritance; TD = thanatophoric dysplasia
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assessment of respiratory rate, skin color, & oxygen saturations
• Arterial blood gases may be helpful in infants who survive immediate postnatal period.
• Polysomnography
• Assessment for foramen magnum stenosis
• Brain stem compression may contribute to respiratory insufficiency.
• Cervical myelopathy may → quadriplegia.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Decisions about management should be made following consultation with parents and a discussion of the complications, clinical course, and prognosis of the condition. Considerations may include the parents' desire for extreme life-support measures or provision of comfort care for the newborn.
Treatment of Manifestations in Individuals with Thanatophoric Dysplasia
Assessment of pulmonary function
Assessment of previous spine imaging for "spine at risk" findings
Availability of ICU care
Availability of anesthesia staff w/experience in mgmt of skeletal dysplasias
Maintenance of cervical spine in a neutral position (may require intubation using specialized intubation equipment)
Consideration of spinal monitoring during the procedure to evaluate safety during intraoperative manipulations
Eval by neurosurgeon for suboccipital decompression
Standard mgmt of complications of spinal cord compression such as spasticity
Consensus perioperative management guidelines for individuals with skeletal dysplasia have been published [
• Assessment of pulmonary function
• Assessment of previous spine imaging for "spine at risk" findings
• Availability of ICU care
• Availability of anesthesia staff w/experience in mgmt of skeletal dysplasias
• Maintenance of cervical spine in a neutral position (may require intubation using specialized intubation equipment)
• Consideration of spinal monitoring during the procedure to evaluate safety during intraoperative manipulations
• Eval by neurosurgeon for suboccipital decompression
• Standard mgmt of complications of spinal cord compression such as spasticity
## Surveillance
Recommended Surveillance for Individuals with Thanatophoric Dysplasia
Assessment of respiratory status
Neuroimaging in event of respiratory deterioration to evaluate for compression of brain stem at craniocervical junction
Assessment of neurologic status
EEG in event of seizure activity
Neuroimaging if signs/symptoms of spinal cord compression
• Assessment of respiratory status
• Neuroimaging in event of respiratory deterioration to evaluate for compression of brain stem at craniocervical junction
• Assessment of neurologic status
• EEG in event of seizure activity
• Neuroimaging if signs/symptoms of spinal cord compression
## Evaluation of Relatives at Risk
See
## Pregnancy Management
When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice. Potential pregnancy complications include prematurity, polyhydramnios, malpresentation, and cephalopelvic disproportion caused by macrocephaly from hydrocephalus or a flexed and rigid neck. Cephalocentesis and cesarean section may be considered to avoid maternal complications.
Management of an affected pregnancy is determined following discussion between the medical team and family regarding prognosis and the need for aggressive life-saving measures in survivors. This is often center-specific. Indicators of lethality on ultrasound can provide additional information.
Consensus guidelines on perinatal management of skeletal dysplasias have been published [
## Therapies Under Investigation
Over the past five years several new precision therapies have begun to emerge for achondroplasia (an allelic
Search
## Genetic Counseling
Thanatophoric dysplasia (TD) is an autosomal dominant disorder typically caused by a
Almost all probands reported to date with TD represent simplex cases (i.e., the only affected family member) and have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Somatic and germline mosaicism for the
Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
An advanced paternal age effect has been reported [
Cell-free DNA testing techniques have been reported for noninvasive prenatal diagnosis of TD [
Note: When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see
• Almost all probands reported to date with TD represent simplex cases (i.e., the only affected family member) and have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Somatic and germline mosaicism for the
• Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
• Somatic and germline mosaicism for the
• Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
• An advanced paternal age effect has been reported [
• Somatic and germline mosaicism for the
• Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
## Mode of Inheritance
Thanatophoric dysplasia (TD) is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Almost all probands reported to date with TD represent simplex cases (i.e., the only affected family member) and have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
Somatic and germline mosaicism for the
Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
An advanced paternal age effect has been reported [
• Almost all probands reported to date with TD represent simplex cases (i.e., the only affected family member) and have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• Somatic and germline mosaicism for the
• Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
• Somatic and germline mosaicism for the
• Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
• An advanced paternal age effect has been reported [
• Somatic and germline mosaicism for the
• Although no instances of mosaicism in an individual without signs of a skeletal dysplasia have been reported in the literature, it remains a theoretic possibility.
## Related Genetic Counseling Issues
## Prenatal Testing and Preimplantation Genetic Testing
Cell-free DNA testing techniques have been reported for noninvasive prenatal diagnosis of TD [
Note: When TD has been diagnosed prenatally, referral should be made to a maternal-fetal medicine specialist for assessment and management advice (see
## Resources
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•
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•
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•
## Molecular Genetics
Thanatophoric Dysplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Thanatophoric Dysplasia (
Pathogenic variants in
Of note, no-stop variants resulting in protein extension are associated with thanatophoric dysplasia (TD).
Missense variants causing TD type 1 introduce a cysteine (Tyr373Cys, Arg428Cys) resulting in dimerization by covalent bonding (see
Missense variants involving residue 650 (e.g., Lys650Met [TD type 1] or Lys650Glu [TD type 2]) mimic conformational changes in the tyrosine kinase domain, which mimic the conformational changes that occur with ligand binding.
The
Notable
Variants listed in the table have been provided by the authors.
See
Also known as non-stop variants.
• Of note, no-stop variants resulting in protein extension are associated with thanatophoric dysplasia (TD).
• Missense variants causing TD type 1 introduce a cysteine (Tyr373Cys, Arg428Cys) resulting in dimerization by covalent bonding (see
• Missense variants involving residue 650 (e.g., Lys650Met [TD type 1] or Lys650Glu [TD type 2]) mimic conformational changes in the tyrosine kinase domain, which mimic the conformational changes that occur with ligand binding.
• The
## Molecular Pathogenesis
Pathogenic variants in
Of note, no-stop variants resulting in protein extension are associated with thanatophoric dysplasia (TD).
Missense variants causing TD type 1 introduce a cysteine (Tyr373Cys, Arg428Cys) resulting in dimerization by covalent bonding (see
Missense variants involving residue 650 (e.g., Lys650Met [TD type 1] or Lys650Glu [TD type 2]) mimic conformational changes in the tyrosine kinase domain, which mimic the conformational changes that occur with ligand binding.
The
Notable
Variants listed in the table have been provided by the authors.
See
Also known as non-stop variants.
• Of note, no-stop variants resulting in protein extension are associated with thanatophoric dysplasia (TD).
• Missense variants causing TD type 1 introduce a cysteine (Tyr373Cys, Arg428Cys) resulting in dimerization by covalent bonding (see
• Missense variants involving residue 650 (e.g., Lys650Met [TD type 1] or Lys650Glu [TD type 2]) mimic conformational changes in the tyrosine kinase domain, which mimic the conformational changes that occur with ligand binding.
• The
## Chapter Notes
Garry R Cutting, MD; Johns Hopkins University (2004–2020)Tegan French, BMBS (2020–present)Barbara Karczeski, MS, MA; Johns Hopkins University (2004–2020)Ravi Savarirayan, MBBS, MD, FRACP, ARCPA (Hon) (2020–present)
18 May 2023 (sw) Revision:
18 June 2020 (sw) Comprehensive update posted live
12 September 2013 (me) Comprehensive update posted live
30 September 2008 (cg) Comprehensive update posted live
7 July 2006 (me) Comprehensive update posted live
21 May 2004 (me) Review posted live
27 February 2004 (bk, gc) Original submission
• 18 May 2023 (sw) Revision:
• 18 June 2020 (sw) Comprehensive update posted live
• 12 September 2013 (me) Comprehensive update posted live
• 30 September 2008 (cg) Comprehensive update posted live
• 7 July 2006 (me) Comprehensive update posted live
• 21 May 2004 (me) Review posted live
• 27 February 2004 (bk, gc) Original submission
## Author History
Garry R Cutting, MD; Johns Hopkins University (2004–2020)Tegan French, BMBS (2020–present)Barbara Karczeski, MS, MA; Johns Hopkins University (2004–2020)Ravi Savarirayan, MBBS, MD, FRACP, ARCPA (Hon) (2020–present)
## Revision History
18 May 2023 (sw) Revision:
18 June 2020 (sw) Comprehensive update posted live
12 September 2013 (me) Comprehensive update posted live
30 September 2008 (cg) Comprehensive update posted live
7 July 2006 (me) Comprehensive update posted live
21 May 2004 (me) Review posted live
27 February 2004 (bk, gc) Original submission
• 18 May 2023 (sw) Revision:
• 18 June 2020 (sw) Comprehensive update posted live
• 12 September 2013 (me) Comprehensive update posted live
• 30 September 2008 (cg) Comprehensive update posted live
• 7 July 2006 (me) Comprehensive update posted live
• 21 May 2004 (me) Review posted live
• 27 February 2004 (bk, gc) Original submission
## References
## Literature Cited
|
[] |
21/5/2004
|
18/6/2020
|
18/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
tecpr2-hsan-id
|
tecpr2-hsan-id
|
[
"Hereditary Sensory and Autonomic Neuropathy Type IX with Developmental Delay (HSAN9)",
"Hereditary Spastic Paraplegia Type 49 (SPG49)",
"Hereditary Sensory and Autonomic Neuropathy Type IX with Developmental Delay (HSAN9)",
"Hereditary Spastic Paraplegia Type 49 (SPG49)",
"Tectonin beta-propeller repeat-containing protein 2",
"TECPR2",
"TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability"
] |
Gali Heimer, Sonja Neuser, Bruria Ben-Zeev, Darius Ebrahimi-Fakhari
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Developmental delay / intellectual disability (mainly in the moderate to severe range)
Neurologic findings
Muscular hypotonia
Gait ataxia
Hyporeflexia / areflexia of the lower limbs
Impaired pain sensitivity
Dysarthria
Autonomic dysfunction
Impaired temperature regulation
Impaired blood pressure regulation
Central nocturnal and/or daytime hypoventilation
Dysphagia
Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
Recurrent respiratory infections resulting from aspiration as a result of gastroesophageal reflux and dysphagia
Behavioral abnormalities (hyperactivity, aggressiveness, autism spectrum disorder)
Distinctive facial features that may include brachycephaly, synophrys, thick eyebrows, hypotelorism, epicanthus, round or triangular-shaped face, and dental crowding [
Thin or dysplastic corpus callosum
Mild ventriculomegaly (often asymmetric)
Delayed myelination (i.e., delayed appearance of signal changes related to final myelination of white matter pathways in affected children)
Mild cerebral atrophy or mild atrophy of the cerebellar hemispheres or vermis
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
A
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 (mainly in the moderate to severe range)
• Neurologic findings
• Muscular hypotonia
• Gait ataxia
• Hyporeflexia / areflexia of the lower limbs
• Impaired pain sensitivity
• Dysarthria
• Muscular hypotonia
• Gait ataxia
• Hyporeflexia / areflexia of the lower limbs
• Impaired pain sensitivity
• Dysarthria
• Autonomic dysfunction
• Impaired temperature regulation
• Impaired blood pressure regulation
• Central nocturnal and/or daytime hypoventilation
• Dysphagia
• Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Impaired temperature regulation
• Impaired blood pressure regulation
• Central nocturnal and/or daytime hypoventilation
• Dysphagia
• Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Recurrent respiratory infections resulting from aspiration as a result of gastroesophageal reflux and dysphagia
• Behavioral abnormalities (hyperactivity, aggressiveness, autism spectrum disorder)
• Distinctive facial features that may include brachycephaly, synophrys, thick eyebrows, hypotelorism, epicanthus, round or triangular-shaped face, and dental crowding [
• Muscular hypotonia
• Gait ataxia
• Hyporeflexia / areflexia of the lower limbs
• Impaired pain sensitivity
• Dysarthria
• Impaired temperature regulation
• Impaired blood pressure regulation
• Central nocturnal and/or daytime hypoventilation
• Dysphagia
• Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Thin or dysplastic corpus callosum
• Mild ventriculomegaly (often asymmetric)
• Delayed myelination (i.e., delayed appearance of signal changes related to final myelination of white matter pathways in affected children)
• Mild cerebral atrophy or mild atrophy of the cerebellar hemispheres or vermis
## Suggestive Findings
Developmental delay / intellectual disability (mainly in the moderate to severe range)
Neurologic findings
Muscular hypotonia
Gait ataxia
Hyporeflexia / areflexia of the lower limbs
Impaired pain sensitivity
Dysarthria
Autonomic dysfunction
Impaired temperature regulation
Impaired blood pressure regulation
Central nocturnal and/or daytime hypoventilation
Dysphagia
Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
Recurrent respiratory infections resulting from aspiration as a result of gastroesophageal reflux and dysphagia
Behavioral abnormalities (hyperactivity, aggressiveness, autism spectrum disorder)
Distinctive facial features that may include brachycephaly, synophrys, thick eyebrows, hypotelorism, epicanthus, round or triangular-shaped face, and dental crowding [
Thin or dysplastic corpus callosum
Mild ventriculomegaly (often asymmetric)
Delayed myelination (i.e., delayed appearance of signal changes related to final myelination of white matter pathways in affected children)
Mild cerebral atrophy or mild atrophy of the cerebellar hemispheres or vermis
• Developmental delay / intellectual disability (mainly in the moderate to severe range)
• Neurologic findings
• Muscular hypotonia
• Gait ataxia
• Hyporeflexia / areflexia of the lower limbs
• Impaired pain sensitivity
• Dysarthria
• Muscular hypotonia
• Gait ataxia
• Hyporeflexia / areflexia of the lower limbs
• Impaired pain sensitivity
• Dysarthria
• Autonomic dysfunction
• Impaired temperature regulation
• Impaired blood pressure regulation
• Central nocturnal and/or daytime hypoventilation
• Dysphagia
• Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Impaired temperature regulation
• Impaired blood pressure regulation
• Central nocturnal and/or daytime hypoventilation
• Dysphagia
• Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Recurrent respiratory infections resulting from aspiration as a result of gastroesophageal reflux and dysphagia
• Behavioral abnormalities (hyperactivity, aggressiveness, autism spectrum disorder)
• Distinctive facial features that may include brachycephaly, synophrys, thick eyebrows, hypotelorism, epicanthus, round or triangular-shaped face, and dental crowding [
• Muscular hypotonia
• Gait ataxia
• Hyporeflexia / areflexia of the lower limbs
• Impaired pain sensitivity
• Dysarthria
• Impaired temperature regulation
• Impaired blood pressure regulation
• Central nocturnal and/or daytime hypoventilation
• Dysphagia
• Abnormal gastrointestinal mobility resulting in gastroesophageal reflux and/or constipation
• Thin or dysplastic corpus callosum
• Mild ventriculomegaly (often asymmetric)
• Delayed myelination (i.e., delayed appearance of signal changes related to final myelination of white matter pathways in affected children)
• Mild cerebral atrophy or mild atrophy of the cerebellar hemispheres or vermis
## 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
A
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.
## Option 1
A
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
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, more than 30 individuals with biallelic pathogenic variants in
DD/ID = developmental delay / intellectual disability; GERD = gastroesophageal reflux disease
Denominator reflects the number of persons assessed for the feature.
Gait is mostly ataxic; however, crouched gait can develop at later stages. Although most individuals achieve independent walking, regression in the second decade of life with loss of independent walking is possible.
Findings suggestive of a sensory neuropathy typically include hypo- or areflexia in the lower limbs and decreased pain sensitivity.
Epilepsy is uncommon, but a few individuals experienced febrile or unprovoked seizures. EEG findings of nonspecific background slowing and epileptiform discharges may be seen in a minority of individuals.
Other features of the autonomic neuropathy are temperature and blood pressure instability, hyperhidrosis, and electrolyte disturbances. Anecdotally, disproportionally decreased consciousness can develop in response to intercurrent illness or mild central nervous system depressants such as antihistamines.
Recurrent respiratory infections are common and can occur as early as the first year of life. These are likely a result of recurrent aspiration due to dysphagia and gastroesophageal reflux and can be precipitated by laryngeal clefts or laryngomalacia seen in a subset of individuals with
Microcephaly (usually mild or in the low ranges of normal)
Short stature (usually mild or in the low ranges of normal)
Short neck with a retrocollis hyperextension posture
Kyphosis, scoliosis, and a barrel-shaped chest, usually developing in the second decade of life
Sensorineural hearing impairment may develop; however, data are insufficient to estimate severity or typical age of onset.
Various ophthalmologic findings including refractive errors (astigmatism, myopia), strabismus, and abnormal ocular movement (periodic upward gaze deviation, oculomotor apraxia, and nystagmus)
No genotype-phenotype correlations have been identified [
About half of affected individuals are born to consanguineous parents.
Two populations with founder variants are identified:
Individuals of Jewish Bukharian background:
Individuals of Jewish Ashkenazi background:
The carrier frequency for the Bukharian Jewish population is 1.33% [Oz Levi et al 2012].
The carrier frequency for the Ashkenazi Jewish population is at least 0.65% [
• Microcephaly (usually mild or in the low ranges of normal)
• Short stature (usually mild or in the low ranges of normal)
• Short neck with a retrocollis hyperextension posture
• Kyphosis, scoliosis, and a barrel-shaped chest, usually developing in the second decade of life
• Sensorineural hearing impairment may develop; however, data are insufficient to estimate severity or typical age of onset.
• Various ophthalmologic findings including refractive errors (astigmatism, myopia), strabismus, and abnormal ocular movement (periodic upward gaze deviation, oculomotor apraxia, and nystagmus)
• Individuals of Jewish Bukharian background:
• Individuals of Jewish Ashkenazi background:
## Clinical Description
To date, more than 30 individuals with biallelic pathogenic variants in
DD/ID = developmental delay / intellectual disability; GERD = gastroesophageal reflux disease
Denominator reflects the number of persons assessed for the feature.
Gait is mostly ataxic; however, crouched gait can develop at later stages. Although most individuals achieve independent walking, regression in the second decade of life with loss of independent walking is possible.
Findings suggestive of a sensory neuropathy typically include hypo- or areflexia in the lower limbs and decreased pain sensitivity.
Epilepsy is uncommon, but a few individuals experienced febrile or unprovoked seizures. EEG findings of nonspecific background slowing and epileptiform discharges may be seen in a minority of individuals.
Other features of the autonomic neuropathy are temperature and blood pressure instability, hyperhidrosis, and electrolyte disturbances. Anecdotally, disproportionally decreased consciousness can develop in response to intercurrent illness or mild central nervous system depressants such as antihistamines.
Recurrent respiratory infections are common and can occur as early as the first year of life. These are likely a result of recurrent aspiration due to dysphagia and gastroesophageal reflux and can be precipitated by laryngeal clefts or laryngomalacia seen in a subset of individuals with
Microcephaly (usually mild or in the low ranges of normal)
Short stature (usually mild or in the low ranges of normal)
Short neck with a retrocollis hyperextension posture
Kyphosis, scoliosis, and a barrel-shaped chest, usually developing in the second decade of life
Sensorineural hearing impairment may develop; however, data are insufficient to estimate severity or typical age of onset.
Various ophthalmologic findings including refractive errors (astigmatism, myopia), strabismus, and abnormal ocular movement (periodic upward gaze deviation, oculomotor apraxia, and nystagmus)
• Microcephaly (usually mild or in the low ranges of normal)
• Short stature (usually mild or in the low ranges of normal)
• Short neck with a retrocollis hyperextension posture
• Kyphosis, scoliosis, and a barrel-shaped chest, usually developing in the second decade of life
• Sensorineural hearing impairment may develop; however, data are insufficient to estimate severity or typical age of onset.
• Various ophthalmologic findings including refractive errors (astigmatism, myopia), strabismus, and abnormal ocular movement (periodic upward gaze deviation, oculomotor apraxia, and nystagmus)
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified [
## Nomenclature
## Prevalence
About half of affected individuals are born to consanguineous parents.
Two populations with founder variants are identified:
Individuals of Jewish Bukharian background:
Individuals of Jewish Ashkenazi background:
The carrier frequency for the Bukharian Jewish population is 1.33% [Oz Levi et al 2012].
The carrier frequency for the Ashkenazi Jewish population is at least 0.65% [
• Individuals of Jewish Bukharian background:
• Individuals of Jewish Ashkenazi background:
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Sensory and Autonomic Neuropathies in the Differential Diagnosis of
HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability
The disorders listed in
## Management
Recommendations for clinical management of
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Perform EEG if history suggests seizures.
Brain MRI may be considered (after careful eval of risks of sedation/anesthesia in this patient population).
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)
Consider swallow study for assessing dysphagia.
If dysphagia or aspiration are present, consider aspiration precautions (i.e., avoidance of certain food consistencies or nothing by mouth).
Baseline chest x-ray
Polysomnography
Community or
Social work involvement for parental support;
Home nursing referral.
ABA = applied behavioral analysis; ADL = activities of daily living; ASD = autism spectrum disorder; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
It is possible that the imaging spectrum in
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Currently there are no specific disease-modifying treatments for
Treatment of Manifestations in Individuals with
ABA = applied behavioral analysis; ASD = autism spectrum disorder; 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
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, 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 and response to supportive care and to detect new manifestations, see
Recommended Surveillance for Individuals with
Neurologic exam for response to treatments & evidence of progression of existing findings or emergence of new findings
Perform EEG if indicated.
Pulmonary eval
Consider venous blood gases.
Consider chest x-ray & sputum cultures.
Consider echocardiography to monitor for pulmonary hypertension.
Consider arterial blood gases.
Avoid drugs that cause decreased consciousness, hypopnea, and CO
See
Search
• Perform EEG if history suggests seizures.
• Brain MRI may be considered (after careful eval of risks of sedation/anesthesia in this patient population).
• 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)
• Consider swallow study for assessing dysphagia.
• If dysphagia or aspiration are present, consider aspiration precautions (i.e., avoidance of certain food consistencies or nothing by mouth).
• Baseline chest x-ray
• Polysomnography
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• 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).
• Neurologic exam for response to treatments & evidence of progression of existing findings or emergence of new findings
• Perform EEG if indicated.
• Pulmonary eval
• Consider venous blood gases.
• Consider chest x-ray & sputum cultures.
• Consider echocardiography to monitor for pulmonary hypertension.
• Consider arterial blood gases.
## 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
Perform EEG if history suggests seizures.
Brain MRI may be considered (after careful eval of risks of sedation/anesthesia in this patient population).
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)
Consider swallow study for assessing dysphagia.
If dysphagia or aspiration are present, consider aspiration precautions (i.e., avoidance of certain food consistencies or nothing by mouth).
Baseline chest x-ray
Polysomnography
Community or
Social work involvement for parental support;
Home nursing referral.
ABA = applied behavioral analysis; ADL = activities of daily living; ASD = autism spectrum disorder; HSAN = hereditary sensory and autonomic neuropathy; ID = intellectual disability; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
It is possible that the imaging spectrum in
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Perform EEG if history suggests seizures.
• Brain MRI may be considered (after careful eval of risks of sedation/anesthesia in this patient population).
• 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)
• Consider swallow study for assessing dysphagia.
• If dysphagia or aspiration are present, consider aspiration precautions (i.e., avoidance of certain food consistencies or nothing by mouth).
• Baseline chest x-ray
• Polysomnography
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Currently there are no specific disease-modifying treatments for
Treatment of Manifestations in Individuals with
ABA = applied behavioral analysis; ASD = autism spectrum disorder; 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
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, 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.
• 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).
## 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
To monitor existing manifestations and response to supportive care and to detect new manifestations, see
Recommended Surveillance for Individuals with
Neurologic exam for response to treatments & evidence of progression of existing findings or emergence of new findings
Perform EEG if indicated.
Pulmonary eval
Consider venous blood gases.
Consider chest x-ray & sputum cultures.
Consider echocardiography to monitor for pulmonary hypertension.
Consider arterial blood gases.
• Neurologic exam for response to treatments & evidence of progression of existing findings or emergence of new findings
• Perform EEG if indicated.
• Pulmonary eval
• Consider venous blood gases.
• Consider chest x-ray & sputum cultures.
• Consider echocardiography to monitor for pulmonary hypertension.
• Consider arterial blood gases.
## Agents/Circumstances to Avoid
Avoid drugs that cause decreased consciousness, hypopnea, and CO
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
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.
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 and to the parents of affected children.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or the reproductive partner is of Bukharian or Ashkenazi Jewish background, as these population groups have higher carrier frequencies as a result of founder variants (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
• 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 optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 and to the parents of affected children.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or the reproductive partner is of Bukharian or Ashkenazi Jewish background, as these population groups have higher carrier frequencies as a result of founder variants (see
## Mode of Inheritance
## 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 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.
## 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 and to the parents of affected children.
Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or the reproductive partner is of Bukharian or Ashkenazi Jewish background, as these population groups have higher carrier frequencies as a result of founder variants (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 carriers or are at risk of being carriers and to the parents of affected children.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or the reproductive partner is of Bukharian or Ashkenazi Jewish background, as these population groups have higher carrier frequencies as a result of founder variants (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
TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability : Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TECPR2-Related Hereditary Sensory and Autonomic Neuropathy with Intellectual Disability (
TECPR2 (tectonin beta-propeller repeat containing 2) is a large, multidomain protein comprising an amino-terminal tryptophan-aspartic-acid dipeptide (WD) domain, a middle unstructured region, and a carboxy-terminal TEPCR domain containing six TECPR repeats followed by a functional LC3 interacting region (LIR) motif at the extreme carboxy terminus [
Animal models supporting a defect in autophagy include:
Accumulation of autophagosomes in a
Observation of similar findings in Spanish water dogs with a homozygous missense variant (p.Arg1337Trp) in a highly conserved position in the
Notable
Variants listed in the table have been provided by the authors.
• Accumulation of autophagosomes in a
• Observation of similar findings in Spanish water dogs with a homozygous missense variant (p.Arg1337Trp) in a highly conserved position in the
## Molecular Pathogenesis
TECPR2 (tectonin beta-propeller repeat containing 2) is a large, multidomain protein comprising an amino-terminal tryptophan-aspartic-acid dipeptide (WD) domain, a middle unstructured region, and a carboxy-terminal TEPCR domain containing six TECPR repeats followed by a functional LC3 interacting region (LIR) motif at the extreme carboxy terminus [
Animal models supporting a defect in autophagy include:
Accumulation of autophagosomes in a
Observation of similar findings in Spanish water dogs with a homozygous missense variant (p.Arg1337Trp) in a highly conserved position in the
Notable
Variants listed in the table have been provided by the authors.
• Accumulation of autophagosomes in a
• Observation of similar findings in Spanish water dogs with a homozygous missense variant (p.Arg1337Trp) in a highly conserved position in the
## Chapter Notes
Readers are encouraged to contact the authors for questions about research on
For specific information about clinical features, contact:
Dr Gali Heimer and Prof Bruria Ben-ZeevThe Edmond and Lily Safra Children's HospitalEmails: [email protected] / [email protected]
For inquiries regarding interpretation of molecular genetic test results or functional analyses, contact:
Dr Sonja NeuserInstitute of Human Genetics, University of Leipzig Medical CenterEmail: [email protected]
The authors thank all families for their participation in research.
22 September 2022 (bp) Review posted live
13 June 2022 (sn) Original submission
• For specific information about clinical features, contact:
• Dr Gali Heimer and Prof Bruria Ben-ZeevThe Edmond and Lily Safra Children's HospitalEmails: [email protected] / [email protected]
• For inquiries regarding interpretation of molecular genetic test results or functional analyses, contact:
• Dr Sonja NeuserInstitute of Human Genetics, University of Leipzig Medical CenterEmail: [email protected]
• 22 September 2022 (bp) Review posted live
• 13 June 2022 (sn) Original submission
## Author Notes
Readers are encouraged to contact the authors for questions about research on
For specific information about clinical features, contact:
Dr Gali Heimer and Prof Bruria Ben-ZeevThe Edmond and Lily Safra Children's HospitalEmails: [email protected] / [email protected]
For inquiries regarding interpretation of molecular genetic test results or functional analyses, contact:
Dr Sonja NeuserInstitute of Human Genetics, University of Leipzig Medical CenterEmail: [email protected]
• For specific information about clinical features, contact:
• Dr Gali Heimer and Prof Bruria Ben-ZeevThe Edmond and Lily Safra Children's HospitalEmails: [email protected] / [email protected]
• For inquiries regarding interpretation of molecular genetic test results or functional analyses, contact:
• Dr Sonja NeuserInstitute of Human Genetics, University of Leipzig Medical CenterEmail: [email protected]
## Acknowledgments
The authors thank all families for their participation in research.
## Revision History
22 September 2022 (bp) Review posted live
13 June 2022 (sn) Original submission
• 22 September 2022 (bp) Review posted live
• 13 June 2022 (sn) Original submission
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"D Stadel, V Millarte, K Tillmann, J Huber, BC Tamin-Yecheskel, M Akutsu, A Demishtein, B Ben-Zeev, Y Anikster, F Perez, V Dötsch, Z Elazar, V Rogov, H Farhan, C Behrends. TECPR2 cooperates with LC3C to regulate COPII-dependent ER export.. Mol Cell. 2015;60:89-104",
"BC Tamim-Yecheskel, M Fraiberg, K Kokabi, S Freud, O Shatz, L Marvaldi, N Subic, O Brenner, M Tsoory, R Eilam-Altstadter, I Biton, A Savidor, N Dezorella, G Heimer, C Behrends, B Ben-Zeev, Z Elazar. A tecpr2 knockout mouse exhibits age-dependent neuroaxonal dystrophy associated with autophagosome accumulation.. Autophagy. 2021;17:3082-95",
"X Zhu, S Petrovski, P Xie, EK Ruzzo, YF Lu, KM McSweeney, B Ben-Zeev, A Nissenkorn, Y Anikster, D Oz-Levi, RS Dhindsa, Y Hitomi, K Schoch, RC Spillmann, G Heimer, D Marek-Yagel, M Tzadok, Y Han, G Worley, J Goldstein, YH Jiang, D Lancet, E Pras, V Shashi, D McHale, AC Need, DB Goldstein. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.. Genet Med. 2015;17:774-81"
] |
22/9/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
tef-ov
|
tef-ov
|
[
"Chromodomain-helicase-DNA-binding protein 7",
"E3 ubiquitin-protein ligase FANCL",
"E3 ubiquitin-protein ligase Midline-1",
"Fanconi anemia group A protein",
"Fanconi anemia group B protein",
"Fanconi anemia group C protein",
"Fanconi anemia group D2 protein",
"Fanconi anemia group E protein",
"Fanconi anemia group F protein",
"Fanconi anemia group G protein",
"Fanconi anemia group J protein",
"Fanconi anemia group M protein",
"N-myc proto-oncogene protein",
"Partner and localizer of BRCA2",
"Transcription factor SOX-2",
"Transcriptional activator GLI3",
"BRIP1",
"CHD7",
"FANCA",
"FANCB",
"FANCC",
"FANCD2",
"FANCE",
"FANCF",
"FANCG",
"FANCL",
"FANCM",
"GLI3",
"MID1",
"MYCN",
"PALB2",
"SOX2",
"Esophageal Atresia/Tracheoesophageal Fistula",
"Overview"
] |
Esophageal Atresia / Tracheoesophageal Fistula Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Daryl A Scott
|
Summary The purpose of this overview is to increase the awareness of clinicians regarding esophageal atresia / tracheoesophageal fistula and its genetic causes and management. The following are the goals of this overview. Describe the Review the Provide an Inform Review
|
## Clinical Characteristics of EA/TEF
Esophageal atresia (EA) is a developmental defect of the upper gastrointestinal tract in which the continuity between the upper and lower esophagus is lost. EA can occur with or without tracheoesophageal fistula (TEF), an abnormal connection between the trachea and the esophagus.
Infants with congenital forms of EA/TEF usually present shortly after birth with copious oral secretions, coughing, gagging, cyanosis, vomiting, and/or respiratory distress.
The following five EA/TEF configurations have been described [
EA with a distal TEF (the most common; 84%)
Isolated EA (i.e., without TEF) (8%)
H-type TEF with no EA (4%)
EA with proximal and distal TEF (3%)
EA with a proximal TEF (1%)
A proband with EA/TEF can present in one of the following clinical settings:
EA/TEF may be suspected prenatally if ultrasound examination reveals polyhydramnios, absence of a fluid-filled stomach, a small abdomen, lower-than-expected fetal weight, and a distended esophageal pouch [
EA may be detected postnatally by:
Failure to pass a nasogastric (NG) tube and radiographs that demonstrate coiling of the NG tube in the pouch;
Tracheal compression and deviation on plain chest radiographs;
Absence of a gastric bubble on plain radiographs, which may suggest EA without a TEF or EA with a proximal TEF;
Three-dimensional chest CT examination [
Note: Administration of barium into the esophagus followed by chest radiographs can confirm the diagnosis but is seldom required.
• EA with a distal TEF (the most common; 84%)
• Isolated EA (i.e., without TEF) (8%)
• H-type TEF with no EA (4%)
• EA with proximal and distal TEF (3%)
• EA with a proximal TEF (1%)
• Failure to pass a nasogastric (NG) tube and radiographs that demonstrate coiling of the NG tube in the pouch;
• Tracheal compression and deviation on plain chest radiographs;
• Absence of a gastric bubble on plain radiographs, which may suggest EA without a TEF or EA with a proximal TEF;
• Three-dimensional chest CT examination [
## Clinical Description
Esophageal atresia (EA) is a developmental defect of the upper gastrointestinal tract in which the continuity between the upper and lower esophagus is lost. EA can occur with or without tracheoesophageal fistula (TEF), an abnormal connection between the trachea and the esophagus.
Infants with congenital forms of EA/TEF usually present shortly after birth with copious oral secretions, coughing, gagging, cyanosis, vomiting, and/or respiratory distress.
The following five EA/TEF configurations have been described [
EA with a distal TEF (the most common; 84%)
Isolated EA (i.e., without TEF) (8%)
H-type TEF with no EA (4%)
EA with proximal and distal TEF (3%)
EA with a proximal TEF (1%)
A proband with EA/TEF can present in one of the following clinical settings:
• EA with a distal TEF (the most common; 84%)
• Isolated EA (i.e., without TEF) (8%)
• H-type TEF with no EA (4%)
• EA with proximal and distal TEF (3%)
• EA with a proximal TEF (1%)
## Establishing the Diagnosis of EA/TEF
EA/TEF may be suspected prenatally if ultrasound examination reveals polyhydramnios, absence of a fluid-filled stomach, a small abdomen, lower-than-expected fetal weight, and a distended esophageal pouch [
EA may be detected postnatally by:
Failure to pass a nasogastric (NG) tube and radiographs that demonstrate coiling of the NG tube in the pouch;
Tracheal compression and deviation on plain chest radiographs;
Absence of a gastric bubble on plain radiographs, which may suggest EA without a TEF or EA with a proximal TEF;
Three-dimensional chest CT examination [
Note: Administration of barium into the esophagus followed by chest radiographs can confirm the diagnosis but is seldom required.
• Failure to pass a nasogastric (NG) tube and radiographs that demonstrate coiling of the NG tube in the pouch;
• Tracheal compression and deviation on plain chest radiographs;
• Absence of a gastric bubble on plain radiographs, which may suggest EA without a TEF or EA with a proximal TEF;
• Three-dimensional chest CT examination [
## Differential Diagnosis of EA/TEF
## Genetic Causes of EA/TEF
The genetic causes of esophageal atresia / tracheoesophageal fistula (EA/TEF) include syndromes that result from mutation of a single gene (see
Esophageal Atresia / Tracheoesophageal Fistula: Syndromic Causes and Distinguishing Clinical Features
Anophthalmia/microphthalmia
EA/TEF
Urogenital anomalies
Coloboma of the eye
Cardiac anomalies
Choanal atresia
Intellectual disability
Growth restriction
Genital anomalies
Ear anomalies
Hearing loss
EA/TEF
Esophageal & duodenal atresias
Microcephaly
Learning disabilities
Syndactyly
Cardiac defects
Bone marrow failure
Malignancies
Short stature
Abnormal skin pigmentation
Radial ray defects
Eye anomalies
Renal anomalies
Cardiac defects
Abnormal ears
Central nervous system anomalies
Hearing loss
Developmental delay
Gastrointestinal anomalies incl EA/TEF
Vertebral anomalies
Anal atresia
Cardiac malformations
Tracheoesophageal fistula
Renal anomalies
Limb anomalies
Hydrocephalus
EA/TEF has also been reported in individuals with Opitz G/BBB and Pallister-Hall syndrome, although it is not a major feature in these disorders.
Chromosome anomalies have been reported in approximately 6%-10% of individuals with EA/TEF. EA/TEF is found in the following aneuploidy syndromes [
Trisomy 21 (~0.5%-1.0% of affected individuals)
Trisomy 18 (~25% of affected individuals)
Trisomy 13
Trisomy X
Copy number variant (CNV) analysis in individuals with both isolated and non-isolated EA/TEF can reveal rare gene-containing CNVs, a subset of which can be shown to have arisen
Recurrent duplications of 3p25-pter and 5q34-qter suggest that these regions may harbor one or more genes in which overexpression causes or predisposes to the development of EA/TEF [
Recurrent deletions of 2q37.2-qter, 4q35-qter, 5p15-pter, 6q13-q15, 14q32.3-qter, and 17q22-q23 suggest that haploinsufficiency or decreased expression of one or more genes in these regions may cause or predispose to the development of EA/TEF [
Recurrent deletions of 13q34-qter and 22q11 are also associated with EA/TEF, but typically with findings consistent with VACTERL association [
• Anophthalmia/microphthalmia
• EA/TEF
• Urogenital anomalies
• Coloboma of the eye
• Cardiac anomalies
• Choanal atresia
• Intellectual disability
• Growth restriction
• Genital anomalies
• Ear anomalies
• Hearing loss
• EA/TEF
• Esophageal & duodenal atresias
• Microcephaly
• Learning disabilities
• Syndactyly
• Cardiac defects
• Bone marrow failure
• Malignancies
• Short stature
• Abnormal skin pigmentation
• Radial ray defects
• Eye anomalies
• Renal anomalies
• Cardiac defects
• Abnormal ears
• Central nervous system anomalies
• Hearing loss
• Developmental delay
• Gastrointestinal anomalies incl EA/TEF
• Vertebral anomalies
• Anal atresia
• Cardiac malformations
• Tracheoesophageal fistula
• Renal anomalies
• Limb anomalies
• Hydrocephalus
• Trisomy 21 (~0.5%-1.0% of affected individuals)
• Trisomy 18 (~25% of affected individuals)
• Trisomy 13
• Trisomy X
## Chromosomal Causes of EA/TEF
Chromosome anomalies have been reported in approximately 6%-10% of individuals with EA/TEF. EA/TEF is found in the following aneuploidy syndromes [
Trisomy 21 (~0.5%-1.0% of affected individuals)
Trisomy 18 (~25% of affected individuals)
Trisomy 13
Trisomy X
Copy number variant (CNV) analysis in individuals with both isolated and non-isolated EA/TEF can reveal rare gene-containing CNVs, a subset of which can be shown to have arisen
Recurrent duplications of 3p25-pter and 5q34-qter suggest that these regions may harbor one or more genes in which overexpression causes or predisposes to the development of EA/TEF [
Recurrent deletions of 2q37.2-qter, 4q35-qter, 5p15-pter, 6q13-q15, 14q32.3-qter, and 17q22-q23 suggest that haploinsufficiency or decreased expression of one or more genes in these regions may cause or predispose to the development of EA/TEF [
Recurrent deletions of 13q34-qter and 22q11 are also associated with EA/TEF, but typically with findings consistent with VACTERL association [
• Trisomy 21 (~0.5%-1.0% of affected individuals)
• Trisomy 18 (~25% of affected individuals)
• Trisomy 13
• Trisomy X
## Evaluation Strategies to Identify the Genetic Cause of EA/TEF in a Proband
Establishing a specific genetic cause of EA/TEF:
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
## Genetic Counseling
Esophageal atresia / tracheoesophageal fistula (EA/TEF) can occur as an isolated finding, as part of a genetic syndrome, or as part of a non-isolated (but not syndromic) set of findings. Most individuals with EA/TEF represent simplex cases (i.e., the only affected member of the family). A small subset of families are multiplex (i.e., ≥2 relatives have EA/TEF).
Nonsyndromic EA/TEF is generally considered to be inherited in a multifactorial manner.
If an affected individual is found to have an inherited or
Risk to Family Members
MOI assoc'd w/the genetic syndrome; &
Genetic status of proband's parents
In most families risk is likely low.
In the minority of families risk is higher (~25%-50%).
EA/TEF = esophageal atresia / tracheoesophageal fistula; MOI = mode of inheritance
Nonsyndromic EA/TEF is generally considered to be inherited in a multifactorial manner. The twin concordance rate for EA/TEF is also low (~2.5%) [
Recurrence risk for EA/TEF and/or malformations in the VACTERL association.
Since these estimates were generated by studying the offspring of individuals with both isolated and non-isolated EA/TEF, the risk to offspring in isolated cases may be lower [
Recurrence risk counseling for individuals with non-isolated EA/TEF – in whom additional anomalies have been identified and for whom a specific genetic disorder is not recognized – is problematic: • Some cases of non-isolated EA/TEF are probably caused by de novo autosomal dominant mutations, and therefore, pose a low recurrence risk to the sibs of the proband. • Some are probably unrecognized or private autosomal recessive conditions. • Some may be multifactorial disorders with a low recurrence risk. • Non-genetic causes including stochastic events, epigenetic modifications, or teratogenic/environmental exposures are possible as well.
Counseling in this setting should be as for other multiple congenital anomaly disorders of unknown etiology.
Prenatal ultrasound examination of a fetus affected by EA/TEF may reveal an absent or small fetal stomach bubble in combination with maternal polyhydramnios [
The presence of a dilated blind-ending esophageal pouch on a sonogram is suggestive of EA. It is the most reliable sonographic sign indicative of EA and has been seen in cases with and without TEF [
Polyhydramnios can be seen in a wide variety of disorders and alone is a poor indicator of EA: only one in 12 fetuses with polyhydramnios has EA [
When EA/TEF is suspected on routine prenatal ultrasound examination:
A high-resolution ultrasound examination is indicated;
Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
All fetuses suspected of having EA/TEF should be evaluated for the presence of additional major malformations that could be part of an underlying syndrome because such malformations and/or the underlying diagnosis may significantly affect the prognosis. Involvement of a clinical geneticist in the evaluation of these families can be helpful.
• MOI assoc'd w/the genetic syndrome; &
• Genetic status of proband's parents
• In most families risk is likely low.
• In the minority of families risk is higher (~25%-50%).
• Prenatal ultrasound examination of a fetus affected by EA/TEF may reveal an absent or small fetal stomach bubble in combination with maternal polyhydramnios [
• The presence of a dilated blind-ending esophageal pouch on a sonogram is suggestive of EA. It is the most reliable sonographic sign indicative of EA and has been seen in cases with and without TEF [
• Polyhydramnios can be seen in a wide variety of disorders and alone is a poor indicator of EA: only one in 12 fetuses with polyhydramnios has EA [
• When EA/TEF is suspected on routine prenatal ultrasound examination:
• A high-resolution ultrasound examination is indicated;
• Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
• Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
• A high-resolution ultrasound examination is indicated;
• Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
• Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
• All fetuses suspected of having EA/TEF should be evaluated for the presence of additional major malformations that could be part of an underlying syndrome because such malformations and/or the underlying diagnosis may significantly affect the prognosis. Involvement of a clinical geneticist in the evaluation of these families can be helpful.
• A high-resolution ultrasound examination is indicated;
• Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
• Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
## Mode of Inheritance
Esophageal atresia / tracheoesophageal fistula (EA/TEF) can occur as an isolated finding, as part of a genetic syndrome, or as part of a non-isolated (but not syndromic) set of findings. Most individuals with EA/TEF represent simplex cases (i.e., the only affected member of the family). A small subset of families are multiplex (i.e., ≥2 relatives have EA/TEF).
Nonsyndromic EA/TEF is generally considered to be inherited in a multifactorial manner.
If an affected individual is found to have an inherited or
## Risk to Family Members
Risk to Family Members
MOI assoc'd w/the genetic syndrome; &
Genetic status of proband's parents
In most families risk is likely low.
In the minority of families risk is higher (~25%-50%).
EA/TEF = esophageal atresia / tracheoesophageal fistula; MOI = mode of inheritance
Nonsyndromic EA/TEF is generally considered to be inherited in a multifactorial manner. The twin concordance rate for EA/TEF is also low (~2.5%) [
Recurrence risk for EA/TEF and/or malformations in the VACTERL association.
Since these estimates were generated by studying the offspring of individuals with both isolated and non-isolated EA/TEF, the risk to offspring in isolated cases may be lower [
Recurrence risk counseling for individuals with non-isolated EA/TEF – in whom additional anomalies have been identified and for whom a specific genetic disorder is not recognized – is problematic: • Some cases of non-isolated EA/TEF are probably caused by de novo autosomal dominant mutations, and therefore, pose a low recurrence risk to the sibs of the proband. • Some are probably unrecognized or private autosomal recessive conditions. • Some may be multifactorial disorders with a low recurrence risk. • Non-genetic causes including stochastic events, epigenetic modifications, or teratogenic/environmental exposures are possible as well.
Counseling in this setting should be as for other multiple congenital anomaly disorders of unknown etiology.
• MOI assoc'd w/the genetic syndrome; &
• Genetic status of proband's parents
• In most families risk is likely low.
• In the minority of families risk is higher (~25%-50%).
## Related Genetic Counseling Issues
## Prenatal Testing and Preimplantation Genetic Testing
Prenatal ultrasound examination of a fetus affected by EA/TEF may reveal an absent or small fetal stomach bubble in combination with maternal polyhydramnios [
The presence of a dilated blind-ending esophageal pouch on a sonogram is suggestive of EA. It is the most reliable sonographic sign indicative of EA and has been seen in cases with and without TEF [
Polyhydramnios can be seen in a wide variety of disorders and alone is a poor indicator of EA: only one in 12 fetuses with polyhydramnios has EA [
When EA/TEF is suspected on routine prenatal ultrasound examination:
A high-resolution ultrasound examination is indicated;
Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
All fetuses suspected of having EA/TEF should be evaluated for the presence of additional major malformations that could be part of an underlying syndrome because such malformations and/or the underlying diagnosis may significantly affect the prognosis. Involvement of a clinical geneticist in the evaluation of these families can be helpful.
• Prenatal ultrasound examination of a fetus affected by EA/TEF may reveal an absent or small fetal stomach bubble in combination with maternal polyhydramnios [
• The presence of a dilated blind-ending esophageal pouch on a sonogram is suggestive of EA. It is the most reliable sonographic sign indicative of EA and has been seen in cases with and without TEF [
• Polyhydramnios can be seen in a wide variety of disorders and alone is a poor indicator of EA: only one in 12 fetuses with polyhydramnios has EA [
• When EA/TEF is suspected on routine prenatal ultrasound examination:
• A high-resolution ultrasound examination is indicated;
• Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
• Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
• A high-resolution ultrasound examination is indicated;
• Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
• Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
• All fetuses suspected of having EA/TEF should be evaluated for the presence of additional major malformations that could be part of an underlying syndrome because such malformations and/or the underlying diagnosis may significantly affect the prognosis. Involvement of a clinical geneticist in the evaluation of these families can be helpful.
• A high-resolution ultrasound examination is indicated;
• Fetal MRI should be considered to help confirm the diagnosis of EA/TEF and to evaluate for additional structural anomalies;
• Chromosome analysis, an array-based copy number detection assay, and/or molecular testing using fetal cells/DNA should be considered.
## Resources
St. George's Centre
91 Victoria Road
Netherfield Nottingham NG4 2NN
United Kingdom
•
•
•
• St. George's Centre
• 91 Victoria Road
• Netherfield Nottingham NG4 2NN
• United Kingdom
•
•
•
## Management of EA/TEF
After an individual has been diagnosed with esophageal atresia / tracheoesophageal fistula (EA/TEF), the following evaluations should be considered as a means of identifying associated anomalies:
X-ray evaluation for vertebral anomalies
Echocardiogram
Renal ultrasound examination
Initial postnatal intervention, aimed at minimizing the risk of aspiration pneumonia, typically includes the elimination of oral feeds, placement of a suction catheter to allow continuous drainage of secretions, and elevation of the head of the bed to minimize reflux [
Surgical repair consists of closure of the TEF and anastomosis of the esophageal segments [
The most common complications after surgical repair include leakage at the site of the anastomosis, recurrent fistula, structure formation, and gastroesophageal reflux [
See
Search
• X-ray evaluation for vertebral anomalies
• Echocardiogram
• Renal ultrasound examination
## Evaluations Following Initial Diagnosis
After an individual has been diagnosed with esophageal atresia / tracheoesophageal fistula (EA/TEF), the following evaluations should be considered as a means of identifying associated anomalies:
X-ray evaluation for vertebral anomalies
Echocardiogram
Renal ultrasound examination
• X-ray evaluation for vertebral anomalies
• Echocardiogram
• Renal ultrasound examination
## Treatment of Manifestations
Initial postnatal intervention, aimed at minimizing the risk of aspiration pneumonia, typically includes the elimination of oral feeds, placement of a suction catheter to allow continuous drainage of secretions, and elevation of the head of the bed to minimize reflux [
Surgical repair consists of closure of the TEF and anastomosis of the esophageal segments [
The most common complications after surgical repair include leakage at the site of the anastomosis, recurrent fistula, structure formation, and gastroesophageal reflux [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Chapter Notes
Baylor College of Medicine Molecular and Human Genetics
20 April 2023 (ma) Chapter retired: chapter does not reflect current use of genetic testing
20 September 2018 (sw) Comprehensive update posted live
12 June 2014 (me) Comprehensive update posted live
12 March 2009 (me) Review posted live
14 October 2008 (das) Original submission
• 20 April 2023 (ma) Chapter retired: chapter does not reflect current use of genetic testing
• 20 September 2018 (sw) Comprehensive update posted live
• 12 June 2014 (me) Comprehensive update posted live
• 12 March 2009 (me) Review posted live
• 14 October 2008 (das) Original submission
## Author Notes
Baylor College of Medicine Molecular and Human Genetics
## Revision History
20 April 2023 (ma) Chapter retired: chapter does not reflect current use of genetic testing
20 September 2018 (sw) Comprehensive update posted live
12 June 2014 (me) Comprehensive update posted live
12 March 2009 (me) Review posted live
14 October 2008 (das) Original submission
• 20 April 2023 (ma) Chapter retired: chapter does not reflect current use of genetic testing
• 20 September 2018 (sw) Comprehensive update posted live
• 12 June 2014 (me) Comprehensive update posted live
• 12 March 2009 (me) Review posted live
• 14 October 2008 (das) Original submission
## References
## Literature Cited
EA/TEF configurations and their frequencies
|
[
"E Brosens, EM de Jong, TS Barakat, BH Eussen, B D'Haene, E De Baere, H Verdin, PJ Poddighe, RJ Galjaard, J Gribnau, AS Brooks, D Tibboel, A de Klein. Structural and numerical changes of chromosome X in patients with esophageal atresia.. Eur J Hum Genet. 2014a;22:1077-84",
"E Brosens, M Ploeg, Y van Bever, AE Koopmans, H Ijsselstijn, RJ Rottier, R Wijnen, D Tibboel, A de Klein. Clinical and etiological heterogeneity in patients with tracheo-esophageal malformations and associated anomalies.. Eur J MED Genet. 2014b;57:440-52",
"M Castori, R Rinaldi, P Capocaccia, M Roggini, P Grammatico. VACTERL association and maternal diabetes: a possible causal relationship?. Birth Defects Res A Clin Mol Teratol. 2008;82:169-72",
"M Choudhry, PA Boyd, PF Chamberlain, K Lakhoo. Prenatal diagnosis of tracheo-oesophageal fistula and oesophageal atresia.. Prenat Diagn 2007;27:608-10",
"DC Clark. Esophageal atresia and tracheoesophageal fistula.. Am Fam Physician 1999;59:910-6, 919-20",
"JF Felix, D Tibboel, A de Klein. Chromosomal anomalies in the aetiology of oesophageal atresia and tracheo-oesophageal fistula.. Eur J Med Genet 2007;50:163-75",
"CH Houben, JI Curry. Current status of prenatal diagnosis, operative management and outcome of esophageal atresia/tracheo-esophageal fistula.. Prenat Diagn 2008;28:667-75",
"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",
"E Robert, O Mutchinick, P Mastroiacovo, LB Knudsen, AK Daltveit, EE Castilla, P Lancaster, B Källén, G Cocchi. An international collaborative study of the epidemiology of esophageal atresia or stenosis.. Reprod Toxicol 1993;7:405-21",
"C Shaw-Smith. Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology.. J Med Genet 2006;43:545-54",
"MD Stringer, KM McKenna, RB Goldstein, RA Filly, NS Adzick, MR Harrison. Prenatal diagnosis of esophageal atresia.. J Pediatr Surg 1995;30:1258-63",
"LE Walsh, GH Vance, DD Weaver. Distal 13q deletion syndrome and the VACTERL association: case report, literature review, and possible implications.. Am J Med Genet 2001;98:137-44"
] |
12/3/2009
|
20/9/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tetra-amelia
|
tetra-amelia
|
[
"Tetra-Amelia, Autosomal Recessive",
"Tetra-Amelia, Autosomal Recessive",
"Proto-oncogene Wnt-3",
"WNT3",
"Tetra-Amelia Syndrome"
] |
Tetra-Amelia Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Stephan Niemann
|
Summary Tetra-amelia syndrome is characterized by the (complete) absence of all four limbs and anomalies involving the cranium and the face (cleft lip/cleft palate, micrognathia, microtia, single naris, choanal atresia, absence of nose); eyes (microphthalmia, microcornea, cataract, coloboma, palpebral fusion); urogenital system (renal agenesis, persistence of cloaca, absence of external genitalia, atresia of vagina); anus (atresia); heart; lungs (hypoplasia/aplasia), skeleton (hypoplasia/absence of pelvic bones, absence of ribs, absence of vertebrae), and central nervous system (agenesis of olfactory nerves, agenesis of optic nerves, agenesis of corpus callosum, hydrocephalus). Affected infants are often stillborn or die shortly after birth. The diagnosis of tetra-amelia syndrome can be established clinically and is usually made on routine prenatal ultrasonography. Affected infants are often stillborn or die shortly after birth. Management of (as yet unreported) persons who survive will depend on the presence and severity of associated malformations and require the support of several medical disciplines. Tetra-amelia syndrome 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. Heterozygotes (carriers) are asymptomatic. Prenatal testing by molecular genetic testing is possible if the pathogenic variants in
|
## Diagnosis
Tetra-amelia is characterized by the (complete) absence of all four limbs (
In the few families described to date, tetra-amelia was associated with craniofacial, urogenital, cardiopulmonary, nervous system, and skeletal malformations, in which instance the correct terminology should be tetra-amelia syndrome.
Cytogenetic analyses, performed in some of the reported cases, showed normal karyotypes without "premature centromere separation" (see
Molecular Genetic Testing Used in Tetra-Amelia Syndrome
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
Only one family studied to date [
Percentage of detectable pathogenic variants is unknown, as a
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
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
## Clinical Diagnosis
Tetra-amelia is characterized by the (complete) absence of all four limbs (
In the few families described to date, tetra-amelia was associated with craniofacial, urogenital, cardiopulmonary, nervous system, and skeletal malformations, in which instance the correct terminology should be tetra-amelia syndrome.
## Testing
Cytogenetic analyses, performed in some of the reported cases, showed normal karyotypes without "premature centromere separation" (see
Molecular Genetic Testing Used in Tetra-Amelia Syndrome
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
Only one family studied to date [
Percentage of detectable pathogenic variants is unknown, as a
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
## Molecular Genetic Testing
Molecular Genetic Testing Used in Tetra-Amelia Syndrome
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
Only one family studied to date [
Percentage of detectable pathogenic variants is unknown, as a
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
## Testing Strategy
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
## Clinical Characteristics
In addition to complete absence of all four extremities, phenotypic manifestations of tetra-amelia syndrome in affected individuals may include craniofacial, urogenital, cardiopulmonary, nervous system, and skeletal malformations. The following list is based on the findings in the affected individuals in the few families reported [
While the affected individuals in these families have all had similar findings, a mutation in
Eyes. Microphthalmia, cataract, microcornea, coloboma, palpebral fusion
Ears. Absence of external ears (microtia), low-set ears
Nose. Single naris, choanal atresia, prominent nose, absence of nose
Mouth. Cleft lip/cleft palate, high and narrow palate, macrostomia, micrognathia
Agenesis of kidney
Rudimentary ovary and salpinx
Persistence of cloaca
Atresia of vagina
Atresia of anus
Atresia of urethra
Hypospadias
Absence of external genitalia
Ambiguous genitalia
Absence of scrotum
Intra-abdominal location of testis
Hypoplasia/aplasia of lungs, bilobular right lung
Hypoplasia/aplasia of pulmonary vessels
Diaphragmatic defect
Ventricular septal defect
Small right heart
Mitral valve aplasia
Hypoplasia/absence of pelvic bones
Absence of vertebra
Absence of rib
Agenesis of olfactory nerves
Agenesis of optic nerves
Agenesis of corpus callosum
Hydrocephalus
Polyhydramnios
Absence of nipples
Gastroschisis
Agenesis of suprarenal gland
Agenesis of spleen
Clinical and Autopsy Findings in Families with Tetra-Amelia
Data on the course of the disease or the prognosis are not available because the condition is rare. In nearly all reported cases, the pregnancy was terminated on diagnosis of tetra-amelia syndrome, or infants died shortly after birth as a consequence of other malformations such as pulmonary hypoplasia. Limb agenesis is generally compatible with life if adequate assistance is provided. The natural history of the disease is likely to be determined by extent and degree of associated manifestations.
Note: An X-linked form of tetra-amelia, also termed "Zimmer phocomelia," has been suggested for the family reported by Zimmer [
To date no genotype-phenotype correlations have been established.
Based on the few reports, penetrance appears to be complete with respect to absence of the limbs and incomplete with respect to the associated malformations. Expressivity of the associated manifestations is highly variable.
In all cases reported so far, tetra-amelia was associated with other malformations, as "tetra-amelia syndrome." However, there is evidence that tetra-amelia may occur as "pure tetra-amelia" (or "isolated tetra-amelia") without other anomalies [personal communication].
Note: Some reports in the literature that refer to "tetra-amelia" describe cases with different combinations of (di-, tri-) phocomelia/-amelia. These cases do not represent true tetra-amelia, which is defined by the (complete) absence of all four limbs.
Tetra-amelia syndrome is an extremely rare disorder and has so far been described in only five families of different ethnic backgrounds (Arab, Moroccan, Syrian-Aramaic). No estimates of prevalence and carrier frequency for tetra-amelia syndrome have been reported.
Parental consanguinity appears to account for at least some of the few cases reported to date.
• Eyes. Microphthalmia, cataract, microcornea, coloboma, palpebral fusion
• Ears. Absence of external ears (microtia), low-set ears
• Nose. Single naris, choanal atresia, prominent nose, absence of nose
• Mouth. Cleft lip/cleft palate, high and narrow palate, macrostomia, micrognathia
• Agenesis of kidney
• Rudimentary ovary and salpinx
• Persistence of cloaca
• Atresia of vagina
• Atresia of anus
• Atresia of urethra
• Hypospadias
• Absence of external genitalia
• Ambiguous genitalia
• Absence of scrotum
• Intra-abdominal location of testis
• Hypoplasia/aplasia of lungs, bilobular right lung
• Hypoplasia/aplasia of pulmonary vessels
• Diaphragmatic defect
• Ventricular septal defect
• Small right heart
• Mitral valve aplasia
• Hypoplasia/absence of pelvic bones
• Absence of vertebra
• Absence of rib
• Agenesis of olfactory nerves
• Agenesis of optic nerves
• Agenesis of corpus callosum
• Hydrocephalus
• Polyhydramnios
• Absence of nipples
• Gastroschisis
• Agenesis of suprarenal gland
• Agenesis of spleen
## Clinical Description
In addition to complete absence of all four extremities, phenotypic manifestations of tetra-amelia syndrome in affected individuals may include craniofacial, urogenital, cardiopulmonary, nervous system, and skeletal malformations. The following list is based on the findings in the affected individuals in the few families reported [
While the affected individuals in these families have all had similar findings, a mutation in
Eyes. Microphthalmia, cataract, microcornea, coloboma, palpebral fusion
Ears. Absence of external ears (microtia), low-set ears
Nose. Single naris, choanal atresia, prominent nose, absence of nose
Mouth. Cleft lip/cleft palate, high and narrow palate, macrostomia, micrognathia
Agenesis of kidney
Rudimentary ovary and salpinx
Persistence of cloaca
Atresia of vagina
Atresia of anus
Atresia of urethra
Hypospadias
Absence of external genitalia
Ambiguous genitalia
Absence of scrotum
Intra-abdominal location of testis
Hypoplasia/aplasia of lungs, bilobular right lung
Hypoplasia/aplasia of pulmonary vessels
Diaphragmatic defect
Ventricular septal defect
Small right heart
Mitral valve aplasia
Hypoplasia/absence of pelvic bones
Absence of vertebra
Absence of rib
Agenesis of olfactory nerves
Agenesis of optic nerves
Agenesis of corpus callosum
Hydrocephalus
Polyhydramnios
Absence of nipples
Gastroschisis
Agenesis of suprarenal gland
Agenesis of spleen
Clinical and Autopsy Findings in Families with Tetra-Amelia
Data on the course of the disease or the prognosis are not available because the condition is rare. In nearly all reported cases, the pregnancy was terminated on diagnosis of tetra-amelia syndrome, or infants died shortly after birth as a consequence of other malformations such as pulmonary hypoplasia. Limb agenesis is generally compatible with life if adequate assistance is provided. The natural history of the disease is likely to be determined by extent and degree of associated manifestations.
Note: An X-linked form of tetra-amelia, also termed "Zimmer phocomelia," has been suggested for the family reported by Zimmer [
• Eyes. Microphthalmia, cataract, microcornea, coloboma, palpebral fusion
• Ears. Absence of external ears (microtia), low-set ears
• Nose. Single naris, choanal atresia, prominent nose, absence of nose
• Mouth. Cleft lip/cleft palate, high and narrow palate, macrostomia, micrognathia
• Agenesis of kidney
• Rudimentary ovary and salpinx
• Persistence of cloaca
• Atresia of vagina
• Atresia of anus
• Atresia of urethra
• Hypospadias
• Absence of external genitalia
• Ambiguous genitalia
• Absence of scrotum
• Intra-abdominal location of testis
• Hypoplasia/aplasia of lungs, bilobular right lung
• Hypoplasia/aplasia of pulmonary vessels
• Diaphragmatic defect
• Ventricular septal defect
• Small right heart
• Mitral valve aplasia
• Hypoplasia/absence of pelvic bones
• Absence of vertebra
• Absence of rib
• Agenesis of olfactory nerves
• Agenesis of optic nerves
• Agenesis of corpus callosum
• Hydrocephalus
• Polyhydramnios
• Absence of nipples
• Gastroschisis
• Agenesis of suprarenal gland
• Agenesis of spleen
## Genotype-Phenotype Correlations
To date no genotype-phenotype correlations have been established.
## Penetrance
Based on the few reports, penetrance appears to be complete with respect to absence of the limbs and incomplete with respect to the associated malformations. Expressivity of the associated manifestations is highly variable.
## Nomenclature
In all cases reported so far, tetra-amelia was associated with other malformations, as "tetra-amelia syndrome." However, there is evidence that tetra-amelia may occur as "pure tetra-amelia" (or "isolated tetra-amelia") without other anomalies [personal communication].
Note: Some reports in the literature that refer to "tetra-amelia" describe cases with different combinations of (di-, tri-) phocomelia/-amelia. These cases do not represent true tetra-amelia, which is defined by the (complete) absence of all four limbs.
## Prevalence
Tetra-amelia syndrome is an extremely rare disorder and has so far been described in only five families of different ethnic backgrounds (Arab, Moroccan, Syrian-Aramaic). No estimates of prevalence and carrier frequency for tetra-amelia syndrome have been reported.
Parental consanguinity appears to account for at least some of the few cases reported to date.
## Genetically Related (Allelic) Disorders
No other disorders have been reported to be associated with pathogenic variants in
## Differential Diagnosis
Many of the associated phenotypic manifestations observed in tetra-amelia syndrome have also been observed in other syndromes. Limb deficiency as the hallmark of the disorder may occur in limb reduction syndromes different from tetra-amelia syndrome. In these syndromes, limb defects are variable and include phocomelia, amelia, and (rarely) tetra-amelia. The finding of several individuals with (complete) absence of all four extremities in a family is highly suggestive of tetra-amelia syndrome.
## Management
Tetra-amelia syndrome is usually diagnosed prenatally. Based on the few published reports, assessment of the clinical manifestations in a fetus diagnosed with tetra-amelia syndrome by ultrasonography should include careful assessment of all organs and body structures that are known to be affected in tetra-amelia syndrome.
In nearly all reported cases, the pregnancy was terminated on diagnosis of tetra-amelia syndrome or infants died shortly after birth as a consequence of other malformations including pulmonary hypoplasia. Data on the management of tetra-amelia syndrome therefore do not exist.
It should be noted that (complete) absence of all extremities is principally not incompatible with life. Persons without extremities depend on extensive, life-long assistance with most daily activities. They would require specifically designed wheelchairs with assistive electronic technology and input control devices operated by head, chin, or tongue movements. Other individualized ambulatory devices may be indicated.
Should individuals with tetra-amelia syndrome survive, management depends on the presence and severity of associated malformations and may involve multiple interdisciplinary surgical interventions and the support of several medical disciplines.
See
Search
## Evaluations Following Initial Diagnosis
Tetra-amelia syndrome is usually diagnosed prenatally. Based on the few published reports, assessment of the clinical manifestations in a fetus diagnosed with tetra-amelia syndrome by ultrasonography should include careful assessment of all organs and body structures that are known to be affected in tetra-amelia syndrome.
## Treatment of Manifestations
In nearly all reported cases, the pregnancy was terminated on diagnosis of tetra-amelia syndrome or infants died shortly after birth as a consequence of other malformations including pulmonary hypoplasia. Data on the management of tetra-amelia syndrome therefore do not exist.
It should be noted that (complete) absence of all extremities is principally not incompatible with life. Persons without extremities depend on extensive, life-long assistance with most daily activities. They would require specifically designed wheelchairs with assistive electronic technology and input control devices operated by head, chin, or tongue movements. Other individualized ambulatory devices may be indicated.
Should individuals with tetra-amelia syndrome survive, management depends on the presence and severity of associated malformations and may involve multiple interdisciplinary surgical interventions and the support of several medical disciplines.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Tetra-amelia syndrome is inherited in an autosomal recessive manner.
The parents of an affected child are obligate heterozygotes and therefore carry one mutant 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.
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.
Carrier testing for at-risk family members and their reproductive partners is possible once the pathogenic variants have been identified in the proband.
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 at risk of being carriers.
Once the
• The parents of an affected child are obligate heterozygotes and therefore carry one mutant 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.
• 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.
• 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 at risk of being carriers.
## Mode of Inheritance
Tetra-amelia syndrome is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are obligate heterozygotes and therefore carry one mutant 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.
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.
• The parents of an affected child are obligate heterozygotes and therefore carry one mutant 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.
• 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.
## Carrier Detection
Carrier testing for at-risk family members and their reproductive partners is possible once the pathogenic variants have been identified in the proband.
## Related Genetic Counseling Issues
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 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 at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Diagnosis
Once the
## Resources
PO Box 3696
Oak Brook IL 60522
PO Box 341
Los Gatos CA 95031
•
•
• PO Box 3696
• Oak Brook IL 60522
•
•
• PO Box 341
• Los Gatos CA 95031
•
## Molecular Genetics
Tetra-Amelia Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tetra-Amelia Syndrome (
One family with tetra-amelia syndrome with a pathogenic variant in
WNTs act as ligands for the frizzled family of transmembrane receptors. Intracellularly, WNT signals can be transduced through a β-catenin-dependent (= canonic) and a β-catenin-independent (non-canonic) WNT signaling. In the WNT/β-catenin pathway, absence of WNT ligand leads to degradation of β-catenin by the proteasome. Conversely, upon binding of WNT ligand to frizzled, degradation of β-catenin is decreased and it accumulates in the nucleus where it can activate transcription.
## Molecular Pathogenesis
One family with tetra-amelia syndrome with a pathogenic variant in
WNTs act as ligands for the frizzled family of transmembrane receptors. Intracellularly, WNT signals can be transduced through a β-catenin-dependent (= canonic) and a β-catenin-independent (non-canonic) WNT signaling. In the WNT/β-catenin pathway, absence of WNT ligand leads to degradation of β-catenin by the proteasome. Conversely, upon binding of WNT ligand to frizzled, degradation of β-catenin is decreased and it accumulates in the nucleus where it can activate transcription.
## References
## Literature Cited
## Chapter Notes
7 March 2019 (ma) Chapter retired: extremely rare
2 August 2012 (me) Comprehensive update posted live
28 August 2007 (me) Review posted live
2 May 2007 (sn) Original submission
• 7 March 2019 (ma) Chapter retired: extremely rare
• 2 August 2012 (me) Comprehensive update posted live
• 28 August 2007 (me) Review posted live
• 2 May 2007 (sn) Original submission
## Revision History
7 March 2019 (ma) Chapter retired: extremely rare
2 August 2012 (me) Comprehensive update posted live
28 August 2007 (me) Review posted live
2 May 2007 (sn) Original submission
• 7 March 2019 (ma) Chapter retired: extremely rare
• 2 August 2012 (me) Comprehensive update posted live
• 28 August 2007 (me) Review posted live
• 2 May 2007 (sn) Original submission
Postmortem radiograph of fetus with tetra-amelia syndrome demonstrating absence of all four limbs (without defects of scapulae and clavicles)
Prenatal ultrasonography showing fetus without limbs
|
[
"S Başaran, A Yuksel, H Ermis, F Kuseyri, M Agan, M Yuksel-Apak. Tetra-amelia, lung hypo-/aplasia, cleft lip-palate, and heart defect: a new syndrome?. Am J Med Genet 1994;51:77-80",
"W Eyaid, MM Al-Qattan, I Al Abdulkareem, N Fetaini, M Al Balwi. A novel homozygous missense mutation (c.610G>A, p.Gly204Ser) in the WNT7A gene causes tetra-amelia in two Saudi families.. Am J Med Genet A. 2011;155A:599-604",
"R Gershoni-Baruch, A Drugan, M Bronshtein, EZ Zimmer. Roberts syndrome or \"X-linked amelia?\". Am J Med Genet 1990;37:569-72",
"K Kosaki, MC Jones, C Stayboldt. Zimmer phocomelia: delineation by principal coordinate analysis.. Am J Med Genet 1996;66:55-9",
"M Krahn, S Julia, S Sigaudy, A Liprandi, R Bernard, K Gonnet, S Heuertz, J Bonaventure, C Chau, C Fredouille, N Levy, N Philip. Tetra-amelia and lung aplasia syndrome: report of a new family and exclusion of candidate genes.. Clin Genet 2005;68:558-60",
"RT Moon, AD Kohn, GV De Ferrari, A Kaykas. WNT and beta-catenin signalling: diseases and therapies.. Nat Rev Genet 2004;5:691-701",
"S Niemann, C Zhao, F Pascu, U Stahl, U Aulepp, L Niswander, JL Weber, U Muller. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.. Am J Hum Genet 2004;74:558-63",
"S Ohdo, H Madokoro, T Sonoda, M Takei, H Yasuda, N Mori. Association of tetra-amelia, ectodermal dysplasia, hypoplastic lacrimal ducts and sacs opening towards the exterior, peculiar face, and developmental retardation.. J Med Genet 1987;24:609-12",
"S Ohdo, T Sonoda, K Ohba. Natural history and postmortem anatomy of a patient with tetra-amelia, ectodermal dysplasia, peculiar face, and developmental retardation (MIM 273390).. J Med Genet 1994;31:980-1",
"M Ragavan, S Reddy, C Kumar. Tetra-amelia with lung hypoplasia and facial clefts, Roberts-SC syndrome: report of two cases.. Pediatr Surg Int 2010;26:1049-52",
"D Rosenak, I Ariel, J Arnon, YZ Diamant, A Ben Chetrit, M Nadjari, R Zilberman, H Yaffe, T Cohen, A Ornoy. Recurrent tetraamelia and pulmonary hypoplasia with multiple malformations in sibs.. Am J Med Genet. 1991;38:25-8",
"SB Sousa, R Pina, L Ramos, N Pereira, M Krahn, W Borozdin, J Kohlhase, M Amorim, K Gonnet, N Lévy, IM Carreira, AB Couceiro, JM Saraiva. Tetra-amelia and lung hypo/aplasia syndrome: new case report and review.. Am J Med Genet 2008;146A:2799-803",
"A Wodarz, R Nusse. Mechanisms of Wnt signaling in development.. Annu Rev Cell Dev Biol 1998;14:59-88",
"EZ Zimmer, E Taub, Y Sova, MY Divon, M Pery, BA Peretz. Tetra-amelia with multiple malformations in six male fetuses of one kindred.. Eur J Pediatr 1985;144:412-4",
"J Zlotogora, M Sagi, YO Shabany, RY Jarallah. Syndrome of tetraamelia with pulmonary hypoplasia.. Am J Med Genet 1993;47:570-1"
] |
28/8/2007
|
2/8/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tfap
|
tfap
|
[
"ATTRv Amyloidosis",
"Familial Amyloid Polyneuropathy",
"Familial Transthyretin Amyloidosis",
"hATTR",
"Hereditary Amyloidogenic Transthyretin Amyloidosis",
"Hereditary ATTR Amyloidosis",
"Hereditary Transthyretin-Mediated Amyloidosis",
"ATTRv Amyloidosis",
"Familial Amyloid Polyneuropathy",
"Familial Transthyretin Amyloidosis",
"hATTR",
"Hereditary Amyloidogenic Transthyretin Amyloidosis",
"Hereditary ATTR Amyloidosis",
"Hereditary Transthyretin-Mediated Amyloidosis",
"Transthyretin",
"TTR",
"Hereditary Transthyretin Amyloidosis"
] |
Hereditary Transthyretin Amyloidosis
|
Yoshiki Sekijima, Katsuya Nakamura
|
Summary Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy. Amyloidosis can involve the heart, central nervous system (CNS), eyes, and kidneys. The disease usually begins in the third to fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. Typically, sensory neuropathy starts in the lower extremities with paresthesia and hypesthesia of the feet, followed within a few years by motor neuropathy. In some persons, particularly those with early-onset disease, autonomic neuropathy is the first manifestation of the condition; findings can include orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive restrictive cardiomyopathy. Individuals with leptomeningeal amyloidosis may have the following CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage. Ocular involvement includes vitreous opacity, glaucoma, dry eye, and ocular amyloid angiopathy. Mild-to-severe kidney disease can develop. The diagnosis of ATTRv amyloidosis is established in a proband with characteristic clinical features, including imaging or histopathology findings of amyloidosis, and a heterozygous pathogenic variant in ATTRv amyloidosis is inherited in an autosomal dominant manner. Each child of an individual who is heterozygous for a
|
## Diagnosis
Hereditary transthyretin amyloidosis (ATTRv amyloidosis)
Cardiac conduction blocks
Cardiomyopathy
Nephropathy
Vitreous opacities
Glaucoma
Echocardiogram may show left ventricular or biventricular thickening with speckled myocardium.
Gadolinium contrast-guided cardiac MRI can show characteristic gadolinium distribution. Note: Gadolinium administration in those with ATTRv amyloidosis-related nephropathy can lead to nephrogenic systemic fibrosis.
Bone scintigraphy using
Amyloid PET imaging using Pittsburgh compound B is useful for detecting amyloid in individuals with early-onset ATTRv amyloidosis due to the
Note: Sensitivity of endoscopic biopsy of gastrointestinal mucosa is approximately 85%; biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy [
The diagnosis of ATTRv amyloidosis
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 the most common pathogenic variant,
For an introduction to multigene panels click
When the diagnosis of ATTRv amyloidosis has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Transthyretin Amyloidosis
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 most common pathogenic variant,
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 ATTRv amyloidosis occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
• Cardiac conduction blocks
• Cardiomyopathy
• Nephropathy
• Vitreous opacities
• Glaucoma
• Echocardiogram may show left ventricular or biventricular thickening with speckled myocardium.
• Gadolinium contrast-guided cardiac MRI can show characteristic gadolinium distribution. Note: Gadolinium administration in those with ATTRv amyloidosis-related nephropathy can lead to nephrogenic systemic fibrosis.
• Bone scintigraphy using
• Amyloid PET imaging using Pittsburgh compound B is useful for detecting amyloid in individuals with early-onset ATTRv amyloidosis due to the
• Note: Sensitivity of endoscopic biopsy of gastrointestinal mucosa is approximately 85%; biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy [
## Suggestive Findings
Hereditary transthyretin amyloidosis (ATTRv amyloidosis)
Cardiac conduction blocks
Cardiomyopathy
Nephropathy
Vitreous opacities
Glaucoma
Echocardiogram may show left ventricular or biventricular thickening with speckled myocardium.
Gadolinium contrast-guided cardiac MRI can show characteristic gadolinium distribution. Note: Gadolinium administration in those with ATTRv amyloidosis-related nephropathy can lead to nephrogenic systemic fibrosis.
Bone scintigraphy using
Amyloid PET imaging using Pittsburgh compound B is useful for detecting amyloid in individuals with early-onset ATTRv amyloidosis due to the
Note: Sensitivity of endoscopic biopsy of gastrointestinal mucosa is approximately 85%; biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy [
• Cardiac conduction blocks
• Cardiomyopathy
• Nephropathy
• Vitreous opacities
• Glaucoma
• Echocardiogram may show left ventricular or biventricular thickening with speckled myocardium.
• Gadolinium contrast-guided cardiac MRI can show characteristic gadolinium distribution. Note: Gadolinium administration in those with ATTRv amyloidosis-related nephropathy can lead to nephrogenic systemic fibrosis.
• Bone scintigraphy using
• Amyloid PET imaging using Pittsburgh compound B is useful for detecting amyloid in individuals with early-onset ATTRv amyloidosis due to the
• Note: Sensitivity of endoscopic biopsy of gastrointestinal mucosa is approximately 85%; biopsy of the sural nerve is less sensitive because amyloid deposition is often patchy [
## Establishing the Diagnosis
The diagnosis of ATTRv amyloidosis
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 the most common pathogenic variant,
For an introduction to multigene panels click
When the diagnosis of ATTRv amyloidosis has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Transthyretin Amyloidosis
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 most common pathogenic variant,
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 ATTRv amyloidosis occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
## Option 1
Note: Targeted analysis for the most common pathogenic variant,
For an introduction to multigene panels click
## Option 2
When the diagnosis of ATTRv amyloidosis has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hereditary Transthyretin Amyloidosis
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 most common pathogenic variant,
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 ATTRv amyloidosis occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
## Clinical Characteristics
Clinical features of hereditary transthyretin amyloidosis (ATTRv amyloidosis) can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes. Cardiac amyloidosis (e.g., restrictive cardiomyopathy, arrhythmia), leptomeningeal amyloidosis (e.g., transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages), ophthalmopathy (e.g., vitreous opacities, glaucoma), and nephropathy are frequently seen in the advanced stage of the disease (see
Hereditary Transthyretin Amyloidosis: Frequency of Select Features
Motor neuropathy (muscle atrophy and weakness) of the extremities develops with foot drop, wrist drop, and disability of the hands and fingers. Eventually sensorimotor neuropathy shows a glove-and-stocking distribution.
Autonomic neuropathy may be the presenting manifestation of ATTRv amyloidosis, including orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, impotence, anhidrosis, and urinary retention or incontinence. Frequently, the autonomic neuropathy produces the most significant morbidity of the disorder. Amyloid deposition in the gastrointestinal tract wall, especially with involvement of the gastrointestinal autonomic nerves, is common [
The typical electrocardiogram shows a pseudoinfarction pattern with prominent Q wave in leads II, III,
Amyloid deposition is seen in the pial and arachnoid membrane, as well as in the walls of blood vessels in the subarachnoid space. Amyloid in the blood vessels disappears as the vessels penetrate the brain parenchyma. More rarely, a few individuals have developed myelopathy, caused by amyloid deposition in the blood vessel walls in the spinal cord [
In leptomeningeal amyloidosis, protein concentration in the cerebrospinal fluid is usually high, and gadolinium-enhanced MRI typically shows extensive enhancement of the surface of the brain, ventricles, and spinal cord [
Nodular cutaneous amyloidosis has been reported in one individual [
Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals [
Despite intensive investigation, few genotype-phenotype correlations have been detected. Most
A cardiac-dominant phenotype is associated with
A leptomeningeal-dominant phenotype is associated with
A leptomeningeal- and ocular-dominant phenotype are the first and primary manifestations in individuals with
The benign
Penetrance for ATTRv amyloidosis is not 100%; an individual with a
The penetrance appears to be much higher in individuals in endemic foci than outside of endemic foci [
Some p.Val50Met homozygotes remain asymptomatic.
Historical protein numbering was based on the mature protein after cleavage of a 20-amino-acid signal sequence (e.g.,
ATTRv amyloidosis-related neuropathy was formerly referred to as one of the following:
Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)
The abbreviation "ATTRv" refers to hereditary transthyretin-related amyloid protein [
The frequency of
• Nodular cutaneous amyloidosis has been reported in one individual [
• Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals [
• A cardiac-dominant phenotype is associated with
• A leptomeningeal-dominant phenotype is associated with
• A leptomeningeal- and ocular-dominant phenotype are the first and primary manifestations in individuals with
• Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
• Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)
## Clinical Description
Clinical features of hereditary transthyretin amyloidosis (ATTRv amyloidosis) can include peripheral sensorimotor neuropathy and autonomic neuropathy, as well as non-neuropathic changes. Cardiac amyloidosis (e.g., restrictive cardiomyopathy, arrhythmia), leptomeningeal amyloidosis (e.g., transient focal neurologic episodes, intracerebral and/or subarachnoid hemorrhages), ophthalmopathy (e.g., vitreous opacities, glaucoma), and nephropathy are frequently seen in the advanced stage of the disease (see
Hereditary Transthyretin Amyloidosis: Frequency of Select Features
Motor neuropathy (muscle atrophy and weakness) of the extremities develops with foot drop, wrist drop, and disability of the hands and fingers. Eventually sensorimotor neuropathy shows a glove-and-stocking distribution.
Autonomic neuropathy may be the presenting manifestation of ATTRv amyloidosis, including orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, impotence, anhidrosis, and urinary retention or incontinence. Frequently, the autonomic neuropathy produces the most significant morbidity of the disorder. Amyloid deposition in the gastrointestinal tract wall, especially with involvement of the gastrointestinal autonomic nerves, is common [
The typical electrocardiogram shows a pseudoinfarction pattern with prominent Q wave in leads II, III,
Amyloid deposition is seen in the pial and arachnoid membrane, as well as in the walls of blood vessels in the subarachnoid space. Amyloid in the blood vessels disappears as the vessels penetrate the brain parenchyma. More rarely, a few individuals have developed myelopathy, caused by amyloid deposition in the blood vessel walls in the spinal cord [
In leptomeningeal amyloidosis, protein concentration in the cerebrospinal fluid is usually high, and gadolinium-enhanced MRI typically shows extensive enhancement of the surface of the brain, ventricles, and spinal cord [
Nodular cutaneous amyloidosis has been reported in one individual [
Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals [
• Nodular cutaneous amyloidosis has been reported in one individual [
• Shortness of breath induced by diffuse pulmonary amyloid deposition has been reported in two individuals [
## Genotype-Phenotype Correlations
Despite intensive investigation, few genotype-phenotype correlations have been detected. Most
A cardiac-dominant phenotype is associated with
A leptomeningeal-dominant phenotype is associated with
A leptomeningeal- and ocular-dominant phenotype are the first and primary manifestations in individuals with
The benign
• A cardiac-dominant phenotype is associated with
• A leptomeningeal-dominant phenotype is associated with
• A leptomeningeal- and ocular-dominant phenotype are the first and primary manifestations in individuals with
## Penetrance
Penetrance for ATTRv amyloidosis is not 100%; an individual with a
The penetrance appears to be much higher in individuals in endemic foci than outside of endemic foci [
Some p.Val50Met homozygotes remain asymptomatic.
## Nomenclature
Historical protein numbering was based on the mature protein after cleavage of a 20-amino-acid signal sequence (e.g.,
ATTRv amyloidosis-related neuropathy was formerly referred to as one of the following:
Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)
The abbreviation "ATTRv" refers to hereditary transthyretin-related amyloid protein [
• Familial amyloid polyneuropathy type I (or the Portuguese-Swedish-Japanese type)
• Familial amyloid polyneuropathy type II (or the Indiana/Swiss or Maryland/German type)
## Prevalence
The frequency of
## Genetically Related (Allelic) Disorders
Wild type ATTR is associated with cardiac amyloidosis but typically does not cause features such as kidney and autonomic dysfunction that are common in hereditary transthyretin amyloidosis (ATTRv amyloidosis). The majority of individuals with wild type ATTR present with carpal tunnel syndrome [
## Differential Diagnosis
Note: A total of 35 amyloidogenic proteins including transthyretin (TTR) have been identified in human amyloidoses [
Genes of Interest in the Differential Diagnosis of Hereditary Transthyretin Amyloidosis
Nephropathy
Peripheral neuropathy
Cardiomyopathy
Hepatomegaly
Swelling of testes
Peripheral neuropathy
Kidney failure
Cranial neuropathy
Corneal lattice dystrophy
Cutis laxa
No cardiomyopathy
Disease progression is slower than in ATTRv amyloidosis.
Usually juvenile onset, esp in males
Angiokeratoma
Low alpha-galactosidase A activity
Cardiomyopathy
Neuropathy &/or nephropathy variably present
Myopathy
Diabetes
Deafness
High serum lactate & pyruvate levels
AD = autosomal dominant; AR = autosomal recessive; ATTRv amyloidosis = hereditary transthyretin amyloidosis; MT = mitochondrial; MOI = mode of inheritance; XL = X-linked
Nonsyndromic hereditary hypertrophic cardiomyopathy is typically inherited in an autosomal dominant manner; pathogenic variants in genes associated with autosomal recessive inheritance have been rarely reported.
Acquired Conditions to Consider in the Differential Diagnosis of Hereditary Transthyretin Amyloidosis
Cardiomyopathy
Carpal tunnel syndrome
Neuropathic symptoms incl polyneuropathy, carpal tunnel syndrome, & autonomic neuropathy in ~1/3 of affected persons.
Cardiomyopathy
Kidney failure
May be difficult to distinguish clinically
Immunohistochemical study or mass spectrometry of biopsied tissue required for diagnosis.
Positive serum &/or urine monoclonal protein
Negative myocardial
Cardiomyopathy
Peripheral neuropathy &/or nephropathy variably present
Uveitis
Hilar lymphadenopathy
High serum angiotensin-converting enzyme level
Peripheral neuropathy
Impotence
Positive serum &/or urine monoclonal protein
High serum vascular endothelial growth factor level
Individuals who received a liver graft from a donor with ATTRv amyloidosis have developed clinical manifestations of ATTR [
Eighteen of 90 individuals with ATTRv amyloidosis without a family history were mistakenly diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [
• Nephropathy
• Peripheral neuropathy
• Cardiomyopathy
• Hepatomegaly
• Swelling of testes
• Peripheral neuropathy
• Kidney failure
• Cranial neuropathy
• Corneal lattice dystrophy
• Cutis laxa
• No cardiomyopathy
• Disease progression is slower than in ATTRv amyloidosis.
• Usually juvenile onset, esp in males
• Angiokeratoma
• Low alpha-galactosidase A activity
• Cardiomyopathy
• Neuropathy &/or nephropathy variably present
• Myopathy
• Diabetes
• Deafness
• High serum lactate & pyruvate levels
• Cardiomyopathy
• Carpal tunnel syndrome
• Neuropathic symptoms incl polyneuropathy, carpal tunnel syndrome, & autonomic neuropathy in ~1/3 of affected persons.
• Cardiomyopathy
• Kidney failure
• May be difficult to distinguish clinically
• Immunohistochemical study or mass spectrometry of biopsied tissue required for diagnosis.
• Positive serum &/or urine monoclonal protein
• Negative myocardial
• Cardiomyopathy
• Peripheral neuropathy &/or nephropathy variably present
• Uveitis
• Hilar lymphadenopathy
• High serum angiotensin-converting enzyme level
• Peripheral neuropathy
• Impotence
• Positive serum &/or urine monoclonal protein
• High serum vascular endothelial growth factor level
## Management
To establish the extent of disease and needs in an individual diagnosed with hereditary transthyretin amyloidosis (ATTRv amyloidosis), the evaluations summarized in
Hereditary Transthyretin Amyloidosis: Recommended Evaluations Following Initial Diagnosis
Gadolinium-enhanced MRI of brain & spinal cord
Amyloid PET imaging using PiB
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Hereditary Transthyretin Amyloidosis: Targeted Therapy
Halts peripheral neurologic impairment
Approved in US
Delays peripheral neurologic impairment
Approved in US & EU
Halts peripheral neurologic impairment & treats cardiac manifestations
Approved in US, EU, Switzerland, Canada, Brazil, & Japan
Halts peripheral neurologic impairment
Approved in US, EU, Brazil, & Japan
Halts progression of peripheral &/or autonomic neuropathy
Not effective for cardiac amyloidosis, leptomeningeal amyloidosis, or ophthalmopathy
Delays peripheral neurologic impairment
Delays peripheral neurologic & cardiac impairment & reduces cardiac related mortality
Approved in >40 countries
ASO = antisense oligonucleotide; EU = European Union; siRNA = small interfering RNA; TTR = transthyretin; US = United States
Individuals with ATTRv amyloidosis and:
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
Hereditary Transthyretin Amyloidosis: Treatment of Manifestations
Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, gabapentin, pregabalin)
Weak opioid analgesics (tramadol, tapentadol)
Topical medications (lidocaine, capsaicin patch)
AFO for foot drop
Physical therapy
Compression stockings
Removal of hypotensive medications
Increasing water intake
Small-volume meals w/low soluble fiber & low fat content
Prokinetic medications
Osmotic laxatives
Polyethylene glycol
Linaclotide, lubiprostone, prucalopride
Erythropoietin or IV iron in those w/normocytic normochromic anemia
Hemodialysis for those w/end-stage kidney disease
AFO = ankle-foot orthoses; AV = atrioventricular; IM = intramuscular; IV = intravenous; TTR = transthyretin
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hereditary Transthyretin Amyloidosis: Recommended Surveillance
Clinical assessment for signs & symptoms of cardiac disease
Serum B-type natriuretic peptide levels
EKG
Echocardiogram
6-MWT = six-minute walk test; 10-MWT = ten-minute walk test; COMPASS = composite autonomic symptom score; NIS = neuropathy impairment score; PND = polyneuropathy disability; R-ODS = Rasch-built overall disability scale
Since most individuals with ATTRv amyloidosis have decreased temperature and pain perception, affected individuals should not use local heating appliances, such as hot-water bottles, which can cause low-temperature burn injuries.
See
Strategies for potential molecular therapies for ATTRv amyloidosis include the following:
A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
Search
• Gadolinium-enhanced MRI of brain & spinal cord
• Amyloid PET imaging using PiB
• Halts peripheral neurologic impairment
• Approved in US
• Delays peripheral neurologic impairment
• Approved in US & EU
• Halts peripheral neurologic impairment & treats cardiac manifestations
• Approved in US, EU, Switzerland, Canada, Brazil, & Japan
• Halts peripheral neurologic impairment
• Approved in US, EU, Brazil, & Japan
• Halts progression of peripheral &/or autonomic neuropathy
• Not effective for cardiac amyloidosis, leptomeningeal amyloidosis, or ophthalmopathy
• Delays peripheral neurologic impairment
• Delays peripheral neurologic & cardiac impairment & reduces cardiac related mortality
• Approved in >40 countries
• Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, gabapentin, pregabalin)
• Weak opioid analgesics (tramadol, tapentadol)
• Topical medications (lidocaine, capsaicin patch)
• AFO for foot drop
• Physical therapy
• Compression stockings
• Removal of hypotensive medications
• Increasing water intake
• Small-volume meals w/low soluble fiber & low fat content
• Prokinetic medications
• Osmotic laxatives
• Polyethylene glycol
• Linaclotide, lubiprostone, prucalopride
• Erythropoietin or IV iron in those w/normocytic normochromic anemia
• Hemodialysis for those w/end-stage kidney disease
• Clinical assessment for signs & symptoms of cardiac disease
• Serum B-type natriuretic peptide levels
• EKG
• Echocardiogram
•
• A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
• A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
• A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
• A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
• A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
• A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with hereditary transthyretin amyloidosis (ATTRv amyloidosis), the evaluations summarized in
Hereditary Transthyretin Amyloidosis: Recommended Evaluations Following Initial Diagnosis
Gadolinium-enhanced MRI of brain & spinal cord
Amyloid PET imaging using PiB
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Gadolinium-enhanced MRI of brain & spinal cord
• Amyloid PET imaging using PiB
## Treatment of Manifestations
Hereditary Transthyretin Amyloidosis: Targeted Therapy
Halts peripheral neurologic impairment
Approved in US
Delays peripheral neurologic impairment
Approved in US & EU
Halts peripheral neurologic impairment & treats cardiac manifestations
Approved in US, EU, Switzerland, Canada, Brazil, & Japan
Halts peripheral neurologic impairment
Approved in US, EU, Brazil, & Japan
Halts progression of peripheral &/or autonomic neuropathy
Not effective for cardiac amyloidosis, leptomeningeal amyloidosis, or ophthalmopathy
Delays peripheral neurologic impairment
Delays peripheral neurologic & cardiac impairment & reduces cardiac related mortality
Approved in >40 countries
ASO = antisense oligonucleotide; EU = European Union; siRNA = small interfering RNA; TTR = transthyretin; US = United States
Individuals with ATTRv amyloidosis and:
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
Hereditary Transthyretin Amyloidosis: Treatment of Manifestations
Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, gabapentin, pregabalin)
Weak opioid analgesics (tramadol, tapentadol)
Topical medications (lidocaine, capsaicin patch)
AFO for foot drop
Physical therapy
Compression stockings
Removal of hypotensive medications
Increasing water intake
Small-volume meals w/low soluble fiber & low fat content
Prokinetic medications
Osmotic laxatives
Polyethylene glycol
Linaclotide, lubiprostone, prucalopride
Erythropoietin or IV iron in those w/normocytic normochromic anemia
Hemodialysis for those w/end-stage kidney disease
AFO = ankle-foot orthoses; AV = atrioventricular; IM = intramuscular; IV = intravenous; TTR = transthyretin
• Halts peripheral neurologic impairment
• Approved in US
• Delays peripheral neurologic impairment
• Approved in US & EU
• Halts peripheral neurologic impairment & treats cardiac manifestations
• Approved in US, EU, Switzerland, Canada, Brazil, & Japan
• Halts peripheral neurologic impairment
• Approved in US, EU, Brazil, & Japan
• Halts progression of peripheral &/or autonomic neuropathy
• Not effective for cardiac amyloidosis, leptomeningeal amyloidosis, or ophthalmopathy
• Delays peripheral neurologic impairment
• Delays peripheral neurologic & cardiac impairment & reduces cardiac related mortality
• Approved in >40 countries
• Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, gabapentin, pregabalin)
• Weak opioid analgesics (tramadol, tapentadol)
• Topical medications (lidocaine, capsaicin patch)
• AFO for foot drop
• Physical therapy
• Compression stockings
• Removal of hypotensive medications
• Increasing water intake
• Small-volume meals w/low soluble fiber & low fat content
• Prokinetic medications
• Osmotic laxatives
• Polyethylene glycol
• Linaclotide, lubiprostone, prucalopride
• Erythropoietin or IV iron in those w/normocytic normochromic anemia
• Hemodialysis for those w/end-stage kidney disease
## Targeted Therapies
Hereditary Transthyretin Amyloidosis: Targeted Therapy
Halts peripheral neurologic impairment
Approved in US
Delays peripheral neurologic impairment
Approved in US & EU
Halts peripheral neurologic impairment & treats cardiac manifestations
Approved in US, EU, Switzerland, Canada, Brazil, & Japan
Halts peripheral neurologic impairment
Approved in US, EU, Brazil, & Japan
Halts progression of peripheral &/or autonomic neuropathy
Not effective for cardiac amyloidosis, leptomeningeal amyloidosis, or ophthalmopathy
Delays peripheral neurologic impairment
Delays peripheral neurologic & cardiac impairment & reduces cardiac related mortality
Approved in >40 countries
ASO = antisense oligonucleotide; EU = European Union; siRNA = small interfering RNA; TTR = transthyretin; US = United States
Individuals with ATTRv amyloidosis and:
• Halts peripheral neurologic impairment
• Approved in US
• Delays peripheral neurologic impairment
• Approved in US & EU
• Halts peripheral neurologic impairment & treats cardiac manifestations
• Approved in US, EU, Switzerland, Canada, Brazil, & Japan
• Halts peripheral neurologic impairment
• Approved in US, EU, Brazil, & Japan
• Halts progression of peripheral &/or autonomic neuropathy
• Not effective for cardiac amyloidosis, leptomeningeal amyloidosis, or ophthalmopathy
• Delays peripheral neurologic impairment
• Delays peripheral neurologic & cardiac impairment & reduces cardiac related mortality
• Approved in >40 countries
## 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
Hereditary Transthyretin Amyloidosis: Treatment of Manifestations
Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, gabapentin, pregabalin)
Weak opioid analgesics (tramadol, tapentadol)
Topical medications (lidocaine, capsaicin patch)
AFO for foot drop
Physical therapy
Compression stockings
Removal of hypotensive medications
Increasing water intake
Small-volume meals w/low soluble fiber & low fat content
Prokinetic medications
Osmotic laxatives
Polyethylene glycol
Linaclotide, lubiprostone, prucalopride
Erythropoietin or IV iron in those w/normocytic normochromic anemia
Hemodialysis for those w/end-stage kidney disease
AFO = ankle-foot orthoses; AV = atrioventricular; IM = intramuscular; IV = intravenous; TTR = transthyretin
• Serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine, gabapentin, pregabalin)
• Weak opioid analgesics (tramadol, tapentadol)
• Topical medications (lidocaine, capsaicin patch)
• AFO for foot drop
• Physical therapy
• Compression stockings
• Removal of hypotensive medications
• Increasing water intake
• Small-volume meals w/low soluble fiber & low fat content
• Prokinetic medications
• Osmotic laxatives
• Polyethylene glycol
• Linaclotide, lubiprostone, prucalopride
• Erythropoietin or IV iron in those w/normocytic normochromic anemia
• Hemodialysis for those w/end-stage kidney disease
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hereditary Transthyretin Amyloidosis: Recommended Surveillance
Clinical assessment for signs & symptoms of cardiac disease
Serum B-type natriuretic peptide levels
EKG
Echocardiogram
6-MWT = six-minute walk test; 10-MWT = ten-minute walk test; COMPASS = composite autonomic symptom score; NIS = neuropathy impairment score; PND = polyneuropathy disability; R-ODS = Rasch-built overall disability scale
• Clinical assessment for signs & symptoms of cardiac disease
• Serum B-type natriuretic peptide levels
• EKG
• Echocardiogram
## Agents/Circumstances to Avoid
Since most individuals with ATTRv amyloidosis have decreased temperature and pain perception, affected individuals should not use local heating appliances, such as hot-water bottles, which can cause low-temperature burn injuries.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Strategies for potential molecular therapies for ATTRv amyloidosis include the following:
A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
Search
•
• A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
• A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
• A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
• A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
• A Phase I clinical trial of NI006, an investigational antibody designed to target and clear the amyloid conformations of both wild type and variant TTR but not physiologically folded TTR, is completed [
• A Phase II clinical trial of PRX004/NN6019, an investigational antibody designed to target and clear the pathogenic, misfolded forms of the TTR protein found in ATTR without affecting the native, or normal, tetrameric form of the protein, is under way (see
## Genetic Counseling
Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is inherited in an autosomal dominant manner.
Some individuals diagnosed with ATTRv amyloidosis have an affected parent.
Note: If an individual diagnosed with ATTRv amyloidosis has biallelic
A proband with ATTRv amyloidosis 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), 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 family history of some individuals diagnosed with ATTRv amyloidosis 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 the pathogenic variant(s) identified in the proband.
If one parent of the proband is known to be heterozygous for a
If both parents of the proband are known to be heterozygous for a
Significant clinical variability may be observed among affected family members, with age of onset differing by ten to 20 years or more.
If the
If the parents have not been tested for the
Each child of an individual who is heterozygous for a
All offspring of an individual who has biallelic
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 Japan, where liver transplantation from living, related donors is the generally accepted therapy for ATTRv amyloidosis, molecular genetic testing is always performed on asymptomatic adult family members volunteering to be liver donors.
In a family with an established diagnosis of ATTRv amyloidosis, 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 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 ATTRv amyloidosis have an affected parent.
• Note: If an individual diagnosed with ATTRv amyloidosis has biallelic
• A proband with ATTRv amyloidosis 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), 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 family history of some individuals diagnosed with ATTRv amyloidosis 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 the pathogenic variant(s) 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 (gonadal) cells only.
• If one parent of the proband is known to be heterozygous for a
• If both parents of the proband are known to be heterozygous for a
• Significant clinical variability may be observed among affected family members, with age of onset differing by ten to 20 years or more.
• If the
• If the parents have not been tested for the
• Each child of an individual who is heterozygous for a
• All offspring of an individual who has biallelic
• 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 Japan, where liver transplantation from living, related donors is the generally accepted therapy for ATTRv amyloidosis, molecular genetic testing is always performed on asymptomatic adult family members volunteering to be liver donors.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with ATTRv amyloidosis have an affected parent.
Note: If an individual diagnosed with ATTRv amyloidosis has biallelic
A proband with ATTRv amyloidosis 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), 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 family history of some individuals diagnosed with ATTRv amyloidosis 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 the pathogenic variant(s) identified in the proband.
If one parent of the proband is known to be heterozygous for a
If both parents of the proband are known to be heterozygous for a
Significant clinical variability may be observed among affected family members, with age of onset differing by ten to 20 years or more.
If the
If the parents have not been tested for the
Each child of an individual who is heterozygous for a
All offspring of an individual who has biallelic
• Some individuals diagnosed with ATTRv amyloidosis have an affected parent.
• Note: If an individual diagnosed with ATTRv amyloidosis has biallelic
• A proband with ATTRv amyloidosis 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), 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 family history of some individuals diagnosed with ATTRv amyloidosis 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 the pathogenic variant(s) 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 (gonadal) cells only.
• If one parent of the proband is known to be heterozygous for a
• If both parents of the proband are known to be heterozygous for a
• Significant clinical variability may be observed among affected family members, with age of onset differing by ten to 20 years or more.
• If the
• If the parents have not been tested for the
• Each child of an individual who is heterozygous for a
• All offspring of an individual who has biallelic
## 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 Japan, where liver transplantation from living, related donors is the generally accepted therapy for ATTRv amyloidosis, molecular genetic testing is always performed on asymptomatic adult family members volunteering to be liver donors.
In a family with an established diagnosis of ATTRv amyloidosis, 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.
• In Japan, where liver transplantation from living, related donors is the generally accepted therapy for ATTRv amyloidosis, molecular genetic testing is always performed on asymptomatic adult family members volunteering to be liver donors.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Hereditary Transthyretin Amyloidosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hereditary Transthyretin Amyloidosis (
Soluble TTR tetramers dissociate into pro-amyloidogenic monomers that in turn polymerize into amyloid fibrils in certain tissues [
Pathogenic variants in
In vitro amyloidogenicity correlates with protein stability. All abnormal TTR proteins are energetically (thermodynamically and kinetically) less stable than wild type TTR. However, extremely destabilized (highly amyloidogenic in vitro) TTR protein does not result in severe systemic amyloidosis because serum concentrations of TTR are very low due to protein degradation before secretion. The most clinically severe
AN = autonomic neuropathy; CTS = carpal tunnel syndrome; FEH = familial euthyroid hypertyroxinemia; LM = leptomeningeal amyloidosis; PN = peripheral neuropathy
Variants listed in the table have been provided by the authors.
Historical protein numbering was based on the mature protein after cleavage of a 20-amino-acid signal sequence (e.g., p.Leu32Pro was historically referred to as Leu12Pro). Standard nomenclature uses numbering beginning at the Met initiation codon. Variants reported in older literature may use historical nomenclature.
See
• Soluble TTR tetramers dissociate into pro-amyloidogenic monomers that in turn polymerize into amyloid fibrils in certain tissues [
• Pathogenic variants in
## Molecular Pathogenesis
Soluble TTR tetramers dissociate into pro-amyloidogenic monomers that in turn polymerize into amyloid fibrils in certain tissues [
Pathogenic variants in
In vitro amyloidogenicity correlates with protein stability. All abnormal TTR proteins are energetically (thermodynamically and kinetically) less stable than wild type TTR. However, extremely destabilized (highly amyloidogenic in vitro) TTR protein does not result in severe systemic amyloidosis because serum concentrations of TTR are very low due to protein degradation before secretion. The most clinically severe
AN = autonomic neuropathy; CTS = carpal tunnel syndrome; FEH = familial euthyroid hypertyroxinemia; LM = leptomeningeal amyloidosis; PN = peripheral neuropathy
Variants listed in the table have been provided by the authors.
Historical protein numbering was based on the mature protein after cleavage of a 20-amino-acid signal sequence (e.g., p.Leu32Pro was historically referred to as Leu12Pro). Standard nomenclature uses numbering beginning at the Met initiation codon. Variants reported in older literature may use historical nomenclature.
See
• Soluble TTR tetramers dissociate into pro-amyloidogenic monomers that in turn polymerize into amyloid fibrils in certain tissues [
• Pathogenic variants in
## Chapter Notes
Shu-ichi Ikeda, MD, PhD; Shinsu University Hospital (2001-2018)Katsuya Nakamura; MD, PhD (2024-present)Yoshiki Sekijima, MD, PhD (2006-present)Takahiko Tokuda, MD, PhD; Kyoto Prefectural University Hospital (2001-2018)Kunihiro Yoshida, MD, PhD; Shinsu University Hospital (2001-2018)
30 May 2024 (sw) Comprehensive update posted live
20 December 2018 (sw) Comprehensive update posted live
26 January 2012 (me) Comprehensive update posted live
15 September 2009 (me) Comprehensive update posted live
15 March 2006 (me) Comprehensive update posted live
9 January 2004 (me) Comprehensive update posted live
5 November 2001 (me) Review posted live
25 June 2001 (ky) Original submission
• 30 May 2024 (sw) Comprehensive update posted live
• 20 December 2018 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 15 September 2009 (me) Comprehensive update posted live
• 15 March 2006 (me) Comprehensive update posted live
• 9 January 2004 (me) Comprehensive update posted live
• 5 November 2001 (me) Review posted live
• 25 June 2001 (ky) Original submission
## Author History
Shu-ichi Ikeda, MD, PhD; Shinsu University Hospital (2001-2018)Katsuya Nakamura; MD, PhD (2024-present)Yoshiki Sekijima, MD, PhD (2006-present)Takahiko Tokuda, MD, PhD; Kyoto Prefectural University Hospital (2001-2018)Kunihiro Yoshida, MD, PhD; Shinsu University Hospital (2001-2018)
## Revision History
30 May 2024 (sw) Comprehensive update posted live
20 December 2018 (sw) Comprehensive update posted live
26 January 2012 (me) Comprehensive update posted live
15 September 2009 (me) Comprehensive update posted live
15 March 2006 (me) Comprehensive update posted live
9 January 2004 (me) Comprehensive update posted live
5 November 2001 (me) Review posted live
25 June 2001 (ky) Original submission
• 30 May 2024 (sw) Comprehensive update posted live
• 20 December 2018 (sw) Comprehensive update posted live
• 26 January 2012 (me) Comprehensive update posted live
• 15 September 2009 (me) Comprehensive update posted live
• 15 March 2006 (me) Comprehensive update posted live
• 9 January 2004 (me) Comprehensive update posted live
• 5 November 2001 (me) Review posted live
• 25 June 2001 (ky) Original submission
## Key Sections in This
## References
Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268:2109-22. [
Ando Y, Adams D, Benson MD, Berk JL, Planté-Bordeneuve V, Coelho T, Conceição I, Ericzon BG, Obici L, Rapezzi C, Sekijima Y, Ueda M, Palladini G, Merlini G. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;29:143-55. [
• Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268:2109-22. [
• Ando Y, Adams D, Benson MD, Berk JL, Planté-Bordeneuve V, Coelho T, Conceição I, Ericzon BG, Obici L, Rapezzi C, Sekijima Y, Ueda M, Palladini G, Merlini G. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;29:143-55. [
## Published Guidelines / Consensus Statements
Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268:2109-22. [
Ando Y, Adams D, Benson MD, Berk JL, Planté-Bordeneuve V, Coelho T, Conceição I, Ericzon BG, Obici L, Rapezzi C, Sekijima Y, Ueda M, Palladini G, Merlini G. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;29:143-55. [
• Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268:2109-22. [
• Ando Y, Adams D, Benson MD, Berk JL, Planté-Bordeneuve V, Coelho T, Conceição I, Ericzon BG, Obici L, Rapezzi C, Sekijima Y, Ueda M, Palladini G, Merlini G. Guidelines and new directions in the therapy and monitoring of ATTRv amyloidosis. Amyloid. 2022;29:143-55. [
## Literature Cited
|
[] |
5/11/2001
|
30/5/2024
|
17/6/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
tfr2
|
tfr2
|
[
"Transferrin receptor protein 2",
"TFR2",
"TFR2-Related Hemochromatosis"
] |
Marco De Gobbi, Antonella Roetto
|
Summary The diagnosis of
|
## Diagnosis
An algorithm for the diagnosis of
Weakness, chronic fatigue
Abdominal pain
Hepatomegaly
Cirrhosis, hepatocellular carcinoma
Endocrine manifestations, including diabetes mellitus, hypogonadotropic hypogonadism (decreased libido and impotence in men, amenorrhea in women)
Cardiomyopathy, EKG abnormalities (conduction disturbances)
Arthritis (especially if involving the metacarpophalangeal joint), arthralgia
Progressive increase in skin pigmentation
Children and adolescents: 15-150 µg/L
Adult females: 20-200 µg/L
Adult males: 20-300 µg/L
Elevated liver enzymes and/or abnormal liver function tests
Hyperglycemia
Histology; fibrosis or cirrhosis
Elevated liver iron concentration (normal values: 10-35 µmol/g dry liver weight or 0.56-1.96 mg/g dry liver weight):
Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
The diagnosis of
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 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
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.
• Weakness, chronic fatigue
• Abdominal pain
• Hepatomegaly
• Cirrhosis, hepatocellular carcinoma
• Endocrine manifestations, including diabetes mellitus, hypogonadotropic hypogonadism (decreased libido and impotence in men, amenorrhea in women)
• Cardiomyopathy, EKG abnormalities (conduction disturbances)
• Arthritis (especially if involving the metacarpophalangeal joint), arthralgia
• Progressive increase in skin pigmentation
• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Elevated liver enzymes and/or abnormal liver function tests
• Hyperglycemia
• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Histology; fibrosis or cirrhosis
• Elevated liver iron concentration (normal values: 10-35 µmol/g dry liver weight or 0.56-1.96 mg/g dry liver weight):
• Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
• Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
• Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
• Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
• Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
• Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
• Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
• Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
• Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
## Suggestive Findings
Weakness, chronic fatigue
Abdominal pain
Hepatomegaly
Cirrhosis, hepatocellular carcinoma
Endocrine manifestations, including diabetes mellitus, hypogonadotropic hypogonadism (decreased libido and impotence in men, amenorrhea in women)
Cardiomyopathy, EKG abnormalities (conduction disturbances)
Arthritis (especially if involving the metacarpophalangeal joint), arthralgia
Progressive increase in skin pigmentation
Children and adolescents: 15-150 µg/L
Adult females: 20-200 µg/L
Adult males: 20-300 µg/L
Elevated liver enzymes and/or abnormal liver function tests
Hyperglycemia
Histology; fibrosis or cirrhosis
Elevated liver iron concentration (normal values: 10-35 µmol/g dry liver weight or 0.56-1.96 mg/g dry liver weight):
Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
• Weakness, chronic fatigue
• Abdominal pain
• Hepatomegaly
• Cirrhosis, hepatocellular carcinoma
• Endocrine manifestations, including diabetes mellitus, hypogonadotropic hypogonadism (decreased libido and impotence in men, amenorrhea in women)
• Cardiomyopathy, EKG abnormalities (conduction disturbances)
• Arthritis (especially if involving the metacarpophalangeal joint), arthralgia
• Progressive increase in skin pigmentation
• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Elevated liver enzymes and/or abnormal liver function tests
• Hyperglycemia
• Children and adolescents: 15-150 µg/L
• Adult females: 20-200 µg/L
• Adult males: 20-300 µg/L
• Histology; fibrosis or cirrhosis
• Elevated liver iron concentration (normal values: 10-35 µmol/g dry liver weight or 0.56-1.96 mg/g dry liver weight):
• Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
• Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
• Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
• Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
• Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
• Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
• Mild. 70-99 µmol/g dry liver weight or 3.9-5.5 mg/g dry liver weight
• Moderate. 100-200 µmol/g dry liver weight or 5.6-11.2 mg/g dry liver weight
• Severe. >200 µmol/g dry liver weight or >11.2 mg/g dry liver weight
## Establishing the Diagnosis
The diagnosis of
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 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
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 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 limited number of individuals reported and the private nature of the pathogenic variants do not permit genotype-phenotype correlations.
Inheritance of compound heterozygosity for the
Individuals with
The penetrance of
In Japan, where hemochromatosis is rare and heterogeneous, it has been proposed that
## Clinical Description
## Genotype-Phenotype Correlations
The limited number of individuals reported and the private nature of the pathogenic variants do not permit genotype-phenotype correlations.
Inheritance of compound heterozygosity for the
Individuals with
## Penetrance
The penetrance of
## Nomenclature
## Prevalence
In Japan, where hemochromatosis is rare and heterogeneous, it has been proposed that
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes associated with primary overload disorders (i.e., disorders characterized by increased absorption of iron from a normal diet) are listed in
No studies have evaluated the prevalence of
Primary Iron Overload Disorders to Consider in the Differential Diagnosis of
Biochemical features of iron overload
Liver iron accumulation
Normal transferrin saturation in some
Mild-to-moderate late onset of iron overload
Hyperferritinemia
Diabetes mellitus
Anemia
Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
Brain iron accumulation manifesting as retinal degeneration & neurologic disease (movement disorders & ataxia)
Lower penetrance
Later onset
Full penetrance
Earlier onset
More severe clinical manifestations, esp cardiomyopathy & hypogonadotropic hypogonadism
At early stage: anemia & low transferrin saturation
Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
Reduced tolerance to phlebotomy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance;
Primary overload disorders of unknown genetic cause:
Secondary iron overload disorders include iron excess resulting from different conditions. The most severe disorders result from transfusions for chronic anemia such as
This group also includes a range of liver diseases associated with parenchymal liver disease (e.g., alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasia,
• Biochemical features of iron overload
• Liver iron accumulation
• Normal transferrin saturation in some
• Mild-to-moderate late onset of iron overload
• Hyperferritinemia
• Diabetes mellitus
• Anemia
• Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
• Brain iron accumulation manifesting as retinal degeneration & neurologic disease (movement disorders & ataxia)
• Lower penetrance
• Later onset
• Full penetrance
• Earlier onset
• More severe clinical manifestations, esp cardiomyopathy & hypogonadotropic hypogonadism
• At early stage: anemia & low transferrin saturation
• Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
• Reduced tolerance to phlebotomy
## Primary Iron Overload Disorders
Genes associated with primary overload disorders (i.e., disorders characterized by increased absorption of iron from a normal diet) are listed in
No studies have evaluated the prevalence of
Primary Iron Overload Disorders to Consider in the Differential Diagnosis of
Biochemical features of iron overload
Liver iron accumulation
Normal transferrin saturation in some
Mild-to-moderate late onset of iron overload
Hyperferritinemia
Diabetes mellitus
Anemia
Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
Brain iron accumulation manifesting as retinal degeneration & neurologic disease (movement disorders & ataxia)
Lower penetrance
Later onset
Full penetrance
Earlier onset
More severe clinical manifestations, esp cardiomyopathy & hypogonadotropic hypogonadism
At early stage: anemia & low transferrin saturation
Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
Reduced tolerance to phlebotomy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance;
Primary overload disorders of unknown genetic cause:
• Biochemical features of iron overload
• Liver iron accumulation
• Normal transferrin saturation in some
• Mild-to-moderate late onset of iron overload
• Hyperferritinemia
• Diabetes mellitus
• Anemia
• Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
• Brain iron accumulation manifesting as retinal degeneration & neurologic disease (movement disorders & ataxia)
• Lower penetrance
• Later onset
• Full penetrance
• Earlier onset
• More severe clinical manifestations, esp cardiomyopathy & hypogonadotropic hypogonadism
• At early stage: anemia & low transferrin saturation
• Iron deposition in hepatic reticuloendothelial (not parenchymal) cells
• Reduced tolerance to phlebotomy
## Secondary Iron Overload Disorders
Secondary iron overload disorders include iron excess resulting from different conditions. The most severe disorders result from transfusions for chronic anemia such as
This group also includes a range of liver diseases associated with parenchymal liver disease (e.g., alcoholic liver disease, acute viral hepatitis or chronic hepatitis C, neoplasia,
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
At time of identification of iron overload
If LH &/or FSH are low, a GnRH stimulation test may be necessary.
Fasting serum glucose
Oral glucose tolerance test
ALP = alkaline phosphatase; ALT = aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; GnRH = gonadotropin hormone-releasing hormone; LH = luteinizing hormone; MOI = mode of inheritance;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Individuals with increased serum ferritin concentration should be treated by the same protocol as for
The usual therapy is phlebotomy weekly or every two weeks; however, twice-weekly phlebotomy or erythrocytapheresis may be useful initially to accelerate iron depletion. Hematocrit or hemoglobin level should be assessed prior to each phlebotomy. In the initial stage of treatment, when serum ferritin is high, ferritin measurement should be performed approximately every ten phlebotomies.
Weekly phlebotomy is carried out until the serum ferritin concentration is 50 ng/mL or lower. If anemia is detected or hematocrit is reduced from the initial level by more than 20%, phlebotomy should be postponed.
As the target ferritin range of 50-100 ng/mL is approached, serum ferritin analysis may be repeated more frequently.
Note: Although experience is limited because of the small number of affected individuals identified worldwide, it should be noted that transferrin saturation can remain high in individuals with
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
Liver disease mgmt aims to prevent complications of cirrhosis & liver decompensation.
There are no reports of liver transplantation for end-stage liver disease in persons w/
Hormone replacement therapy
Gonadotropin treatment for infertility
Diuretics, ACE inhibitors, cardiac glycosides
Iron chelation by intravenous or subcutaneous desferrioxamine, or oral deferiprone & deferasirox
Lifelong treatment is required in those w/cardiac disease.
To date, oral deferiprone & deferasirox are not approved for treatment of
Nonsteroidal anti-inflammatory drugs
Physiotherapy
ACE = angiotensin-converting enzyme; HCC = hepatocellular cancer;
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for
Serum AFP
Liver ultrasound to assess for HCC
AFP = alpha-fetoprotein; FSH = follicle-stimulating hormone; HCC = hepatocellular carcinoma; Hgb = hemoglobin; LH = luteinizing hormone
Avoid the following:
Medicinal iron and nutritional supplements containing iron
Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption, even in small amounts.
Vitamin C supplements, which may enhance iron absorption
Uncooked seafood, which carry a risk of infection from microorganisms thriving under conditions of excess iron (e.g.,
Lifestyle-related behaviors that increase the risk of viral hepatitis infection
It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the familial
See
In pregnant women with mild-to-moderate iron overload, phlebotomy can be paused because fetal utilization of maternal iron effectively reduces the mother's iron load during pregnancy.
Search
• At time of identification of iron overload
• If LH &/or FSH are low, a GnRH stimulation test may be necessary.
• Fasting serum glucose
• Oral glucose tolerance test
• Liver disease mgmt aims to prevent complications of cirrhosis & liver decompensation.
• There are no reports of liver transplantation for end-stage liver disease in persons w/
• Hormone replacement therapy
• Gonadotropin treatment for infertility
• Diuretics, ACE inhibitors, cardiac glycosides
• Iron chelation by intravenous or subcutaneous desferrioxamine, or oral deferiprone & deferasirox
• Lifelong treatment is required in those w/cardiac disease.
• To date, oral deferiprone & deferasirox are not approved for treatment of
• Nonsteroidal anti-inflammatory drugs
• Physiotherapy
• Serum AFP
• Liver ultrasound to assess for HCC
• Medicinal iron and nutritional supplements containing iron
• Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption, even in small amounts.
• Vitamin C supplements, which may enhance iron absorption
• Uncooked seafood, which carry a risk of infection from microorganisms thriving under conditions of excess iron (e.g.,
• Lifestyle-related behaviors that increase the risk of viral hepatitis infection
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
At time of identification of iron overload
If LH &/or FSH are low, a GnRH stimulation test may be necessary.
Fasting serum glucose
Oral glucose tolerance test
ALP = alkaline phosphatase; ALT = aminotransferase; AST = aspartate aminotransferase; FSH = follicle-stimulating hormone; GnRH = gonadotropin hormone-releasing hormone; LH = luteinizing hormone; MOI = mode of inheritance;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• At time of identification of iron overload
• If LH &/or FSH are low, a GnRH stimulation test may be necessary.
• Fasting serum glucose
• Oral glucose tolerance test
## Treatment of Manifestations
Individuals with increased serum ferritin concentration should be treated by the same protocol as for
The usual therapy is phlebotomy weekly or every two weeks; however, twice-weekly phlebotomy or erythrocytapheresis may be useful initially to accelerate iron depletion. Hematocrit or hemoglobin level should be assessed prior to each phlebotomy. In the initial stage of treatment, when serum ferritin is high, ferritin measurement should be performed approximately every ten phlebotomies.
Weekly phlebotomy is carried out until the serum ferritin concentration is 50 ng/mL or lower. If anemia is detected or hematocrit is reduced from the initial level by more than 20%, phlebotomy should be postponed.
As the target ferritin range of 50-100 ng/mL is approached, serum ferritin analysis may be repeated more frequently.
Note: Although experience is limited because of the small number of affected individuals identified worldwide, it should be noted that transferrin saturation can remain high in individuals with
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
Liver disease mgmt aims to prevent complications of cirrhosis & liver decompensation.
There are no reports of liver transplantation for end-stage liver disease in persons w/
Hormone replacement therapy
Gonadotropin treatment for infertility
Diuretics, ACE inhibitors, cardiac glycosides
Iron chelation by intravenous or subcutaneous desferrioxamine, or oral deferiprone & deferasirox
Lifelong treatment is required in those w/cardiac disease.
To date, oral deferiprone & deferasirox are not approved for treatment of
Nonsteroidal anti-inflammatory drugs
Physiotherapy
ACE = angiotensin-converting enzyme; HCC = hepatocellular cancer;
• Liver disease mgmt aims to prevent complications of cirrhosis & liver decompensation.
• There are no reports of liver transplantation for end-stage liver disease in persons w/
• Hormone replacement therapy
• Gonadotropin treatment for infertility
• Diuretics, ACE inhibitors, cardiac glycosides
• Iron chelation by intravenous or subcutaneous desferrioxamine, or oral deferiprone & deferasirox
• Lifelong treatment is required in those w/cardiac disease.
• To date, oral deferiprone & deferasirox are not approved for treatment of
• Nonsteroidal anti-inflammatory drugs
• Physiotherapy
## Targeted Therapy
The usual therapy is phlebotomy weekly or every two weeks; however, twice-weekly phlebotomy or erythrocytapheresis may be useful initially to accelerate iron depletion. Hematocrit or hemoglobin level should be assessed prior to each phlebotomy. In the initial stage of treatment, when serum ferritin is high, ferritin measurement should be performed approximately every ten phlebotomies.
Weekly phlebotomy is carried out until the serum ferritin concentration is 50 ng/mL or lower. If anemia is detected or hematocrit is reduced from the initial level by more than 20%, phlebotomy should be postponed.
As the target ferritin range of 50-100 ng/mL is approached, serum ferritin analysis may be repeated more frequently.
Note: Although experience is limited because of the small number of affected individuals identified worldwide, it should be noted that transferrin saturation can remain high in individuals with
## 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
Liver disease mgmt aims to prevent complications of cirrhosis & liver decompensation.
There are no reports of liver transplantation for end-stage liver disease in persons w/
Hormone replacement therapy
Gonadotropin treatment for infertility
Diuretics, ACE inhibitors, cardiac glycosides
Iron chelation by intravenous or subcutaneous desferrioxamine, or oral deferiprone & deferasirox
Lifelong treatment is required in those w/cardiac disease.
To date, oral deferiprone & deferasirox are not approved for treatment of
Nonsteroidal anti-inflammatory drugs
Physiotherapy
ACE = angiotensin-converting enzyme; HCC = hepatocellular cancer;
• Liver disease mgmt aims to prevent complications of cirrhosis & liver decompensation.
• There are no reports of liver transplantation for end-stage liver disease in persons w/
• Hormone replacement therapy
• Gonadotropin treatment for infertility
• Diuretics, ACE inhibitors, cardiac glycosides
• Iron chelation by intravenous or subcutaneous desferrioxamine, or oral deferiprone & deferasirox
• Lifelong treatment is required in those w/cardiac disease.
• To date, oral deferiprone & deferasirox are not approved for treatment of
• Nonsteroidal anti-inflammatory drugs
• Physiotherapy
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, surveillance is based on guidelines proposed for
Serum AFP
Liver ultrasound to assess for HCC
AFP = alpha-fetoprotein; FSH = follicle-stimulating hormone; HCC = hepatocellular carcinoma; Hgb = hemoglobin; LH = luteinizing hormone
• Serum AFP
• Liver ultrasound to assess for HCC
## Agents/Circumstances to Avoid
Avoid the following:
Medicinal iron and nutritional supplements containing iron
Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption, even in small amounts.
Vitamin C supplements, which may enhance iron absorption
Uncooked seafood, which carry a risk of infection from microorganisms thriving under conditions of excess iron (e.g.,
Lifestyle-related behaviors that increase the risk of viral hepatitis infection
• Medicinal iron and nutritional supplements containing iron
• Excessive alcohol intake, which increases iron absorption and is toxic to hepatocytes. Individuals with cirrhosis should avoid alcohol consumption, even in small amounts.
• Vitamin C supplements, which may enhance iron absorption
• Uncooked seafood, which carry a risk of infection from microorganisms thriving under conditions of excess iron (e.g.,
• Lifestyle-related behaviors that increase the risk of viral hepatitis infection
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual by molecular genetic testing of the familial
See
## Pregnancy Management
In pregnant women with mild-to-moderate iron overload, phlebotomy can be paused because fetal utilization of maternal iron effectively reduces the mother's iron load during pregnancy.
## 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.
Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
If both parents are known to be heterozygous for a
Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Carrier detection using biochemical testing is not possible because iron parameters are normal in heterozygotes.
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.
It is appropriate to offer
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
• 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) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
• 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) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• It is appropriate to offer
## 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.
Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
If both parents are known to be heterozygous for a
Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
• 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.
• Heterozygotes (carriers) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
• 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) without other genetic or environmental risk factors (e.g., hemoglobinopathies, chronic hepatitis) are asymptomatic, do not have abnormal serum iron studies, and are not at risk of developing
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Carrier detection using biochemical testing is not possible because iron parameters are normal in heterozygotes.
## 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.
It is appropriate to offer
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• It is appropriate to offer
## 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
Italy
Canada
United Kingdom
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• Italy
•
•
• Canada
•
•
•
•
•
•
• United Kingdom
•
•
•
•
•
•
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## Molecular Genetics
TFR2-Related Hemochromatosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TFR2-Related Hemochromatosis (
Iron homeostasis is regulated by the hepcidin pathway. The hepatic peptide hepcidin (encoded by
TfR2 is expressed in the liver, especially in hepatocytes. TfR2 is also expressed in erythroid cells and interacts with the erythropoietin receptor [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Iron homeostasis is regulated by the hepcidin pathway. The hepatic peptide hepcidin (encoded by
TfR2 is expressed in the liver, especially in hepatocytes. TfR2 is also expressed in erythroid cells and interacts with the erythropoietin receptor [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Prof Marco De GobbiWeb page:
Dr Antonella RoettoWeb page:
Prof Marco De Gobbi (
Contact Dr Antonella Roetto (
Clara Camaschella, MD; Istituto Scientifico San Raffaele (2005-2018)Marco De Gobbi, MD (2018-present)Antonella Roetto, PhD (2005-present)
7 December 2023 (sw) Comprehensive update posted live
15 February 2018 (sw) Comprehensive update posted live
9 June 2011 (me) Comprehensive update posted live
15 May 2008 (me) Comprehensive update posted live
29 August 2005 (me) Review posted live
1 February 2005 (ar) Original submission
• 7 December 2023 (sw) Comprehensive update posted live
• 15 February 2018 (sw) Comprehensive update posted live
• 9 June 2011 (me) Comprehensive update posted live
• 15 May 2008 (me) Comprehensive update posted live
• 29 August 2005 (me) Review posted live
• 1 February 2005 (ar) Original submission
## Author Notes
Prof Marco De GobbiWeb page:
Dr Antonella RoettoWeb page:
Prof Marco De Gobbi (
Contact Dr Antonella Roetto (
## Author History
Clara Camaschella, MD; Istituto Scientifico San Raffaele (2005-2018)Marco De Gobbi, MD (2018-present)Antonella Roetto, PhD (2005-present)
## Revision History
7 December 2023 (sw) Comprehensive update posted live
15 February 2018 (sw) Comprehensive update posted live
9 June 2011 (me) Comprehensive update posted live
15 May 2008 (me) Comprehensive update posted live
29 August 2005 (me) Review posted live
1 February 2005 (ar) Original submission
• 7 December 2023 (sw) Comprehensive update posted live
• 15 February 2018 (sw) Comprehensive update posted live
• 9 June 2011 (me) Comprehensive update posted live
• 15 May 2008 (me) Comprehensive update posted live
• 29 August 2005 (me) Review posted live
• 1 February 2005 (ar) Original submission
## Key Sections in this
## References
## Literature Cited
Flowchart for diagnosis of
MDS = myelodysplastic syndrome; LIC = liver iron content
1. Obesity, insulin resistance, dyslipidemia, hypertension
2. See
3. Topic of this
|
[] |
29/8/2005
|
7/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
thctd
|
thctd
|
[
"MCT8 Deficiency",
"MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency",
"MCT8 Deficiency",
"MCT8-Specific Thyroid Hormone Cell-Membrane Transporter Deficiency",
"Monocarboxylate transporter 8",
"SLC16A2",
"Allan-Herndon-Dudley Syndrome"
] |
Allan-Herndon-Dudley Syndrome
|
Catherine Sarret, Isabelle Oliver Petit, Davide Tonduti
|
Summary Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities. The diagnosis of AHDS is established in a male proband with suggestive findings and a hemizygous AHDS is inherited in an X-linked manner. If the mother of a proband has an
|
## Diagnosis
Formal diagnostic criteria for Allan-Herndon-Dudley syndrome have not been established.
Allan-Herndon-Dudley syndrome (AHDS)
Onset before age two years often with hypotonia and feeding difficulties
Developmental delay / intellectual disability ranging from mild to profound intellectual disability
Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)
Pyramidal signs
Late-onset seizures, often with drug resistance
Poor weight gain
Reduced muscle mass
Variably present: cold intolerance, sweating, elevated heart rate, irritability
Males with AHDS have pathognomonic thyroid test results (
High serum 3,3',5-triiodothyronine (usually free T
Note: All males with
Serum tetraiodothyronines (total T
Free T
Serum TSH concentrations that are normal or slightly elevated (
Brain MRI in children under age five years usually shows severely delayed myelination mimicking hypomyelination, which subsequently improves over time (
Note: Early reports of normal brain MRI findings in this disorder were from older individuals. Cerebral atrophy is also a frequent sign associated with hypomyelination.
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. Because the phenotype of AHDS is broad, individuals with the distinctive clinical and laboratory 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 Allan-Herndon-Dudley 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.
Due to the presence of repetitive elements, deletions of exon 1 with varying breakpoints are frequently observed [
• Onset before age two years often with hypotonia and feeding difficulties
• Developmental delay / intellectual disability ranging from mild to profound intellectual disability
• Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)
• Pyramidal signs
• Late-onset seizures, often with drug resistance
• Poor weight gain
• Reduced muscle mass
• Variably present: cold intolerance, sweating, elevated heart rate, irritability
• High serum 3,3',5-triiodothyronine (usually free T
• Note: All males with
• Serum tetraiodothyronines (total T
• Free T
• Serum TSH concentrations that are normal or slightly elevated (
## Suggestive Findings
Allan-Herndon-Dudley syndrome (AHDS)
Onset before age two years often with hypotonia and feeding difficulties
Developmental delay / intellectual disability ranging from mild to profound intellectual disability
Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)
Pyramidal signs
Late-onset seizures, often with drug resistance
Poor weight gain
Reduced muscle mass
Variably present: cold intolerance, sweating, elevated heart rate, irritability
Males with AHDS have pathognomonic thyroid test results (
High serum 3,3',5-triiodothyronine (usually free T
Note: All males with
Serum tetraiodothyronines (total T
Free T
Serum TSH concentrations that are normal or slightly elevated (
Brain MRI in children under age five years usually shows severely delayed myelination mimicking hypomyelination, which subsequently improves over time (
Note: Early reports of normal brain MRI findings in this disorder were from older individuals. Cerebral atrophy is also a frequent sign associated with hypomyelination.
• Onset before age two years often with hypotonia and feeding difficulties
• Developmental delay / intellectual disability ranging from mild to profound intellectual disability
• Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)
• Pyramidal signs
• Late-onset seizures, often with drug resistance
• Poor weight gain
• Reduced muscle mass
• Variably present: cold intolerance, sweating, elevated heart rate, irritability
• High serum 3,3',5-triiodothyronine (usually free T
• Note: All males with
• Serum tetraiodothyronines (total T
• Free T
• Serum TSH concentrations that are normal or slightly elevated (
## Clinical Findings
Onset before age two years often with hypotonia and feeding difficulties
Developmental delay / intellectual disability ranging from mild to profound intellectual disability
Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)
Pyramidal signs
Late-onset seizures, often with drug resistance
Poor weight gain
Reduced muscle mass
Variably present: cold intolerance, sweating, elevated heart rate, irritability
• Onset before age two years often with hypotonia and feeding difficulties
• Developmental delay / intellectual disability ranging from mild to profound intellectual disability
• Extrapyramidal findings: dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, hypomimia (masked facies)
• Pyramidal signs
• Late-onset seizures, often with drug resistance
• Poor weight gain
• Reduced muscle mass
• Variably present: cold intolerance, sweating, elevated heart rate, irritability
## Laboratory Findings
Males with AHDS have pathognomonic thyroid test results (
High serum 3,3',5-triiodothyronine (usually free T
Note: All males with
Serum tetraiodothyronines (total T
Free T
Serum TSH concentrations that are normal or slightly elevated (
• High serum 3,3',5-triiodothyronine (usually free T
• Note: All males with
• Serum tetraiodothyronines (total T
• Free T
• Serum TSH concentrations that are normal or slightly elevated (
## Imaging
Brain MRI in children under age five years usually shows severely delayed myelination mimicking hypomyelination, which subsequently improves over time (
Note: Early reports of normal brain MRI findings in this disorder were from older individuals. Cerebral atrophy is also a frequent sign associated with hypomyelination.
## 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 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 AHDS is broad, individuals with the distinctive clinical and laboratory 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 Allan-Herndon-Dudley 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.
Due to the presence of repetitive elements, deletions of exon 1 with varying breakpoints are frequently observed [
## 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 Allan-Herndon-Dudley 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.
Due to the presence of repetitive elements, deletions of exon 1 with varying breakpoints are frequently observed [
## Clinical Characteristics
Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay [DD] / intellectual disability [ID]) and later-onset pyramidal signs, extrapyramidal findings, and seizures, often with drug resistance. Dysthyroidism can manifest as poor weight gain, reduced muscle mass and variable cold intolerance, sweating, elevated heart rate, irritability, and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.
To date, information on about 200 individuals with a pathogenic variant in
Select Features of Allan-Herndon-Dudley Syndrome in Affected Males
DD = developmental delay; ID = intellectual disability
Features and percentages of persons with feature were evaluated from the cohorts of
Expressed as % of all males with AHDS. All affected persons had ID ranging from mild to profound.
Less frequently, affected males have mild-to-moderate intellectual disability, and develop the ability to walk (with or without aid) and use of language allowing academic learning with aid.
Progressive hypertonicity of the limbs with brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) leads to spastic quadriplegia and joint contractures.
Overall muscle mass (particularly proximally) is reduced and associated with generalized muscle weakness.
It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias [
Some authors also reported abnormal movements as ataxia [
Seizures typically begin during infancy or early childhood. Drug resistance is common [
Rotary nystagmus and disconjugate eye movements have been reported but are not common [
Heterozygous females are generally asymptomatic and have no specific phenotypic findings. About 25% of heterozygous female have an abnormal thyroid profile with elevated T
Developmental delay and intellectual disability have been reported in heterozygous females in rare instances, perhaps due to skewed X-chromosome inactivation [
It has been repeatedly reported that the severity of the clinical phenotype is related to the residual transport capacity of the mutated MCT8 protein. Large deletions in
Several
This condition was named MCT8
Because of the overlap of clinical findings in individuals with an
Prevalence of Allan-Herndon-Dudley syndrome (AHDS) is unknown; however, the identification of more than 160 affected individuals in approximately 15 years suggests that the syndrome is more common than previously thought.
## Clinical Description
Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay [DD] / intellectual disability [ID]) and later-onset pyramidal signs, extrapyramidal findings, and seizures, often with drug resistance. Dysthyroidism can manifest as poor weight gain, reduced muscle mass and variable cold intolerance, sweating, elevated heart rate, irritability, and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.
To date, information on about 200 individuals with a pathogenic variant in
Select Features of Allan-Herndon-Dudley Syndrome in Affected Males
DD = developmental delay; ID = intellectual disability
Features and percentages of persons with feature were evaluated from the cohorts of
Expressed as % of all males with AHDS. All affected persons had ID ranging from mild to profound.
Less frequently, affected males have mild-to-moderate intellectual disability, and develop the ability to walk (with or without aid) and use of language allowing academic learning with aid.
Progressive hypertonicity of the limbs with brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) leads to spastic quadriplegia and joint contractures.
Overall muscle mass (particularly proximally) is reduced and associated with generalized muscle weakness.
It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias [
Some authors also reported abnormal movements as ataxia [
Seizures typically begin during infancy or early childhood. Drug resistance is common [
Rotary nystagmus and disconjugate eye movements have been reported but are not common [
Heterozygous females are generally asymptomatic and have no specific phenotypic findings. About 25% of heterozygous female have an abnormal thyroid profile with elevated T
Developmental delay and intellectual disability have been reported in heterozygous females in rare instances, perhaps due to skewed X-chromosome inactivation [
## Affected Males
To date, information on about 200 individuals with a pathogenic variant in
Select Features of Allan-Herndon-Dudley Syndrome in Affected Males
DD = developmental delay; ID = intellectual disability
Features and percentages of persons with feature were evaluated from the cohorts of
Expressed as % of all males with AHDS. All affected persons had ID ranging from mild to profound.
Less frequently, affected males have mild-to-moderate intellectual disability, and develop the ability to walk (with or without aid) and use of language allowing academic learning with aid.
Progressive hypertonicity of the limbs with brisk reflexes, ankle clonus, and extensor plantar responses (Babinski sign) leads to spastic quadriplegia and joint contractures.
Overall muscle mass (particularly proximally) is reduced and associated with generalized muscle weakness.
It is common for affected males to experience purposeless movements described as dystonic and/or athetoid and characteristic paroxysms or kinesigenic dyskinesias [
Some authors also reported abnormal movements as ataxia [
Seizures typically begin during infancy or early childhood. Drug resistance is common [
Rotary nystagmus and disconjugate eye movements have been reported but are not common [
## Affected Heterozygous Females
Heterozygous females are generally asymptomatic and have no specific phenotypic findings. About 25% of heterozygous female have an abnormal thyroid profile with elevated T
Developmental delay and intellectual disability have been reported in heterozygous females in rare instances, perhaps due to skewed X-chromosome inactivation [
## Genotype-Phenotype Correlations
It has been repeatedly reported that the severity of the clinical phenotype is related to the residual transport capacity of the mutated MCT8 protein. Large deletions in
Several
## Nomenclature
This condition was named MCT8
Because of the overlap of clinical findings in individuals with an
## Prevalence
Prevalence of Allan-Herndon-Dudley syndrome (AHDS) is unknown; however, the identification of more than 160 affected individuals in approximately 15 years suggests that the syndrome is more common than previously thought.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Many disorders demonstrate hypotonia and severe intellectual disability in an X-linked or autosomal recessive inheritance pattern. The main differential diagnoses, described in
Genes of Interest in the Differential Diagnosis of Allan-Herndon-Dudley Syndrome (AHDS)
Males may present in infancy or early childhood w/nystagmus, hypotonia, & severe DD/ID.
Progresses to severe spasticity & ataxia
MRI shows persistant diffuse hypomyelination.
Mild-to-moderate ID
Motor delay, dystonia
Short stature w/delayed bone age
↑ free T
Consider in differential diagnosis of mild forms of AHDS.
Improvement w/L-thyroxine therapy
Normal MRI
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; PMD-like = Pelizaeus-Merzbacher–like disease; XL = X-linked
Genes are in alphabetic order
Of note, in one study
• Males may present in infancy or early childhood w/nystagmus, hypotonia, & severe DD/ID.
• Progresses to severe spasticity & ataxia
• MRI shows persistant diffuse hypomyelination.
• Mild-to-moderate ID
• Motor delay, dystonia
• Short stature w/delayed bone age
• ↑ free T
• Consider in differential diagnosis of mild forms of AHDS.
• Improvement w/L-thyroxine therapy
• Normal MRI
## Management
No current published guidelines exist to establish the extent of disease or proper management in an individual diagnosed with Allan-Herndon-Dudley syndrome (AHDS). The following recommendations are based on current literature and the authors' experience.
To establish the extent of disease and needs in an individual diagnosed with Allan-Herndon-Dudley syndrome (AHDS), the evaluations summarized
Recommended Evaluations Following Initial Diagnosis in Individuals with Allan-Herndon-Dudley Syndrome
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
Gross motor & fine motor skills
Contractures & kyphoscoliosis
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Osteodensitometry (DXA)
Phospho-calcic equilibrium
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
To incl lung function & respiratory status
Consider eval of noninvasive ventilation or antibiotic therapy in patients w/recurrent respiratory infections & hypoventilation.
Use of community or online resources such as Parent to Parent;
Need for social work involvement for parental support;
Need for home nursing referral.
BMI = body mass index; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
Treatment of Manifestations in Individuals with Allan-Herndon-Dudley Syndrome (AHDS)
Feeding therapy
Nissen fundoplication & gastrostomy tube placement may be required for persistent feeding issues.
Constipation: laxatives, enemas, transanal irrigation
Feeding difficulties: See
Symptomatic GERD: antireflux therapy
To prevent contractures
Consider need for positioning & mobility devices, disability parking placard.
Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Hip dislocation &/or kyphoscoliosis: orthopedic surgery
Osteoporosis: calcium & vitamin D supplementation; bisphosphonate therapy as needed
Thyroid hormone replacement therapy during childhood has no beneficial effect & could worsen dysthyroidism.
See
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.
ASM = anti-seizure medication; DBS = deep brain stimulation; DD = developmental delay; GERD = gastroesophageal reflux disease; 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 (DD/ID) 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
Recommended Surveillance for Individuals with Allan-Herndon-Dudley Syndrome
DD/ID = developmental delay / intellectual disability; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
Administration of L-T
See
Two unaffected heterozygous pregnant women with unaffected fetuses were treated with L-T
Recently, an T
The main objective was the normalization of the free T
On neurologic examination, of the seven individuals with a completely inactivating
Seven mild and transient adverse effects related to TRIAC occurred in six individuals: three had increased perspiration and three reported irritability.
Beginning in 2017 the European Medicines Agency (EMA) granted TRIAC orphan designation for the treatment of AHDS (EMA/695502/2017).
To follow this first clinical study, an international Phase II trial (NCT02396459) to investigate the effects of TRIAC on neurodevelopmental outcomes in children younger than 30 months with AHDS will begin recruiting in early 2020.
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
• Gross motor & fine motor skills
• Contractures & kyphoscoliosis
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Osteodensitometry (DXA)
• Phospho-calcic equilibrium
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• To incl lung function & respiratory status
• Consider eval of noninvasive ventilation or antibiotic therapy in patients w/recurrent respiratory infections & hypoventilation.
• Use of community or online resources such as Parent to Parent;
• Need for social work involvement for parental support;
• Need for home nursing referral.
• Feeding therapy
• Nissen fundoplication & gastrostomy tube placement may be required for persistent feeding issues.
• Constipation: laxatives, enemas, transanal irrigation
• Feeding difficulties: See
• Symptomatic GERD: antireflux therapy
• To prevent contractures
• Consider need for positioning & mobility devices, disability parking placard.
• Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Hip dislocation &/or kyphoscoliosis: orthopedic surgery
• Osteoporosis: calcium & vitamin D supplementation; bisphosphonate therapy as needed
• Thyroid hormone replacement therapy during childhood has no beneficial effect & could worsen dysthyroidism.
• See
• 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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 Allan-Herndon-Dudley syndrome (AHDS), the evaluations summarized
Recommended Evaluations Following Initial Diagnosis in Individuals with Allan-Herndon-Dudley Syndrome
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
Gross motor & fine motor skills
Contractures & kyphoscoliosis
Mobility, activities of daily living, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Osteodensitometry (DXA)
Phospho-calcic equilibrium
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
To incl lung function & respiratory status
Consider eval of noninvasive ventilation or antibiotic therapy in patients w/recurrent respiratory infections & hypoventilation.
Use of community or online resources such as Parent to Parent;
Need for social work involvement for parental support;
Need for home nursing referral.
BMI = body mass index; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
• 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
• Gross motor & fine motor skills
• Contractures & kyphoscoliosis
• Mobility, activities of daily living, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Osteodensitometry (DXA)
• Phospho-calcic equilibrium
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in patients w/dysphagia &/or aspiration risk.
• To incl lung function & respiratory status
• Consider eval of noninvasive ventilation or antibiotic therapy in patients w/recurrent respiratory infections & hypoventilation.
• Use of community or online resources such as Parent to Parent;
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Allan-Herndon-Dudley Syndrome (AHDS)
Feeding therapy
Nissen fundoplication & gastrostomy tube placement may be required for persistent feeding issues.
Constipation: laxatives, enemas, transanal irrigation
Feeding difficulties: See
Symptomatic GERD: antireflux therapy
To prevent contractures
Consider need for positioning & mobility devices, disability parking placard.
Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Hip dislocation &/or kyphoscoliosis: orthopedic surgery
Osteoporosis: calcium & vitamin D supplementation; bisphosphonate therapy as needed
Thyroid hormone replacement therapy during childhood has no beneficial effect & could worsen dysthyroidism.
See
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.
ASM = anti-seizure medication; DBS = deep brain stimulation; DD = developmental delay; GERD = gastroesophageal reflux disease; 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 (DD/ID) 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
• Feeding therapy
• Nissen fundoplication & gastrostomy tube placement may be required for persistent feeding issues.
• Constipation: laxatives, enemas, transanal irrigation
• Feeding difficulties: See
• Symptomatic GERD: antireflux therapy
• To prevent contractures
• Consider need for positioning & mobility devices, disability parking placard.
• Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Hip dislocation &/or kyphoscoliosis: orthopedic surgery
• Osteoporosis: calcium & vitamin D supplementation; bisphosphonate therapy as needed
• Thyroid hormone replacement therapy during childhood has no beneficial effect & could worsen dysthyroidism.
• See
• 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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 (DD/ID) 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
## Surveillance
Recommended Surveillance for Individuals with Allan-Herndon-Dudley Syndrome
DD/ID = developmental delay / intellectual disability; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
## Agents/Circumstances to Avoid
Administration of L-T
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Two unaffected heterozygous pregnant women with unaffected fetuses were treated with L-T
## Therapies Under Investigation
Recently, an T
The main objective was the normalization of the free T
On neurologic examination, of the seven individuals with a completely inactivating
Seven mild and transient adverse effects related to TRIAC occurred in six individuals: three had increased perspiration and three reported irritability.
Beginning in 2017 the European Medicines Agency (EMA) granted TRIAC orphan designation for the treatment of AHDS (EMA/695502/2017).
To follow this first clinical study, an international Phase II trial (NCT02396459) to investigate the effects of TRIAC on neurodevelopmental outcomes in children younger than 30 months with AHDS will begin recruiting in early 2020.
Search
## Genetic Counseling
Allan-Herndon-Dudley syndrome (AHDS) 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 study of 24 affected individuals, 17 males had inherited the
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
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 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
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will typically be asymptomatic, although they may have minor thyroid test abnormalities (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 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 father of an affected male will not have the disorder nor will he be hemizygous for the
• In a study of 24 affected individuals, 17 males had inherited the
• 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
• 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 an
• If the proband represents a simplex case (i.e., a single occurrence in a family) 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 carriers or are at risk of being carriers.
## Mode of Inheritance
Allan-Herndon-Dudley syndrome (AHDS) 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 study of 24 affected individuals, 17 males had inherited the
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
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 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 study of 24 affected individuals, 17 males had inherited the
• 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
• 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 an
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
## Heterozygote Detection
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will typically be asymptomatic, although they may have minor thyroid test abnormalities (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 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
Canada
Via Foina, 34
25040 Monticelli Brusati (BS)
Italy
France
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• Canada
•
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• Via Foina, 34
• 25040 Monticelli Brusati (BS)
• Italy
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• France
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## Molecular Genetics
Allan-Herndon-Dudley Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Allan-Herndon-Dudley Syndrome (
Monocarboxylate transporter 8 (MCT8), the protein product of
Notable
Variants listed in the table have been provided by the authors.
Variant designation on previously used transcript
## Molecular Pathogenesis
Monocarboxylate transporter 8 (MCT8), the protein product of
Notable
Variants listed in the table have been provided by the authors.
Variant designation on previously used transcript
## Chapter Notes
For the original publication of this chapter, Drs Dumitrescu and Refetoff were supported in part by grants DR15070, DK07011, RR04999 and DK091016 from the National Institutes of Health. Dr Fu was funded by an award from China Scholarship Council.
Dr Sarret was supported by the French PHRC "XMLR." Drs Oliver and Tonduti were supported as investigators by the ERASMUS University (The Netherlands). They thank the Xtraordinaire association and patients' families for their help in conducting their research.
Melissa A Dempsey, MS; Parkview Health, Ft Wayne, Indiana (2009-2020)Alexandra M Dumitrescu, MD, PhD; University of Chicago Medical Center (2009-2020)Jiao Fu, MD; University of Chicago Medical Center (2013-2020)Isabelle Oliver Petit, MD (2020-present)Samuel Refetoff, MD; University of Chicago Medical Center (2009-2020)Catherine Sarret, MD, PhD (2020-present)Davide Tonduti, MD, PhD (2020-present)
16 January 2020 (bp) Comprehensive update posted live
11 April 2013 (me) Comprehensive update posted live
9 March 2010 (me) Review posted live
6 July 2009 (mad) Original submission
• 16 January 2020 (bp) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 9 March 2010 (me) Review posted live
• 6 July 2009 (mad) Original submission
## Acknowledgments
For the original publication of this chapter, Drs Dumitrescu and Refetoff were supported in part by grants DR15070, DK07011, RR04999 and DK091016 from the National Institutes of Health. Dr Fu was funded by an award from China Scholarship Council.
Dr Sarret was supported by the French PHRC "XMLR." Drs Oliver and Tonduti were supported as investigators by the ERASMUS University (The Netherlands). They thank the Xtraordinaire association and patients' families for their help in conducting their research.
## Author History
Melissa A Dempsey, MS; Parkview Health, Ft Wayne, Indiana (2009-2020)Alexandra M Dumitrescu, MD, PhD; University of Chicago Medical Center (2009-2020)Jiao Fu, MD; University of Chicago Medical Center (2013-2020)Isabelle Oliver Petit, MD (2020-present)Samuel Refetoff, MD; University of Chicago Medical Center (2009-2020)Catherine Sarret, MD, PhD (2020-present)Davide Tonduti, MD, PhD (2020-present)
## Revision History
16 January 2020 (bp) Comprehensive update posted live
11 April 2013 (me) Comprehensive update posted live
9 March 2010 (me) Review posted live
6 July 2009 (mad) Original submission
• 16 January 2020 (bp) Comprehensive update posted live
• 11 April 2013 (me) Comprehensive update posted live
• 9 March 2010 (me) Review posted live
• 6 July 2009 (mad) Original submission
## References
## Literature Cited
Thyroid profiles of 24 patients with AHDS (black triangles) compared to 25 male patients with other genetically defined intellectual disability (gray circles). Serum levels of:
A. TSH *
B. Free T
C. Free T
D. Free T
* Note that low TSH level in AHDS patients 15 and 16 were due to L-thyroxine supplementation.
From
(A) T
|
[
"A Anık, S Kersseboom, K Demir, G Catlı, U Yiş, E Böber, A van Mullem, RE van Herebeek, S Hız, A Abacı, TJ Visser. Psychomotor retardation caused by a defective thyroid hormone transporter: report of two families with different MCT8 mutations.. Horm Res Paediatr. 2014;82:261-71",
"K Brockmann, AM Dumitrescu, TT Best, F Hanefeld, S Refetoff. X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene.. J Neurol. 2005;252:663-6",
"A Ceballos, MM Belinchon, E Sanchez-Mendoza, C Grijota-Martinez, AM Dumitrescu, S Refetoff, B Morte, J Bernal. Importance of monocarboxylate transporter 8 (Mct8) for the blood-brain barrier dependent availability of 3,5,3'-triiodo-L-thyronine (T3).. Endocrinology 2009;150:2491-6",
"AM Dumitrescu, X-H Liao, TD Best, K Brockmann, S Refetoff. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene.. Am J Hum Genet 2004;74:168-75",
"EC Friesema, A Grueters, H Biebermann, H Krude, A von Moers, M Reeser, TG Barrett, EE Mancilla, J Svensson, MH Kester, GG Kuiper, S Balkassmi, AG Uitterlinden, J Koehrle, P Rodien, AP Halestrap, TJ Visser. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation.. Lancet. 2004;364:1435-7",
"EC Friesema, J Jansen, H Heuer, M Trajkovic, K Bauer, TJ Visser. Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8.. Nat Clin Pract Endocrinol Metab. 2006;2:512-23",
"EC Friesema, WE Visser, TJ Visser. Genetics and phenomics of thyroid hormone transport by MCT8.. Mol Cell Endocrinol. 2010;322:107-13",
"SGM Frints, S Lenzner, M Bauters, LR Jensen, HV Esch, V des Portes, U Moog, MVE Macville, K van Roozendaal, CTRM Schrander-Stumpel, A Tzschach, P Marynen, J Fryns, B Hamel, H van Bokhoven, J Chelly, C Beldjord, G Turner, J Gecz, C Moraine, M Raynaud, HH Ropers, G Froyen, AW Kuss. MCT8 mutation analysis and identification of the first female with Allan-Herndon-Dudley syndrome due to loss of MCT8 expression.. Eur J Hum Genet 2008;16:1029-37",
"O Fuchs, N Pfarr, J Pohlenz, H Schmidt. Elevated serum triiodothyronine and intellectual and motor disability with paroxysmal dyskinesia caused by a monocarboxylate transporter 8 gene mutation.. Dev Med Child Neurol 2009;51:240-4",
"B García-de Teresa, A González-Del Angel, ME Reyna-Fabián. Deletion of exon 1 of the SLC16A2 gene: a common occurrence in patients with Allan-Herndon-Dudley syndrome.. Thyroid 2015;25:361-7",
"AD Gika, A Siddiqui, AJ Hulse, S Edward, P Fallon, ME McEntagart, W Jan, D Josifova, T Lerman-Sagie, J Drummond, E Thompson, S Refetoff, CG Bönnemann, H Jungbluth. White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene.. Dev Med Child Neurol. 2010;52:475-82",
"S Groeneweg, RP Peeters, C Moran, A Stoupa, F Auriol, D Tonduti. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial.. Lancet Diabetes Endocrinol. 2019;7:695-706",
"V Herzovich, E Vaiani, R Marino, G Dratler, JM Lazzati, S Tilitzky, P Ramirez, S Iorcansky, MA Rivarola, A Belgorosky. Unexpected peripheral markers of thyroid function in a patient with a novel mutation of the MCT8 thyroid hormone transporter gene.. Horm Res. 2007;67:1-6",
"KR Holden, OF Zuñiga, MM May, H Su, MR Molinero, RC Rogers, CE Schwartz. X-linked MCT8 gene mutations: characterization of the pediatric neurologic phenotype.. J Child Neurol. 2005;20:852-7",
"J Jansen, EC Friesema, MH Kester, C Milici, M Reeser, A Grüters, TG Barrett, EE Mancilla, J Svensson, JL Wemeau, MH Busi da Silva Canalli, J Lundgren, ME McEntagart, N Hopper, WF Arts, TJ Visser. Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine.. J Clin Endocrinol Metab. 2007;92:2378-81",
"J Jansen, EC Friesema, MH Kester, CE Schwartz, TJ Visser. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8.. Endocrinology. 2008;149:2184-90",
"H Kakinuma, M Itoh, H Takahashi. A novel mutation in the monocarboxylate transporter 8 gene in a boy with putamen lesions and low free T4 levels in cerebrospinal fluid.. J Pediatr 2005;147:552-4",
"S Masnada, S Groenweg, V Saletti, L Chiapparini, B Castellotti, E Salsano, WE Visser, D Tonduti. Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency.. Metab Brain Dis. 2019;34:1565-75",
"F Novara, S Groeneweg, E Freri, M Estienne, P Reho, S Matricardi, B Castellotti, WE Visser, O Zuffardi, TJ Visser. Clinical and molecular characteristics of SLC16A2 (MCT8) mutations in three families with the Allan-Herndon-Dudley syndrome.. Hum Mutat. 2017;38:260-4",
"AK Philips, A Sirén, K Avela, M Somer, M Peippo, M Ahvenainen, F Doagu, M Arvio, H Kääriäinen, H Van Esch, G Froyen, SA Haas, H Hu, VM Kalscheuer, I Järvelä. X-exome sequencing in Finnish families with intellectual disability--four novel mutations and two novel syndromic phenotypes.. Orphanet J Rare Dis 2014;9:49",
"HE Ramos, M Morandini, A Carre, E Tron, C Floch, L Mandelbrot, N Neri, B De Sarcus, A Simon, JP Bonnefont, J Amiel, I Desguerre, V Valayannopoulos, M Castanet, M Polak. Pregnancy in women heterozygous for MCT8 mutations: risk of maternal hypothyroxinemia and fetal care.. Eur J Endocrinol. 2011;164:309-14",
"S Refetoff, AM Dumitrescu. Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination.. Best Pract Res Clin Endocrinol Metab 2007;21:277-305",
"G Remerand, O Boespflug-Tanguy, D Tonduti, R Touraine, D Rodriguez, A Curie, N Perreton, V Des Portes, C Sarret. Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations.. Dev Med Child Neurol. 2019;61:1439-47",
"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",
"LM Roberts, K Woodford, M Zhou, DS Black, JE Haggerty, EH Tate, KK Grindstaff, W Mengesha, C Raman, N Zerangue. Expression of the thyroid hormone transporters MCT8 (SLC16A2) and OATP14 (SLCO1C1) at the blood-brain barrier.. Endocrinology 2008;149:6251-61",
"CE Schwartz, MM May, NJ Carpenter, RC Rogers, J Martin, MG Bialer, J Ward, J Sanabria, S Marsa, JA Lewis, R Echeverri, HA Lubs, K Voeller, RJ Simensen, RE Stevenson. Allan-Herndon-Dudley syndrome and the MCT8 thyroid hormone transporter.. Am J Hum Genet 2005;77:41-53",
"CE Schwartz, RE Stevenson. The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome.. Best Pract Res Clin Endocrinol Metab 2007;21:307-21",
"PE Sijens, LA Rödiger, LC Meiners, RJ Lunsing. 1H magnetic resonance spectroscopy in monocarboxylate transporter 8 gene deficiency.. J Clin Endocrinol Metab. 2008;93:1854-9",
"D Tonduti, A Vanderver, A Berardinelli, JL Schmidt, CD Collins, F Novara, A Di Genni, A Mita, F Triulzi, JE Brunstrom-Hernandez, O Zuffardi, U Balottin, S Orcesi. MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features.. J Child Neurol. 2013;28:795-800",
"Y Tsurusaki, H Osaka, H Hamanoue, H Shimbo, M Tsuji, H Doi, H Saitsu, N Matsumoto, N Miyake. Rapid detection of a mutation causing X-linked leucoencephalopathy by exome sequencing.. J Med Genet. 2011;48:606-9",
"C Vaurs-Barrière, M Deville, C Sarret, G Giraud, V Des Portes, JM Prats-Vinas, G De Michele, B Dan, AF Brady, O Boespflug-Tanguy, R Touraine. Pelizaeus-Merzbacher-like disease presentation of MCT8 mutated male subjects.. Ann Neurol 2009;65:114-18",
"WE Visser, J Jansen, EC Friesema, MH Kester, E Mancilla, J Lundgren, MS van der Knaap, RJ Lunsing, OF Brouwer, TJ Visser. Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations.. Hum Mutat 2009;30:29-38",
"WE Visser, P Vrijmoeth, FE Visser, WF Arts, H van Toor, TJ Visser. Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation.. Clin Endocrinol (Oxf) 2013;78:310-5",
"S Yamamoto, K Okuhara, H Tonoki, S Iizuka, N Nihei, T. Tajima. A novel deletion mutation of SLC16A2 encoding monocarboxylate transporter (MCT) 8 in a 26-year-old Japanese patient with Allan-Herndon-Dudley syndrome.. Clin Pediatr Endocrinol. 2013;22:83-6",
"A Zung, TJ Visser, AG Uitterlinden, F Rivadeneira, EC Friesema. A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment.. Eur J Endocrinol. 2011;165:823-30"
] |
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GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
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thdrd
|
thdrd
|
[
"TH-Deficient Dopa-Responsive Dystonia",
"TH-Deficient Infantile Parkinsonism with Motor Delay",
"TH-Deficient Progressive Infantile Encephalopathy",
"Tyrosine 3-monooxygenase",
"TH",
"Tyrosine Hydroxylase Deficiency"
] |
Tyrosine Hydroxylase Deficiency
|
Yoshiaki Furukawa, Stephen Kish
|
Summary Tyrosine hydroxylase (TH) deficiency is associated with a broad phenotypic spectrum. Based on severity of symptoms/signs as well as responsiveness to levodopa therapy, clinical phenotypes caused by pathogenic variants in In individuals with TH-deficient dopa-responsive dystonia (DYT5b, DYT-TH), onset is between age 12 months and 12 years; initial symptoms are typically lower-limb dystonia and/or difficulty in walking. Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) may be present. In most individuals with TH-deficient infantile parkinsonism with motor delay, onset is between age three and 12 months. In contrast to TH-deficient DRD, motor milestones are overtly delayed in this severe form. Affected infants demonstrate truncal hypotonia and parkinsonian symptoms and signs (hypokinesia, rigidity of extremities, and/or tremor). In individuals with TH-deficient progressive infantile encephalopathy, onset is before age three to six months. Fetal distress is reported in most. Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia, oculogyric crises, ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternating with irritability. The diagnosis of TH deficiency is established in a proband by identification of biallelic pathogenic variants in All individuals with TH-deficient DRD demonstrate complete responsiveness of symptoms to levodopa (with a decarboxylase inhibitor). Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years before the full effects of treatment become established. Some individuals are hypersensitive to levodopa and prone to side effects (i.e., dopa-induced dyskinesias which develop at initiation of levodopa treatment). Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy. In this very severe form, treatment with levodopa is often limited by intolerable dyskinesias. TH deficiency is inherited in an autosomal recessive manner. Heterozygotes (carriers) are generally 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, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both
|
TH-deficient dopa-responsive dystonia
TH-deficient infantile parkinsonism with motor delay
TH-deficient progressive infantile encephalopathy
For synonyms and outdated names see
For other genetic causes of these phenotypes, see
• TH-deficient dopa-responsive dystonia
• TH-deficient infantile parkinsonism with motor delay
• TH-deficient progressive infantile encephalopathy
## Diagnosis
Tyrosine hydroxylase (TH) deficiency is associated with a wide phenotypic spectrum. Based on severity of symptoms and signs as well as responsiveness to levodopa therapy, the three clinical phenotypes attributable to pathogenic variants in
Since clinical suspicion is a key to the diagnosis of TH deficiency, physicians should be aware of this broad phenotypic spectrum.
The diagnosis of TH deficiency
Lower-limb dystonia
Generalized dystonia
Other forms of dystonia
Postural and/or rest tremor
Slowness of movements
Rigidity in affected limbs
Postural instability
Diurnal fluctuation (worsening of the symptoms toward the evening and their alleviation in the morning after sleep)
Hypokinesia
Truncal hypotonia
Developmental motor delay
Hyperreflexia
Spasticity in affected limbs
Extensor plantar responses
The striatal toe
Myoclonic jerks
Oculogyric crises
Bilateral ptosis
Intellectual disability
Autonomic disturbances
Fetal distress
Feeding difficulties
Growth retardation (head circumference, height, and/or weight)
Dystonic crises
Lethargy-irritability crises
Reduced homovanillic acid (HVA)
Normal 5-hydroxyindoleacetic acid (5-HIAA)
Reduced HVA/5-HIAA ratio
Reduced 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline)
Normal total biopterin (BP) (most of which exists as tetrahydrobiopterin [BH
Normal total neopterin (NP) (the by-products of the GTP cyclohydrolase 1 [GTPCH1] reaction)
This pattern of CSF neurotransmitter metabolites and pterins supports the clinical diagnosis of TH deficiency [
If CSF pterin analysis reveals low BP and NP levels, GTPCH1-deficient disorders (including
The diagnosis of TH deficiency
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 Tyrosine Hydroxylase 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
Note that sequence variants in the TH promoter region have been associated with TH deficiency at c.-69, c.-70, and c.-71 [
See references 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.
• Lower-limb dystonia
• Generalized dystonia
• Other forms of dystonia
• Postural and/or rest tremor
• Slowness of movements
• Rigidity in affected limbs
• Postural instability
• Diurnal fluctuation (worsening of the symptoms toward the evening and their alleviation in the morning after sleep)
• Hypokinesia
• Truncal hypotonia
• Developmental motor delay
• Hyperreflexia
• Spasticity in affected limbs
• Extensor plantar responses
• The striatal toe
• Myoclonic jerks
• Oculogyric crises
• Bilateral ptosis
• Intellectual disability
• Autonomic disturbances
• Fetal distress
• Feeding difficulties
• Growth retardation (head circumference, height, and/or weight)
• Dystonic crises
• Lethargy-irritability crises
• Reduced homovanillic acid (HVA)
• Normal 5-hydroxyindoleacetic acid (5-HIAA)
• Reduced HVA/5-HIAA ratio
• Reduced 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline)
• Normal total biopterin (BP) (most of which exists as tetrahydrobiopterin [BH
• Normal total neopterin (NP) (the by-products of the GTP cyclohydrolase 1 [GTPCH1] reaction)
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
The diagnosis of TH deficiency
Lower-limb dystonia
Generalized dystonia
Other forms of dystonia
Postural and/or rest tremor
Slowness of movements
Rigidity in affected limbs
Postural instability
Diurnal fluctuation (worsening of the symptoms toward the evening and their alleviation in the morning after sleep)
Hypokinesia
Truncal hypotonia
Developmental motor delay
Hyperreflexia
Spasticity in affected limbs
Extensor plantar responses
The striatal toe
Myoclonic jerks
Oculogyric crises
Bilateral ptosis
Intellectual disability
Autonomic disturbances
Fetal distress
Feeding difficulties
Growth retardation (head circumference, height, and/or weight)
Dystonic crises
Lethargy-irritability crises
Reduced homovanillic acid (HVA)
Normal 5-hydroxyindoleacetic acid (5-HIAA)
Reduced HVA/5-HIAA ratio
Reduced 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline)
Normal total biopterin (BP) (most of which exists as tetrahydrobiopterin [BH
Normal total neopterin (NP) (the by-products of the GTP cyclohydrolase 1 [GTPCH1] reaction)
This pattern of CSF neurotransmitter metabolites and pterins supports the clinical diagnosis of TH deficiency [
If CSF pterin analysis reveals low BP and NP levels, GTPCH1-deficient disorders (including
• Lower-limb dystonia
• Generalized dystonia
• Other forms of dystonia
• Postural and/or rest tremor
• Slowness of movements
• Rigidity in affected limbs
• Postural instability
• Diurnal fluctuation (worsening of the symptoms toward the evening and their alleviation in the morning after sleep)
• Hypokinesia
• Truncal hypotonia
• Developmental motor delay
• Hyperreflexia
• Spasticity in affected limbs
• Extensor plantar responses
• The striatal toe
• Myoclonic jerks
• Oculogyric crises
• Bilateral ptosis
• Intellectual disability
• Autonomic disturbances
• Fetal distress
• Feeding difficulties
• Growth retardation (head circumference, height, and/or weight)
• Dystonic crises
• Lethargy-irritability crises
• Reduced homovanillic acid (HVA)
• Normal 5-hydroxyindoleacetic acid (5-HIAA)
• Reduced HVA/5-HIAA ratio
• Reduced 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG; a metabolite of noradrenaline)
• Normal total biopterin (BP) (most of which exists as tetrahydrobiopterin [BH
• Normal total neopterin (NP) (the by-products of the GTP cyclohydrolase 1 [GTPCH1] reaction)
## Establishing the Diagnosis
The diagnosis of TH deficiency
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 Tyrosine Hydroxylase 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
Note that sequence variants in the TH promoter region have been associated with TH deficiency at c.-69, c.-70, and c.-71 [
See references 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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Tyrosine hydroxylase (TH) deficiency is associated with a wide phenotypic spectrum. Based on the severity of symptoms and signs as well as responsiveness to levodopa therapy, the three clinical phenotypes from mildest to most severe are: TH-deficient dopa-responsive dystonia (DRD) (DYT5b, DYT-TH); TH-deficient infantile parkinsonism with motor delay; and TH-deficient progressive infantile encephalopathy (see
None of the symptoms and signs of TH deficiency improve without proper treatment with levodopa (see
Clinical features of more than 15 individuals with molecularly confirmed TH-deficient DRD have been reported [
The perinatal and postnatal periods are normal. Early psychomotor development is normal. Onset of symptoms is generally between ages 12 months and 12 years. Initial symptoms are usually lower-limb dystonia and/or difficulty in walking. In general, gradual progression to generalized dystonia occurs. Bradykinesia and tremor (mainly postural) can be observed. A variable degree of rigidity is detected in affected limbs. There is a tendency to fall. Without treatment individuals with TH-deficient DRD become wheelchair bound.
In addition to dystonic and parkinsonian elements, many affected individuals have some clinical features suggestive of pyramidal signs (hyperreflexia, spasticity, and/or extensor plantar responses). Plantar responses become flexor after beginning levodopa therapy, suggesting that the previous findings may be consistent with a dystonic phenomenon (the striatal toe) rather than a Babinski response.
Intellect is not impaired in individuals with TH-deficient DRD. Of note,
In rare instances, sustained upward ocular deviations (oculogyric crises) are observed.
Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) has been reported in approximately one third of individuals with TH-deficient DRD (a much lower incidence than observed in
DRD is characterized by a dramatic and sustained response to relatively low doses of levodopa [
Approximately 50 individuals with molecularly confirmed TH-deficient infantile parkinsonism with motor delay have been reported [
In general, the pregnancies of affected individuals are uncomplicated. Perinatal and early postnatal periods are usually normal. Onset in most children is between ages three and 12 months. In contrast to TH-deficient DRD, in this severe form, motor milestones are overtly delayed in infancy.
All affected individuals demonstrate truncal hypotonia as well as parkinsonian symptoms and signs (e.g., hypokinesia, rigidity of extremities, tremor). Although dystonia is recognized in most, it tends to be less prominent. Brisk deep tendon reflexes, spasticity, and/or extensor plantar responses are frequently detected. Deep tendon reflexes have been reported to be normal or reduced in some.
Oculogyric crises are often observed. Ptosis and other features of mild autonomic dysfunction can be observed. Intellectual disability is found in many of the affected individuals.
Typical diurnal fluctuation of symptoms is not observed in most individuals with TH-deficient infantile parkinsonism with motor delay. Of note, diurnal variation of axial hypotonia but not of limb dystonia has been described in one affected individual [
Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years for the full effects of treatment to become established. For example, four individuals reported by
Some affected individuals are hypersensitive to levodopa (combined with a decarboxylase inhibitor) and are prone to intolerable side effects (e.g., severe dopa-induced dyskinesias which develop at initiation of levodopa treatment); because of this hypersensitivity, such individuals require very low initial doses of levodopa [
More than 15 individuals with molecularly confirmed TH-deficient progressive infantile encephalopathy have been reported [
The onset of TH-deficient progressive infantile encephalopathy is before age three to six months. Fetal distress is reported in most; infants may demonstrate feeding difficulties, hypotonia, and/or growth retardation affecting head circumference, height, and/or weight from birth. Determining the age of onset is sometimes difficult because of complicated perinatal events.
Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia with extensor plantar responses, oculogyric crises, bilateral ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternated with irritability – referred to as "lethargy-irritability crises" [
In general, dystonia is not a prominent clinical feature of TH-deficient progressive infantile encephalopathy; however, in the most severely affected infants, dystonic crises (every 4-5 days) have been reported [
Although autonomic disturbances occur, especially in the periods of lethargy-irritability crises, the clinical characteristics of impaired production of peripheral catecholamines (e.g., abnormalities in the maintenance of blood pressure) are not present [
Usually, typical diurnal fluctuation of symptoms is not recognized in TH-deficient progressive infantile encephalopathy.
Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy; thus, treatment with levodopa is often limited by intolerable dyskinesias. Some develop severe dyskinesias even at doses of 0.2 to 1.5 mg/kg/day levodopa (combined with a decarboxylase inhibitor); no or only minimal improvement can be detected in these individuals [
Characteristics of the Three Phenotypes of TH Deficiency
Effect is generally incomplete, or levodopa treatment takes months/years to achieve full effect.
Levodopa treatment is often limited by intolerable dopa-induced dyskinesias which develop at initiation of the therapy.
In all individuals with TH-deficient DRD and in most individuals with TH-deficient infantile parkinsonism with motor delay, brain MRI is normal. Brain MRI demonstrated no abnormalities in the basal ganglia of two individuals with TH-deficient DRD even 38 and 43 years after onset of the disorder [
In individuals with TH-deficient progressive infantile encephalopathy, brain MRI often reveals mild-moderate cerebral and/or cerebellar atrophy. In one individual with this very severe form, no abnormalities were observed on two brain MRIs in the first year of life; however, the third brain MRI at age 2.5 years showed periventricular white matter changes and symmetric high signal abnormalities in the superior cerebellar peduncles and dorsal pons [
In a 16-week-old miscarried human fetus found to be heterozygous for
Individuals who are homozygous or compound heterozygous for a single-nucleotide variant in the promoter region of
No additional genotype-phenotype correlations have been identified in individuals with TH deficiency.
Penetrance appears to be complete in individuals with biallelic
In contrast to autosomal dominant GTPCH1-deficient DRD [
The prevalence of TH deficiency has not been clearly documented. DRD has been reported to account for an estimated 5%-10% of primary dystonia in childhood or adolescence [
DYT5b and DYT-TH are other designations for TH-deficient dopa-responsive dystonia (see
## Clinical Description
Tyrosine hydroxylase (TH) deficiency is associated with a wide phenotypic spectrum. Based on the severity of symptoms and signs as well as responsiveness to levodopa therapy, the three clinical phenotypes from mildest to most severe are: TH-deficient dopa-responsive dystonia (DRD) (DYT5b, DYT-TH); TH-deficient infantile parkinsonism with motor delay; and TH-deficient progressive infantile encephalopathy (see
None of the symptoms and signs of TH deficiency improve without proper treatment with levodopa (see
Clinical features of more than 15 individuals with molecularly confirmed TH-deficient DRD have been reported [
The perinatal and postnatal periods are normal. Early psychomotor development is normal. Onset of symptoms is generally between ages 12 months and 12 years. Initial symptoms are usually lower-limb dystonia and/or difficulty in walking. In general, gradual progression to generalized dystonia occurs. Bradykinesia and tremor (mainly postural) can be observed. A variable degree of rigidity is detected in affected limbs. There is a tendency to fall. Without treatment individuals with TH-deficient DRD become wheelchair bound.
In addition to dystonic and parkinsonian elements, many affected individuals have some clinical features suggestive of pyramidal signs (hyperreflexia, spasticity, and/or extensor plantar responses). Plantar responses become flexor after beginning levodopa therapy, suggesting that the previous findings may be consistent with a dystonic phenomenon (the striatal toe) rather than a Babinski response.
Intellect is not impaired in individuals with TH-deficient DRD. Of note,
In rare instances, sustained upward ocular deviations (oculogyric crises) are observed.
Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) has been reported in approximately one third of individuals with TH-deficient DRD (a much lower incidence than observed in
DRD is characterized by a dramatic and sustained response to relatively low doses of levodopa [
Approximately 50 individuals with molecularly confirmed TH-deficient infantile parkinsonism with motor delay have been reported [
In general, the pregnancies of affected individuals are uncomplicated. Perinatal and early postnatal periods are usually normal. Onset in most children is between ages three and 12 months. In contrast to TH-deficient DRD, in this severe form, motor milestones are overtly delayed in infancy.
All affected individuals demonstrate truncal hypotonia as well as parkinsonian symptoms and signs (e.g., hypokinesia, rigidity of extremities, tremor). Although dystonia is recognized in most, it tends to be less prominent. Brisk deep tendon reflexes, spasticity, and/or extensor plantar responses are frequently detected. Deep tendon reflexes have been reported to be normal or reduced in some.
Oculogyric crises are often observed. Ptosis and other features of mild autonomic dysfunction can be observed. Intellectual disability is found in many of the affected individuals.
Typical diurnal fluctuation of symptoms is not observed in most individuals with TH-deficient infantile parkinsonism with motor delay. Of note, diurnal variation of axial hypotonia but not of limb dystonia has been described in one affected individual [
Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years for the full effects of treatment to become established. For example, four individuals reported by
Some affected individuals are hypersensitive to levodopa (combined with a decarboxylase inhibitor) and are prone to intolerable side effects (e.g., severe dopa-induced dyskinesias which develop at initiation of levodopa treatment); because of this hypersensitivity, such individuals require very low initial doses of levodopa [
More than 15 individuals with molecularly confirmed TH-deficient progressive infantile encephalopathy have been reported [
The onset of TH-deficient progressive infantile encephalopathy is before age three to six months. Fetal distress is reported in most; infants may demonstrate feeding difficulties, hypotonia, and/or growth retardation affecting head circumference, height, and/or weight from birth. Determining the age of onset is sometimes difficult because of complicated perinatal events.
Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia with extensor plantar responses, oculogyric crises, bilateral ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternated with irritability – referred to as "lethargy-irritability crises" [
In general, dystonia is not a prominent clinical feature of TH-deficient progressive infantile encephalopathy; however, in the most severely affected infants, dystonic crises (every 4-5 days) have been reported [
Although autonomic disturbances occur, especially in the periods of lethargy-irritability crises, the clinical characteristics of impaired production of peripheral catecholamines (e.g., abnormalities in the maintenance of blood pressure) are not present [
Usually, typical diurnal fluctuation of symptoms is not recognized in TH-deficient progressive infantile encephalopathy.
Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy; thus, treatment with levodopa is often limited by intolerable dyskinesias. Some develop severe dyskinesias even at doses of 0.2 to 1.5 mg/kg/day levodopa (combined with a decarboxylase inhibitor); no or only minimal improvement can be detected in these individuals [
Characteristics of the Three Phenotypes of TH Deficiency
Effect is generally incomplete, or levodopa treatment takes months/years to achieve full effect.
Levodopa treatment is often limited by intolerable dopa-induced dyskinesias which develop at initiation of the therapy.
In all individuals with TH-deficient DRD and in most individuals with TH-deficient infantile parkinsonism with motor delay, brain MRI is normal. Brain MRI demonstrated no abnormalities in the basal ganglia of two individuals with TH-deficient DRD even 38 and 43 years after onset of the disorder [
In individuals with TH-deficient progressive infantile encephalopathy, brain MRI often reveals mild-moderate cerebral and/or cerebellar atrophy. In one individual with this very severe form, no abnormalities were observed on two brain MRIs in the first year of life; however, the third brain MRI at age 2.5 years showed periventricular white matter changes and symmetric high signal abnormalities in the superior cerebellar peduncles and dorsal pons [
In a 16-week-old miscarried human fetus found to be heterozygous for
## Mild Form: TH-Deficient DRD (DYT5b, DYT-TH)
Clinical features of more than 15 individuals with molecularly confirmed TH-deficient DRD have been reported [
The perinatal and postnatal periods are normal. Early psychomotor development is normal. Onset of symptoms is generally between ages 12 months and 12 years. Initial symptoms are usually lower-limb dystonia and/or difficulty in walking. In general, gradual progression to generalized dystonia occurs. Bradykinesia and tremor (mainly postural) can be observed. A variable degree of rigidity is detected in affected limbs. There is a tendency to fall. Without treatment individuals with TH-deficient DRD become wheelchair bound.
In addition to dystonic and parkinsonian elements, many affected individuals have some clinical features suggestive of pyramidal signs (hyperreflexia, spasticity, and/or extensor plantar responses). Plantar responses become flexor after beginning levodopa therapy, suggesting that the previous findings may be consistent with a dystonic phenomenon (the striatal toe) rather than a Babinski response.
Intellect is not impaired in individuals with TH-deficient DRD. Of note,
In rare instances, sustained upward ocular deviations (oculogyric crises) are observed.
Diurnal fluctuation of symptoms (worsening of the symptoms toward the evening and their alleviation in the morning after sleep) has been reported in approximately one third of individuals with TH-deficient DRD (a much lower incidence than observed in
DRD is characterized by a dramatic and sustained response to relatively low doses of levodopa [
## Severe Form: TH-Deficient Infantile Parkinsonism with Motor Delay
Approximately 50 individuals with molecularly confirmed TH-deficient infantile parkinsonism with motor delay have been reported [
In general, the pregnancies of affected individuals are uncomplicated. Perinatal and early postnatal periods are usually normal. Onset in most children is between ages three and 12 months. In contrast to TH-deficient DRD, in this severe form, motor milestones are overtly delayed in infancy.
All affected individuals demonstrate truncal hypotonia as well as parkinsonian symptoms and signs (e.g., hypokinesia, rigidity of extremities, tremor). Although dystonia is recognized in most, it tends to be less prominent. Brisk deep tendon reflexes, spasticity, and/or extensor plantar responses are frequently detected. Deep tendon reflexes have been reported to be normal or reduced in some.
Oculogyric crises are often observed. Ptosis and other features of mild autonomic dysfunction can be observed. Intellectual disability is found in many of the affected individuals.
Typical diurnal fluctuation of symptoms is not observed in most individuals with TH-deficient infantile parkinsonism with motor delay. Of note, diurnal variation of axial hypotonia but not of limb dystonia has been described in one affected individual [
Individuals with TH-deficient infantile parkinsonism with motor delay demonstrate a marked response to levodopa. However, in contrast to TH-deficient DRD, the responsiveness is generally not complete and/or it takes several months or even years for the full effects of treatment to become established. For example, four individuals reported by
Some affected individuals are hypersensitive to levodopa (combined with a decarboxylase inhibitor) and are prone to intolerable side effects (e.g., severe dopa-induced dyskinesias which develop at initiation of levodopa treatment); because of this hypersensitivity, such individuals require very low initial doses of levodopa [
## Very Severe Form: TH-Deficient Progressive Infantile Encephalopathy
More than 15 individuals with molecularly confirmed TH-deficient progressive infantile encephalopathy have been reported [
The onset of TH-deficient progressive infantile encephalopathy is before age three to six months. Fetal distress is reported in most; infants may demonstrate feeding difficulties, hypotonia, and/or growth retardation affecting head circumference, height, and/or weight from birth. Determining the age of onset is sometimes difficult because of complicated perinatal events.
Affected individuals have marked delay in motor development, truncal hypotonia, severe hypokinesia, limb hypertonia (rigidity and/or spasticity), hyperreflexia with extensor plantar responses, oculogyric crises, bilateral ptosis, intellectual disability, and paroxysmal periods of lethargy (with increased sweating and drooling) alternated with irritability – referred to as "lethargy-irritability crises" [
In general, dystonia is not a prominent clinical feature of TH-deficient progressive infantile encephalopathy; however, in the most severely affected infants, dystonic crises (every 4-5 days) have been reported [
Although autonomic disturbances occur, especially in the periods of lethargy-irritability crises, the clinical characteristics of impaired production of peripheral catecholamines (e.g., abnormalities in the maintenance of blood pressure) are not present [
Usually, typical diurnal fluctuation of symptoms is not recognized in TH-deficient progressive infantile encephalopathy.
Individuals with TH-deficient progressive infantile encephalopathy are extremely sensitive to levodopa therapy; thus, treatment with levodopa is often limited by intolerable dyskinesias. Some develop severe dyskinesias even at doses of 0.2 to 1.5 mg/kg/day levodopa (combined with a decarboxylase inhibitor); no or only minimal improvement can be detected in these individuals [
Characteristics of the Three Phenotypes of TH Deficiency
Effect is generally incomplete, or levodopa treatment takes months/years to achieve full effect.
Levodopa treatment is often limited by intolerable dopa-induced dyskinesias which develop at initiation of the therapy.
## Atypical Severe Forms
## Neuroimaging
In all individuals with TH-deficient DRD and in most individuals with TH-deficient infantile parkinsonism with motor delay, brain MRI is normal. Brain MRI demonstrated no abnormalities in the basal ganglia of two individuals with TH-deficient DRD even 38 and 43 years after onset of the disorder [
In individuals with TH-deficient progressive infantile encephalopathy, brain MRI often reveals mild-moderate cerebral and/or cerebellar atrophy. In one individual with this very severe form, no abnormalities were observed on two brain MRIs in the first year of life; however, the third brain MRI at age 2.5 years showed periventricular white matter changes and symmetric high signal abnormalities in the superior cerebellar peduncles and dorsal pons [
## Neurochemistry
In a 16-week-old miscarried human fetus found to be heterozygous for
## Genotype-Phenotype Correlations
Individuals who are homozygous or compound heterozygous for a single-nucleotide variant in the promoter region of
No additional genotype-phenotype correlations have been identified in individuals with TH deficiency.
## Penetrance
Penetrance appears to be complete in individuals with biallelic
In contrast to autosomal dominant GTPCH1-deficient DRD [
## Prevalence
The prevalence of TH deficiency has not been clearly documented. DRD has been reported to account for an estimated 5%-10% of primary dystonia in childhood or adolescence [
## Nomenclature
DYT5b and DYT-TH are other designations for TH-deficient dopa-responsive dystonia (see
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The major differential diagnoses for tyrosine hydroxylase (TH) deficiency include several types of dystonia, early-onset parkinsonism, cerebral palsy or spastic paraplegia, and primary and secondary deficiencies of CSF neurotransmitter metabolites.
## Management
To establish the extent of disease and needs in an individual diagnosed with tyrosine hydroxylase (TH) deficiency, the following are recommended if they have not already been completed:
Clinical examination to assess the severity of motor disturbances
Evaluation for associated psychiatric symptoms or cognitive impairments
Consultation with a clinical geneticist and/or genetic counselor
In individuals with TH deficiency, initial use of a levodopa (combined with a decarboxylase inhibitor) dose of 0.5-3 mg/kg (body weight)/day, divided into three to six doses, has been recommended [
When tolerated, the dose of levodopa can be increased gradually. However, with the exception of those with mild TH-deficient DRD (see
As reported in compound heterozygotes for
As described in
Levodopa therapy from early infancy may prevent manifestations of some symptoms and signs in TH-deficient infantile parkinsonism with motor delay; however, no levodopa trials in the early postnatal period of infants with this type of TH deficiency and biallelic
Additional side effects associated with peak-dose levodopa include gastroesophageal reflux, vomiting, or significant suppression of appetite leading to poor growth. Although these problems may be most evident in the first few weeks of onset of levodopa treatment, close monitoring of symptoms and ongoing adjustment of levodopa dosing in conjunction with appropriate supportive intervention as needed help in management.
Examination by a movement disorder specialist in pediatric or adult neurology at least several times yearly is recommended.
The prokinetic agent Reglan
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 prompt initiation of treatment.
Evaluations include:
Clinical examination to identify mild dystonic and/or parkinsonian symptoms or unexplained gait disorders;
Molecular genetic testing if the
See
Search
• Clinical examination to assess the severity of motor disturbances
• Evaluation for associated psychiatric symptoms or cognitive impairments
• Consultation with a clinical geneticist and/or genetic counselor
• Clinical examination to identify mild dystonic and/or parkinsonian symptoms or unexplained gait disorders;
• Molecular genetic testing if the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with tyrosine hydroxylase (TH) deficiency, the following are recommended if they have not already been completed:
Clinical examination to assess the severity of motor disturbances
Evaluation for associated psychiatric symptoms or cognitive impairments
Consultation with a clinical geneticist and/or genetic counselor
• Clinical examination to assess the severity of motor disturbances
• Evaluation for associated psychiatric symptoms or cognitive impairments
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
In individuals with TH deficiency, initial use of a levodopa (combined with a decarboxylase inhibitor) dose of 0.5-3 mg/kg (body weight)/day, divided into three to six doses, has been recommended [
When tolerated, the dose of levodopa can be increased gradually. However, with the exception of those with mild TH-deficient DRD (see
As reported in compound heterozygotes for
## Prevention of Primary Manifestations
As described in
Levodopa therapy from early infancy may prevent manifestations of some symptoms and signs in TH-deficient infantile parkinsonism with motor delay; however, no levodopa trials in the early postnatal period of infants with this type of TH deficiency and biallelic
## Prevention of Secondary Complications
Additional side effects associated with peak-dose levodopa include gastroesophageal reflux, vomiting, or significant suppression of appetite leading to poor growth. Although these problems may be most evident in the first few weeks of onset of levodopa treatment, close monitoring of symptoms and ongoing adjustment of levodopa dosing in conjunction with appropriate supportive intervention as needed help in management.
## Surveillance
Examination by a movement disorder specialist in pediatric or adult neurology at least several times yearly is recommended.
## Agents/Circumstances to Avoid
The prokinetic agent Reglan
## 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 prompt initiation of treatment.
Evaluations include:
Clinical examination to identify mild dystonic and/or parkinsonian symptoms or unexplained gait disorders;
Molecular genetic testing if the
See
• Clinical examination to identify mild dystonic and/or parkinsonian symptoms or unexplained gait disorders;
• Molecular genetic testing if the
## Therapies Under Investigation
Search
## Genetic Counseling
Tyrosine hydroxylase (TH) deficiency is inherited in an autosomal recessive manner.
The parents of a proband are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are generally 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.
Heterozygotes (carriers) are generally asymptomatic.
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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
It may be 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 a proband are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are generally 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.
• Heterozygotes (carriers) are generally 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It may be 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
Tyrosine hydroxylase (TH) deficiency is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of a proband are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are generally 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.
Heterozygotes (carriers) are generally asymptomatic.
• The parents of a proband are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are generally 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.
• Heterozygotes (carriers) are generally 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, clarification of carrier status, 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 may be 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
• It may be 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
Tyrosine Hydroxylase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tyrosine Hydroxylase Deficiency (
Tyrosine hydroxylase (TH) (tyrosine 3-monooxygenase) catalyzes the initial and rate-limiting step in the synthesis of catecholamine, including dopamine, adrenaline (epinephrine), and noradrenaline (norepinephrine).
Complete disruption of TH function in mice results in severe catecholamine deficiency and perinatal lethality. Mice heterozygous for
Selected
Variants listed in the table have been provided by the authors.
Founder variant in Dutch population [
Founder variant in Greek population [
In one family with TH-deficient DRD and homozygosity for a
In an individual with TH-deficient infantile parkinsonism with motor delay and a homozygous
• In one family with TH-deficient DRD and homozygosity for a
• In an individual with TH-deficient infantile parkinsonism with motor delay and a homozygous
## Molecular Pathogenesis
Tyrosine hydroxylase (TH) (tyrosine 3-monooxygenase) catalyzes the initial and rate-limiting step in the synthesis of catecholamine, including dopamine, adrenaline (epinephrine), and noradrenaline (norepinephrine).
Complete disruption of TH function in mice results in severe catecholamine deficiency and perinatal lethality. Mice heterozygous for
Selected
Variants listed in the table have been provided by the authors.
Founder variant in Dutch population [
Founder variant in Greek population [
In one family with TH-deficient DRD and homozygosity for a
In an individual with TH-deficient infantile parkinsonism with motor delay and a homozygous
• In one family with TH-deficient DRD and homozygosity for a
• In an individual with TH-deficient infantile parkinsonism with motor delay and a homozygous
## Chapter Notes
Yoshiaki Furukawa, MD, PhD (2001-present)Stephen Kish, PhD (2014-present)Kathryn Swoboda, MD; University of Utah School of Medicine (2008-2014)
11 May 2017 (sw) Comprehensive update posted live
17 July 2014 (me) Comprehensive update posted live
8 February 2008 (me) Review posted live
15 February 2007 (me) Scope of Dopa-Responsive Dystonia
15 June 2004 (me) Comprehensive update posted live
5 March 2004 (me) Comprehensive update posted live
21 February 2002 (me) Review posted live as Dopa-Responsive Dystonia
30 June 2001 (yf) Original submission
• 11 May 2017 (sw) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 8 February 2008 (me) Review posted live
• 15 February 2007 (me) Scope of Dopa-Responsive Dystonia
• 15 June 2004 (me) Comprehensive update posted live
• 5 March 2004 (me) Comprehensive update posted live
• 21 February 2002 (me) Review posted live as Dopa-Responsive Dystonia
• 30 June 2001 (yf) Original submission
## Author History
Yoshiaki Furukawa, MD, PhD (2001-present)Stephen Kish, PhD (2014-present)Kathryn Swoboda, MD; University of Utah School of Medicine (2008-2014)
## Revision History
11 May 2017 (sw) Comprehensive update posted live
17 July 2014 (me) Comprehensive update posted live
8 February 2008 (me) Review posted live
15 February 2007 (me) Scope of Dopa-Responsive Dystonia
15 June 2004 (me) Comprehensive update posted live
5 March 2004 (me) Comprehensive update posted live
21 February 2002 (me) Review posted live as Dopa-Responsive Dystonia
30 June 2001 (yf) Original submission
• 11 May 2017 (sw) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 8 February 2008 (me) Review posted live
• 15 February 2007 (me) Scope of Dopa-Responsive Dystonia
• 15 June 2004 (me) Comprehensive update posted live
• 5 March 2004 (me) Comprehensive update posted live
• 21 February 2002 (me) Review posted live as Dopa-Responsive Dystonia
• 30 June 2001 (yf) Original submission
## References
## Literature Cited
|
[
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"L Arrabal, L Teresa, R Sánchez-Alcudia, M Castro, C Medrano, L Gutiérrez-Solana, S Roldán, A Ormazábal, C Pérez-Cerdá, B Merinero, B Pérez, R Artuch, M Ugarte, LR Desviat. Genotype-phenotype correlations in sepiapterin reductase deficiency. A splicing defect accounts for a new phenotypic variant.. Neurogenetics. 2011;12:183-91",
"L Bonafé, B Thony, JM Penzien, B Czarnecki, N Blau. Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia.. Am J Hum Genet 2001;69:269-77",
"C Bräutigam, GC Steenbergen-Spanjers, GF Hoffmann, C Dionisi-Vici, LP van den Heuvel, JA Smeitink, RA Wevers. Biochemical and molecular genetic characteristics of the severe form of tyrosine hydroxylase deficiency.. Clin Chem. 1999;45:2073-8",
"C Bräutigam, RA Wevers, RJ Jansen, JA Smeitink, JF de Rijk-Van Andel, FJ Gabreëls, GF Hoffmann. Biochemical hallmarks of tyrosine hydroxylase deficiency.. Clin Chem. 1998;44:1897-904",
"P Castaigne, P Rondot, JL Ribadeau-Dumas, G Saïd. Progressive extra-pyramidal disorder in 2 young brothers. Remarkable effects of treatment with L-dopa.. Rev Neurol (Paris) 1971;124:162-6",
"C-S Chi, H-F Lee, C-R Tsai. Tyrosine hydroxylase deficiency in Taiwanese infants.. Pediatr Neurol 2012;46:77-82",
"F Clot, D Grabli, C Cazeneuve, E Roze, P Castelnau, B Chabrol, P Landrieu, K Nguyen, G Ponsot, M Abada, D Doummar, P Damier, R Gil, S Thobois, AJ Ward, M Hutchinson, A Toutain, F Picard, A Camuzat, E Fedirko, C Sân, D Bouteiller, E LeGuern, A Durr, M Vidailhet, A Brice. Exhaustive analysis of BH4 and dopamine biosynthesis genes in patients with dopa-responsive dystonia.. Brain. 2009;132:1753-63",
"P de Lonlay, MC Nassogne, AH van Gennip, AC van Cruchten, T Billatte de Villemeur, M Cretz, C Stoll, JM Launay, GC Steenberger-Spante, LP van den Heuvel, RA Wevers, JM Saudubray, NG Abeling. Tyrosine hydroxylase deficiency unresponsive to L-dopa treatment with unusual clinical and biochemical presentation.. J Inherit Metab Dis 2000;23:819-25",
"JF de Rijk-Van Andel, FJ Gabreels, B Geurtz, GC Steenbergen-Spanjers, LP van Den Heuvel, JA Smeitink, RA Wevers. L-dopa-responsive infantile hypokinetic rigid parkinsonism due to tyrosine hydroxylase deficiency.. Neurology 2000;55:1926-8",
"K Diepold, B Schutz, K Rostasy, B Wilken, P Hougaard, F Güttler, A Romstad, L Birk Møller. Levodopa-responsive infantile parkinsonism due to a novel mutation in the tyrosine hydroxylase gene and exacerbation by viral infections.. Mov Disord 2005;20:764-7",
"P Dill, M Wagner, A Somerville, B Thöny, N Blau, P Weber. Paroxysmal stiffening, upward gaze, and hypotonia: hallmarks of sepiapterin reductase deficiency.. Neurology 2012;78:e29-32",
"C Dionisi-Vici, GF Hoffmann, V Leuzzi, H Hoffken, C Brautigam, C Rizzo, GC Steebergen-Spanjers, JA Smeitink, RA Wevers. Tyrosine hydroxylase deficiency with severe clinical course: clinical and biochemical investigations and optimization of therapy.. J Pediatr 2000;136:560-2",
"D Doummar, F Clot, M Vidailhet, A Afenjar, A Durr, A Brice, C Mignot, A Guet, TB de Villemeur, D Rodriguez. Infantile hypokinetic-hypotonic syndrome due to two novel mutations of the tyrosine hydroxylase gene.. Mov Disord. 2009;24:943-5",
"J Friedman, E Roze, JE Abdenur, R Chang, S Gasperini, V Saletti, GM Wali, H Eiroa, B Neville, A Felice, R Parascandalo, DI Zafeiriou, L Arrabal-Fernandez, P Dill, FS Eichler, B Echenne, LG Gutierrez-Solana, GF Hoffmann, K Hyland, K Kusmierska, MA Tijssen, T Lutz, M Mazzuca, J Penzien, BT Poll-The, J Sykut-Cegielska, K Szymanska, B Thöny, N Blau. Sepiapterin reductase deficiency: a treatable mimic of cerebral palsy.. Ann Neurol 2012;71:520-30",
"JR Friedman. What is not in the name? Dopa-responsive dystonia may respond to more than L-dopa.. Pediatr Neurol 2016;59:76-80",
"Y Furukawa. Update on dopa-responsive dystonia: locus heterogeneity and biochemical features.. Adv Neurol 2004;94:127-38",
"Y Furukawa, JJ Filiano, SJ Kish. Amantadine for levodopa-induced choreic dyskinesia in compound heterozygotes for GCH1 mutations.. Mov Disord 2004a;19:1256-58",
"Y Furukawa, WD Graf, H Wong, M Shimadzu, SJ Kish. Dopa-responsive dystonia simulating spastic paraplegia due to tyrosine hydroxylase (TH) gene mutations.. Neurology 2001;56:260-3",
"Y Furukawa, G Kapatos, JW Haycock, J Worsley, H Wong, SJ Kish, TG Nygaard. Brain biopterin and tyrosine hydroxylase in asymptomatic dopa-responsive dystonia.. Ann Neurol. 2002;51:637-41",
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"Y Furukawa, SJ Kish. Parkinsonism in GTP cyclohydrolase 1-deficient DOPA-responsive dystonia.. Brain 2015;138",
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"Y Furukawa, TG Nygaard, M Gütlich, AH Rajput, C Pifl, L DiStefano, LJ Chang, K Price, M Shimadzu, O Hornykiewicz, JW Haycock, SJ Kish. Striatal biopterin and tyrosine hydroxylase protein reduction in dopa-responsive dystonia.. Neurology. 1999;53:1032-41",
"Y Furukawa, AH Rajput, J Tong, Y Tomizawa, O Hornykiewicz, SJ Kish. A marked contrast between serotonergic and dopaminergic changes in dopa-responsive dystonia.. Neurology 2016;87:1060-1",
"Y Furukawa, M Shimadzu, AH Rajput, Y Shimizu, T Tagawa, H Mori, M Yokochi, H Narabayashi, O Hornykiewicz, Y Mizuno, SJ Kish. GTP-cyclohydrolase I gene mutations in hereditary progressive amd dopa-responsive dystonia.. Ann Neurol 1996;39:609-17",
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"DA Grimes, CL Barclay, J Duff, Y Furukawa, AE Lang. Phenocopies in a large GCH1 mutation positive family with dopa responsive dystonia: confusing the picture?. J Neurol Neurosurg Psychiatry 2002;72:801-4",
"T Hanihara, K Inoue, C Kawanishi, N Sugiyama, T Miyakawa, H Onishi, Y Yamada, H Osaka, K Kosaka, K Iwabuchi, M. Owada. 6-Pyruvoyl-tetrahydropterin synthase deficiency with generalized dystonia and diurnal fluctuation of symptoms: a clinical and molecular study.. Mov Disord. 1997;12:408-11",
"K Haugarvoll, LA Bindoff. A novel compound heterozygous tyrosine hydroxylase mutation (p.R441P) with complex phenotype.. J Parkinsons Dis 2011;1:119-22",
"M Häussler, GF Hoffmann, RA Wevers. L-dopa and selegiline for tyrosine hydroxylase deficiency.. J Pediatr 2001;138:451-2",
"GF Hoffmann, B Assmann, C Bräutigam, C Dionisi-Vici, M Häussler, JB de Klerk, M Naumann, GC Steenbergen-Spanjers, HM Strassburg, RA Wevers. Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia.. Ann Neurol. 2003;54:S56-65",
"RJ Janssen, RA Wevers, M Häussler, JA Luyten, GC Steenbergen-Spanjers, GF Hoffmann, T Nagatsu, LP Van den Heuvel. A branch site mutation leading to aberrant splicing of the human tyrosine hydroxylase gene in a child with a severe extrapyramidal movement disorder.. Ann Hum Genet 2000;64:375-82",
"N Kaneda, K Kobayashi, H Ichinose, F Kishi, A Nakazawa, Y Kurosawa, K Fujita, T Nagatsu. Isolation of a novel cDNA clone for human tyrosine hydroxylase: alternative RNA splicing produces four kinds of mRNA from a single gene.. Biochem Biophys Res Commun 1987;146:971-5",
"PM Knappskog, T Flatmark, J Mallet, B Lüdecke, K Bartholomé. Recessively inherited L-DOPA-responsive dystonia caused by a point mutation (Q381K) in the tyrosine hydroxylase gene.. Hum Mol Genet 1995;4:1209-12",
"K Kobayashi, T Nagatsu. Molecular genetics of tyrosine 3-monooxygenase and inherited diseases.. Biochem Biophys Res Commun 2005;338:267-70",
"V Leuzzi, M Mastrangelo, MT Giannini, R Carbonetti, GF Hoffmann. Neuromotor and cognitive outcomes of early treatment in tyrosine hydroxylase deficiency type B.. Neurology 2017;88:501-2",
"B Lüdecke, B Dworniczak, K Bartholomé. A point mutation in the tyrosine hydroxylase gene associated with Segawa's syndrome.. Hum Genet 1995;95:123-5",
"B Lüdecke, PM Knappskog, PT Clayton, RA Surtees, JD Clelland, SJ Heales, MP Brand, K Bartholomé, T Flatmark. Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene.. Hum Mol Genet 1996;5:1023-8",
"C Marras, K Lohmann, A Lang, C Klein. Fixing the broken system of genetic locus symbols: Parkinson disease and dystonia as examples.. Neurology. 2012;78:1016-24",
"LB Møller, A Romstad, M Paulsen, P Hougaard, A Ormazabal, M Pineda, N Blau, F Güttler, R Artuch. Pre- and postnatal diagnosis of tyrosine hydroxylase deficiency.. Prenat Diagn 2005;25:671-5",
"H Najmabadi, H Hu, M Garshasbi, T Zemojtel, SS Abedini, W Chen, M Hosseini, F Behjati, S Haas, P Jamali, A Zecha, M Mohseni, L Püttmann, LN Vahid, C Jensen, LA Moheb, M Bienek, F Larti, I Mueller, R Weissmann, H Darvish, K Wrogemann, V Hadavi, B Lipkowitz, S Esmaeeli-Nieh, D Wieczorek, R Kariminejad, SG Firouzabadi, M Cohen, Z Fattahi, I Rost, F Mojahedi, C Hertzberg, A Dehghan, A Rajab, MJ Banavandi, J Hoffer, M Falah, L Musante, V Kalscheuer, R Ullmann, AW Kuss, A Tzschach, K Kahrizi, HH Ropers. Deep sequencing reveals 50 novel genes for recessive cognitive disorders.. Nature. 2011;478:57-63",
"BG Neville, R Parascandalo, R Farrugia, A Felice. Sepiapterin reductase deficiency: a congenital dopa-responsive motor and cognitive disorder.. Brain 2005;128:2291-6",
"TG Nygaard. Dopa-responsive dystonia: delineation of the clinical syndrome and clues to pathogenesis.. Adv Neurol 1993;60:577-85",
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"A Ormazabal, M Serrano, A Garcia-Cazorla, J Campistol, R Artuch, P Castro de Castro, E Barredo-Valderrama, J Armstrong, C Toma, B. Cormand. Deletion in the tyrosine hydroxylase gene in a patient with a mild phenotype.. Mov Disord 2011;26:1558-60",
"C Ortez, ST Duarte, A Ormazábal, M Serrano, A Pérez, R Pons, M Pineda, Z Yapici, E Fernández-Álvarez, R Domingo-Jiménez, P De Castro, R Artuch, A García-Cazorla. Cerebrospinal fluid synaptic proteins as useful biomarkers in tyrosine hydroxylase deficiency.. Mol Genet Metab 2015;114:34-40",
"R Pons, M Serrano, A Ormazabal, C Toma, A Garcia-Cazorla, E Area, M Ribasés, E Kanavakis, K Drakaki, A Giannakopoulos, I Orfanou, S Youroukos, B Cormand, R. Artuch. Tyrosine hydroxylase deficiency in three Greek patients with a common ancestral mutation.. Mov Disord. 2010;25:1086-90",
"R Pons, D Syrengelas, S Youroukos, I Orfanou, A Dinopoulos, B Cormand, A Ormazabal, A Garzía-Cazorla, M Serrano, R. Artuch. Levodopa-induced dyskinesias in tyrosine hydroxylase deficiency.. Mov Disord. 2013;28:1058-63",
"M Ribasés, M Serrano, E Fernandez-Alvarez, S Pahisa, A Ormazabal, A Garcia-Cazorla, B Perez-Duenas, J Campistol, R Artuch, B Cormand. A homozygous tyrosine hydroxylase gene promoter mutation in a patient with dopa-responsive encephalopathy: clinical, biochemical and genetic analysis.. Mol Genet Metab 2007;92:274-7",
"P Rondot, J Aicardi, F Goutières, M. Ziegler. Dopa-sensitive dystonia. Rev Neurol (Paris) 1992;148:680-6",
"P Rondot, M. Ziegler. Dystonia--L-dopa responsive or juvenile parkinsonism?. J Neural Transm Suppl. 1983;19:273-81",
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] |
8/2/2008
|
11/5/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
thoc6-id
|
thoc6-id
|
[
"Beaulieu-Boycott-Innes Syndrome",
"Beaulieu-Boycott-Innes Syndrome",
"THO complex subunit 6",
"THOC6",
"THOC6 Intellectual Disability Syndrome"
] |
Gabrielle Lemire, A Micheil Innes, Kym M Boycott
|
Summary The diagnosis of
|
## Diagnosis
Formal diagnostic criteria for
Moderate-to-severe developmental delay (DD) or intellectual disability (ID)
AND
One or more of the following features presenting in infancy or childhood:
Microcephaly
Multiple dental caries and/or dental malocclusion
Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
Cryptorchidism in males
Structural cardiac anomalies
Structural renal anomalies
Ventriculomegaly on brain imaging
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 in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). CMA uses oligonucleotide and/or SNP arrays to detect genome-wide large deletions/duplications (including
For individuals from the
For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of
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
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and other malformations,
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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Moderate-to-severe developmental delay (DD) or intellectual disability (ID)
• AND
• One or more of the following features presenting in infancy or childhood:
• Microcephaly
• Multiple dental caries and/or dental malocclusion
• Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
• Cryptorchidism in males
• Structural cardiac anomalies
• Structural renal anomalies
• Ventriculomegaly on brain imaging
• Microcephaly
• Multiple dental caries and/or dental malocclusion
• Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
• Cryptorchidism in males
• Structural cardiac anomalies
• Structural renal anomalies
• Ventriculomegaly on brain imaging
• Microcephaly
• Multiple dental caries and/or dental malocclusion
• Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
• Cryptorchidism in males
• Structural cardiac anomalies
• Structural renal anomalies
• Ventriculomegaly on brain imaging
• For individuals from the
• For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of
## Suggestive Findings
Moderate-to-severe developmental delay (DD) or intellectual disability (ID)
AND
One or more of the following features presenting in infancy or childhood:
Microcephaly
Multiple dental caries and/or dental malocclusion
Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
Cryptorchidism in males
Structural cardiac anomalies
Structural renal anomalies
Ventriculomegaly on brain imaging
• Moderate-to-severe developmental delay (DD) or intellectual disability (ID)
• AND
• One or more of the following features presenting in infancy or childhood:
• Microcephaly
• Multiple dental caries and/or dental malocclusion
• Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
• Cryptorchidism in males
• Structural cardiac anomalies
• Structural renal anomalies
• Ventriculomegaly on brain imaging
• Microcephaly
• Multiple dental caries and/or dental malocclusion
• Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
• Cryptorchidism in males
• Structural cardiac anomalies
• Structural renal anomalies
• Ventriculomegaly on brain imaging
• Microcephaly
• Multiple dental caries and/or dental malocclusion
• Nonspecific dysmorphic features, including tall forehead, deep set eyes, short and upslanted palpebral fissures, epicanthal folds and long nose with low hanging columella
• Cryptorchidism in males
• Structural cardiac anomalies
• Structural renal anomalies
• Ventriculomegaly on brain imaging
## 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 in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). CMA uses oligonucleotide and/or SNP arrays to detect genome-wide large deletions/duplications (including
For individuals from the
For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of
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
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and other malformations,
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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For individuals from the
• For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of
## Molecular Genetic Testing
Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). CMA uses oligonucleotide and/or SNP arrays to detect genome-wide large deletions/duplications (including
For individuals from the
For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of
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
• For individuals from the
• For individuals who do not originate from the Hutterite population, single-gene testing (sequence analysis of
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and other malformations,
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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Features of
Ventriculomegaly may not have been assessed in all 19 reported cases in the literature so this may underestimate the actual incidence.
Moderate-to-severe intellectual disability has been noted in all reported individuals. Most of these individuals were able to walk independently, but remained nonverbal or had very limited speech (<10 words). The oldest reported individuals are young adults.
Most reported individuals had congenital microcephaly, predominantly 2-3 SD below the mean; 5 SD below the mean was observed in one child [
One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [
One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [
Corpus callosum dysgenesis was identified in five reported individuals [
Low birth weight was present in most reported individuals, and intrauterine growth restriction was documented in four [
Five individuals had failure to thrive in childhood [
Eight reported individuals were of short stature, in the range of 2-3 SD below the mean.
Three individuals presented with feeding difficulties, two requiring feeding through a gastrostomy tube because of inadequate caloric intake by mouth [
Dysmorphic facial features were present in most reported individuals and included the following: tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella (
Other reported ocular anomalies include bilateral optic disc hypoplasia [
Atrial septal defect, ventricular septal defect, and patent ductus arteriosus were present in eight reported individuals. A dysmorphic and mildly insufficient mitral valve was also seen in one individual [
Cryptorchidism, bilateral or unilateral, was present in seven affected males.
Two males presented with a micropenis [
Premature ovarian failure was identified in one teenage girl [
Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [
Endometriosis was reported in one female [
Unilateral renal agenesis was identified in four individuals [
An ectopic kidney located in the pelvis or a horseshoe kidney was reported in three individuals [
Recurrent urinary tract infections were seen in three individuals [
Cervical hemivertebrae and multilevel vertebral segmentation defects causing a scoliosis were reported in two different individuals [
Two individuals presented with camptodactyly [
Other reported anomalies include pes planus, trigger thumb, calcaneovalgus and equinovarus deformities, cubitus valgus, congenital hip dislocation, radioulnar joint dysostosis, cervical rib, and Sprengel deformity.
It is unknown whether life span in
No genotype-phenotype correlations have been identified.
As of early 2020, seven years after this syndrome was first described and molecularly explained, 19 affected individuals have been reported in the literature.
Initially reported in the Hutterite population [
• One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [
• One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [
• Cryptorchidism, bilateral or unilateral, was present in seven affected males.
• Two males presented with a micropenis [
• Premature ovarian failure was identified in one teenage girl [
• Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [
• Endometriosis was reported in one female [
## Clinical Description
Features of
Ventriculomegaly may not have been assessed in all 19 reported cases in the literature so this may underestimate the actual incidence.
Moderate-to-severe intellectual disability has been noted in all reported individuals. Most of these individuals were able to walk independently, but remained nonverbal or had very limited speech (<10 words). The oldest reported individuals are young adults.
Most reported individuals had congenital microcephaly, predominantly 2-3 SD below the mean; 5 SD below the mean was observed in one child [
One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [
One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [
Corpus callosum dysgenesis was identified in five reported individuals [
Low birth weight was present in most reported individuals, and intrauterine growth restriction was documented in four [
Five individuals had failure to thrive in childhood [
Eight reported individuals were of short stature, in the range of 2-3 SD below the mean.
Three individuals presented with feeding difficulties, two requiring feeding through a gastrostomy tube because of inadequate caloric intake by mouth [
Dysmorphic facial features were present in most reported individuals and included the following: tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella (
Other reported ocular anomalies include bilateral optic disc hypoplasia [
Atrial septal defect, ventricular septal defect, and patent ductus arteriosus were present in eight reported individuals. A dysmorphic and mildly insufficient mitral valve was also seen in one individual [
Cryptorchidism, bilateral or unilateral, was present in seven affected males.
Two males presented with a micropenis [
Premature ovarian failure was identified in one teenage girl [
Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [
Endometriosis was reported in one female [
Unilateral renal agenesis was identified in four individuals [
An ectopic kidney located in the pelvis or a horseshoe kidney was reported in three individuals [
Recurrent urinary tract infections were seen in three individuals [
Cervical hemivertebrae and multilevel vertebral segmentation defects causing a scoliosis were reported in two different individuals [
Two individuals presented with camptodactyly [
Other reported anomalies include pes planus, trigger thumb, calcaneovalgus and equinovarus deformities, cubitus valgus, congenital hip dislocation, radioulnar joint dysostosis, cervical rib, and Sprengel deformity.
It is unknown whether life span in
• One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [
• One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [
• Cryptorchidism, bilateral or unilateral, was present in seven affected males.
• Two males presented with a micropenis [
• Premature ovarian failure was identified in one teenage girl [
• Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [
• Endometriosis was reported in one female [
## Developmental Delay (DD) / Intellectual Disability (ID)
Moderate-to-severe intellectual disability has been noted in all reported individuals. Most of these individuals were able to walk independently, but remained nonverbal or had very limited speech (<10 words). The oldest reported individuals are young adults.
## Neurologic
Most reported individuals had congenital microcephaly, predominantly 2-3 SD below the mean; 5 SD below the mean was observed in one child [
One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [
One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [
Corpus callosum dysgenesis was identified in five reported individuals [
• One child had postnatal hydrocephalus that required ventriculoperitoneal shunt placement [
• One individual had compensated supratentorial hydrocephalus due to aqueductal stenosis and was also reported to have cerebellar hypoplasia with severe vermian dysgenesis, small pons, hippocampal dysgenesis, and partial agenesis of the septum pellucidum [
## Growth
Low birth weight was present in most reported individuals, and intrauterine growth restriction was documented in four [
Five individuals had failure to thrive in childhood [
Eight reported individuals were of short stature, in the range of 2-3 SD below the mean.
## Gastrointestinal Problems
Three individuals presented with feeding difficulties, two requiring feeding through a gastrostomy tube because of inadequate caloric intake by mouth [
## Facial Features
Dysmorphic facial features were present in most reported individuals and included the following: tall forehead, deep-set eyes, short and upslanted palpebral fissures, epicanthal folds, and long nose with low-hanging columella (
## Sensory Impairment
Other reported ocular anomalies include bilateral optic disc hypoplasia [
## ENT/Mouth
## Cardiovascular Anomalies
Atrial septal defect, ventricular septal defect, and patent ductus arteriosus were present in eight reported individuals. A dysmorphic and mildly insufficient mitral valve was also seen in one individual [
## Genital Anomalies / Puberty
Cryptorchidism, bilateral or unilateral, was present in seven affected males.
Two males presented with a micropenis [
Premature ovarian failure was identified in one teenage girl [
Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [
Endometriosis was reported in one female [
• Cryptorchidism, bilateral or unilateral, was present in seven affected males.
• Two males presented with a micropenis [
• Premature ovarian failure was identified in one teenage girl [
• Hypergonadotropic hypogonadism with primary amenorrhea requiring hormone replacement therapy was reported in another girl [
• Endometriosis was reported in one female [
## Renal Anomalies
Unilateral renal agenesis was identified in four individuals [
An ectopic kidney located in the pelvis or a horseshoe kidney was reported in three individuals [
Recurrent urinary tract infections were seen in three individuals [
## Skeletal Features
Cervical hemivertebrae and multilevel vertebral segmentation defects causing a scoliosis were reported in two different individuals [
Two individuals presented with camptodactyly [
Other reported anomalies include pes planus, trigger thumb, calcaneovalgus and equinovarus deformities, cubitus valgus, congenital hip dislocation, radioulnar joint dysostosis, cervical rib, and Sprengel deformity.
## Prognosis
It is unknown whether life span in
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
As of early 2020, seven years after this syndrome was first described and molecularly explained, 19 affected individuals have been reported in the literature.
Initially reported in the Hutterite population [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Several intellectual disability disorders are associated with additional features that overlap those observed in
However, because the phenotypic features associated with
Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance
Typically the result of a
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl brain MRI to assess for hydrocephalus or other cerebral anomalies
Consider EEG if seizures are a concern.
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for unilateral renal agenesis, ectopic kidney, or horseshoe kidney.
Assess renal function
Gross motor & fine motor skills
Contractures, vertebral defects, & kyphoscoliosis
Mobility, ADLs, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or online
Social work involvement for parental support;
Home nursing referral.
ADLs = activities of daily living; OT = occupational therapy; PT = physical therapy
Such as blood urea nitrogen (BUN), creatinine, and urinalysis
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.
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; HRT = hormone replacement 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
Pes planus, trigger thumb, equinovarus deformity, & congenital hip dislocation
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
Assess for signs & symptoms of hydrocephalus.
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
OT = occupational therapy; PT = physical therapy
Such as blood urea nitrogen (BUN), creatinine, and urinalysis
See
Search
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl brain MRI to assess for hydrocephalus or other cerebral anomalies
• Consider EEG if seizures are a concern.
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for unilateral renal agenesis, ectopic kidney, or horseshoe kidney.
• Assess renal function
• Gross motor & fine motor skills
• Contractures, vertebral defects, & kyphoscoliosis
• Mobility, ADLs, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or online
• 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 (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
• Assess for signs & symptoms of hydrocephalus.
• 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
## 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
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl brain MRI to assess for hydrocephalus or other cerebral anomalies
Consider EEG if seizures are a concern.
Incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Assess for unilateral renal agenesis, ectopic kidney, or horseshoe kidney.
Assess renal function
Gross motor & fine motor skills
Contractures, vertebral defects, & kyphoscoliosis
Mobility, ADLs, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Community or online
Social work involvement for parental support;
Home nursing referral.
ADLs = activities of daily living; OT = occupational therapy; PT = physical therapy
Such as blood urea nitrogen (BUN), creatinine, and urinalysis
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl brain MRI to assess for hydrocephalus or other cerebral anomalies
• Consider EEG if seizures are a concern.
• Incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Assess for unilateral renal agenesis, ectopic kidney, or horseshoe kidney.
• Assess renal function
• Gross motor & fine motor skills
• Contractures, vertebral defects, & kyphoscoliosis
• Mobility, ADLs, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Community or online
• 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.
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; HRT = hormone replacement 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
Pes planus, trigger thumb, equinovarus deformity, & congenital hip dislocation
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 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 (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 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
Assess for signs & symptoms of hydrocephalus.
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
OT = occupational therapy; PT = physical therapy
Such as blood urea nitrogen (BUN), creatinine, and urinalysis
• Assess for signs & symptoms of hydrocephalus.
• 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
## 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
Rarely, only one parent is heterozygous for a
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If the proband has the disorder as the result of uniparental isodisomy for chromosome 16 and only one parent 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 the availability of prenatal/preimplantation genetic testing is before 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 obligate heterozygotes (i.e., presumed to be carriers of one
• Rarely, only one parent is heterozygous for a
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• If the proband has the disorder as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for 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
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
Rarely, only one parent is heterozygous for a
Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
And the child appears to have homozygous
And the child has compound heterozygous
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
If the proband has the disorder as the result of uniparental isodisomy for chromosome 16 and only one parent is heterozygous for a
• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one
• Rarely, only one parent is heterozygous for a
• Accurate recurrence risk counseling relies on carrier testing of both parents to determine if each is heterozygous for a
• And the child appears to have homozygous
• And the child has compound heterozygous
• And the child appears to have homozygous
• And the child has compound heterozygous
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• And the child appears to have homozygous
• And the child has compound heterozygous
• If both parents are known to be heterozygous for a
• If the proband has the disorder as the result of uniparental isodisomy for chromosome 16 and only one parent 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 the availability of prenatal/preimplantation genetic testing is before 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.
## Resources
•
•
•
•
## Molecular Genetics
THOC6 Intellectual Disability Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for THOC6 Intellectual Disability Syndrome (
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
Of note, there is an online RareConnect community for
13 August 2020 (ma) Review posted live
18 March 2020 (kb) Original submission
• 13 August 2020 (ma) Review posted live
• 18 March 2020 (kb) Original submission
## Author Notes
Of note, there is an online RareConnect community for
## Revision History
13 August 2020 (ma) Review posted live
18 March 2020 (kb) Original submission
• 13 August 2020 (ma) Review posted live
• 18 March 2020 (kb) Original submission
## References
## Literature Cited
Photographs of individuals with
Reproduced from
|
[] |
13/8/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
timothy
|
timothy
|
[
"Timothy Syndrome",
"Timothy Syndrome",
"CACNA1C-Related Neurodevelopmental Syndrome",
"CACNA1C-Related Nonsyndromic Long QT Syndrome",
"CACNA1C-Related Nonsyndromic Short QT Syndrome",
"CACNA1C-Related Brugada Syndrome with Short QT",
"Voltage-dependent L-type calcium channel subunit alpha-1C",
"CACNA1C",
"CACNA1C-Related Disorders"
] |
Carlo Napolitano, Silvia G Priori
|
Summary The clinical manifestations of The diagnosis of a
|
Timothy syndrome
Nonsyndromic long QT syndrome
Nonsyndromic short QT syndrome
Brugada syndrome with short QT
For synonyms and outdated names see
The phenotypic spectrum of heterozygous
For other genetic causes of these phenotypes, see
• Timothy syndrome
• Nonsyndromic long QT syndrome
• Nonsyndromic short QT syndrome
• Brugada syndrome with short QT
## Diagnosis
Cardiovascular malformations such as ventricular septal defect, tetralogy of Fallot, or hypertrophic cardiomyopathy
Unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three
Isolated neurologic manifestations, including:
Mild intellectual disability
Apraxia (constructional, dressing, and orobuccal)
Hypotonia
Poor balance or coordination
Autism spectrum disorder
Epilepsy, including generalized and/or focal seizures
Nonspecific dysmorphic facial features (See
A prolonged QT interval on electrocardiogram (EKG) (rate-corrected QT [QTc] interval >480 ms)
ST segment elevation in right precordial leads (V1-V2) diagnostic for Brugada syndrome (type 1 EKG) associated with a short QT interval
Short QT interval (QTc <350 ms) and risk of sudden death
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
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.
Intragenic deletions and duplications have been reported [
• Cardiovascular malformations such as ventricular septal defect, tetralogy of Fallot, or hypertrophic cardiomyopathy
• Unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three
• Isolated neurologic manifestations, including:
• Mild intellectual disability
• Apraxia (constructional, dressing, and orobuccal)
• Hypotonia
• Poor balance or coordination
• Mild intellectual disability
• Apraxia (constructional, dressing, and orobuccal)
• Hypotonia
• Poor balance or coordination
• Autism spectrum disorder
• Epilepsy, including generalized and/or focal seizures
• Nonspecific dysmorphic facial features (See
• Mild intellectual disability
• Apraxia (constructional, dressing, and orobuccal)
• Hypotonia
• Poor balance or coordination
• A prolonged QT interval on electrocardiogram (EKG) (rate-corrected QT [QTc] interval >480 ms)
• ST segment elevation in right precordial leads (V1-V2) diagnostic for Brugada syndrome (type 1 EKG) associated with a short QT interval
• Short QT interval (QTc <350 ms) and risk of sudden death
## Suggestive Findings
Cardiovascular malformations such as ventricular septal defect, tetralogy of Fallot, or hypertrophic cardiomyopathy
Unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three
Isolated neurologic manifestations, including:
Mild intellectual disability
Apraxia (constructional, dressing, and orobuccal)
Hypotonia
Poor balance or coordination
Autism spectrum disorder
Epilepsy, including generalized and/or focal seizures
Nonspecific dysmorphic facial features (See
A prolonged QT interval on electrocardiogram (EKG) (rate-corrected QT [QTc] interval >480 ms)
ST segment elevation in right precordial leads (V1-V2) diagnostic for Brugada syndrome (type 1 EKG) associated with a short QT interval
Short QT interval (QTc <350 ms) and risk of sudden death
• Cardiovascular malformations such as ventricular septal defect, tetralogy of Fallot, or hypertrophic cardiomyopathy
• Unilateral or bilateral cutaneous syndactyly variably involving fingers two (index), three (middle), four (ring), and five (little) and bilateral cutaneous syndactyly of toes two and three
• Isolated neurologic manifestations, including:
• Mild intellectual disability
• Apraxia (constructional, dressing, and orobuccal)
• Hypotonia
• Poor balance or coordination
• Mild intellectual disability
• Apraxia (constructional, dressing, and orobuccal)
• Hypotonia
• Poor balance or coordination
• Autism spectrum disorder
• Epilepsy, including generalized and/or focal seizures
• Nonspecific dysmorphic facial features (See
• Mild intellectual disability
• Apraxia (constructional, dressing, and orobuccal)
• Hypotonia
• Poor balance or coordination
• A prolonged QT interval on electrocardiogram (EKG) (rate-corrected QT [QTc] interval >480 ms)
• ST segment elevation in right precordial leads (V1-V2) diagnostic for Brugada syndrome (type 1 EKG) associated with a short QT interval
• Short QT interval (QTc <350 ms) and risk of sudden death
## 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
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.
Intragenic deletions and duplications have been reported [
## 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.
Intragenic deletions and duplications have been reported [
## Clinical Characteristics
The first
With the increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with
Therefore, the clinical manifestations include a spectrum of nonsyndromic and syndromic phenotypes, which generally correlate with the impact of the pathogenic variant on calcium current (see
Classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without syndactyly
Note: For this phenotype, gain-of-function, neutral effect, and loss-of-function pathogenic variants have all been reported in affected individuals [
Nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms)
Short QT syndrome (QTc <350 ms), with risk of sudden death [
Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval
The clinical phenotype associated with large deletions/duplications is less defined, as few individuals with this phenotype have been reported (see
AV = atrioventricular
Including intragenic deletions and duplications
Occasionally, the diagnosis of a
Affected children have been reported to be impaired in all areas of adaptive function, including communication, socialization, and daily living skills.
Verbal disabilities are poorly characterized but the few cases described show a large degree of variability, including some affected individuals who are completely nonverbal.
Some reported children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language [
Hypotonia
Ataxia
Feeding issues. Individuals with the Timothy syndrome phenotype can have feeding issues that may require feeding therapy, thickened feeds, or (in severe cases) a nasogastric or gastrostomy tube placement (see
Apraxia, which may be constructional, dressing, and/or orobuccal
Staring followed by syncope
Focal seizures with eye blinking and facial twitching
Daily tonic seizures
Late-onset partial epilepsy
Epileptic encephalopathy, including severe epileptic encephalopathy during infancy
Baldness at birth and for the first two years of life, followed by thin scalp hair
Round face
Depressed nasal bridge
Premaxillary underdevelopment
Low-set ears
Thin vermilion of the upper lip
Small, widely spaced teeth and poor dental enamel with severe caries
Gingival hyperplasia
Frequent infections (sinus, ear, respiratory). Two individuals with "common variable immunodeficiency" (CVID) and
Intermittent hypoglycemia [
The long-term outcome of individuals with neurologic involvement without apparent cardiac manifestations is poorly characterized. Disabilities (verbal, language, hypotonia, and balance/coordination) are descried in adulthood but the evolution (worsening or improvement) at follow up is not known [
The following electrophysiologic findings:
Long QTc
Bradycardia
2:1 AV block
Macroscopic T-wave alternans
Tacchyarrythmia / sudden death
Congenital heart defects
Cutaneous syndactyly
Typical facial features
Developmental delay / intellectual disability
Autism spectrum disorder
Seizures
Recurrent infections
Note: All reported
Short QT syndrome
Brugada syndrome
Sudden death
The penetrance of pathogenic variants associated with typical Timothy syndrome is 100% [
The term "Timothy syndrome" (also referred to as Timothy syndrome type 1) was named for Katherine Timothy, who followed children with that phenotype for more than 14 years, identifying the non-cardiac manifestations and collecting samples that led to the discovery of the gene in which pathogenic variants are causative.
"Atypical Timothy syndrome" (formerly referred to as Timothy syndrome type 2) was the term used to describe individuals who had QT interval prolongation without syndactyly.
"LQT8" is used in medical literature to refer to both Timothy syndrome and nonsyndromic
"BRGDA3" refers to
"SQT6" refers to
Timothy syndrome is a very rare condition, probably because of its very high mortality. Approximately 100 cases have been described worldwide. A recent United States survey using a questionnaire sent to families of individuals with the Timothy syndrome phenotype identified 105 people; the majority of identified affected individuals have the p.Gly406Arg pathogenic variant in exon 8A (see
The prevalence of nonsyndromic
• Classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without syndactyly
• Note: For this phenotype, gain-of-function, neutral effect, and loss-of-function pathogenic variants have all been reported in affected individuals [
• Nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms)
• Short QT syndrome (QTc <350 ms), with risk of sudden death [
• Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval
• Occasionally, the diagnosis of a
• Occasionally, the diagnosis of a
• Occasionally, the diagnosis of a
• Affected children have been reported to be impaired in all areas of adaptive function, including communication, socialization, and daily living skills.
• Verbal disabilities are poorly characterized but the few cases described show a large degree of variability, including some affected individuals who are completely nonverbal.
• Some reported children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language [
• Hypotonia
• Ataxia
• Feeding issues. Individuals with the Timothy syndrome phenotype can have feeding issues that may require feeding therapy, thickened feeds, or (in severe cases) a nasogastric or gastrostomy tube placement (see
• Apraxia, which may be constructional, dressing, and/or orobuccal
• Staring followed by syncope
• Focal seizures with eye blinking and facial twitching
• Daily tonic seizures
• Late-onset partial epilepsy
• Epileptic encephalopathy, including severe epileptic encephalopathy during infancy
• Baldness at birth and for the first two years of life, followed by thin scalp hair
• Round face
• Depressed nasal bridge
• Premaxillary underdevelopment
• Low-set ears
• Thin vermilion of the upper lip
• Small, widely spaced teeth and poor dental enamel with severe caries
• Gingival hyperplasia
• Frequent infections (sinus, ear, respiratory). Two individuals with "common variable immunodeficiency" (CVID) and
• Intermittent hypoglycemia [
• The following electrophysiologic findings:
• Long QTc
• Bradycardia
• 2:1 AV block
• Macroscopic T-wave alternans
• Tacchyarrythmia / sudden death
• Long QTc
• Bradycardia
• 2:1 AV block
• Macroscopic T-wave alternans
• Tacchyarrythmia / sudden death
• Congenital heart defects
• Cutaneous syndactyly
• Typical facial features
• Developmental delay / intellectual disability
• Autism spectrum disorder
• Seizures
• Recurrent infections
• Long QTc
• Bradycardia
• 2:1 AV block
• Macroscopic T-wave alternans
• Tacchyarrythmia / sudden death
• Short QT syndrome
• Brugada syndrome
• Sudden death
## Clinical Description
The first
With the increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with
Therefore, the clinical manifestations include a spectrum of nonsyndromic and syndromic phenotypes, which generally correlate with the impact of the pathogenic variant on calcium current (see
Classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without syndactyly
Note: For this phenotype, gain-of-function, neutral effect, and loss-of-function pathogenic variants have all been reported in affected individuals [
Nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms)
Short QT syndrome (QTc <350 ms), with risk of sudden death [
Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval
The clinical phenotype associated with large deletions/duplications is less defined, as few individuals with this phenotype have been reported (see
AV = atrioventricular
Including intragenic deletions and duplications
Occasionally, the diagnosis of a
Affected children have been reported to be impaired in all areas of adaptive function, including communication, socialization, and daily living skills.
Verbal disabilities are poorly characterized but the few cases described show a large degree of variability, including some affected individuals who are completely nonverbal.
Some reported children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language [
Hypotonia
Ataxia
Feeding issues. Individuals with the Timothy syndrome phenotype can have feeding issues that may require feeding therapy, thickened feeds, or (in severe cases) a nasogastric or gastrostomy tube placement (see
Apraxia, which may be constructional, dressing, and/or orobuccal
Staring followed by syncope
Focal seizures with eye blinking and facial twitching
Daily tonic seizures
Late-onset partial epilepsy
Epileptic encephalopathy, including severe epileptic encephalopathy during infancy
Baldness at birth and for the first two years of life, followed by thin scalp hair
Round face
Depressed nasal bridge
Premaxillary underdevelopment
Low-set ears
Thin vermilion of the upper lip
Small, widely spaced teeth and poor dental enamel with severe caries
Gingival hyperplasia
Frequent infections (sinus, ear, respiratory). Two individuals with "common variable immunodeficiency" (CVID) and
Intermittent hypoglycemia [
The long-term outcome of individuals with neurologic involvement without apparent cardiac manifestations is poorly characterized. Disabilities (verbal, language, hypotonia, and balance/coordination) are descried in adulthood but the evolution (worsening or improvement) at follow up is not known [
• Classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without syndactyly
• Note: For this phenotype, gain-of-function, neutral effect, and loss-of-function pathogenic variants have all been reported in affected individuals [
• Nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval >480 ms)
• Short QT syndrome (QTc <350 ms), with risk of sudden death [
• Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval
• Occasionally, the diagnosis of a
• Occasionally, the diagnosis of a
• Occasionally, the diagnosis of a
• Affected children have been reported to be impaired in all areas of adaptive function, including communication, socialization, and daily living skills.
• Verbal disabilities are poorly characterized but the few cases described show a large degree of variability, including some affected individuals who are completely nonverbal.
• Some reported children did not produce speech sounds (babbling) during infancy; others had significant problems in articulation and receptive and expressive language [
• Hypotonia
• Ataxia
• Feeding issues. Individuals with the Timothy syndrome phenotype can have feeding issues that may require feeding therapy, thickened feeds, or (in severe cases) a nasogastric or gastrostomy tube placement (see
• Apraxia, which may be constructional, dressing, and/or orobuccal
• Staring followed by syncope
• Focal seizures with eye blinking and facial twitching
• Daily tonic seizures
• Late-onset partial epilepsy
• Epileptic encephalopathy, including severe epileptic encephalopathy during infancy
• Baldness at birth and for the first two years of life, followed by thin scalp hair
• Round face
• Depressed nasal bridge
• Premaxillary underdevelopment
• Low-set ears
• Thin vermilion of the upper lip
• Small, widely spaced teeth and poor dental enamel with severe caries
• Gingival hyperplasia
• Frequent infections (sinus, ear, respiratory). Two individuals with "common variable immunodeficiency" (CVID) and
• Intermittent hypoglycemia [
## Genotype-Phenotype Correlations
The following electrophysiologic findings:
Long QTc
Bradycardia
2:1 AV block
Macroscopic T-wave alternans
Tacchyarrythmia / sudden death
Congenital heart defects
Cutaneous syndactyly
Typical facial features
Developmental delay / intellectual disability
Autism spectrum disorder
Seizures
Recurrent infections
Note: All reported
Short QT syndrome
Brugada syndrome
Sudden death
• The following electrophysiologic findings:
• Long QTc
• Bradycardia
• 2:1 AV block
• Macroscopic T-wave alternans
• Tacchyarrythmia / sudden death
• Long QTc
• Bradycardia
• 2:1 AV block
• Macroscopic T-wave alternans
• Tacchyarrythmia / sudden death
• Congenital heart defects
• Cutaneous syndactyly
• Typical facial features
• Developmental delay / intellectual disability
• Autism spectrum disorder
• Seizures
• Recurrent infections
• Long QTc
• Bradycardia
• 2:1 AV block
• Macroscopic T-wave alternans
• Tacchyarrythmia / sudden death
• Short QT syndrome
• Brugada syndrome
• Sudden death
## Penetrance
The penetrance of pathogenic variants associated with typical Timothy syndrome is 100% [
## Nomenclature
The term "Timothy syndrome" (also referred to as Timothy syndrome type 1) was named for Katherine Timothy, who followed children with that phenotype for more than 14 years, identifying the non-cardiac manifestations and collecting samples that led to the discovery of the gene in which pathogenic variants are causative.
"Atypical Timothy syndrome" (formerly referred to as Timothy syndrome type 2) was the term used to describe individuals who had QT interval prolongation without syndactyly.
"LQT8" is used in medical literature to refer to both Timothy syndrome and nonsyndromic
"BRGDA3" refers to
"SQT6" refers to
## Prevalence
Timothy syndrome is a very rare condition, probably because of its very high mortality. Approximately 100 cases have been described worldwide. A recent United States survey using a questionnaire sent to families of individuals with the Timothy syndrome phenotype identified 105 people; the majority of identified affected individuals have the p.Gly406Arg pathogenic variant in exon 8A (see
The prevalence of nonsyndromic
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Long QT Syndrome with Extracardiac Findings
Congenital profound bilateral sensorineural hearing loss
Classic presentation is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of persons have a cardiac event before age 3 yrs; >50% of untreated children die before age 15 yrs.
Episodic flaccid muscle weakness; anomalies incl low-set ears, widely spaced eyes, small mandible, 5th-digit clinodactyly, syndactyly, short stature, & scoliosis
Presents in 1st or 2nd decade w/cardiac symptoms or weakness that occurs spontaneously after prolonged rest or rest following exertion. Mild permanent weakness is common. Mild learning difficulties & a distinct neurocognitive phenotype (i.e., deficits in executive function & abstract reasoning) have been described.
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Note: Acquired causes of QT prolongation such as electrolyte imbalance (e.g., hypokalemia) or QT-prolonging drugs (e.g., macrolide antibiotics) should be excluded before considering the diagnosis of a
The phenotypic features associated with
• Congenital profound bilateral sensorineural hearing loss
• Classic presentation is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of persons have a cardiac event before age 3 yrs; >50% of untreated children die before age 15 yrs.
• Episodic flaccid muscle weakness; anomalies incl low-set ears, widely spaced eyes, small mandible, 5th-digit clinodactyly, syndactyly, short stature, & scoliosis
• Presents in 1st or 2nd decade w/cardiac symptoms or weakness that occurs spontaneously after prolonged rest or rest following exertion. Mild permanent weakness is common. Mild learning difficulties & a distinct neurocognitive phenotype (i.e., deficits in executive function & abstract reasoning) have been described.
## Genetic Disorders in the Differential Diagnosis of
Long QT Syndrome with Extracardiac Findings
Congenital profound bilateral sensorineural hearing loss
Classic presentation is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of persons have a cardiac event before age 3 yrs; >50% of untreated children die before age 15 yrs.
Episodic flaccid muscle weakness; anomalies incl low-set ears, widely spaced eyes, small mandible, 5th-digit clinodactyly, syndactyly, short stature, & scoliosis
Presents in 1st or 2nd decade w/cardiac symptoms or weakness that occurs spontaneously after prolonged rest or rest following exertion. Mild permanent weakness is common. Mild learning difficulties & a distinct neurocognitive phenotype (i.e., deficits in executive function & abstract reasoning) have been described.
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Note: Acquired causes of QT prolongation such as electrolyte imbalance (e.g., hypokalemia) or QT-prolonging drugs (e.g., macrolide antibiotics) should be excluded before considering the diagnosis of a
• Congenital profound bilateral sensorineural hearing loss
• Classic presentation is a deaf child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of persons have a cardiac event before age 3 yrs; >50% of untreated children die before age 15 yrs.
• Episodic flaccid muscle weakness; anomalies incl low-set ears, widely spaced eyes, small mandible, 5th-digit clinodactyly, syndactyly, short stature, & scoliosis
• Presents in 1st or 2nd decade w/cardiac symptoms or weakness that occurs spontaneously after prolonged rest or rest following exertion. Mild permanent weakness is common. Mild learning difficulties & a distinct neurocognitive phenotype (i.e., deficits in executive function & abstract reasoning) have been described.
## Genetic Disorders in the Differential Diagnosis of
The phenotypic features associated with
## Management
No specific clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
Eval w/pediatric cardiologist incl EKG & echocardiogram
24-hour Holter monitoring is relevant for initial clinical assessment of persons w/Brugada syndrome.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider EEG if seizures are a concern.
Consider MR if seizures are present or encephalopathy is suspected.
Community or
Social work involvement for parental support
ASD = autism spectrum disorder; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Standard care is recommended for cardiovascular malformations, surgical release of syndactyly, and hypoglycemia.
Note: All medical procedures requiring anesthesia should be performed with caution (see
Beta-blockers (nadolol preferred)
Mexiletine can be considered to shorten QT (response is variable & every person must be carefully monitored).
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.
ASM = anti-seizure medication; AV = atrioventricular; DD = developmental delay; ICD = implantable cardioverter defibrillator; ID = intellectual disability
Although
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.
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 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.
Arrhythmias must be prevented with the standard therapy described in
Anesthesia is a known trigger for cardiac arrhythmia in individuals with a
Fever can be a trigger for arrhythmias in individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ASD = autism spectrum disorder; ICD = implantable cardioverter defibrillator; OT = occupational therapy; PT = physical therapy
The following should be avoided:
All drugs reported to prolong QT interval (See
Drugs and dietary practices that could lead to hypoglycemia
It is appropriate to clarify the genetic status of the older and younger at-risk relatives of a proband in order to identify as early as possible those who would benefit from a complete cardiac evaluation, institution of measures to prevent cardiac arrhythmias, and awareness of agents/circumstances to avoid. Predictive genetic testing is recommended for all at-risk family members of all ages from birth onward. Parents of a proband should be screened whenever possible for the known familial pathogenic variant in genomic DNA from peripheral blood lymphocytes or saliva/buccal tissue.
Note: Predictive genetic testing can be used to identify relatives who are heterozygous for a familial
See
Search
Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans.
Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects.
Fetuses at risk of being affected with a
See
• Eval w/pediatric cardiologist incl EKG & echocardiogram
• 24-hour Holter monitoring is relevant for initial clinical assessment of persons w/Brugada syndrome.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider EEG if seizures are a concern.
• Consider MR if seizures are present or encephalopathy is suspected.
• Community or
• Social work involvement for parental support
• Beta-blockers (nadolol preferred)
• Mexiletine can be considered to shorten QT (response is variable & every person must be carefully monitored).
• 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.
• 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.
• 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
• All drugs reported to prolong QT interval (See
• Drugs and dietary practices that could lead to hypoglycemia
• Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans.
• Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects.
• Fetuses at risk of being affected with a
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Eval w/pediatric cardiologist incl EKG & echocardiogram
24-hour Holter monitoring is relevant for initial clinical assessment of persons w/Brugada syndrome.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider EEG if seizures are a concern.
Consider MR if seizures are present or encephalopathy is suspected.
Community or
Social work involvement for parental support
ASD = autism spectrum disorder; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Eval w/pediatric cardiologist incl EKG & echocardiogram
• 24-hour Holter monitoring is relevant for initial clinical assessment of persons w/Brugada syndrome.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider EEG if seizures are a concern.
• Consider MR if seizures are present or encephalopathy is suspected.
• Community or
• Social work involvement for parental support
## Treatment of Manifestations
Standard care is recommended for cardiovascular malformations, surgical release of syndactyly, and hypoglycemia.
Note: All medical procedures requiring anesthesia should be performed with caution (see
Beta-blockers (nadolol preferred)
Mexiletine can be considered to shorten QT (response is variable & every person must be carefully monitored).
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.
ASM = anti-seizure medication; AV = atrioventricular; DD = developmental delay; ICD = implantable cardioverter defibrillator; ID = intellectual disability
Although
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.
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 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.
• Beta-blockers (nadolol preferred)
• Mexiletine can be considered to shorten QT (response is variable & every person must be carefully monitored).
• 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.
• 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.
• 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
## 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).
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.
• 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).
## Prevention of Primary Manifestations
Arrhythmias must be prevented with the standard therapy described in
Anesthesia is a known trigger for cardiac arrhythmia in individuals with a
Fever can be a trigger for arrhythmias in individuals with
## Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ASD = autism spectrum disorder; ICD = implantable cardioverter defibrillator; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
The following should be avoided:
All drugs reported to prolong QT interval (See
Drugs and dietary practices that could lead to hypoglycemia
• All drugs reported to prolong QT interval (See
• Drugs and dietary practices that could lead to hypoglycemia
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of the older and younger at-risk relatives of a proband in order to identify as early as possible those who would benefit from a complete cardiac evaluation, institution of measures to prevent cardiac arrhythmias, and awareness of agents/circumstances to avoid. Predictive genetic testing is recommended for all at-risk family members of all ages from birth onward. Parents of a proband should be screened whenever possible for the known familial pathogenic variant in genomic DNA from peripheral blood lymphocytes or saliva/buccal tissue.
Note: Predictive genetic testing can be used to identify relatives who are heterozygous for a familial
See
## Therapies Under Investigation
Search
## Pregnancy Management
Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans.
Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects.
Fetuses at risk of being affected with a
See
• Nadolol (the beta-blocker of choice for individuals with long QT syndrome in general) has not been associated with an increased risk above the general population risk of congenital anomalies in humans.
• Quinidine for short QT syndrome is also a preferred drug for use as an antiarrhythmic during human pregnancy and has not been associated with adverse fetal effects.
• Fetuses at risk of being affected with a
## Genetic Counseling
Many individuals diagnosed with a
Some individuals diagnosed with 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, inform recurrence risk assessment, and clarify their need for cardiac evaluation and institution of measures to prevent cardiac arrhythmias (all individuals with 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 [
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the
Heterozygous sibs are at risk for cardiac arrhythmias and other possible manifestations of
If the
If the parents of a proband are clinically unaffected and do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting 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 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.
• Many individuals diagnosed with a
• Some individuals diagnosed with 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, inform recurrence risk assessment, and clarify their need for cardiac evaluation and institution of measures to prevent cardiac arrhythmias (all individuals with 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 [
• * 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 [
• * 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 [
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the
• Heterozygous sibs are at risk for cardiac arrhythmias and other possible manifestations of
• If the
• If the parents of a proband are clinically unaffected and do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting 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 or at risk.
## Mode of Inheritance
## Risk to Family Members
Many individuals diagnosed with a
Some individuals diagnosed with 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, inform recurrence risk assessment, and clarify their need for cardiac evaluation and institution of measures to prevent cardiac arrhythmias (all individuals with 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 [
* A parent with somatic and gonadal mosaicism for a
If a parent of the proband is affected and/or is known to have the
Heterozygous sibs are at risk for cardiac arrhythmias and other possible manifestations of
If the
If the parents of a proband are clinically unaffected and do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting a
• Many individuals diagnosed with a
• Some individuals diagnosed with 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, inform recurrence risk assessment, and clarify their need for cardiac evaluation and institution of measures to prevent cardiac arrhythmias (all individuals with 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 [
• * 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 [
• * 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 [
• * A parent with somatic and gonadal mosaicism for a
• If a parent of the proband is affected and/or is known to have the
• Heterozygous sibs are at risk for cardiac arrhythmias and other possible manifestations of
• If the
• If the parents of a proband are clinically unaffected and do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting a
## 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 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
Spain
Heart Research Follow-Up Program
•
•
•
•
•
• Canada
•
•
• Spain
•
•
•
•
• Heart Research Follow-Up Program
•
## Molecular Genetics
CACNA1C-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for CACNA1C-Related Disorders (
Most gain-of-function pathogenic variants in
Loss-of-function pathogenic variants in
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Most gain-of-function pathogenic variants in
Loss-of-function pathogenic variants in
Variants listed in the table have been provided by the authors.
## Chapter Notes
Carlo Napolitano is a senior investigator currently in Molecular Cardiology at the IRCCS Maugeri Scientific Institutes and the Department of Molecular Medicine at the University of Pavia. He has more than 400 publications with 20,000 citations in the field of the genetic basis of cardiac arrhythmias, cardiac electrophysiology, and sudden death (
We are grateful to all of the individuals with Timothy syndrome and their families for donated time and samples. We would also like to thank the physicians who identified and are providing care for individuals with Timothy syndrome.
Raffaella Bloise, MD (2006-2024)Carlo Napolitano, MD, PhD (2006-present)Silvia G Priori, MD, PhD (2006-present)Igor Splawski, PhD; Harvard Medical School (2006-2021)Katherine W Timothy, BS (2006-2024)
19 December 2024 (ma) Comprehensive update posted live
11 February 2021 (ha) Comprehensive update posted live
16 July 2015 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
29 July 2008 (me) Comprehensive update posted live
15 February 2006 (me) Review posted live
5 July 2005 (is) Original submission
• 19 December 2024 (ma) Comprehensive update posted live
• 11 February 2021 (ha) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 29 July 2008 (me) Comprehensive update posted live
• 15 February 2006 (me) Review posted live
• 5 July 2005 (is) Original submission
## Author Notes
Carlo Napolitano is a senior investigator currently in Molecular Cardiology at the IRCCS Maugeri Scientific Institutes and the Department of Molecular Medicine at the University of Pavia. He has more than 400 publications with 20,000 citations in the field of the genetic basis of cardiac arrhythmias, cardiac electrophysiology, and sudden death (
## Acknowledgments
We are grateful to all of the individuals with Timothy syndrome and their families for donated time and samples. We would also like to thank the physicians who identified and are providing care for individuals with Timothy syndrome.
## Author History
Raffaella Bloise, MD (2006-2024)Carlo Napolitano, MD, PhD (2006-present)Silvia G Priori, MD, PhD (2006-present)Igor Splawski, PhD; Harvard Medical School (2006-2021)Katherine W Timothy, BS (2006-2024)
## Revision History
19 December 2024 (ma) Comprehensive update posted live
11 February 2021 (ha) Comprehensive update posted live
16 July 2015 (me) Comprehensive update posted live
21 April 2011 (me) Comprehensive update posted live
29 July 2008 (me) Comprehensive update posted live
15 February 2006 (me) Review posted live
5 July 2005 (is) Original submission
• 19 December 2024 (ma) Comprehensive update posted live
• 11 February 2021 (ha) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 21 April 2011 (me) Comprehensive update posted live
• 29 July 2008 (me) Comprehensive update posted live
• 15 February 2006 (me) Review posted live
• 5 July 2005 (is) Original submission
## References
## Literature Cited
|
[] |
15/2/2006
|
19/12/2024
|
20/8/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tk2-mtddepl
|
tk2-mtddepl
|
[
"Mitochondrial DNA Depletion Syndrome 2 (MTDPS2), Myopathic Type",
"TK2 Deficiency",
"TK2 Deficiency",
"Mitochondrial DNA Depletion Syndrome 2 (MTDPS2), Myopathic Type",
"Thymidine kinase 2, mitochondrial",
"TK2",
"TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form"
] |
Julia Wang, Ayman W El-Hattab, Lee-Jun C Wong
|
Summary Three main subtypes of presentation have been described: Infantile-onset myopathy with neurologic involvement and rapid progression to early death. Affected individuals experience progressive muscle weakness leading to respiratory failure. Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared. Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria. The diagnosis of
|
## Diagnosis
Infantile-onset myopathy with neurologic involvement and rapid progression to early death
Juvenile/childhood onset with generalized proximal weakness and survival to adolescence or adulthood
Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions
Generalized hypotonia
Rapidly progressive proximal muscle weakness
Loss of previously acquired motor skills
Poor feeding
Respiratory difficulties
Encephalopathy
Epilepsy
Sensorineural hearing loss
Chronic progressive external ophthalmoplegia
Mild proximal limb muscle weakness and progressive myopathy
Slow progression to respiratory insufficiency
Facial weakness including ptosis, dysphagia, and dysarthria
Liver enzymes are elevated.
Serum creatine phosphokinase (CK) concentration is five to ten times the upper limit of normal.
Note: Serum CK concentration can be normal in affected individuals with severe muscle wasting.
Findings are nonspecific but suggestive of a myopathy.
Histopathologic findings include prominent variance in fiber size, sarcoplasmic vacuoles, and increased connective tissue.
Ragged red fibers are invariably present.
Succinate dehydrogenase (SDH) activity is increased and cytochrome
Electron microscopy shows abnormal mitochondria with circular cristae [
Content is severely reduced, usually from 5% to 30% of tissue- and age-matched controls.
Note: Mitochondrial DNA content ranging from 60% to normal has been reported in rare instances, especially in those with later-onset disease [
In addition to severe mtDNA depletion, multiple mtDNA deletions may be observed, particularly in those with the adult-onset form.
Activity of multiple complexes is decreased; complexes I, I+III, and IV are the most affected.
The diagnosis of
A proband with infantile onset of disease with:
Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
Biallelic pathogenic (or likely pathogenic) variants in
A proband older than age two years with:
Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
Biallelic pathogenic (or likely pathogenic) variants 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 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
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 myopathy,
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.
One of approximately 107 affected individuals reported to date had a 5.8-kb deletion in
• Infantile-onset myopathy with neurologic involvement and rapid progression to early death
• Juvenile/childhood onset with generalized proximal weakness and survival to adolescence or adulthood
• Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions
• Generalized hypotonia
• Rapidly progressive proximal muscle weakness
• Loss of previously acquired motor skills
• Poor feeding
• Respiratory difficulties
• Encephalopathy
• Epilepsy
• Sensorineural hearing loss
• Chronic progressive external ophthalmoplegia
• Mild proximal limb muscle weakness and progressive myopathy
• Slow progression to respiratory insufficiency
• Facial weakness including ptosis, dysphagia, and dysarthria
• A proband with infantile onset of disease with:
• Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• A proband older than age two years with:
• Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• For an introduction to multigene panels click
## Suggestive Findings
Generalized hypotonia
Rapidly progressive proximal muscle weakness
Loss of previously acquired motor skills
Poor feeding
Respiratory difficulties
Encephalopathy
Epilepsy
Sensorineural hearing loss
Chronic progressive external ophthalmoplegia
Mild proximal limb muscle weakness and progressive myopathy
Slow progression to respiratory insufficiency
Facial weakness including ptosis, dysphagia, and dysarthria
Liver enzymes are elevated.
Serum creatine phosphokinase (CK) concentration is five to ten times the upper limit of normal.
Note: Serum CK concentration can be normal in affected individuals with severe muscle wasting.
Findings are nonspecific but suggestive of a myopathy.
Histopathologic findings include prominent variance in fiber size, sarcoplasmic vacuoles, and increased connective tissue.
Ragged red fibers are invariably present.
Succinate dehydrogenase (SDH) activity is increased and cytochrome
Electron microscopy shows abnormal mitochondria with circular cristae [
Content is severely reduced, usually from 5% to 30% of tissue- and age-matched controls.
Note: Mitochondrial DNA content ranging from 60% to normal has been reported in rare instances, especially in those with later-onset disease [
In addition to severe mtDNA depletion, multiple mtDNA deletions may be observed, particularly in those with the adult-onset form.
Activity of multiple complexes is decreased; complexes I, I+III, and IV are the most affected.
• Generalized hypotonia
• Rapidly progressive proximal muscle weakness
• Loss of previously acquired motor skills
• Poor feeding
• Respiratory difficulties
• Encephalopathy
• Epilepsy
• Sensorineural hearing loss
• Chronic progressive external ophthalmoplegia
• Mild proximal limb muscle weakness and progressive myopathy
• Slow progression to respiratory insufficiency
• Facial weakness including ptosis, dysphagia, and dysarthria
## Clinical Features
Generalized hypotonia
Rapidly progressive proximal muscle weakness
Loss of previously acquired motor skills
Poor feeding
Respiratory difficulties
Encephalopathy
Epilepsy
Sensorineural hearing loss
Chronic progressive external ophthalmoplegia
Mild proximal limb muscle weakness and progressive myopathy
Slow progression to respiratory insufficiency
Facial weakness including ptosis, dysphagia, and dysarthria
• Generalized hypotonia
• Rapidly progressive proximal muscle weakness
• Loss of previously acquired motor skills
• Poor feeding
• Respiratory difficulties
• Encephalopathy
• Epilepsy
• Sensorineural hearing loss
• Chronic progressive external ophthalmoplegia
• Mild proximal limb muscle weakness and progressive myopathy
• Slow progression to respiratory insufficiency
• Facial weakness including ptosis, dysphagia, and dysarthria
## Supportive Laboratory Findings
Liver enzymes are elevated.
Serum creatine phosphokinase (CK) concentration is five to ten times the upper limit of normal.
Note: Serum CK concentration can be normal in affected individuals with severe muscle wasting.
## Electromyography
Findings are nonspecific but suggestive of a myopathy.
## Skeletal Muscle Pathology
Histopathologic findings include prominent variance in fiber size, sarcoplasmic vacuoles, and increased connective tissue.
Ragged red fibers are invariably present.
Succinate dehydrogenase (SDH) activity is increased and cytochrome
Electron microscopy shows abnormal mitochondria with circular cristae [
## Mitochondrial DNA Content (copy number) Analysis in Skeletal Muscle
Content is severely reduced, usually from 5% to 30% of tissue- and age-matched controls.
Note: Mitochondrial DNA content ranging from 60% to normal has been reported in rare instances, especially in those with later-onset disease [
In addition to severe mtDNA depletion, multiple mtDNA deletions may be observed, particularly in those with the adult-onset form.
## Electron Transport Chain Activity in Skeletal Muscle
Activity of multiple complexes is decreased; complexes I, I+III, and IV are the most affected.
## Establishing the Diagnosis
The diagnosis of
A proband with infantile onset of disease with:
Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
Biallelic pathogenic (or likely pathogenic) variants in
A proband older than age two years with:
Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
Biallelic pathogenic (or likely pathogenic) variants 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 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
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 myopathy,
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.
One of approximately 107 affected individuals reported to date had a 5.8-kb deletion in
• A proband with infantile onset of disease with:
• Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• A proband older than age two years with:
• Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Severely reduced (typically <20% of age- and tissue-matched healthy controls) mtDNA content in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• Reduced mtDNA content or multiple mtDNA deletions, ragged red fibers, and/or COX-deficient fibers in skeletal muscle; AND/OR
• Biallelic pathogenic (or likely pathogenic) variants in
• 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 myopathy,
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.
One of approximately 107 affected individuals reported to date had a 5.8-kb deletion in
## Clinical Characteristics
To date, approximately 107 individuals with molecularly confirmed
The clinical presentation of
Clinical Manifestations of
Initial development is normal, followed by gradual onset of hypotonia:
A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop.
Muscle atrophy becomes evident [
Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.
Sensorineural hearing loss develops.
Cognitive function is typically spared.
Muscle weakness rapidly progresses leading to respiratory failure and death within a few years after onset. Most children succumb to complications of respiratory muscle weakness; several are ventilator dependent before age six years. The most common cause of death is pulmonary infection.
Moderate-to-severe progression of generalized weakness
The severity of muscle weakness can vary widely among affected individuals.
In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
Survival to at least age 13 years, with respiratory failure as the primary cause of death
Mild proximal limb muscle weakness due to progressive mitochondrial myopathy;
Slow progression to respiratory failure in some affected individuals;
Involvement of the facial and extraocular muscles with manifestations including chronic progressive external ophthalmoplegia, ptosis, dysphagia, and dysarthria.
It is possible that the range of phenotypes observed may be explained by the variability in the amount of residual activity of mutated enzymes [
The small number of individuals reported to date precludes identification of genotype-phenotype correlations; however, the following have been observed:
The pathogenic variant
Homozygosity for
Homozygosity for
When the
The prevalence of
• Initial development is normal, followed by gradual onset of hypotonia:
• A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
• Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
• Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
• A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
• Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
• Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
• Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop.
• Muscle atrophy becomes evident [
• Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.
• Sensorineural hearing loss develops.
• Cognitive function is typically spared.
• A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
• Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
• Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
• Moderate-to-severe progression of generalized weakness
• The severity of muscle weakness can vary widely among affected individuals.
• In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• The severity of muscle weakness can vary widely among affected individuals.
• In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• Survival to at least age 13 years, with respiratory failure as the primary cause of death
• The severity of muscle weakness can vary widely among affected individuals.
• In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• Mild proximal limb muscle weakness due to progressive mitochondrial myopathy;
• Slow progression to respiratory failure in some affected individuals;
• Involvement of the facial and extraocular muscles with manifestations including chronic progressive external ophthalmoplegia, ptosis, dysphagia, and dysarthria.
• The pathogenic variant
• Homozygosity for
• Homozygosity for
• When the
## Clinical Description
To date, approximately 107 individuals with molecularly confirmed
The clinical presentation of
Clinical Manifestations of
Initial development is normal, followed by gradual onset of hypotonia:
A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop.
Muscle atrophy becomes evident [
Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.
Sensorineural hearing loss develops.
Cognitive function is typically spared.
Muscle weakness rapidly progresses leading to respiratory failure and death within a few years after onset. Most children succumb to complications of respiratory muscle weakness; several are ventilator dependent before age six years. The most common cause of death is pulmonary infection.
Moderate-to-severe progression of generalized weakness
The severity of muscle weakness can vary widely among affected individuals.
In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
Survival to at least age 13 years, with respiratory failure as the primary cause of death
Mild proximal limb muscle weakness due to progressive mitochondrial myopathy;
Slow progression to respiratory failure in some affected individuals;
Involvement of the facial and extraocular muscles with manifestations including chronic progressive external ophthalmoplegia, ptosis, dysphagia, and dysarthria.
• Initial development is normal, followed by gradual onset of hypotonia:
• A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
• Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
• Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
• A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
• Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
• Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
• Subsequently generalized fatigue, decreased physical stamina, proximal muscle weakness (manifest as difficulty getting to standing or walking), and feeding difficulties develop.
• Muscle atrophy becomes evident [
• Some children develop bulbar weakness including dysarthria and dysphagia. Previously acquired motor skills are lost.
• Sensorineural hearing loss develops.
• Cognitive function is typically spared.
• A subset of affected individuals have early severe muscle weakness with encephalopathy and intractable epilepsy.
• Some affected individuals have elevated serum concentrations of aminotransferases and CK in the first year of life.
• Note: The observed elevation in serum transaminases may reflect skeletal muscle involvement [
• Moderate-to-severe progression of generalized weakness
• The severity of muscle weakness can vary widely among affected individuals.
• In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• The severity of muscle weakness can vary widely among affected individuals.
• In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• Survival to at least age 13 years, with respiratory failure as the primary cause of death
• The severity of muscle weakness can vary widely among affected individuals.
• In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required.
• Mild proximal limb muscle weakness due to progressive mitochondrial myopathy;
• Slow progression to respiratory failure in some affected individuals;
• Involvement of the facial and extraocular muscles with manifestations including chronic progressive external ophthalmoplegia, ptosis, dysphagia, and dysarthria.
## Genotype-Phenotype Correlations
It is possible that the range of phenotypes observed may be explained by the variability in the amount of residual activity of mutated enzymes [
The small number of individuals reported to date precludes identification of genotype-phenotype correlations; however, the following have been observed:
The pathogenic variant
Homozygosity for
Homozygosity for
When the
• The pathogenic variant
• Homozygosity for
• Homozygosity for
• When the
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Mitochondrial DNA Maintenance Defects Presenting with Myopathy
Hypotonia
Loss of acquired motor skills
Hypotonia
Hypertrophic cardiomyopathy
Cataracts
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Ptosis
Ophthalmoplegia
Exercise intolerance / easy fatigability
Hypertrophic cardiomyopathy
Hypotonia
Hypertrophic cardiomyopathy
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
In additional to other myopathic mtDNA maintenance defects, the differential diagnosis of
• Hypotonia
• Loss of acquired motor skills
• Hypotonia
• Hypertrophic cardiomyopathy
• Cataracts
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Ptosis
• Ophthalmoplegia
• Exercise intolerance / easy fatigability
• Hypertrophic cardiomyopathy
• Hypotonia
• Hypertrophic cardiomyopathy
## Management
To establish the extent of disease and needs of an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
OT = occupational therapist; PT = physical therapist
Treatment is primarily supportive; management should involve a multidisciplinary team.
Treatment of Manifestations in Individuals with
Chest physiotherapy may improve pulmonary function and reduce the risk of pulmonary infection.
For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental concerns 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).
Chest physiotherapy can help reduce the risk of pulmonary infection (see
Physical therapy can help maintain muscle function and prevent joint contractures (see
No disease-specific clinical guidelines are available; treating physicians should consider the evaluations included in
Recommended Surveillance for Individuals with
Particularly in infancy, childhood, and adolescence; for adults, monitor for persistent weight loss, which may indicate inadequate nutrition.
In those with infantile-onset disease
For those who are able to cooperate
To evaluate for respiratory insufficiency (alveolar hypoventilation and chronic hypercapnia)
Consider periodic speech/language evaluation by a developmental pediatrician or pediatric neurologist.
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.
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
OT = occupational therapist; PT = physical therapist
## Treatment of Manifestations
Treatment is primarily supportive; management should involve a multidisciplinary team.
Treatment of Manifestations in Individuals with
Chest physiotherapy may improve pulmonary function and reduce the risk of pulmonary infection.
For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see
The following information represents typical management recommendations for individuals with developmental concerns 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).
• 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).
## Developmental Concerns / Educational Issues
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).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## Prevention of Secondary Complications
Chest physiotherapy can help reduce the risk of pulmonary infection (see
Physical therapy can help maintain muscle function and prevent joint contractures (see
## Surveillance
No disease-specific clinical guidelines are available; treating physicians should consider the evaluations included in
Recommended Surveillance for Individuals with
Particularly in infancy, childhood, and adolescence; for adults, monitor for persistent weight loss, which may indicate inadequate nutrition.
In those with infantile-onset disease
For those who are able to cooperate
To evaluate for respiratory insufficiency (alveolar hypoventilation and chronic hypercapnia)
Consider periodic speech/language evaluation by a developmental pediatrician or pediatric neurologist.
## 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.
Most individuals with
If individuals with less severe manifestations of a
Carrier testing for at-risk family members 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Most individuals with
• If individuals with less severe manifestations 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 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.
Most individuals with
If individuals with less severe manifestations of a
• 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.
• Most individuals with
• If individuals with less severe manifestations of a
## Carrier Detection
Carrier testing for at-risk family members 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
United Kingdom
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form (
Mitochondrial DNA (mtDNA) maintenance defect is characterized by a significant reduction in the number of copies of mtDNA in one or more tissues.
About 70% of reported pathogenic variants are missense; the remainder include nonsense and splice site variants and small (1- to 4-nucleotide) deletions and insertions.
A gross deletion spanning 5.8 kb [
All pathogenic variants are private except for the two variants
Variants listed in the table have been provided by the authors.
Deoxynucloside triphosphate (dNTPs) can be synthesized via either the
## Molecular Pathogenesis
Mitochondrial DNA (mtDNA) maintenance defect is characterized by a significant reduction in the number of copies of mtDNA in one or more tissues.
About 70% of reported pathogenic variants are missense; the remainder include nonsense and splice site variants and small (1- to 4-nucleotide) deletions and insertions.
A gross deletion spanning 5.8 kb [
All pathogenic variants are private except for the two variants
Variants listed in the table have been provided by the authors.
Deoxynucloside triphosphate (dNTPs) can be synthesized via either the
## Chapter Notes
Sirisak Chanprasert, MD; Baylor College of Medicine (2012-2018)Ayman W El-Hattab, MD, FAAP, FACMG (2018-present)Fernando Scaglia, MD, FACMG; Baylor College of Medicine (2012-2018)Jing Wang, MD; Baylor College of Medicine (2012-2018)Julia Wang, BS (2018-present)Lee-Jun C Wong, PhD, FACMG (2012-present)
26 July 2018 (ma) Comprehensive update posted live
6 December 2012 (me) Review posted live
23 August 2012 (fs) Original submission
• 26 July 2018 (ma) Comprehensive update posted live
• 6 December 2012 (me) Review posted live
• 23 August 2012 (fs) Original submission
## Author History
Sirisak Chanprasert, MD; Baylor College of Medicine (2012-2018)Ayman W El-Hattab, MD, FAAP, FACMG (2018-present)Fernando Scaglia, MD, FACMG; Baylor College of Medicine (2012-2018)Jing Wang, MD; Baylor College of Medicine (2012-2018)Julia Wang, BS (2018-present)Lee-Jun C Wong, PhD, FACMG (2012-present)
## Revision History
26 July 2018 (ma) Comprehensive update posted live
6 December 2012 (me) Review posted live
23 August 2012 (fs) Original submission
• 26 July 2018 (ma) Comprehensive update posted live
• 6 December 2012 (me) Review posted live
• 23 August 2012 (fs) Original submission
## References
## Literature Cited
|
[] |
6/12/2012
|
26/7/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tnxb-eds
|
tnxb-eds
|
[
"Classical-Like Ehlers-Danlos syndrome (clEDS) Type 1",
"TNXB-Related clEDS",
"TNXB-Related Classic-Like Ehlers-Danlos Syndrome",
"Classical-Like Ehlers-Danlos Syndrome Type 1",
"TNXB-Related clEDS",
"TNXB-Related Classic-Like Ehlers-Danlos Syndrome",
"clEDS Type 1",
"Tenascin-X",
"TNXB",
"TNXB-Related Classical-Like Ehlers-Danlos Syndrome"
] |
Fleur S van Dijk, Neeti Ghali, Serwet Demirdas, Duncan Baker
|
Summary The clinical features of The diagnosis of
|
## Diagnosis
Minimum suggestive clinical diagnostic criteria for
Skin hyperextensibility with velvety skin texture and absence of atrophic scarring (See
Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
Generalized joint hypermobility with or without recurrent dislocations (most commonly shoulder and ankle)
Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
A score of ≥5 at some point in life is considered positive.
Easy or spontaneous bruising of the skin
Hand anomalies including:
Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
Mallet finger(s) (See
Clinodactyly
Brachydactyly
Atrophy of the muscles in the hands and feet
Foot anomalies including:
Broad/plump forefoot
Brachydactyly with excessive skin
Pes planus
Hallux valgus (See
Piezogenic papules
Edema in the legs in the absence of cardiac failure
Mild proximal and distal muscle weakness
Axonal polyneuropathy
Vaginal, uterus, and/or rectal prolapse
Predisposition to tissue fragility, particularly of the gastrointestinal tract (a feature usually suggestive of vascular Ehlers-Danlos syndrome; see
Note: This finding was proposed as an additional important feature of
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
When the phenotypic and family history findings suggest the diagnosis of
* See
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by connective tissue findings, 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 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
Consideration must be given to the sequence analysis of the
Note that certain DNA variants characterize the recurrent
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
In 20%-30% of individuals with severe salt-wasting congenital adrenal hyperplasia (CAH), deletions of
• Skin hyperextensibility with velvety skin texture and absence of atrophic scarring (See
• Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
• For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
• For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Generalized joint hypermobility with or without recurrent dislocations (most commonly shoulder and ankle)
• Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
• A score of ≥5 at some point in life is considered positive.
• Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
• A score of ≥5 at some point in life is considered positive.
• Easy or spontaneous bruising of the skin
• Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
• For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
• A score of ≥5 at some point in life is considered positive.
• Hand anomalies including:
• Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
• Mallet finger(s) (See
• Clinodactyly
• Brachydactyly
• Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
• Mallet finger(s) (See
• Clinodactyly
• Brachydactyly
• Atrophy of the muscles in the hands and feet
• Foot anomalies including:
• Broad/plump forefoot
• Brachydactyly with excessive skin
• Pes planus
• Hallux valgus (See
• Piezogenic papules
• Broad/plump forefoot
• Brachydactyly with excessive skin
• Pes planus
• Hallux valgus (See
• Piezogenic papules
• Edema in the legs in the absence of cardiac failure
• Mild proximal and distal muscle weakness
• Axonal polyneuropathy
• Vaginal, uterus, and/or rectal prolapse
• Predisposition to tissue fragility, particularly of the gastrointestinal tract (a feature usually suggestive of vascular Ehlers-Danlos syndrome; see
• Note: This finding was proposed as an additional important feature of
• Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
• Mallet finger(s) (See
• Clinodactyly
• Brachydactyly
• Broad/plump forefoot
• Brachydactyly with excessive skin
• Pes planus
• Hallux valgus (See
• Piezogenic papules
• * See
• For an introduction to multigene panels click
## Suggestive Findings
Skin hyperextensibility with velvety skin texture and absence of atrophic scarring (See
Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
Generalized joint hypermobility with or without recurrent dislocations (most commonly shoulder and ankle)
Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
A score of ≥5 at some point in life is considered positive.
Easy or spontaneous bruising of the skin
Hand anomalies including:
Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
Mallet finger(s) (See
Clinodactyly
Brachydactyly
Atrophy of the muscles in the hands and feet
Foot anomalies including:
Broad/plump forefoot
Brachydactyly with excessive skin
Pes planus
Hallux valgus (See
Piezogenic papules
Edema in the legs in the absence of cardiac failure
Mild proximal and distal muscle weakness
Axonal polyneuropathy
Vaginal, uterus, and/or rectal prolapse
Predisposition to tissue fragility, particularly of the gastrointestinal tract (a feature usually suggestive of vascular Ehlers-Danlos syndrome; see
Note: This finding was proposed as an additional important feature of
• Skin hyperextensibility with velvety skin texture and absence of atrophic scarring (See
• Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
• For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
• For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Generalized joint hypermobility with or without recurrent dislocations (most commonly shoulder and ankle)
• Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
• A score of ≥5 at some point in life is considered positive.
• Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
• A score of ≥5 at some point in life is considered positive.
• Easy or spontaneous bruising of the skin
• Hyperextensibility can be objectively measured by pinching the cutaneous and subcutaneous layers of skin located in the middle of the volar surface of the nondominant forearm and stretching it to at least 1.5 cm or at least 1 cm on the volar surface of the hand (palm).
• For the neck, elbow, and knees, the stretched measurement should be at least 3 cm.
• Generalized joint hypermobility is typically measured using a Beighton score (see Classic Ehlers-Danlos Syndrome,
• A score of ≥5 at some point in life is considered positive.
• Hand anomalies including:
• Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
• Mallet finger(s) (See
• Clinodactyly
• Brachydactyly
• Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
• Mallet finger(s) (See
• Clinodactyly
• Brachydactyly
• Atrophy of the muscles in the hands and feet
• Foot anomalies including:
• Broad/plump forefoot
• Brachydactyly with excessive skin
• Pes planus
• Hallux valgus (See
• Piezogenic papules
• Broad/plump forefoot
• Brachydactyly with excessive skin
• Pes planus
• Hallux valgus (See
• Piezogenic papules
• Edema in the legs in the absence of cardiac failure
• Mild proximal and distal muscle weakness
• Axonal polyneuropathy
• Vaginal, uterus, and/or rectal prolapse
• Predisposition to tissue fragility, particularly of the gastrointestinal tract (a feature usually suggestive of vascular Ehlers-Danlos syndrome; see
• Note: This finding was proposed as an additional important feature of
• Acrogeric hands (characterized by thinning and wrinkling of the skin) with excessive skin
• Mallet finger(s) (See
• Clinodactyly
• Brachydactyly
• Broad/plump forefoot
• Brachydactyly with excessive skin
• Pes planus
• Hallux valgus (See
• Piezogenic papules
## 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
When the phenotypic and family history findings suggest the diagnosis of
* See
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by connective tissue findings, 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 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
Consideration must be given to the sequence analysis of the
Note that certain DNA variants characterize the recurrent
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
In 20%-30% of individuals with severe salt-wasting congenital adrenal hyperplasia (CAH), deletions of
• * See
• For an introduction to multigene panels click
## Option 1
When the phenotypic and family history findings suggest the diagnosis of
* See
For an introduction to multigene panels click
• * See
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by connective tissue findings, 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 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
Consideration must be given to the sequence analysis of the
Note that certain DNA variants characterize the recurrent
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
In 20%-30% of individuals with severe salt-wasting congenital adrenal hyperplasia (CAH), deletions of
## Clinical Characteristics
To date, 56 individuals from 44 families have been identified with
Likely 100%, as not all reports commented on this feature
Also incl hematomas/ecchymoses
Most specific: broad foot w/brachydactyly
Most common: pes planus
Trachea rupture after intubation
Defect of nasal cartilages after nose blowing
Not all reports commented on all the clinical features mentioned above. When not commented on, the feature was considered absent.
Including broad/plump forefoot, brachydactyly with excessive skin, pes planus, hallux valgus, and painful soles of the feet
Although absence of atrophic scarring is one of the features that distinguishes
Easy bruising is reported in the majority of affected individuals. In one individual a suspicion of nonaccidental injury had been raised due to excessive bruising.
Hematomas are frequently encountered.
Significant variability between both unrelated and related affected individuals in the severity of musculoskeletal symptoms and their effect on day-to-day function has been reported.
The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound due to severe and painful foot deformities, joint dislocations, and fatigue [
More than half of affected individuals reported fatigue as an important feature (e.g.,
Edema of the ankles and/or feet has been described in 14 of 56 individuals and could not be attributed to a cardiac etiology.
Ten individuals experienced frequent subconjunctival hemorrhages.
Rupture of a right brachial vein was reported in a woman age 26 years [
A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
The most elaborate study included ten individuals with
Those with
Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
Muscle ultrasound demonstrated increased echo intensity.
Muscle biopsy showed mild myopathic changes in some affected individuals.
It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
An individual age 48 years who had a bowel perforation as a result of diverticulitis [
An individual age 38 years with a colonic perforation during a colonoscopy [
A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
Jejunal perforation at age 40 years [
Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
Note:
No genotype-phenotype correlations have been identified.
Outdated terms for
The prevalence of
• Likely 100%, as not all reports commented on this feature
• Also incl hematomas/ecchymoses
• Most specific: broad foot w/brachydactyly
• Most common: pes planus
• Trachea rupture after intubation
• Defect of nasal cartilages after nose blowing
• Although absence of atrophic scarring is one of the features that distinguishes
• Easy bruising is reported in the majority of affected individuals. In one individual a suspicion of nonaccidental injury had been raised due to excessive bruising.
• Hematomas are frequently encountered.
• Significant variability between both unrelated and related affected individuals in the severity of musculoskeletal symptoms and their effect on day-to-day function has been reported.
• The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound due to severe and painful foot deformities, joint dislocations, and fatigue [
• More than half of affected individuals reported fatigue as an important feature (e.g.,
• Edema of the ankles and/or feet has been described in 14 of 56 individuals and could not be attributed to a cardiac etiology.
• Ten individuals experienced frequent subconjunctival hemorrhages.
• Rupture of a right brachial vein was reported in a woman age 26 years [
• A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
• An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
• One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
• One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
• This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
• She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• Ten individuals experienced frequent subconjunctival hemorrhages.
• Rupture of a right brachial vein was reported in a woman age 26 years [
• A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
• An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
• One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
• One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
• This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
• She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• Ten individuals experienced frequent subconjunctival hemorrhages.
• Rupture of a right brachial vein was reported in a woman age 26 years [
• A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
• An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
• One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
• One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
• This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
• She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• The most elaborate study included ten individuals with
• Those with
• Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
• Muscle ultrasound demonstrated increased echo intensity.
• Muscle biopsy showed mild myopathic changes in some affected individuals.
• It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
• Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
• Muscle ultrasound demonstrated increased echo intensity.
• Muscle biopsy showed mild myopathic changes in some affected individuals.
• It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
• Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
• Muscle ultrasound demonstrated increased echo intensity.
• Muscle biopsy showed mild myopathic changes in some affected individuals.
• It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
• A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
• A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
• A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
• An individual age 48 years who had a bowel perforation as a result of diverticulitis [
• An individual age 38 years with a colonic perforation during a colonoscopy [
• A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
• Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
• Jejunal perforation at age 40 years [
• Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
• Note:
• A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
• A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
• A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
• An individual age 48 years who had a bowel perforation as a result of diverticulitis [
• An individual age 38 years with a colonic perforation during a colonoscopy [
• A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
• Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
• Jejunal perforation at age 40 years [
• Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
• A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
• A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
• A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
• An individual age 48 years who had a bowel perforation as a result of diverticulitis [
• An individual age 38 years with a colonic perforation during a colonoscopy [
• A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
• Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
• Jejunal perforation at age 40 years [
• Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
## Clinical Description
To date, 56 individuals from 44 families have been identified with
Likely 100%, as not all reports commented on this feature
Also incl hematomas/ecchymoses
Most specific: broad foot w/brachydactyly
Most common: pes planus
Trachea rupture after intubation
Defect of nasal cartilages after nose blowing
Not all reports commented on all the clinical features mentioned above. When not commented on, the feature was considered absent.
Including broad/plump forefoot, brachydactyly with excessive skin, pes planus, hallux valgus, and painful soles of the feet
Although absence of atrophic scarring is one of the features that distinguishes
Easy bruising is reported in the majority of affected individuals. In one individual a suspicion of nonaccidental injury had been raised due to excessive bruising.
Hematomas are frequently encountered.
Significant variability between both unrelated and related affected individuals in the severity of musculoskeletal symptoms and their effect on day-to-day function has been reported.
The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound due to severe and painful foot deformities, joint dislocations, and fatigue [
More than half of affected individuals reported fatigue as an important feature (e.g.,
Edema of the ankles and/or feet has been described in 14 of 56 individuals and could not be attributed to a cardiac etiology.
Ten individuals experienced frequent subconjunctival hemorrhages.
Rupture of a right brachial vein was reported in a woman age 26 years [
A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
The most elaborate study included ten individuals with
Those with
Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
Muscle ultrasound demonstrated increased echo intensity.
Muscle biopsy showed mild myopathic changes in some affected individuals.
It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
An individual age 48 years who had a bowel perforation as a result of diverticulitis [
An individual age 38 years with a colonic perforation during a colonoscopy [
A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
Jejunal perforation at age 40 years [
Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
Note:
• Likely 100%, as not all reports commented on this feature
• Also incl hematomas/ecchymoses
• Most specific: broad foot w/brachydactyly
• Most common: pes planus
• Trachea rupture after intubation
• Defect of nasal cartilages after nose blowing
• Although absence of atrophic scarring is one of the features that distinguishes
• Easy bruising is reported in the majority of affected individuals. In one individual a suspicion of nonaccidental injury had been raised due to excessive bruising.
• Hematomas are frequently encountered.
• Significant variability between both unrelated and related affected individuals in the severity of musculoskeletal symptoms and their effect on day-to-day function has been reported.
• The severity of symptoms in middle-aged individuals can range from joint hypermobility without complications to being wheelchair-bound due to severe and painful foot deformities, joint dislocations, and fatigue [
• More than half of affected individuals reported fatigue as an important feature (e.g.,
• Edema of the ankles and/or feet has been described in 14 of 56 individuals and could not be attributed to a cardiac etiology.
• Ten individuals experienced frequent subconjunctival hemorrhages.
• Rupture of a right brachial vein was reported in a woman age 26 years [
• A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
• An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
• One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
• One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
• This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
• She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• Ten individuals experienced frequent subconjunctival hemorrhages.
• Rupture of a right brachial vein was reported in a woman age 26 years [
• A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
• An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
• One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
• One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
• This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
• She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• Ten individuals experienced frequent subconjunctival hemorrhages.
• Rupture of a right brachial vein was reported in a woman age 26 years [
• A man age 58 years had a thoraco-abdominal aortic aneurysm and aneurysm of both the common iliac artery and superior mesenteric artery [
• An affected individual who died in his sixth decade due to a bowel rupture had aneurysmal abdominal arteries on postmortem examination [
• One individual required surgery for two separate incidences of spontaneous compartment syndrome in his right and left arm at age 30 and 31 years, respectively [
• One individual developed a spontaneous left-calf hematoma that had to be drained surgically [
• This individual also developed a right-arm cephalic vein thrombosis and pulmonary embolism during admission for adrenal crisis.
• She was subsequently started on anticoagulant therapy and shortly after required a hospital admission for spontaneous subcutaneous hematoma of the lower half of the body, causing acute anemia and requiring blood transfusion.
• The most elaborate study included ten individuals with
• Those with
• Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
• Muscle ultrasound demonstrated increased echo intensity.
• Muscle biopsy showed mild myopathic changes in some affected individuals.
• It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
• Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
• Muscle ultrasound demonstrated increased echo intensity.
• Muscle biopsy showed mild myopathic changes in some affected individuals.
• It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
• Moderate polyneuropathy and mild abnormal motor unit action potentials were seen on clinical neurophysiologic studies.
• Muscle ultrasound demonstrated increased echo intensity.
• Muscle biopsy showed mild myopathic changes in some affected individuals.
• It has been hypothesized that neuropathy may be linked to increased vulnerability of peripheral nerves to stretching/pressure due to TNX deficiency [
• A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
• A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
• A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
• An individual age 48 years who had a bowel perforation as a result of diverticulitis [
• An individual age 38 years with a colonic perforation during a colonoscopy [
• A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
• Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
• Jejunal perforation at age 40 years [
• Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
• Note:
• A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
• A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
• A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
• An individual age 48 years who had a bowel perforation as a result of diverticulitis [
• An individual age 38 years with a colonic perforation during a colonoscopy [
• A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
• Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
• Jejunal perforation at age 40 years [
• Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
• A man age 36 years with a perforation of a colonic diverticulum, who developed multiple abscesses requiring partial colectomy, which was complicated by a second small-bowel perforation [
• A man age 57 years who experienced an esophageal rupture possibly resulting from an ultrasound probe [
• A woman age 45 years who had a diverticular perforation of the sigmoid colon and duodenal perforation after ileus tube insertion [
• An individual age 48 years who had a bowel perforation as a result of diverticulitis [
• An individual age 38 years with a colonic perforation during a colonoscopy [
• A woman age 42 years who had a spontaneous perforation of the small bowel for which an intestinal specimen was reported to be "very fragile" [
• Spontaneous transverse colon perforation at age 51 years followed by a second perforation of the small bowel three days postoperative [
• Jejunal perforation at age 40 years [
• Esophageal perforation at age 55 years during a gastroscopy, followed by a spontaneous small bowel perforation at age 56 years, and one small bowel perforation after a nasojejunal barium study at age 59 years [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
Outdated terms for
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes and Disorders in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; clEDS = classical-like Ehlers-Danlos syndrome; DiffDx = differential diagnosis; GJH = generalized joint hypermobility; MOI = mode of inheritance
Pathogenic variants in
## Management
No consensus 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
Tone & joint laxity
Mobility, ADL, & need for adaptive devices
Need for PT (to improve strength and tone) &/or OT (to improve fine motor skills)
Podiatry assessment for foot abnormalities
Community or
Social work involvement for parental support.
ADL = activities of daily living; clEDS = classical-like Ehlers-Danlos syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with
Non-weight-bearing exercise
For recommendations on pain medication, see
Careful selection of analgesic medication is recommended in light of ↑ risks of diverticulitis & diverticular bleeding in users of aspirin or NSAIDs.
Consider referral to rheumatologist &/or pain mgmt specialist or clinic.
Avoid use of opioid medication for chronic pain; it does not relieve pain long term & can → addiction.
Long-term chronic pain may → need for mental health services.
EDS = Ehlers-Danlos syndrome; NSAID = nonsteroidal anti-inflammatory drug
For recommendations on prevention of primary manifestations of joint laxity and dislocations as well as joint pain, see Hypermobile Ehlers-Danlos Syndrome,
Prevention of Primary Manifestations in Individuals with
Recommended Surveillance for Individuals with
EDS = Ehlers-Danlos syndrome
The following should be avoided:
Sports with heavy joint strain (e.g., contact sports, fighting sports, football, running)
Invasive procedures such as intubation, endoscopy, and/or colonoscopy unless essential because of reported tissue fragility of the trachea, esophagus, and small and large bowels
Acetylsalicylate (aspirin) and long-term use of nonsteroidal anti-inflammatory drugs because of elevated risks of diverticulitis and diverticular bleeding
The use of opioid medication for chronic pain, which does not lead to long-term pain relief and has the potential for addiction issues
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 preventive measures.
See
It is important that the obstetrician and midwives be made aware of the diagnosis of
Gynecologic follow up during pregnancy can be considered. Specialist delivery is strongly advised in view of the reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe. These complications emphasize the need for careful handling of pregnant women with
Search
• Tone & joint laxity
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve strength and tone) &/or OT (to improve fine motor skills)
• Podiatry assessment for foot abnormalities
• Community or
• Social work involvement for parental support.
• Non-weight-bearing exercise
• For recommendations on pain medication, see
• Careful selection of analgesic medication is recommended in light of ↑ risks of diverticulitis & diverticular bleeding in users of aspirin or NSAIDs.
• Consider referral to rheumatologist &/or pain mgmt specialist or clinic.
• Avoid use of opioid medication for chronic pain; it does not relieve pain long term & can → addiction.
• Long-term chronic pain may → need for mental health services.
• Sports with heavy joint strain (e.g., contact sports, fighting sports, football, running)
• Invasive procedures such as intubation, endoscopy, and/or colonoscopy unless essential because of reported tissue fragility of the trachea, esophagus, and small and large bowels
• Acetylsalicylate (aspirin) and long-term use of nonsteroidal anti-inflammatory drugs because of elevated risks of diverticulitis and diverticular bleeding
• The use of opioid medication for chronic pain, which does not lead to long-term pain relief and has the potential for addiction issues
## 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
Tone & joint laxity
Mobility, ADL, & need for adaptive devices
Need for PT (to improve strength and tone) &/or OT (to improve fine motor skills)
Podiatry assessment for foot abnormalities
Community or
Social work involvement for parental support.
ADL = activities of daily living; clEDS = classical-like Ehlers-Danlos syndrome; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Tone & joint laxity
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve strength and tone) &/or OT (to improve fine motor skills)
• Podiatry assessment for foot abnormalities
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Non-weight-bearing exercise
For recommendations on pain medication, see
Careful selection of analgesic medication is recommended in light of ↑ risks of diverticulitis & diverticular bleeding in users of aspirin or NSAIDs.
Consider referral to rheumatologist &/or pain mgmt specialist or clinic.
Avoid use of opioid medication for chronic pain; it does not relieve pain long term & can → addiction.
Long-term chronic pain may → need for mental health services.
EDS = Ehlers-Danlos syndrome; NSAID = nonsteroidal anti-inflammatory drug
• Non-weight-bearing exercise
• For recommendations on pain medication, see
• Careful selection of analgesic medication is recommended in light of ↑ risks of diverticulitis & diverticular bleeding in users of aspirin or NSAIDs.
• Consider referral to rheumatologist &/or pain mgmt specialist or clinic.
• Avoid use of opioid medication for chronic pain; it does not relieve pain long term & can → addiction.
• Long-term chronic pain may → need for mental health services.
## Prevention of Primary Manifestations
For recommendations on prevention of primary manifestations of joint laxity and dislocations as well as joint pain, see Hypermobile Ehlers-Danlos Syndrome,
Prevention of Primary Manifestations in Individuals with
## Surveillance
Recommended Surveillance for Individuals with
EDS = Ehlers-Danlos syndrome
## Agents/Circumstances to Avoid
The following should be avoided:
Sports with heavy joint strain (e.g., contact sports, fighting sports, football, running)
Invasive procedures such as intubation, endoscopy, and/or colonoscopy unless essential because of reported tissue fragility of the trachea, esophagus, and small and large bowels
Acetylsalicylate (aspirin) and long-term use of nonsteroidal anti-inflammatory drugs because of elevated risks of diverticulitis and diverticular bleeding
The use of opioid medication for chronic pain, which does not lead to long-term pain relief and has the potential for addiction issues
• Sports with heavy joint strain (e.g., contact sports, fighting sports, football, running)
• Invasive procedures such as intubation, endoscopy, and/or colonoscopy unless essential because of reported tissue fragility of the trachea, esophagus, and small and large bowels
• Acetylsalicylate (aspirin) and long-term use of nonsteroidal anti-inflammatory drugs because of elevated risks of diverticulitis and diverticular bleeding
• The use of opioid medication for chronic pain, which does not lead to long-term pain relief and has the potential for addiction issues
## 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 preventive measures.
See
## Pregnancy Management
It is important that the obstetrician and midwives be made aware of the diagnosis of
Gynecologic follow up during pregnancy can be considered. Specialist delivery is strongly advised in view of the reported trachea rupture during intubation and esophagus rupture after insertion of a transesophageal ultrasound probe. These complications emphasize the need for careful handling of pregnant women with
## 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 may or may not be asymptomatic.
If both parents are known to be heterozygous for a
Although sibs with biallelic
Heterozygotes may or may not be asymptomatic (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 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 may or may not 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 a
• Although sibs with biallelic
• Heterozygotes may or may not be asymptomatic (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.
## 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 may or may not be asymptomatic.
If both parents are known to be heterozygous for a
Although sibs with biallelic
Heterozygotes may or may not be asymptomatic (see
• 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 may or may not 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 a
• Although sibs with biallelic
• Heterozygotes may or may not be asymptomatic (see
## Carrier (Heterozygote) 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 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
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• United Kingdom
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• United Kingdom
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## Molecular Genetics
TNXB-Related Classical-Like Ehlers-Danlos Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TNXB-Related Classical-Like Ehlers-Danlos Syndrome (
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
15 September 2022 (ma) Review posted live
24 September 2021 (fvd) Original submission
• 15 September 2022 (ma) Review posted live
• 24 September 2021 (fvd) Original submission
## Revision History
15 September 2022 (ma) Review posted live
24 September 2021 (fvd) Original submission
• 15 September 2022 (ma) Review posted live
• 24 September 2021 (fvd) Original submission
## References
## Literature Cited
Hyperextensible skin at the elbow
Mallet finger (digit 5)
Flat, broad feet with left hallux valgus and bilateral hammer toes of digits 2-4
|
[
"A Besselink-Lobanova, NJ Maandag, NC Voermans, HF van der Heijden, JG van der Hoeven, LM Heunks. Trachea rupture in tenascin-X-deficient type Ehlers-Danlos syndrome.. Anesthesiology. 2010;113:746-9",
"AF Brady, S Demirdas, S Fournel-Gigleux, N Ghali, C Giunta, I Kapferer-Seebacher, T Kosho, R Mendoza-Londono, MF Pope, M Rohrbach, T Van Damme, A Vandersteen, C van Mourik, N Voermans, J Zschocke, F Malfait. The Ehlers-Danlos syndromes, rare types.. Am J Med Genet C Semin Med Genet. 2017;175:70-115",
"M Brisset, C Metay, RY Carlier, C Badosa, C Marques, J Schalkwijk, I vanVlijmen-Willems, C Jimenez-Mallebrera, B Keren, V Jobic, P Laforêt, E Malfatti. Biallelic mutations in Tenascin-X cause classical-like Ehlers-Danlos syndrome with slowly progressive muscular weakness.. Neuromuscul Disord. 2020;30:833-8",
"GH Burch, Y Gong, W Liu, RW Dettman, CJ Curry, L Smith, WL Miller, J Bristow. Tenascin-X deficiency is associated with Ehlers-Danlos syndrome.. Nat Genet. 1997;17:104-8",
"M Castori, NC Voermans. Neurological manifestations of Ehlers-Danlos syndrome(s): a review.. Iran J Neurol 2014;13:190-208",
"W Chen, AF Perritt, R Morissette, JL Dreiling, MF Bohn, A Mallappa, Z Xu, M Quezado, DP Merke. Ehlers Danlos syndrome caused by biallelic TNXB variants in patients with congenital adrenal hyperplasia.. Hum Mutat. 2016;37:893-7",
"S Demirdas, E Dulfer, L Robert, M Kempers, D van Beek, D Micha, BG van Engelen, B Hamel, J Schalkwijk, B Loeys, A Maugeri, NC Voermans. Recognizing the tenascin-X deficient type of Ehlers-Danlos syndrome: a cross-sectional study in 17 patients.. Clin Genet. 2017;91:411-25",
"RA Gbadegesin, PD Brophy, A Adeyemo, G Hall, IR Gupta, D Hains, B Bartkowiak, CE Rabinovich, S Chandrasekharappa, A Homstad, K Westreich, G Wu, Y Liu, D Holanda, J Clarke, P Lavin, A Selim, S Miller, JS Wiener, SS Ross, J Foreman, C Rotimi, MP Winn. TNXB mutations can cause vesicoureteral reflux.. J Am Soc Nephrol. 2013;24:1313-22",
"N Ghali, D Baker, AF Brady, N Burrows, E Cervi, D Cilliers, M Frank, DP Germain, DJS Hulmes, ML Jacquemont, P Kannu, H Lefroy, A Legrand, FM Pope, L Robertson, A Vandersteen, K von Klemperer, R Warburton, M Whiteford, FS van Dijk. Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers-Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility.. Genet Med. 2019;21:2081-91",
"C Green, N Ghali, R Akilapa, C Angwin, D Baker, M Bartlett, J Bowen, AF Brady, J Brock, E Chamberlain, H Cheema, V McConnell, R Crookes, H Kazkaz, D Johnson, FM Pope, A Vandersteen, G Sobey, FS van Dijk. Classical-like Ehlers-Danlos syndrome: a clinical description of 20 newly identified individuals with evidence of tissue fragility.. Genet Med. 2020;22:1576-82",
"AGM Hendriks, NC Voermans, J Schalkwijk, BC Hamel, MM van Rossum. Well-defined clinical presentation of Ehlers-Danlos syndrome in patients with tenascin-X deficiency: a report of four cases.. Clin Dysmorphol. 2012;21:15-8",
"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",
"NM Lindor, J Bristow. Tenascin-X deficiency in autosomal recessive Ehlers-Danlos syndrome.. Am J Med Genet A. 2005;135:75-80",
"F Malfait, M Castori, CA Francomano, C Giunta, T Kosho, PH Byers. The Ehlers-Danlos syndromes.. Nat Rev Dis Primers. 2020;6:64",
"F Malfait, C Francomano, P Byers, J Belmont, B Berglund, J Black, L Bloom, JM Bowen, AF Brady, NP Burrows, M Castori, H Cohen, M Colombi, S Demirdas, J De Backer, A De Paepe, S Fournel-Gigleux, M Frank, N Ghali, C Giunta, R Grahame, A Hakim, X Jeunemaitre, D Johnson, B Juul-Kristensen, I Kapferer-Seebacher, H Kazkaz, T Kosho, ME Lavallee, H Levy, R Mendoza-Londono, M Pepin, FM Pope, E Reinstein, L Robert, M Rohrbach, L Sanders, GJ Sobey, T Van Damme, A Vandersteen, C van Mourik, N Voermans, N Wheeldon, J Zschocke, B Tinkle. The 2017 international classification of the Ehlers–Danlos syndromes.. Am J Med Genet C Semin Med Genet. 2017;175:8-26",
"L Micale, V Guarnieri, B Augello, O Palumbo, E Agolini, VM Sofia, T Mazza, A Novelli, M Carella, M Castori. Novel TNXB variants in two Italian patients with classical-like Ehlers-Danlos syndrome.. Genes (Basel) 2019;10:967",
"WL Miller, DP Merke. Tenascin-X, congenital adrenal hyperplasia, and the CAH-X syndrome.. Horm Res Paediatr. 2018;89:352-61",
"R Morissette, W Chen, AF Perritt, JL Dreiling, AE Arai, V Sachdev, H Hannoush, A Mallappa, Z Xu, NB McDonnell, M Quezado, DP Merke. Broadening the spectrum of Ehlers Danlos syndrome in patients with congenital adrenal hyperplasia.. J Clin Endocrinol Metab. 2015;100:E1143-52",
"M O'Connell, NP Burrows, MJJ van Vlijmen-Willems, SM Clark. Schalkwijk. Tenascin-X deficiency and Ehlers-Danlos syndrome: a case report and review of the literature.. Br J Dermatol. 2010;163:1340-5",
"I Pénisson-Besnier, V Allamand, P Beurrier, L Martin, J Schalkwijk, I van Vlijmen-Willems, C Gartioux, F Malfait, D Syx, L Macchi, P Marcorelles, B Arbeille, A Croué, A De Paepe, F. Dubas. Compound heterozygous mutations of the TNXB gene cause primary myopathy.. Neuromuscul Disord. 2013;23:664-9",
"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",
"D Rymen, M Ritelli, N Zoppi, V Cinquina, C Giunta, M Rohrbach, M Colombi. Clinical and molecular characterization of classical-like Ehlers-Danlos syndrome due to a novel TNXB variant.. Genes (Basel) 2019;10:843",
"T Sakiyama, A Kubo, T Sasaki, T Yamada, N Yabe, K Matsumoto, Y Futei. Recurrent gastrointestinal perforation in a patient with Ehlers-Danlos syndrome due to tenascin-X deficiency.. J Dermatol. 2015;42:511-4",
"J Schalkwijk, MC Zweers, PM Steijlen, WB Dean, G Taylor, IM van Vlijmen, B van Haren, WL Miller, J Bristow. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency.. N Engl J Med. 2001;345:1167-75",
"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",
"NC Voermans, G Drost, A van Kampen, AA Gabreëls-Festen, M Lammens, BC Hamel, J Schalkwijk, BG van Engelen. Recurrent neuropathy associated with Ehlers-Danlos syndrome.. J Neurol. 2006;253:670-1",
"NC Voermans, GJ Jenniskens, BC Hamel, J Schalkwijk, P Guicheney, BG van Engelen. Ehlers-Danlos syndrome due to tenascin-X deficiency: muscle weakness and contractures support overlap with collagen VI myopathies.. Am J Med Genet A. 2007;143A:2215-9",
"NC Voermans, N van Alfen, S Pillen, M Lammens, J Schalkwijk, MJ Zwarts, IA van Rooij, BC Hamel, BG van Engelen. Neuromuscular involvement in various types of Ehlers-Danlos syndrome.. Ann Neurol. 2009;65:687-97",
"S Watanabe, Y Ito, O Samura, H Nakano, D Sawamura, A Asahina, M Itoh. Novel gross deletion mutation c.-105_4042+498del in the TNXB gene in a Japanese woman with classical-like Ehlers-Danlos syndrome: a case of uneventful pregnancy and delivery.. J Dermatol. 2021;48:e227-e228",
"MC Zweers, J Bristow, PM Steijlen, WB Dean, BC Hamel, M Otero, M Kucharekova, JB Boezeman, J Schalkwijk. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome.. Am J Hum Genet. 2003;73:214-7"
] |
15/9/2022
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GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
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[
"Review",
"Clinical Review"
] |
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tooth-agenesis-ov
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tooth-agenesis-ov
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[
"Nonsyndromic Tooth Agenesis",
"Overview"
] |
Nonsyndromic Tooth Agenesis Overview
|
Ariadne Letra, Brett Chiquet, Emily Hansen-Kiss, Simone Menezes, Elizabeth Hunter
|
Summary The purpose of this overview is to: Describe the Review the Provide an Review Inform
|
## Clinical Characteristics of Nonsyndromic Tooth Agenesis
Tooth agenesis is a developmental anomaly characterized by the absence of one or more permanent teeth (excluding third molars) due to failure at the early stages of tooth development. The term nonsyndromic tooth agenesis (NSTA) refers to the condition in which tooth agenesis of permanent teeth is the only clinical finding.
Missing teeth in the primary dentition is rare, however, a missing deciduous tooth is usually an indicator of NSTA of the respective permanent tooth.
The presence of unusual spacing in a child's dentition should lead the pediatrician and the dentist to suspect NSTA. Diagnosis of NSTA can be confirmed by panoramic radiograph after age six years, when all of the permanent tooth buds (excluding third molars) should be visible in the radiograph.
In adults, consultation of dental records at younger ages in addition to careful evaluation of edentulous spaces are advisable to evaluate for missing teeth due to extractions or as a consequence of periodontal disease [
In general, tooth agenesis tends to manifest unilaterally, and affects the maxilla and mandible at similar rates. The most commonly missing teeth (excluding third molars) are permanent mandibular second premolars, followed by maxillary lateral incisors, and maxillary second premolars.
Bilateral agenesis of maxillary lateral incisors is also more common than unilateral.
A thorough medical history and physical examination to assess for syndromic features that lead to NSTA and/or premature loss of teeth is also required (see
Note: NSTA is a common feature in individuals with nonsyndromic cleft lip with/without cleft palate. Careful examination and evaluation of medical history should help determine the nonsyndromic nature of both findings.
In most studies, the prevalence of NSTA ranges from 3% to 10% in the mild form (hypodontia) whereas the more severe forms (oligodontia) show a prevalence of 0.1%-0.5%, excluding third molars.
Tooth agenesis may have variable prevalence according to the population studied, with Asians being more commonly affected, followed by individuals of northern European background and African Americans.
A meta-analysis investigating the prevalence of NSTA, which included 33 studies from different populations worldwide, showed that the prevalence of NSTA in Europe was 5.5% higher and in Australia was 6.3% higher compared to the prevalence in North America, which was 1% [
The prevalence in the Japanese population was reported to be 8.5% [
The most frequently missing tooth types also vary by population; agenesis of lower incisors is more frequent in Asians than in other populations [
Females are more frequently affected than males with a 3:2 ratio [
• Missing teeth in the primary dentition is rare, however, a missing deciduous tooth is usually an indicator of NSTA of the respective permanent tooth.
• The presence of unusual spacing in a child's dentition should lead the pediatrician and the dentist to suspect NSTA. Diagnosis of NSTA can be confirmed by panoramic radiograph after age six years, when all of the permanent tooth buds (excluding third molars) should be visible in the radiograph.
• In adults, consultation of dental records at younger ages in addition to careful evaluation of edentulous spaces are advisable to evaluate for missing teeth due to extractions or as a consequence of periodontal disease [
• In general, tooth agenesis tends to manifest unilaterally, and affects the maxilla and mandible at similar rates. The most commonly missing teeth (excluding third molars) are permanent mandibular second premolars, followed by maxillary lateral incisors, and maxillary second premolars.
• Bilateral agenesis of maxillary lateral incisors is also more common than unilateral.
• A thorough medical history and physical examination to assess for syndromic features that lead to NSTA and/or premature loss of teeth is also required (see
• In most studies, the prevalence of NSTA ranges from 3% to 10% in the mild form (hypodontia) whereas the more severe forms (oligodontia) show a prevalence of 0.1%-0.5%, excluding third molars.
• Tooth agenesis may have variable prevalence according to the population studied, with Asians being more commonly affected, followed by individuals of northern European background and African Americans.
• A meta-analysis investigating the prevalence of NSTA, which included 33 studies from different populations worldwide, showed that the prevalence of NSTA in Europe was 5.5% higher and in Australia was 6.3% higher compared to the prevalence in North America, which was 1% [
• The prevalence in the Japanese population was reported to be 8.5% [
• A meta-analysis investigating the prevalence of NSTA, which included 33 studies from different populations worldwide, showed that the prevalence of NSTA in Europe was 5.5% higher and in Australia was 6.3% higher compared to the prevalence in North America, which was 1% [
• The prevalence in the Japanese population was reported to be 8.5% [
• The most frequently missing tooth types also vary by population; agenesis of lower incisors is more frequent in Asians than in other populations [
• Females are more frequently affected than males with a 3:2 ratio [
• A meta-analysis investigating the prevalence of NSTA, which included 33 studies from different populations worldwide, showed that the prevalence of NSTA in Europe was 5.5% higher and in Australia was 6.3% higher compared to the prevalence in North America, which was 1% [
• The prevalence in the Japanese population was reported to be 8.5% [
## Causes of Nonsyndromic Tooth Agenesis
The etiology of nonsyndromic tooth agenesis (NSTA) is attributed to mutation of genes involved in craniofacial and tooth development in about 80% of affected individuals. In the remaining 20%, NSTA is attributed to exogenous factors (e.g., chemotherapy, radiation therapy, maternal rubella virus infection, and exposure to medications such as thalidomide and antineoplastic agents) early in life while permanent tooth buds are developing [
Numerous genes and genetic variants have been implicated in the etiology of NSTA, most of which were suggested from syndromic forms or animal models (
Traditionally, NSTA was considered a monogenic condition. Recently, several studies have suggested multilocus or oligogenic inheritance [
For many single genes associated with tooth agenesis, inter- and intrafamilial variability and reduced penetrance are common [
Nonsyndromic Tooth Agenesis: Genes and Associated Dental Phenotypes
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
See
Complex inheritance, mostly autosomal dominant
The most common
Complex inheritance has also been proposed (see
Disorders to Consider in the Differential Diagnosis of Apparent Nonsyndromic Tooth Agenesis
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Emerging evidence exists that mutation in this gene could cause isolated nonsyndromic tooth agenesis, but data are insufficient to state this definitively.
Larger deletions of the chromosome 4p16.2 region that include
Mutation of this gene also leads to dystrophic epidermolysis bullosa (AD and AR) and epithelial recurrent erosion dystrophy (OMIM
Mutation of this gene also leads to
## Evaluation Strategies to Identify the Genetic Cause of Nonsyndromic Tooth Agenesis in a Proband
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical and dental history, physical examination, intra- and extraoral radiographs, family history, and genomic/genetic testing.
A thorough physical exam should be completed to assess the presence of any extraoral features that may indicate a syndromic presentation.
A detailed oral exam and review of current and previous intra- and extraoral radiographs should then follow to identify exactly how many and which permanent teeth are absent and identify the presence of other dental anomalies in individuals with tooth agenesis.
Microdontia (which includes peg laterals), malocclusion, and retention of primary teeth are common findings in affected individuals.
A three-generation family history should be taken (when possible), with attention to relatives with manifestations of tooth agenesis and other dental anomalies, such as enamel defects or differences in tooth shape. Direct examination by a dental professional with specific expertise in tooth agenesis may need to be completed on all pertinent relatives due to the difficulty in diagnosing tooth agenesis vs other causes of tooth loss in adults. Review and documentation of medical and dental records and results of molecular genetic testing is recommended, when available.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.
In individuals with posterior tooth agenesis, molecular genetic testing of
In individuals with hypodontia and oligodontia affecting both anterior and posterior dentition alike
In individuals with microdontia (peg laterals) or abnormally shaped teeth in addition to missing teeth, molecular genetic testing of
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 and dental history, physical examination, intra- and extraoral radiographs, family history, and genomic/genetic testing.
• In individuals with posterior tooth agenesis, molecular genetic testing of
• In individuals with hypodontia and oligodontia affecting both anterior and posterior dentition alike
• In individuals with microdontia (peg laterals) or abnormally shaped teeth in addition to missing teeth, molecular genetic testing of
## Physical Examination
A thorough physical exam should be completed to assess the presence of any extraoral features that may indicate a syndromic presentation.
A detailed oral exam and review of current and previous intra- and extraoral radiographs should then follow to identify exactly how many and which permanent teeth are absent and identify the presence of other dental anomalies in individuals with tooth agenesis.
Microdontia (which includes peg laterals), malocclusion, and retention of primary teeth are common findings in affected individuals.
## Family History
A three-generation family history should be taken (when possible), with attention to relatives with manifestations of tooth agenesis and other dental anomalies, such as enamel defects or differences in tooth shape. Direct examination by a dental professional with specific expertise in tooth agenesis may need to be completed on all pertinent relatives due to the difficulty in diagnosing tooth agenesis vs other causes of tooth loss in adults. Review and documentation of medical and dental records and results of molecular genetic testing is recommended, when available.
## Genomic/Genetic Testing
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.
In individuals with posterior tooth agenesis, molecular genetic testing of
In individuals with hypodontia and oligodontia affecting both anterior and posterior dentition alike
In individuals with microdontia (peg laterals) or abnormally shaped teeth in addition to missing teeth, molecular genetic testing of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
• In individuals with posterior tooth agenesis, molecular genetic testing of
• In individuals with hypodontia and oligodontia affecting both anterior and posterior dentition alike
• In individuals with microdontia (peg laterals) or abnormally shaped teeth in addition to missing teeth, molecular genetic testing of
## Management
There is no standard of care procedure or clinical practice guideline for management of nonsyndromic tooth agenesis (NSTA).
To establish the extent of disease and needs in an individual diagnosed with NSTA, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Nonsyndromic Tooth Agenesis
Clinical exam incl hard tissue exams & radiographs (bitewings, individualized periapicals, & orthopantomographs)
Referral to orthodontic & prosthodontic providers
Community or
Social work involvement for parental support.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Nonsyndromic Tooth Agenesis
In those ages 6-18 yrs
Also serves psychological & functional purposes
In those ages 12-18 yrs
Emphasis on functional & esthetic success
Implants should only be placed after the majority of skeletal growth is completed.
Extraction of primary teeth and/or bone augmentation procedures may be necessary before implant placement.
It is recommended that individuals with (or suspected of having) nonsyndromic tooth agenesis be followed by a dentist at least every six months to ensure maintenance of remaining dentition. Oral health disease prevention for remaining dentition often includes dietary counseling, fluoride sealants, and mouth guards (see
Recommended Surveillance in Individuals with Nonsyndromic Tooth Agenesis
It is appropriate to clarify the clinical and/or genetic status (when possible) 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 dental treatment. Evaluations can include:
Complete clinical intra- and extraoral examinations and radiographs (see
Molecular genetic testing if the pathogenic variant(s) in the family are known.
See
• Clinical exam incl hard tissue exams & radiographs (bitewings, individualized periapicals, & orthopantomographs)
• Referral to orthodontic & prosthodontic providers
• Community or
• Social work involvement for parental support.
• In those ages 6-18 yrs
• Also serves psychological & functional purposes
• In those ages 12-18 yrs
• Emphasis on functional & esthetic success
• Complete clinical intra- and extraoral examinations and radiographs (see
• 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 in an individual diagnosed with NSTA, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Nonsyndromic Tooth Agenesis
Clinical exam incl hard tissue exams & radiographs (bitewings, individualized periapicals, & orthopantomographs)
Referral to orthodontic & prosthodontic providers
Community or
Social work involvement for parental support.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Clinical exam incl hard tissue exams & radiographs (bitewings, individualized periapicals, & orthopantomographs)
• Referral to orthodontic & prosthodontic providers
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Nonsyndromic Tooth Agenesis
In those ages 6-18 yrs
Also serves psychological & functional purposes
In those ages 12-18 yrs
Emphasis on functional & esthetic success
Implants should only be placed after the majority of skeletal growth is completed.
Extraction of primary teeth and/or bone augmentation procedures may be necessary before implant placement.
• In those ages 6-18 yrs
• Also serves psychological & functional purposes
• In those ages 12-18 yrs
• Emphasis on functional & esthetic success
## Prevention of Secondary Complications
It is recommended that individuals with (or suspected of having) nonsyndromic tooth agenesis be followed by a dentist at least every six months to ensure maintenance of remaining dentition. Oral health disease prevention for remaining dentition often includes dietary counseling, fluoride sealants, and mouth guards (see
## Surveillance
Recommended Surveillance in Individuals with Nonsyndromic Tooth Agenesis
## Evaluation of Relatives at Risk
It is appropriate to clarify the clinical and/or genetic status (when possible) 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 dental treatment. Evaluations can include:
Complete clinical intra- and extraoral examinations and radiographs (see
Molecular genetic testing if the pathogenic variant(s) in the family are known.
See
• Complete clinical intra- and extraoral examinations and radiographs (see
• Molecular genetic testing if the pathogenic variant(s) in the family are known.
## Genetic Risk Assessment
Nonsyndromic tooth agenesis (NSTA) caused by pathogenic variants in
NSTA caused by pathogenic variants in
NSTA caused by pathogenic variants in
Note: This section provides genetic risk assessment information for individuals and families with a molecular diagnosis of NSTA (see
Many individuals with a molecular diagnosis of autosomal dominant NSTA have an affected parent [
Some individuals diagnosed with autosomal dominant NSTA have 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 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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 NSTA may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, and variable expressivity. 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical manifestations may vary in heterozygous sibs; both reduced penetrance and intrafamilial variability are observed in autosomal dominant NSTA.
If the proband has a known 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 [
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 reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
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 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 for a
If both parents are known to be heterozygous for a
While clinical manifestations of tooth agenesis vary among affected family members, sibs who inherit biallelic
Sibs who inherit one
The father of an affected male will not have
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
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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;
Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
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
Oligogenic inheritance due to multilocus variation has recently been proposed for nonsyndromic tooth agenesis. For example, pathogenic 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 affected.
Once the nonsyndromic tooth agenesis-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.
• Many individuals with a molecular diagnosis of autosomal dominant NSTA have an affected parent [
• Some individuals diagnosed with autosomal dominant NSTA have 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 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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 NSTA may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, and variable expressivity. 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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%. Clinical manifestations may vary in heterozygous sibs; both reduced penetrance and intrafamilial variability are observed in autosomal dominant NSTA.
• If the proband has a known 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 [
• 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 reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• 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 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 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.
• If both parents are known to be heterozygous for a
• While clinical manifestations of tooth agenesis vary among affected family members, sibs who inherit biallelic
• Sibs who inherit one
• The father of an affected male will not have
• 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
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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;
• Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
• 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 may have a range of clinical manifestations.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Nonsyndromic tooth agenesis (NSTA) caused by pathogenic variants in
NSTA caused by pathogenic variants in
NSTA caused by pathogenic variants in
Note: This section provides genetic risk assessment information for individuals and families with a molecular diagnosis of NSTA (see
## Autosomal Dominant Inheritance – Risk to Family Members
Many individuals with a molecular diagnosis of autosomal dominant NSTA have an affected parent [
Some individuals diagnosed with autosomal dominant NSTA have 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 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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 NSTA may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, and variable expressivity. 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Clinical manifestations may vary in heterozygous sibs; both reduced penetrance and intrafamilial variability are observed in autosomal dominant NSTA.
If the proband has a known 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 [
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 reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Many individuals with a molecular diagnosis of autosomal dominant NSTA have an affected parent [
• Some individuals diagnosed with autosomal dominant NSTA have 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 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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 NSTA may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, and variable expressivity. 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. Though theoretically possible, no instances of germline mosaicism have been reported. 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%. Clinical manifestations may vary in heterozygous sibs; both reduced penetrance and intrafamilial variability are observed in autosomal dominant NSTA.
• If the proband has a known 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 [
• 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 reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
## Autosomal Recessive Inheritance – Risk to Family Members
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 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 for a
If both parents are known to be heterozygous for a
While clinical manifestations of tooth agenesis vary among affected family members, sibs who inherit biallelic
Sibs who inherit one
• 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 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 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.
• If both parents are known to be heterozygous for a
• While clinical manifestations of tooth agenesis vary among affected family members, sibs who inherit biallelic
• Sibs who inherit one
## X-Linked Inheritance – Risk to Family Members
The father of an affected male will not have
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
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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;
Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
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
• The father of an affected male will not have
• 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
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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;
• Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be heterozygotes and may have a range of clinical manifestations.
• 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 may have a range of clinical manifestations.
## Complex/Multifactorial Inheritance
Oligogenic inheritance due to multilocus variation has recently been proposed for nonsyndromic tooth agenesis. For example, pathogenic variants in
## 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 nonsyndromic tooth agenesis-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
•
•
## Chapter Notes
Ariadne Letra is a dentist with additional formal training in Human Molecular Genetics and a Professor in the Department of Diagnostic and Biomedical Sciences and Center for Craniofacial Research at UTHealth School of Dentistry at Houston. Dr Letra has adjunct faculty appointments at the Pediatric Research Center, UTHealth McGovern Medical School, and at the University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences. Dr Letra's research focuses on the cellular and molecular basis of complex oral traits and anomalies, particularly craniofacial and dental anomalies. Her work has identified numerous genes and gene variants associated with these conditions. Additional work in her lab focuses on identifying common molecular players linking oral and general health conditions. Dr Letra has published 98 peer-reviewed original articles, two invited book chapters, four invited review articles, and more than 180 abstracts related to craniofacial anomalies and oral diseases/conditions. Her research has been continuously supported by grants from the National Institutes of Health and additional funding agencies.
Brett Chiquet is a board-certified pediatric dentist and Associate Professor in the Department of Pediatric Dentistry at UTHealth School of Dentistry. Dr Chiquet treats all children, including patients with special health care needs. Dr Chiquet helps teach dental residents how to comprehensively treat all pediatric patients, including anticipatory guidance, prevention, restorative dentistry, growth and development, special health care needs, hospital dentistry, behavior guidance, trauma, and oral pathology. The resident clinic provides comprehensive care for children ages 0-21, including management of developing oral tissues and occlusion. Patients with tooth agenesis are monitored for treatment at appropriate time points, balancing growth and development of the oral structures and the developing psyche of the patient. Dr Chiquet's clinical and research interest is cleft lip and palate, which often co-occur with tooth agenesis.
Emily Hansen-Kiss is a board-certified genetic counselor and Assistant Professor in the Department of Diagnostic and Biomedical Sciences at UTHealth School of Dentistry. Ms Hansen-Kiss has served as the genetic counselor in the Cleft and Craniofacial Clinics at Shriners Hospitals for Children – Houston, and UTHealth/Memorial Herman Hospital for the last two years, where she has gained extensive experience counseling patients and families about syndromic and nonsyndromic orofacial conditions. Ms Hansen-Kiss has also been involved in teaching genetics with an orofacial focus to the UTHealth School of Dentistry and the UTHealth Genetic Counseling graduate program students.
This study was supported by the UTHealth School of Dentistry Summer Student Research Program (SM and EH) and UTHealth School of Dentistry start up funds to AL and BC.
22 July 2021 (ma) Review posted live
2 October 2020 (al) Original submission
• 22 July 2021 (ma) Review posted live
• 2 October 2020 (al) Original submission
## Author Notes
Ariadne Letra is a dentist with additional formal training in Human Molecular Genetics and a Professor in the Department of Diagnostic and Biomedical Sciences and Center for Craniofacial Research at UTHealth School of Dentistry at Houston. Dr Letra has adjunct faculty appointments at the Pediatric Research Center, UTHealth McGovern Medical School, and at the University of Texas MD Anderson Cancer Center Graduate School of Biomedical Sciences. Dr Letra's research focuses on the cellular and molecular basis of complex oral traits and anomalies, particularly craniofacial and dental anomalies. Her work has identified numerous genes and gene variants associated with these conditions. Additional work in her lab focuses on identifying common molecular players linking oral and general health conditions. Dr Letra has published 98 peer-reviewed original articles, two invited book chapters, four invited review articles, and more than 180 abstracts related to craniofacial anomalies and oral diseases/conditions. Her research has been continuously supported by grants from the National Institutes of Health and additional funding agencies.
Brett Chiquet is a board-certified pediatric dentist and Associate Professor in the Department of Pediatric Dentistry at UTHealth School of Dentistry. Dr Chiquet treats all children, including patients with special health care needs. Dr Chiquet helps teach dental residents how to comprehensively treat all pediatric patients, including anticipatory guidance, prevention, restorative dentistry, growth and development, special health care needs, hospital dentistry, behavior guidance, trauma, and oral pathology. The resident clinic provides comprehensive care for children ages 0-21, including management of developing oral tissues and occlusion. Patients with tooth agenesis are monitored for treatment at appropriate time points, balancing growth and development of the oral structures and the developing psyche of the patient. Dr Chiquet's clinical and research interest is cleft lip and palate, which often co-occur with tooth agenesis.
Emily Hansen-Kiss is a board-certified genetic counselor and Assistant Professor in the Department of Diagnostic and Biomedical Sciences at UTHealth School of Dentistry. Ms Hansen-Kiss has served as the genetic counselor in the Cleft and Craniofacial Clinics at Shriners Hospitals for Children – Houston, and UTHealth/Memorial Herman Hospital for the last two years, where she has gained extensive experience counseling patients and families about syndromic and nonsyndromic orofacial conditions. Ms Hansen-Kiss has also been involved in teaching genetics with an orofacial focus to the UTHealth School of Dentistry and the UTHealth Genetic Counseling graduate program students.
## Acknowledgments
This study was supported by the UTHealth School of Dentistry Summer Student Research Program (SM and EH) and UTHealth School of Dentistry start up funds to AL and BC.
## Revision History
22 July 2021 (ma) Review posted live
2 October 2020 (al) Original submission
• 22 July 2021 (ma) Review posted live
• 2 October 2020 (al) Original submission
## References
## Literature Cited
|
[] |
22/7/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tps
|
tps
|
[
"Tricho-Rhino-Phalangeal Syndrome (TRPS)",
"Tricho-Rhino-Phalangeal Syndrome (TRPS)",
"Trichorhinophalangeal Dysplasia Type I",
"Trichorhinophalangeal Dysplasia Type II (Langer-Giedion Syndrome)",
"Double-strand-break repair protein rad21 homolog",
"Exostosin-1",
"Zinc finger transcription factor Trps1",
"EXT1",
"RAD21",
"TRPS1",
"Trichorhinophalangeal Syndrome"
] |
Trichorhinophalangeal Syndrome
|
Beyhan Tüysüz, Nilay Güneş, Dilek Uludağ Alkaya
|
Summary Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in The clinical diagnosis of TRPS can be established in a proband with characteristic facial features, ectodermal and joint manifestations, and skeletal findings of cone-shaped epiphyses. The molecular diagnosis of TRPS I is established in an individual with suggestive findings and identification of a heterozygous pathogenic variant in TRPS is inherited in an autosomal dominant manner. Many individuals with TRPS I have an affected parent; about one third of affected individuals have the disorder as the result of a
|
Trichorhinophalangeal dysplasia type I
Trichorhinophalangeal dysplasia type II (Langer-Giedion syndrome)
For synonyms and outdated names see
• Trichorhinophalangeal dysplasia type I
• Trichorhinophalangeal dysplasia type II (Langer-Giedion syndrome)
## Diagnosis
No consensus diagnostic criteria for trichorhinophalangeal syndrome (TRPS) have been published.
TRPS includes TRPS I (caused by a heterozygous pathogenic variant in
TRPS should be suspected in individuals with the following clinical, radiographic, and family history findings.
In individuals with
Family history is 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.
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
Molecular Genetic Testing Used in Trichorhinophalangeal 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
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., contiguous deletion of
Chromosome 8 inversions have been reported in two individuals with TRPS I, inv(8)(q13:q24.1) and inv(8)(q21.1:q24.1) [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• In individuals with
## Suggestive Findings
TRPS should be suspected in individuals with the following clinical, radiographic, and family history findings.
In individuals with
Family history is 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.
• In individuals with
## Clinical Findings
## Radiographic Findings
In individuals with
• In individuals with
## Family History
Family history is 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
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
Molecular Genetic Testing Used in Trichorhinophalangeal 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
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., contiguous deletion of
Chromosome 8 inversions have been reported in two individuals with TRPS I, inv(8)(q13:q24.1) and inv(8)(q21.1:q24.1) [
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
## Clinical Characteristics
Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in
The largest cohort of individuals with TRPS reported to date includes 103 affected individuals from a large European collaborative study [
Trichorhinophalangeal Syndrome: Frequency of Select Features
Only occurs in TRPS II; due to
Significantly more common in those with TRPS II
Characteristic facial features that are similar in both TRPS I and TRPS II include a large nose, broad nasal ridge and tip, underdeveloped alae, long philtrum, thin vermilion of the upper lip, and large, prominent ears. Other craniofacial features include a high forehead, a broad nasal septum, a horizontal smile, narrow, high-arched palate, micrognathia, and a horizontal chin furrow. Clear differences can be observed in the parts of the eyebrow: the medial eyebrow is almost always denser and wider than the lateral eyebrow [
One third of males lose their hair completely or almost completely within a few years of puberty. Women typically have more hair, but a high anterior hairline is common.
Variability exists and some individuals have near-normal scalp hair, and in some individuals the thickness and quality of hair improves with time.
There are a few reports of growth hormone deficiency in individuals with TRPS [
Hip dysplasia occurs especially in individuals with TRPS II, typically in pre-adolescence and early adulthood [
The proportion of individuals with TRPS I with mild intellectual disability is reported to be slightly higher than in the general population. However, more than half of individuals with TRPS II have mild-to-moderate intellectual disability [
There is no clear genotype-phenotype correlation in TRPS I. However, missense variants have been reported to be associated with a more severe phenotype such as significant brachydactyly and severe short stature [
The size of the minimal critical region responsible for the phenotypic features of TRPS II has been reported to be around 3 Mb [
No instances of reduced penetrance have been reported; thus, penetrance is believed to be 100% [
It has been suggested that individuals with severe short stature and brachydactyly may have a distinguishable phenotype called TRPS III [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
There are no population-based estimates of the prevalence of TRPS. To date, 350 affected individuals have been reported [Orphanet Report
## Clinical Description
Trichorhinophalangeal syndrome (TRPS) comprises TRPS I (caused by a heterozygous pathogenic variant in
The largest cohort of individuals with TRPS reported to date includes 103 affected individuals from a large European collaborative study [
Trichorhinophalangeal Syndrome: Frequency of Select Features
Only occurs in TRPS II; due to
Significantly more common in those with TRPS II
Characteristic facial features that are similar in both TRPS I and TRPS II include a large nose, broad nasal ridge and tip, underdeveloped alae, long philtrum, thin vermilion of the upper lip, and large, prominent ears. Other craniofacial features include a high forehead, a broad nasal septum, a horizontal smile, narrow, high-arched palate, micrognathia, and a horizontal chin furrow. Clear differences can be observed in the parts of the eyebrow: the medial eyebrow is almost always denser and wider than the lateral eyebrow [
One third of males lose their hair completely or almost completely within a few years of puberty. Women typically have more hair, but a high anterior hairline is common.
Variability exists and some individuals have near-normal scalp hair, and in some individuals the thickness and quality of hair improves with time.
There are a few reports of growth hormone deficiency in individuals with TRPS [
Hip dysplasia occurs especially in individuals with TRPS II, typically in pre-adolescence and early adulthood [
The proportion of individuals with TRPS I with mild intellectual disability is reported to be slightly higher than in the general population. However, more than half of individuals with TRPS II have mild-to-moderate intellectual disability [
## Facial Features
Characteristic facial features that are similar in both TRPS I and TRPS II include a large nose, broad nasal ridge and tip, underdeveloped alae, long philtrum, thin vermilion of the upper lip, and large, prominent ears. Other craniofacial features include a high forehead, a broad nasal septum, a horizontal smile, narrow, high-arched palate, micrognathia, and a horizontal chin furrow. Clear differences can be observed in the parts of the eyebrow: the medial eyebrow is almost always denser and wider than the lateral eyebrow [
## Ectodermal Features
One third of males lose their hair completely or almost completely within a few years of puberty. Women typically have more hair, but a high anterior hairline is common.
Variability exists and some individuals have near-normal scalp hair, and in some individuals the thickness and quality of hair improves with time.
## Skeletal Features
There are a few reports of growth hormone deficiency in individuals with TRPS [
Hip dysplasia occurs especially in individuals with TRPS II, typically in pre-adolescence and early adulthood [
## Psychomotor Development
The proportion of individuals with TRPS I with mild intellectual disability is reported to be slightly higher than in the general population. However, more than half of individuals with TRPS II have mild-to-moderate intellectual disability [
## Other
## Genotype-Phenotype Correlations
There is no clear genotype-phenotype correlation in TRPS I. However, missense variants have been reported to be associated with a more severe phenotype such as significant brachydactyly and severe short stature [
The size of the minimal critical region responsible for the phenotypic features of TRPS II has been reported to be around 3 Mb [
## Penetrance
No instances of reduced penetrance have been reported; thus, penetrance is believed to be 100% [
## Nomenclature
It has been suggested that individuals with severe short stature and brachydactyly may have a distinguishable phenotype called TRPS III [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
There are no population-based estimates of the prevalence of TRPS. To date, 350 affected individuals have been reported [Orphanet Report
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Phenotypes associated with germline pathogenic variants in
Genetically Related (Allelic) Disorders
ID = intellectual disability; TRPS = trichorhinophalangeal syndrome
## Differential Diagnosis
Trichorhinophalangeal syndrome (TRPS) is often considered in the differential diagnosis of disorders with abnormalities of the hair, nose, and limbs (see
Disorders of Interest in the Differential Diagnosis of Trichorhinophalangeal Syndrome
Short stature
Brachydactyly
Nasal shape
Oral frenula
Polydactyly
Absence of ID
Absence of characteristic craniofacial & digital anomalies assoc w/TRPS II.
Short stature
Brachydactyly
Cone-shaped epiphyses
Round face
Long eyelashes
Anteverted nostrils
Thickened skin
Absence of sparse hair
Slow-growing, dry hair
Underdeveloped alae nasi
Long philtrum
Ocular manifestations
Distinct dental anomalies: enamel hypoplasia, tooth agenesis, microdontia
Short stature
Brachydactyly
Cone-shaped epiphyses
ID
Ectopic ossifications
↑ serum PTH level, hypocalcemia, hyperphosphatemia
Short stature
Brachydactyly
Prominent nose
Cone-shaped epiphyses
Sparse hair
Dental anomalies
Intrauterine growth restriction
Long, triangular face
Short stature
Thick eyebrows
Large nose
Hypoplastic alae nasi
Long philtrum
Prominent ears
Gonadal dysgenesis
Wide nasal bridge
Fine hair
Cone-shaped epiphyses
Short stature
Nasal shape
Immunodeficiency
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; PTH = parathyroid hormone; TRPS = trichorhinophalangeal syndrome
Ellis-van Creveld (EVC) syndrome caused by pathogenic variants in
• Short stature
• Brachydactyly
• Nasal shape
• Oral frenula
• Polydactyly
• Absence of ID
• Absence of characteristic craniofacial & digital anomalies assoc w/TRPS II.
• Short stature
• Brachydactyly
• Cone-shaped epiphyses
• Round face
• Long eyelashes
• Anteverted nostrils
• Thickened skin
• Absence of sparse hair
• Slow-growing, dry hair
• Underdeveloped alae nasi
• Long philtrum
• Ocular manifestations
• Distinct dental anomalies: enamel hypoplasia, tooth agenesis, microdontia
• Short stature
• Brachydactyly
• Cone-shaped epiphyses
• ID
• Ectopic ossifications
• ↑ serum PTH level, hypocalcemia, hyperphosphatemia
• Short stature
• Brachydactyly
• Prominent nose
• Cone-shaped epiphyses
• Sparse hair
• Dental anomalies
• Intrauterine growth restriction
• Long, triangular face
• Short stature
• Thick eyebrows
• Large nose
• Hypoplastic alae nasi
• Long philtrum
• Prominent ears
• Gonadal dysgenesis
• Wide nasal bridge
• Fine hair
• Cone-shaped epiphyses
• Short stature
• Nasal shape
• Immunodeficiency
## Management
To establish the extent of disease and support needs of an individual diagnosed with trichorhinophalangeal syndrome (TRPS), the evaluations summarized in
Trichorhinophalangeal Syndrome: Recommended Evaluations Following Initial Diagnosis
Measurement of height
Radiographs of hands, feet, pelvis, & hips, if joint pain, swelling, &/or limited mobility are present
DXA = dual-energy x-ray absorptiometry; GH = growth hormone; MOI = mode of inheritance; TRPS = trichorhinophalangeal syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Management of TRPS is principally supportive (see
Trichorhinophalangeal Syndrome: Treatment of Manifestations
Practical advice on hair care & use of wigs
Topical minoxidil treatment & hair transplantation may be useful.
OT can be beneficial for fine motor impairment.
Mechanical aids such as electric can openers may ameliorate problems caused by joint anomalies.
Analgesics (e.g., NSAIDs or other non-opioids)
Physiotherapy can help relieve pain & maintain hip range of motion.
Encourage regular exercise.
Support w/mobility at school & work as needed
Recommendations for sunlight exposure
Ensure adequate dietary intake of calcium & vitamin D &/or calcium & vitamin D supplementation.
Modify activities to prevent fractures.
Consider bisphosphonates.
GH = growth hormone; NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapy; TRPS = trichorhinophalangeal syndrome
Topical minoxidil treatment was reported to improve hair density and length in one individual with TRPS [
When the growth pattern of a child with TRPS is below the normal range for age and sex and is of concern to the family, growth hormone (GH) stimulation tests can be performed. If the result is subnormal, GH therapy may be considered [
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Trichorhinophalangeal Syndrome: Recommended Surveillance
Monitor linear growth.
Assess for joint manifestations.
DXA = dual-energy x-ray absorptiometry; TRPS = trichorhinophalangeal syndrome
High-impact or contact sports may pose a risk to those with impaired mobility.
See
Search
• Measurement of height
• Radiographs of hands, feet, pelvis, & hips, if joint pain, swelling, &/or limited mobility are present
• Practical advice on hair care & use of wigs
• Topical minoxidil treatment & hair transplantation may be useful.
• OT can be beneficial for fine motor impairment.
• Mechanical aids such as electric can openers may ameliorate problems caused by joint anomalies.
• Analgesics (e.g., NSAIDs or other non-opioids)
• Physiotherapy can help relieve pain & maintain hip range of motion.
• Encourage regular exercise.
• Support w/mobility at school & work as needed
• Recommendations for sunlight exposure
• Ensure adequate dietary intake of calcium & vitamin D &/or calcium & vitamin D supplementation.
• Modify activities to prevent fractures.
• Consider bisphosphonates.
• Monitor linear growth.
• Assess for joint manifestations.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and support needs of an individual diagnosed with trichorhinophalangeal syndrome (TRPS), the evaluations summarized in
Trichorhinophalangeal Syndrome: Recommended Evaluations Following Initial Diagnosis
Measurement of height
Radiographs of hands, feet, pelvis, & hips, if joint pain, swelling, &/or limited mobility are present
DXA = dual-energy x-ray absorptiometry; GH = growth hormone; MOI = mode of inheritance; TRPS = trichorhinophalangeal syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Measurement of height
• Radiographs of hands, feet, pelvis, & hips, if joint pain, swelling, &/or limited mobility are present
## Treatment of Manifestations
Management of TRPS is principally supportive (see
Trichorhinophalangeal Syndrome: Treatment of Manifestations
Practical advice on hair care & use of wigs
Topical minoxidil treatment & hair transplantation may be useful.
OT can be beneficial for fine motor impairment.
Mechanical aids such as electric can openers may ameliorate problems caused by joint anomalies.
Analgesics (e.g., NSAIDs or other non-opioids)
Physiotherapy can help relieve pain & maintain hip range of motion.
Encourage regular exercise.
Support w/mobility at school & work as needed
Recommendations for sunlight exposure
Ensure adequate dietary intake of calcium & vitamin D &/or calcium & vitamin D supplementation.
Modify activities to prevent fractures.
Consider bisphosphonates.
GH = growth hormone; NSAIDs = nonsteroidal anti-inflammatory drugs; OT = occupational therapy; TRPS = trichorhinophalangeal syndrome
Topical minoxidil treatment was reported to improve hair density and length in one individual with TRPS [
When the growth pattern of a child with TRPS is below the normal range for age and sex and is of concern to the family, growth hormone (GH) stimulation tests can be performed. If the result is subnormal, GH therapy may be considered [
• Practical advice on hair care & use of wigs
• Topical minoxidil treatment & hair transplantation may be useful.
• OT can be beneficial for fine motor impairment.
• Mechanical aids such as electric can openers may ameliorate problems caused by joint anomalies.
• Analgesics (e.g., NSAIDs or other non-opioids)
• Physiotherapy can help relieve pain & maintain hip range of motion.
• Encourage regular exercise.
• Support w/mobility at school & work as needed
• Recommendations for sunlight exposure
• Ensure adequate dietary intake of calcium & vitamin D &/or calcium & vitamin D supplementation.
• Modify activities to prevent fractures.
• Consider bisphosphonates.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Trichorhinophalangeal Syndrome: Recommended Surveillance
Monitor linear growth.
Assess for joint manifestations.
DXA = dual-energy x-ray absorptiometry; TRPS = trichorhinophalangeal syndrome
• Monitor linear growth.
• Assess for joint manifestations.
## Agents/Circumstances to Avoid
High-impact or contact sports may pose a risk to those with impaired mobility.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Trichorhinophalangeal syndrome (TRPS) is inherited in an autosomal dominant manner.
TRPS I is caused by a heterozygous pathogenic variant in
TRPS II is caused by a contiguous 8q23.3-q24.11 deletion that spans the
Many individuals diagnosed with TRPS I have an affected parent. Although the TRPS I phenotype can vary markedly within a family [
Approximately one third of individuals diagnosed with TRPS I 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 parents of a proband include complete physical examination, radiologic studies of hands and feet, and molecular genetic testing to evaluate the genetic status of the parents and inform recurrence risk assessment.
Note: If the proband has a structural variant involving
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 [
The family history of some individuals diagnosed with TRPS I may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing 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 the sibs is 50%. The phenotype of TRPS I can vary markedly among affected family members, and variability can be seen in all clinical and radiographic features [
If a parent has a structural chromosome rearrangement involving the 8q23.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
If the
If the parents have not been tested for the
To date, most individuals diagnosed with TRPS II whose parents have undergone genetic testing have the disorder as the result of a
Some individuals diagnosed with TRPS II have an affected parent. The phenotype within a family can vary but only to a limited extent; however, a clinical diagnosis of TRPS II is usually possible in affected individuals (see
Evaluation of the parents by genomic testing that will detect the deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. Testing for a balanced chromosome rearrangement in the parents is also recommended.
If the deletion 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 deletion 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 deletion that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with TRPS II may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or genomic testing have been performed on the parents of the proband.
If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%. The TRPS II phenotype within a family can vary but only to a limited extent.
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If neither parent is found to have the deletion identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. To date this has not been reported.
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.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 child with TRPS.
Once the TRPS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing (PGT) are possible. Note: While prenatal testing and PGT can be used to detect a familial genetic alteration associated with TRPS, the severity of the TRPS I or TRPS II phenotype cannot be predicted on the basis of test results.
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, a discussion of these issues may be helpful.
• TRPS I is caused by a heterozygous pathogenic variant in
• TRPS II is caused by a contiguous 8q23.3-q24.11 deletion that spans the
• Many individuals diagnosed with TRPS I have an affected parent. Although the TRPS I phenotype can vary markedly within a family [
• Approximately one third of individuals diagnosed with TRPS I 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 parents of a proband include complete physical examination, radiologic studies of hands and feet, and molecular genetic testing to evaluate the genetic status of the parents and inform recurrence risk assessment.
• Note: If the proband has a structural variant involving
• 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 [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The family history of some individuals diagnosed with TRPS I may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing 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 [
• 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 phenotype of TRPS I can vary markedly among affected family members, and variability can be seen in all clinical and radiographic features [
• If a parent has a structural chromosome rearrangement involving the 8q23.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If the
• If the parents have not been tested for the
• To date, most individuals diagnosed with TRPS II whose parents have undergone genetic testing have the disorder as the result of a
• Some individuals diagnosed with TRPS II have an affected parent. The phenotype within a family can vary but only to a limited extent; however, a clinical diagnosis of TRPS II is usually possible in affected individuals (see
• Evaluation of the parents by genomic testing that will detect the deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. Testing for a balanced chromosome rearrangement in the parents is also recommended.
• If the deletion 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 deletion 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 deletion that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a deletion 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 deletion that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with TRPS II may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or genomic testing have been performed on the parents of the proband.
• The proband has a
• The proband inherited a deletion 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 deletion that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%. The TRPS II phenotype within a family can vary but only to a limited extent.
• If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent is found to have the deletion identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. To date this has not been reported.
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 child with TRPS.
## Mode of Inheritance
Trichorhinophalangeal syndrome (TRPS) is inherited in an autosomal dominant manner.
TRPS I is caused by a heterozygous pathogenic variant in
TRPS II is caused by a contiguous 8q23.3-q24.11 deletion that spans the
• TRPS I is caused by a heterozygous pathogenic variant in
• TRPS II is caused by a contiguous 8q23.3-q24.11 deletion that spans the
## Risk to Family Members – TRPS I
Many individuals diagnosed with TRPS I have an affected parent. Although the TRPS I phenotype can vary markedly within a family [
Approximately one third of individuals diagnosed with TRPS I 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 parents of a proband include complete physical examination, radiologic studies of hands and feet, and molecular genetic testing to evaluate the genetic status of the parents and inform recurrence risk assessment.
Note: If the proband has a structural variant involving
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 [
The family history of some individuals diagnosed with TRPS I may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing 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 the sibs is 50%. The phenotype of TRPS I can vary markedly among affected family members, and variability can be seen in all clinical and radiographic features [
If a parent has a structural chromosome rearrangement involving the 8q23.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
If the
If the parents have not been tested for the
• Many individuals diagnosed with TRPS I have an affected parent. Although the TRPS I phenotype can vary markedly within a family [
• Approximately one third of individuals diagnosed with TRPS I 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 parents of a proband include complete physical examination, radiologic studies of hands and feet, and molecular genetic testing to evaluate the genetic status of the parents and inform recurrence risk assessment.
• Note: If the proband has a structural variant involving
• 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 [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• The family history of some individuals diagnosed with TRPS I may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing 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 [
• 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 phenotype of TRPS I can vary markedly among affected family members, and variability can be seen in all clinical and radiographic features [
• If a parent has a structural chromosome rearrangement involving the 8q23.3 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement.
• If the
• If the parents have not been tested for the
## Risk to Family Members – TRPS II
To date, most individuals diagnosed with TRPS II whose parents have undergone genetic testing have the disorder as the result of a
Some individuals diagnosed with TRPS II have an affected parent. The phenotype within a family can vary but only to a limited extent; however, a clinical diagnosis of TRPS II is usually possible in affected individuals (see
Evaluation of the parents by genomic testing that will detect the deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. Testing for a balanced chromosome rearrangement in the parents is also recommended.
If the deletion 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 deletion 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 deletion that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with TRPS II may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or genomic testing have been performed on the parents of the proband.
If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%. The TRPS II phenotype within a family can vary but only to a limited extent.
If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
If neither parent is found to have the deletion identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. To date this has not been reported.
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.
• To date, most individuals diagnosed with TRPS II whose parents have undergone genetic testing have the disorder as the result of a
• Some individuals diagnosed with TRPS II have an affected parent. The phenotype within a family can vary but only to a limited extent; however, a clinical diagnosis of TRPS II is usually possible in affected individuals (see
• Evaluation of the parents by genomic testing that will detect the deletion present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. Testing for a balanced chromosome rearrangement in the parents is also recommended.
• If the deletion 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 deletion 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 deletion that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a deletion 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 deletion that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with TRPS II may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or genomic testing have been performed on the parents of the proband.
• The proband has a
• The proband inherited a deletion 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 deletion that is present in the germ (gonadal) cells only.
• If a parent of the proband is affected and/or has the genetic alteration identified in the proband, the risk to the sibs is 50%. The TRPS II phenotype within a family can vary but only to a limited extent.
• If a parent has a balanced structural chromosome rearrangement, the risk to sibs is increased and depends on the specific chromosome rearrangement and the possibility of other variables.
• If neither parent is found to have the deletion identified in the proband and parental chromosome analysis is normal, the recurrence risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism. To date this has not been reported.
• 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.
## 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 of having a child with TRPS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 child with TRPS.
## Prenatal Testing and Preimplantation Genetic Testing
Once the TRPS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing (PGT) are possible. Note: While prenatal testing and PGT can be used to detect a familial genetic alteration associated with TRPS, the severity of the TRPS I or TRPS II phenotype cannot be predicted on the basis of test results.
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, a discussion of these issues may be helpful.
## Resources
•
•
•
•
## Molecular Genetics
Trichorhinophalangeal Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Trichorhinophalangeal Syndrome (
To date, 166 different
Most phenotypic features of TRPS II are explained by the deletion of
Note: Missense variants are predicted to exhibit a dominant-negative effect as a part of a multimeric protein complex, unlike the haploinsufficiency (loss of function) associated with truncating variants [
## Molecular Pathogenesis
To date, 166 different
Most phenotypic features of TRPS II are explained by the deletion of
Note: Missense variants are predicted to exhibit a dominant-negative effect as a part of a multimeric protein complex, unlike the haploinsufficiency (loss of function) associated with truncating variants [
## Chapter Notes
Dilek Uludağ Alkaya, MD, PhD (2024-present)Hennie Bikker, PhD; University of Amsterdam (2017-2024)Nilay Güneş, MD (2024-present)Raoul CM Hennekam, PhD, MD; University of Amsterdam (2017-2024)Saskia Maas, MD; University of Amsterdam (2017-2024)Adam Shaw, BM, MD; Guy's & Saint Thomas' Hospitals (2017-2024)Beyhan Tüysüz, MD, PhD (2024-present)
21 March 2024 (sw) Comprehensive update posted live
20 April 2017 (bp) Review posted live
20 September 2016 (rh) Original submission
• 21 March 2024 (sw) Comprehensive update posted live
• 20 April 2017 (bp) Review posted live
• 20 September 2016 (rh) Original submission
## Author History
Dilek Uludağ Alkaya, MD, PhD (2024-present)Hennie Bikker, PhD; University of Amsterdam (2017-2024)Nilay Güneş, MD (2024-present)Raoul CM Hennekam, PhD, MD; University of Amsterdam (2017-2024)Saskia Maas, MD; University of Amsterdam (2017-2024)Adam Shaw, BM, MD; Guy's & Saint Thomas' Hospitals (2017-2024)Beyhan Tüysüz, MD, PhD (2024-present)
## Revision History
21 March 2024 (sw) Comprehensive update posted live
20 April 2017 (bp) Review posted live
20 September 2016 (rh) Original submission
• 21 March 2024 (sw) Comprehensive update posted live
• 20 April 2017 (bp) Review posted live
• 20 September 2016 (rh) Original submission
## References
## Literature Cited
Clinical features of TRPS I and TRPS II
A. Facial features of a male age 16 years with TRPS I. Note the broad nasal ridge and nasal tip without a broad nasal bridge; underdeveloped alae nasi; wide and low-hanging columella; long philtrum; and medial flaring of the eyebrows.
B. Facial features of a boy (at age six years) with TRPS II. Note the sparse, light-colored, and broad medial eyebrows; sparse and thin hair; broad nasal tip; broad columella; long philtrum; thin vermilion of the upper lip; and large, prominent ears.
C. Exostoses on the shoulder
Hands of a woman age 21 years with TRPS
Note metacarpal shortening, ulnar deviation of the third fingers, radial deviation of the fourth fingers, and short thumbs.
AP radiograph of the hand of a boy age four years with TRPS
Note cone-shaped epiphyses of the second to fifth proximal phalanges (circles) and more subtle, partially fused cone-shaped epiphyses of the second to fourth middle phalanges (arrows).
Residual angulated deformity of the proximal aspects of the second and fifth middle phalanges (arrows) related to fusion of prior cone-shaped epiphyses
Flattened capital femoral epiphyses (coxa plana) and broad femoral neck in a boy with TRPS II (age six years)
Exostosis of the radius (arrow)
|
[] |
20/4/2017
|
21/3/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
traps
|
traps
|
[
"TNF Receptor-Associated Periodic Syndrome (TRAPS)",
"Tumor Necrosis Factor Receptor-Associated Periodic Syndrome",
"TNF Receptor-Associated Periodic Syndrome (TRAPS)",
"Tumor Necrosis Factor Receptor-Associated Periodic Syndrome",
"Tumor necrosis factor receptor superfamily member 1A",
"TNFRSF1A",
"TNF Receptor-Associated Periodic Fever Syndrome"
] |
TNF Receptor-Associated Periodic Fever Syndrome
|
Natalie Deuitch, Cornelia Cudrici, Amanda Ombrello, Ivona Aksentijevich
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Summary TNF receptor-associated periodic fever syndrome (TRAPS) is characterized by episodes of inflammation typically occurring every four to six weeks and lasting between five and 25 days. Flares may be prompted by stress, infection, trauma, hormonal changes, and vaccination. Symptoms may include fever, abdominal pain, arthralgia, myalgia, migratory rash, and eye inflammation, with variable severity. Symptoms often begin in early childhood (median age 4.3 years), though symptom onset can occur later in life. During a flare, acute-phase reactants such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and serum amyloid A are typically elevated. Generally, acute-phase reactants stabilize between flares but may remain somewhat elevated even in the absence of clinical symptoms. AA amyloidosis, the most severe sequela of TRAPS, can largely be avoided with adequate treatment. Proteinuria and kidney failure occur in 80%-90% of affected individuals with amyloidosis, while intestinal, thyroid, myocardium, liver, and spleen deposits are less common. The diagnosis of TRAPS is established in a proband with at least one suggestive clinical feature and a heterozygous pathogenic (or likely pathogenic) variant in TRAPS is inherited in an autosomal dominant manner. Most individuals diagnosed with TRAPS have an affected parent. Each child of an individual with TRAPS has a 50% chance of inheriting the
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## Diagnosis
Many clinical diagnostic criteria for TNF receptor-associated periodic fever syndrome (TRAPS) have been proposed. A classification system that incorporates molecular genetic testing and clinical features has been found to have a sensitivity of 95%, a specificity of 99%, and an accuracy of 99% [
TRAPS
Recurrent or chronic systemic inflammation causing:
Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
Abdominal pain;
Chest pain;
Arthralgia;
Myalgia;
Migratory erythematous rash;
Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
Poor response to colchicine therapy
Leukocytosis, typically characterized by an absolute leukocyte count in the 9,000-12,000/mm
Elevated erythrocyte sedimentation rate and/or C-reactive protein
Extremely high levels of serum amyloid A
The diagnosis of TRAPS
At least one of the following clinical features:
Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
Myalgia
Migratory rash
Periorbital edema
Suggestive family history
AND
A heterozygous pathogenic (or likely pathogenic) variant in
In the absence of the identification of a pathogenic (or likely pathogenic) variant 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 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 and supportive laboratory findings suggest the diagnosis of TRAPS, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders characterized by periodic fever, genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TNF Receptor-Associated Periodic Fever 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.
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications in
• Recurrent or chronic systemic inflammation causing:
• Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
• Abdominal pain;
• Chest pain;
• Arthralgia;
• Myalgia;
• Migratory erythematous rash;
• Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
• Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
• Abdominal pain;
• Chest pain;
• Arthralgia;
• Myalgia;
• Migratory erythematous rash;
• Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
• Poor response to colchicine therapy
• Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
• Abdominal pain;
• Chest pain;
• Arthralgia;
• Myalgia;
• Migratory erythematous rash;
• Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
• Leukocytosis, typically characterized by an absolute leukocyte count in the 9,000-12,000/mm
• Elevated erythrocyte sedimentation rate and/or C-reactive protein
• Extremely high levels of serum amyloid A
• At least one of the following clinical features:
• Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
• Myalgia
• Migratory rash
• Periorbital edema
• Suggestive family history
• AND
• Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
• Myalgia
• Migratory rash
• Periorbital edema
• Suggestive family history
• A heterozygous pathogenic (or likely pathogenic) variant in
• Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
• Myalgia
• Migratory rash
• Periorbital edema
• Suggestive family history
• For an introduction to multigene panels click
## Suggestive Findings
TRAPS
Recurrent or chronic systemic inflammation causing:
Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
Abdominal pain;
Chest pain;
Arthralgia;
Myalgia;
Migratory erythematous rash;
Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
Poor response to colchicine therapy
Leukocytosis, typically characterized by an absolute leukocyte count in the 9,000-12,000/mm
Elevated erythrocyte sedimentation rate and/or C-reactive protein
Extremely high levels of serum amyloid A
• Recurrent or chronic systemic inflammation causing:
• Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
• Abdominal pain;
• Chest pain;
• Arthralgia;
• Myalgia;
• Migratory erythematous rash;
• Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
• Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
• Abdominal pain;
• Chest pain;
• Arthralgia;
• Myalgia;
• Migratory erythematous rash;
• Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
• Poor response to colchicine therapy
• Prolonged and recurrent episodes of fever, typically occurring every four to six weeks and lasting from five to 25 days;
• Abdominal pain;
• Chest pain;
• Arthralgia;
• Myalgia;
• Migratory erythematous rash;
• Eye inflammation manifesting as conjunctivitis, periorbital edema, and periorbital pain.
• Leukocytosis, typically characterized by an absolute leukocyte count in the 9,000-12,000/mm
• Elevated erythrocyte sedimentation rate and/or C-reactive protein
• Extremely high levels of serum amyloid A
## Establishing the Diagnosis
The diagnosis of TRAPS
At least one of the following clinical features:
Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
Myalgia
Migratory rash
Periorbital edema
Suggestive family history
AND
A heterozygous pathogenic (or likely pathogenic) variant in
In the absence of the identification of a pathogenic (or likely pathogenic) variant 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 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 and supportive laboratory findings suggest the diagnosis of TRAPS, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from other inherited disorders characterized by periodic fever, genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TNF Receptor-Associated Periodic Fever 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.
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications in
• At least one of the following clinical features:
• Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
• Myalgia
• Migratory rash
• Periorbital edema
• Suggestive family history
• AND
• Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
• Myalgia
• Migratory rash
• Periorbital edema
• Suggestive family history
• A heterozygous pathogenic (or likely pathogenic) variant in
• Duration of the flare (i.e., period of fevers and related symptoms) longer than seven days
• Myalgia
• Migratory rash
• Periorbital edema
• Suggestive family history
• For an introduction to multigene panels click
## Option 1
When the phenotypic and supportive laboratory findings suggest the diagnosis of TRAPS, 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 other inherited disorders characterized by periodic fever, genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TNF Receptor-Associated Periodic Fever 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.
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications in
## Clinical Characteristics
To date, more than 200 individuals have been identified with a pathogenic variant in
TNF Receptor-Associated Periodic Fever Syndrome: Frequency of Select Features
Maculopapular/migratory rashes consisting of both flat and raised lesions on the skin. In individuals with TRAPS, the rash frequently migrates distally down the limbs as a flare progresses. This rash is typically not itchy.
Urticarial rashes (also known as hives) that are raised and often itchy.
Erysipelas-like erythema consisting of raised rashes typically affecting the lower limbs. Such rashes may be warm to the touch and can be quite tender.
Mucocutaneous findings such as pharyngitis and aphthous stomatitis have been reported in a number of individuals with TRAPS [
Most pathogenic variants in
Most individuals with severe pathogenetic variants in
There are a few notable low-penetrance variants in
TRAPS was initially referred to as familial Hibernian fever.
An estimated 1:1,000,000 individuals worldwide have TRAPS [
• Maculopapular/migratory rashes consisting of both flat and raised lesions on the skin. In individuals with TRAPS, the rash frequently migrates distally down the limbs as a flare progresses. This rash is typically not itchy.
• Urticarial rashes (also known as hives) that are raised and often itchy.
• Erysipelas-like erythema consisting of raised rashes typically affecting the lower limbs. Such rashes may be warm to the touch and can be quite tender.
## Clinical Description
To date, more than 200 individuals have been identified with a pathogenic variant in
TNF Receptor-Associated Periodic Fever Syndrome: Frequency of Select Features
Maculopapular/migratory rashes consisting of both flat and raised lesions on the skin. In individuals with TRAPS, the rash frequently migrates distally down the limbs as a flare progresses. This rash is typically not itchy.
Urticarial rashes (also known as hives) that are raised and often itchy.
Erysipelas-like erythema consisting of raised rashes typically affecting the lower limbs. Such rashes may be warm to the touch and can be quite tender.
Mucocutaneous findings such as pharyngitis and aphthous stomatitis have been reported in a number of individuals with TRAPS [
• Maculopapular/migratory rashes consisting of both flat and raised lesions on the skin. In individuals with TRAPS, the rash frequently migrates distally down the limbs as a flare progresses. This rash is typically not itchy.
• Urticarial rashes (also known as hives) that are raised and often itchy.
• Erysipelas-like erythema consisting of raised rashes typically affecting the lower limbs. Such rashes may be warm to the touch and can be quite tender.
## Genotype-Phenotype Correlations
Most pathogenic variants in
## Penetrance
Most individuals with severe pathogenetic variants in
There are a few notable low-penetrance variants in
## Nomenclature
TRAPS was initially referred to as familial Hibernian fever.
## Prevalence
An estimated 1:1,000,000 individuals worldwide have TRAPS [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Hereditary Disorders of Interest in the Differential Diagnosis of TNF Receptor-Associated Periodic Fever Syndrome (TRAPS)
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance
FMF is usually inherited in an autosomal recessive manner, although some studies have suggested that some heterozygotes manifest a spectrum of findings from classic FMF to mild FMF.
Infection (viral, bacterial, or parasitic)
Malignancy
Behçet syndrome
Inflammatory bowel disease
Adult-onset Still disease
• Infection (viral, bacterial, or parasitic)
• Malignancy
• Behçet syndrome
• Inflammatory bowel disease
• Adult-onset Still disease
## Management
Clinical practice guidelines for the management of monogenic autoinflammatory conditions, including TNF receptor-associated periodic fever syndrome (TRAPS), have been published; see
To establish the extent of disease and needs in an individual diagnosed with TRAPS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with TNF Receptor-Associated Periodic Fever Syndrome
To assess for inflammatory markers &/or evidence of end-organ damage
Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; TRAPS = TNF receptor-associated periodic fever syndrome
Renal function testing may include serum blood urea nitrogen, creatinine, cystatin-C, and electrolytes; liver function testing may include assessment of serum aspartate aminotransferase, alanine transaminase, protein, and albumin.
Thyroid function tests may include serum thyroid-stimulating hormone, free T4, and/or T4.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with TNF Receptor-Associated Periodic Fever Syndrome
Anakinra 1.5 mg/kg/day w/titration as needed
Canakinumab 2 mg/kg every 4 or 8 wks
Considered first-line treatment & is generally more effective than anti-TNF inhibitors.
~90% of persons w/TRAPS respond to IL-1 inhibition.
Etanercept is the most effective anti-TNF, whereas monoclonal antibodies have been assoc w/severe, paradoxical reactions.
In general IL-1 inhibition is considered first line, but etanercept may be considered in refractory cases.
Affected persons w/infrequent attacks may only require as-needed dosing during disease flares.
Children: through early intervention programs &/or school district
Adults: low-vision clinic &/or community vision services / OT / mobility services
IL = interleukin; OT = occupational therapy; TNF = tumor necrosis factor
The use of nonsteroidal anti-inflammatory (NSAID) medication has not resulted in a benefit for most affected individuals [Author, personal observation].
These findings may not be reversible even when anti-inflammatory treatments are initiated or even subsequently optimized.
Interleukin-1 (IL-1) inhibitors and the TNF inhibitor etanercept are effective in preventing AA amyloidosis and can also control the severity of disease flares [
In addition to a complete physical examination (performed annually or sooner if clinically indicated) with blood pressure and other vital signs, full skin examination, assessment for the presence of lymphadenopathy and hepatosplenomegaly, and musculoskeletal evaluation, the evaluations outlined in
Recommended Surveillance for Individuals with TNF Receptor-Associated Periodic Fever Syndrome
Measure acute-phase reactants incl CRP, ESR, serum level of AA amyloid, fibrinogen, haptoglobin, & CBC w/differential.
Assess w/Autoinflammatory Diseases Activity Index (AIDAI).
Liver function tests
Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; TRAPS = TNF receptor-associated periodic fever syndrome
To assess for leukocytosis and elevated neutrophil count, thrombocytosis, and normochromic anemia, which may be related to secondary chronic inflammation.
This checklist reviews 12 symptoms and provides an assessment of whether an affected individual is experiencing frequent disease activity that may require optimization of the treatment regimen or if the affected individual is fairly well controlled in terms of their autoimmune symptoms.
Liver function testing may include assessment of serum aspartate aminotransferase, alanine transaminase, protein, and albumin.
Renal function testing may include serum blood urea nitrogen, creatinine, cystatin-C, and electrolytes.
To assess for proteinuria
For affected individuals managed with continuous biologic agents, consideration should be given to whether live-attenuated versus non-live vaccines should be administered. Data on the effect of live-attenuated vaccines are limited, and risks/benefits should be considered. Before undertaking any live vaccinations, individuals should discuss the risk/benefit of receiving such vaccines. It should be noted that affected individuals may have severe, paradoxical reactions that have been associated with anti-TNF monoclonal antibodies.
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 preventive measures. Evaluations can include the following:
Targeted molecular genetic testing if the pathogenic variant in the family is known;
If the pathogenic variant in the family is unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation), full skin examination for rashes, ophthalmology evaluation, assessment of inflammatory markers (serum C-reactive protein and erythrocyte sedimentation rate), complete blood count with differential, serum immunoglobulins, creatinine, blood urea nitrogen, urinalysis for proteinuria, and serum level of AA amyloid can be considered.
See
Information regarding the safety of the use of IL-1 inhibitors in human pregnancy is limited. Retrospective analyses suggest that anakinra and canakinumab are effective treatments in pregnant women with familial Mediterranean fever and other autoinflammatory diseases with low risk to the fetus [
See
Search
• To assess for inflammatory markers &/or evidence of end-organ damage
• Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Anakinra 1.5 mg/kg/day w/titration as needed
• Canakinumab 2 mg/kg every 4 or 8 wks
• Considered first-line treatment & is generally more effective than anti-TNF inhibitors.
• ~90% of persons w/TRAPS respond to IL-1 inhibition.
• Etanercept is the most effective anti-TNF, whereas monoclonal antibodies have been assoc w/severe, paradoxical reactions.
• In general IL-1 inhibition is considered first line, but etanercept may be considered in refractory cases.
• Affected persons w/infrequent attacks may only require as-needed dosing during disease flares.
• Children: through early intervention programs &/or school district
• Adults: low-vision clinic &/or community vision services / OT / mobility services
• Measure acute-phase reactants incl CRP, ESR, serum level of AA amyloid, fibrinogen, haptoglobin, & CBC w/differential.
• Assess w/Autoinflammatory Diseases Activity Index (AIDAI).
• Liver function tests
• Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
• Targeted molecular genetic testing if the pathogenic variant in the family is known;
• If the pathogenic variant in the family is unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation), full skin examination for rashes, ophthalmology evaluation, assessment of inflammatory markers (serum C-reactive protein and erythrocyte sedimentation rate), complete blood count with differential, serum immunoglobulins, creatinine, blood urea nitrogen, urinalysis for proteinuria, and serum level of AA amyloid can be considered.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TRAPS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with TNF Receptor-Associated Periodic Fever Syndrome
To assess for inflammatory markers &/or evidence of end-organ damage
Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
Community or
Social work involvement for parental support;
Home nursing referral.
CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; TRAPS = TNF receptor-associated periodic fever syndrome
Renal function testing may include serum blood urea nitrogen, creatinine, cystatin-C, and electrolytes; liver function testing may include assessment of serum aspartate aminotransferase, alanine transaminase, protein, and albumin.
Thyroid function tests may include serum thyroid-stimulating hormone, free T4, and/or T4.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To assess for inflammatory markers &/or evidence of end-organ damage
• Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with TNF Receptor-Associated Periodic Fever Syndrome
Anakinra 1.5 mg/kg/day w/titration as needed
Canakinumab 2 mg/kg every 4 or 8 wks
Considered first-line treatment & is generally more effective than anti-TNF inhibitors.
~90% of persons w/TRAPS respond to IL-1 inhibition.
Etanercept is the most effective anti-TNF, whereas monoclonal antibodies have been assoc w/severe, paradoxical reactions.
In general IL-1 inhibition is considered first line, but etanercept may be considered in refractory cases.
Affected persons w/infrequent attacks may only require as-needed dosing during disease flares.
Children: through early intervention programs &/or school district
Adults: low-vision clinic &/or community vision services / OT / mobility services
IL = interleukin; OT = occupational therapy; TNF = tumor necrosis factor
The use of nonsteroidal anti-inflammatory (NSAID) medication has not resulted in a benefit for most affected individuals [Author, personal observation].
These findings may not be reversible even when anti-inflammatory treatments are initiated or even subsequently optimized.
• Anakinra 1.5 mg/kg/day w/titration as needed
• Canakinumab 2 mg/kg every 4 or 8 wks
• Considered first-line treatment & is generally more effective than anti-TNF inhibitors.
• ~90% of persons w/TRAPS respond to IL-1 inhibition.
• Etanercept is the most effective anti-TNF, whereas monoclonal antibodies have been assoc w/severe, paradoxical reactions.
• In general IL-1 inhibition is considered first line, but etanercept may be considered in refractory cases.
• Affected persons w/infrequent attacks may only require as-needed dosing during disease flares.
• Children: through early intervention programs &/or school district
• Adults: low-vision clinic &/or community vision services / OT / mobility services
## Prevention of Secondary Manifestations
Interleukin-1 (IL-1) inhibitors and the TNF inhibitor etanercept are effective in preventing AA amyloidosis and can also control the severity of disease flares [
## Surveillance
In addition to a complete physical examination (performed annually or sooner if clinically indicated) with blood pressure and other vital signs, full skin examination, assessment for the presence of lymphadenopathy and hepatosplenomegaly, and musculoskeletal evaluation, the evaluations outlined in
Recommended Surveillance for Individuals with TNF Receptor-Associated Periodic Fever Syndrome
Measure acute-phase reactants incl CRP, ESR, serum level of AA amyloid, fibrinogen, haptoglobin, & CBC w/differential.
Assess w/Autoinflammatory Diseases Activity Index (AIDAI).
Liver function tests
Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
CBC = complete blood count; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; MOI = mode of inheritance; TRAPS = TNF receptor-associated periodic fever syndrome
To assess for leukocytosis and elevated neutrophil count, thrombocytosis, and normochromic anemia, which may be related to secondary chronic inflammation.
This checklist reviews 12 symptoms and provides an assessment of whether an affected individual is experiencing frequent disease activity that may require optimization of the treatment regimen or if the affected individual is fairly well controlled in terms of their autoimmune symptoms.
Liver function testing may include assessment of serum aspartate aminotransferase, alanine transaminase, protein, and albumin.
Renal function testing may include serum blood urea nitrogen, creatinine, cystatin-C, and electrolytes.
To assess for proteinuria
• Measure acute-phase reactants incl CRP, ESR, serum level of AA amyloid, fibrinogen, haptoglobin, & CBC w/differential.
• Assess w/Autoinflammatory Diseases Activity Index (AIDAI).
• Liver function tests
• Imaging of abdomen to assess for splenomegaly/hepatomegaly may also be considered if there are findings of serum AA amyloid or suspected spleen or liver enlargement on physical exam.
## Agents/Circumstances to Avoid
For affected individuals managed with continuous biologic agents, consideration should be given to whether live-attenuated versus non-live vaccines should be administered. Data on the effect of live-attenuated vaccines are limited, and risks/benefits should be considered. Before undertaking any live vaccinations, individuals should discuss the risk/benefit of receiving such vaccines. It should be noted that affected individuals may have severe, paradoxical reactions that have been associated with anti-TNF monoclonal antibodies.
## 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 preventive measures. Evaluations can include the following:
Targeted molecular genetic testing if the pathogenic variant in the family is known;
If the pathogenic variant in the family is unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation), full skin examination for rashes, ophthalmology evaluation, assessment of inflammatory markers (serum C-reactive protein and erythrocyte sedimentation rate), complete blood count with differential, serum immunoglobulins, creatinine, blood urea nitrogen, urinalysis for proteinuria, and serum level of AA amyloid can be considered.
See
• Targeted molecular genetic testing if the pathogenic variant in the family is known;
• If the pathogenic variant in the family is unknown, clinical assessment (history and physical exam for signs/symptoms of systemic inflammation), full skin examination for rashes, ophthalmology evaluation, assessment of inflammatory markers (serum C-reactive protein and erythrocyte sedimentation rate), complete blood count with differential, serum immunoglobulins, creatinine, blood urea nitrogen, urinalysis for proteinuria, and serum level of AA amyloid can be considered.
## Pregnancy Management
Information regarding the safety of the use of IL-1 inhibitors in human pregnancy is limited. Retrospective analyses suggest that anakinra and canakinumab are effective treatments in pregnant women with familial Mediterranean fever and other autoinflammatory diseases with low risk to the fetus [
See
## Therapies Under Investigation
Search
## Genetic Counseling
TNF receptor-associated periodic fever syndrome (TRAPS) is inherited in an autosomal dominant manner.
Most individuals diagnosed with TRAPS have an affected parent.
Some individuals diagnosed with TRAPS have 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.
Note: Mosaicism for a
The family history of some individuals diagnosed with TRAPS may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, variable expressivity, 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 pathogenic variant identified in the proband, the risk to each of the sibs is 50%.
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 reduced penetrance in a heterozygous parent or the possibility of parental germline 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
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 TRAPS have an affected parent.
• Some individuals diagnosed with TRAPS have 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.
• Note: 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 and will not detect a pathogenic variant that is present in the germ cells only.
• Note: Mosaicism for a
• The family history of some individuals diagnosed with TRAPS may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, variable expressivity, 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 and will not detect a pathogenic variant that is present in the germ cells only.
• Note: 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 each of the sibs is 50%.
• 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 reduced penetrance in a heterozygous parent or the possibility of parental germline 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
TNF receptor-associated periodic fever syndrome (TRAPS) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with TRAPS have an affected parent.
Some individuals diagnosed with TRAPS have 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.
Note: Mosaicism for a
The family history of some individuals diagnosed with TRAPS may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, variable expressivity, 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 pathogenic variant identified in the proband, the risk to each of the sibs is 50%.
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 reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• Most individuals diagnosed with TRAPS have an affected parent.
• Some individuals diagnosed with TRAPS have 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.
• Note: 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 and will not detect a pathogenic variant that is present in the germ cells only.
• Note: Mosaicism for a
• The family history of some individuals diagnosed with TRAPS may appear to be negative because of failure to recognize the disorder in affected family members, reduced penetrance, variable expressivity, 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 and will not detect a pathogenic variant that is present in the germ cells only.
• Note: 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 each of the sibs is 50%.
• 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 reduced penetrance in a heterozygous parent or the possibility of parental germline 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
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
Italy
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## Molecular Genetics
TNF Receptor-Associated Periodic Fever Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TNF Receptor-Associated Periodic Fever Syndrome (
Disease-causing genetic variants are predominantly found in the extracellular domain of TNFR1 and affect protein folding – often through interruption of hydrogen and disulfide bonds – which in turn affects receptor structure and cell surface expression. Mutated proteins are then unable to be shed and accumulate in the cells, leading to endoplasmic stress, upregulation of unfolded protein response (UPR), and increased production of mitochondrial reactive oxygen species [
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
Low-penetrance variants in
## Molecular Pathogenesis
Disease-causing genetic variants are predominantly found in the extracellular domain of TNFR1 and affect protein folding – often through interruption of hydrogen and disulfide bonds – which in turn affects receptor structure and cell surface expression. Mutated proteins are then unable to be shed and accumulate in the cells, leading to endoplasmic stress, upregulation of unfolded protein response (UPR), and increased production of mitochondrial reactive oxygen species [
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions.
## Low-Penetrance Variants
Low-penetrance variants in
## Chapter Notes
Natalie Deuitch is a genetic counselor at the National Human Genome Research Institute (NHGRI). She works with patients enrolled on the NIH Autoinflammatory Study, including those with TRAPS.
Dr Cornelia Cudrici is a rheumatologist in the Laboratory of Cardiovascular Regenerative Medicine at the National Heart, Lung, and Blood Institute (NHLBI). She works with patients with periodic fever syndromes including TRAPS.
Dr Amanda Ombrello is a dually certified adult and pediatric rheumatologist who oversees the autoinflammatory clinic at the National Institutes of Health and cares for many patients with TRAPS.
Dr Ivona Aksentijevich is an Associate Investigator in the National Human Genome Research Institute (NHGRI), National Institutes of Health. The laboratory focuses on identifying genes responsible for mediating inherited human disorders of inflammation. Dr Aksentijevich also runs a CLIA-certified diagnostic sequencing laboratory within the NHGRI.
We would like to thank the many patients with TRAPS who have participated in the NIH Autoinflammatory Study.
10 November 2022 (ma) Review posted live
9 June 2022 (nd) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 10 November 2022 (ma) Review posted live
• 9 June 2022 (nd) Original submission
## Author Notes
Natalie Deuitch is a genetic counselor at the National Human Genome Research Institute (NHGRI). She works with patients enrolled on the NIH Autoinflammatory Study, including those with TRAPS.
Dr Cornelia Cudrici is a rheumatologist in the Laboratory of Cardiovascular Regenerative Medicine at the National Heart, Lung, and Blood Institute (NHLBI). She works with patients with periodic fever syndromes including TRAPS.
Dr Amanda Ombrello is a dually certified adult and pediatric rheumatologist who oversees the autoinflammatory clinic at the National Institutes of Health and cares for many patients with TRAPS.
Dr Ivona Aksentijevich is an Associate Investigator in the National Human Genome Research Institute (NHGRI), National Institutes of Health. The laboratory focuses on identifying genes responsible for mediating inherited human disorders of inflammation. Dr Aksentijevich also runs a CLIA-certified diagnostic sequencing laboratory within the NHGRI.
## Acknowledgments
We would like to thank the many patients with TRAPS who have participated in the NIH Autoinflammatory Study.
## Revision History
10 November 2022 (ma) Review posted live
9 June 2022 (nd) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 10 November 2022 (ma) Review posted live
• 9 June 2022 (nd) Original submission
## References
## Literature Cited
|
[
"AC Bulua, A Simon, R Maddipati, M Pelletier, H Park, KY Kim, MN Sack, DL Kastner, RM Siegel. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS).. J Exp Med. 2011;208:519-33",
"C Cudrici, N Deuitch, I. Aksentijevich. Revisiting TNF receptor-associated periodic syndrome (TRAPS): current perspectives.. Int J Mol Sci. 2020;21:3262",
"M Gattorno, M Hofer, S Federici, F Vanoni, F Bovis, I Aksentijevich, J Anton, JI Arostegui, K Barron, E Ben-Cherit, PA Brogan, L Cantarini, I Ceccherini, F De Benedetti, F Dedeoglu, E Demirkaya, J Frenkel, R Goldbach-Mansky, A Gul, V Hentgen, H Hoffman, T Kallinich, I Kone-Paut, J Kuemmerle-Deschner, HJ Lachmann, RM Laxer, A Livneh, L Obici, S Ozen, D Rowczenio, R Russo, Y Shinar, A Simon, N Toplak, I Touitou, Y Uziel, M van Gijn, D Foell, C Garassino, D Kastner, A Martini, MP Sormani, N Ruperto. Classification criteria for autoinflammatory recurrent fevers.. Ann Rheum Dis. 2019;78:1025-32",
"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",
"A Kontzias, SK Zarabi, C Calabrese, Y Wang, L Judis, Q Yao, YW Cheng. Somatic mosaicism in adult-onset TNF receptor-associated periodic syndrome (TRAPS).. Mol Genet Genomic Med. 2019;7",
"HJ Lachmann, R Papa, K Gerhold, L Obici, I Touitou, L Cantarini, J Frenkel, J Anton, I Kone-Paut, M Cattalini, B Bader-Meunier, A Insalaco, V Hentgen, R Merino, C Modesto, N Toplak, R Berendes, S Ozen, R Cimaz, A Jansson, PA Brogan, PN Hawkins, N Ruperto, A Martini, P Woo, M Gattorno. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.. Ann Rheum Dis. 2014;73:2160-7",
"I Maccora, E Marrani, MV Mastrolia, S Abu-Rumeileh, V Maniscalco, E Fusco, F Barbati, I Pagnini, G Simonini. Ocular involvement in monogenic autoinflammatory disease.. Autoimmun Rev. 2021;20",
"MF McDermott, I Aksentijevich, J Galon, EM McDermott, BW Ogunkolade, M Centola, E Mansfield, M Gadina, L Karenko, T Pettersson, J McCarthy, DM Frucht, M Aringer, Y Torosyan, AM Teppo, M Wilson, HM Karaarslan, Y Wan, I Todd, G Wood, R Schlimgen, TR Kumarajeewa, SM Cooper, JP Vella, CI Amos, J Mulley, KA Quane, MG Molloy, A Ranki, RJ Powell, GA Hitman, JJ O'Shea, DL Kastner. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes.. Cell. 1999;97:133-44",
"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",
"DM Rowczenio, H Trojer, E Omoyinmi, JI Aróstegui, G Arakelov, A Mensa-Vilaro, A Baginska, C Silva Pilorz, G Wang, T Lane, P Brogan, PN Hawkins, HJ Lachmann. Brief Report: association of tumor necrosis factor receptor-associated periodic syndrome with gonosomal mosaicism of a novel 24-nucleotide TNFRSF1A deletion.. Arthritis Rheumatol. 2016;68:2044-9",
"A Simon, C Dodé, JW van der Meer, JP Drenth. Familial periodic fever and amyloidosis due to a new mutation in the TNFRSF1A gene.. Am J Med. 2001;110:313-6",
"NM ter Haar, M Oswald, J Jeyaratnam, J Anton, KS Barron, PA Brogan, L Cantarini, C Galeotti, G Grateau, V Hentgen, M Hofer, T Kallinich, I Kone-Paut, HJ Lachmann, H Ozdogan, S Ozen, R Russo, A Simon, Y Uziel, C Wouters, BM Feldman, SJ Vastert, NM Wulffraat, SM Benseler, J Frenkel, M Gattorno, JB Kuemmerle-Deschner. Recommendations for the management of autoinflammatory diseases.. Ann Rheum Dis. 2015;74:1636-44",
"N Venhoff, RE Voll, C Glaser, J Thiel. Z Rheumatol. 2018;77:127-34",
"E Weber, A Millet, D Beghin, S Viel, J Guitton, M Gerfaud-Valentin, P Sève, Y Jamilloux. Safety of canakinumab during pregnancy: seven new cases.. Rheumatology (Oxford) 2022;61:e229-e231",
"T Youngstein, P Hoffmann, A Gül, T Lane, R Williams, DM Rowczenio, H Ozdogan, S Ugurlu, J Ryan, L Harty, S Riminton, AP Headley, J Roesler, N Blank, JB Kuemmerle-Deschner, A Simon, AS Woolf, PN Hawkins, HJ Lachmann. International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.. Rheumatology (Oxford) 2017;56:2102-8",
"J Zegarska, E Wiesik-Szewczyk, E Hryniewiecka, B Wolska-Kusnierz, D Soldacki, M Kacprzak, A Sobczynska-Tomaszewska, K Czerska, P Siedlecki, K Jahnz-Rozyk, E Bernatowska, R Zagozdzon, L Paczek. Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with a new pathogenic variant in TNFRSF1A gene in a family of the adult male with renal AA amyloidosis-diagnostic and therapeutic challenge for clinicians.. J Clin Med. 2021;10:465"
] |
10/11/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
trimethylaminuria
|
trimethylaminuria
|
[
"Fish Odor Syndrome",
"FMO3 Deficiency",
"TMAU",
"TMAuria",
"Fish Odor Syndrome",
"TMAuria",
"TMAU",
"FMO3 Deficiency",
"Flavin-containing monooxygenase 3",
"FMO3",
"Primary Trimethylaminuria"
] |
Primary Trimethylaminuria
|
Ian R Phillips, Elizabeth A Shephard
|
Summary Primary trimethylaminuria is characterized by a fishy odor resembling that of rotten or decaying fish that results from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids. No physical symptoms are associated with trimethylaminuria. Affected individuals appear normal and healthy; however, the unpleasant odor often results in social and psychological problems. Symptoms are usually present from birth and may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around the time of menopause. The diagnosis of primary trimethylaminuria is established in a proband who: Excretes (under normal dietary conditions) in the urine more than 10% of total trimethylamine (TMA) as the free amine; and Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in Dietary restriction of: Trimethylamine (present in milk obtained from wheat-fed cows) and its precursors including choline (present in eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas [Brussels sprouts, broccoli, cabbage, cauliflower]), lecithin and lecithin-containing fish oil supplements; Trimethylamine Inhibitors of FMO3 enzyme activity such as indoles (found in brassicas). Note: Planning and monitoring of diet to ensure that the daily intake of choline and folate meets recommendations for age and sex; no restriction of dietary choline during pregnancy and lactation. Use of: Acid soaps and body lotions to remove secreted trimethylamine by washing; Activated charcoal and copper chlorophyllin to sequester trimethylamine produced in the gut; Antibiotics (metronidazole, amoxicillin, and neomycin) to suppress production of trimethylamine by reducing bacteria in the gut; Riboflavin supplements to enhance residual FMO3 enzyme activity. Primary trimethylaminuria is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
|
## Diagnosis
Diagnosis of primary trimethylaminuria has been discussed in detail [
Primary trimethylaminuria
Note: Diagnosis of primary trimethylaminuria cannot be based on the examiner’s sense of smell due to the following:
The presence of the odor is often episodic and thus may not be noticeable when the person is examined.
The human nose is normally very sensitive to trimethylamine, with some individuals being able to detect concentrations as low as 1 part in 10
The odor may be caused by compounds other than trimethylamine.
Note: Because unaffected women may have transient trimethylaminuria at the onset of and during menstruation [
Urinary excretion of TMA is measured as
Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
The diagnosis of primary trimethylaminuria
Excretes (under normal dietary conditions) in urine more than 10% of total trimethylamine (TMA) as the free amine; and
Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in
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
When the phenotypic and laboratory findings suggest the diagnosis of primary trimethylaminuria, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of primary trimethylaminuria has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Trimethylaminuria
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.
One individual with primary trimethylaminuria homozygous for a deletion of exons 1 and 2 has been reported [
• The presence of the odor is often episodic and thus may not be noticeable when the person is examined.
• The human nose is normally very sensitive to trimethylamine, with some individuals being able to detect concentrations as low as 1 part in 10
• The odor may be caused by compounds other than trimethylamine.
• Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
• Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
• Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
• Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
• Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
• Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
• Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• Excretes (under normal dietary conditions) in urine more than 10% of total trimethylamine (TMA) as the free amine; and
• Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in
• Note: Identification of biallelic
• For an introduction to multigene panels click
## Suggestive Findings
Primary trimethylaminuria
Note: Diagnosis of primary trimethylaminuria cannot be based on the examiner’s sense of smell due to the following:
The presence of the odor is often episodic and thus may not be noticeable when the person is examined.
The human nose is normally very sensitive to trimethylamine, with some individuals being able to detect concentrations as low as 1 part in 10
The odor may be caused by compounds other than trimethylamine.
Note: Because unaffected women may have transient trimethylaminuria at the onset of and during menstruation [
Urinary excretion of TMA is measured as
Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• The presence of the odor is often episodic and thus may not be noticeable when the person is examined.
• The human nose is normally very sensitive to trimethylamine, with some individuals being able to detect concentrations as low as 1 part in 10
• The odor may be caused by compounds other than trimethylamine.
• Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
• Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
• Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
• Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
• Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
• Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
• Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
## Establishing the Diagnosis
The diagnosis of primary trimethylaminuria
Excretes (under normal dietary conditions) in urine more than 10% of total trimethylamine (TMA) as the free amine; and
Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in
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
When the phenotypic and laboratory findings suggest the diagnosis of primary trimethylaminuria, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of primary trimethylaminuria has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Trimethylaminuria
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.
One individual with primary trimethylaminuria homozygous for a deletion of exons 1 and 2 has been reported [
• Excretes (under normal dietary conditions) in urine more than 10% of total trimethylamine (TMA) as the free amine; and
• Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in
• Note: Identification of biallelic
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of primary trimethylaminuria, 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 primary trimethylaminuria has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Primary Trimethylaminuria
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.
One individual with primary trimethylaminuria homozygous for a deletion of exons 1 and 2 has been reported [
## Clinical Characteristics
Primary trimethylaminuria is characterized by fishy odor resulting from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids [
No physical symptoms are associated with primary trimethylaminuria; affected individuals appear normal and healthy. However, the unpleasant odor characteristic of the disorder often results in social and psychological problems [
In childhood, being shunned, ridiculed, or bullied at school, leading to aggressive or disruptive behavior and poor educational performance
A sense of shame or embarrassment, leading to low self-esteem and reluctance to seek medical help
Avoidance of contact with people, leading to social isolation, loneliness, frustration, and depression
Difficulties in initiating or maintaining relationships
In extreme cases: paranoid behavior, desperation, and suicidal tendencies
The enzyme FMO3 is also involved in the metabolism of various therapeutic drugs. Individuals with primary trimethylaminuria exhibit abnormal metabolism of the nonsteroidal anti-inflammatory benzydamine [
Dysfunctional metabolism of endogenous amines such as tyramine that are substrates of the enzyme FMO3 may contribute to the depression seen in some individuals.
For individuals with primary trimethylaminuria, symptoms are usually present from birth. The condition may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around menopause.
On a normal diet, individuals with biallelic loss-of-function
Several pathogenic nonsense or missense variants that abolish or severely impair the ability of the FMO3 enzyme to catalyze
Some nonsynonymous variants, when present on the same allele (e.g.,
Although the rare variant
Primary trimethylaminuria has been described as fish-odor syndrome, fish malodor syndrome, and stale fish syndrome.
The incidence of heterozygotes (carriers) in the white British population is 0.5% to 1.0%. It is higher in other populations studied: 1.7% in Jordan, 3.8% in Ecuador, and 11.0% in New Guinea [
• In childhood, being shunned, ridiculed, or bullied at school, leading to aggressive or disruptive behavior and poor educational performance
• A sense of shame or embarrassment, leading to low self-esteem and reluctance to seek medical help
• Avoidance of contact with people, leading to social isolation, loneliness, frustration, and depression
• Difficulties in initiating or maintaining relationships
• In extreme cases: paranoid behavior, desperation, and suicidal tendencies
## Clinical Description
Primary trimethylaminuria is characterized by fishy odor resulting from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids [
No physical symptoms are associated with primary trimethylaminuria; affected individuals appear normal and healthy. However, the unpleasant odor characteristic of the disorder often results in social and psychological problems [
In childhood, being shunned, ridiculed, or bullied at school, leading to aggressive or disruptive behavior and poor educational performance
A sense of shame or embarrassment, leading to low self-esteem and reluctance to seek medical help
Avoidance of contact with people, leading to social isolation, loneliness, frustration, and depression
Difficulties in initiating or maintaining relationships
In extreme cases: paranoid behavior, desperation, and suicidal tendencies
The enzyme FMO3 is also involved in the metabolism of various therapeutic drugs. Individuals with primary trimethylaminuria exhibit abnormal metabolism of the nonsteroidal anti-inflammatory benzydamine [
Dysfunctional metabolism of endogenous amines such as tyramine that are substrates of the enzyme FMO3 may contribute to the depression seen in some individuals.
For individuals with primary trimethylaminuria, symptoms are usually present from birth. The condition may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around menopause.
• In childhood, being shunned, ridiculed, or bullied at school, leading to aggressive or disruptive behavior and poor educational performance
• A sense of shame or embarrassment, leading to low self-esteem and reluctance to seek medical help
• Avoidance of contact with people, leading to social isolation, loneliness, frustration, and depression
• Difficulties in initiating or maintaining relationships
• In extreme cases: paranoid behavior, desperation, and suicidal tendencies
## Genotype-Phenotype Correlations
On a normal diet, individuals with biallelic loss-of-function
Several pathogenic nonsense or missense variants that abolish or severely impair the ability of the FMO3 enzyme to catalyze
Some nonsynonymous variants, when present on the same allele (e.g.,
Although the rare variant
## Nomenclature
Primary trimethylaminuria has been described as fish-odor syndrome, fish malodor syndrome, and stale fish syndrome.
## Prevalence
The incidence of heterozygotes (carriers) in the white British population is 0.5% to 1.0%. It is higher in other populations studied: 1.7% in Jordan, 3.8% in Ecuador, and 11.0% in New Guinea [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Molecular diagnosis can distinguish primary trimethylaminuria from trimethylaminuria not caused by genetic FMO3 deficiency [
Liver cirrhosis, impaired hepatocellular function, or the existence of portosystemic shunts may affect clearance of TMA absorbed from the gut. The resulting trimethylaminuria may contribute to the development of hepatic encephalopathy and coma and associated foetor hepaticus [
In uremia, increased release of TMA from dietary precursors as a consequence of bacterial overgrowth in the small intestine, coupled with reduced renal clearance of TMA, can result in trimethylaminuria [
Other causes of unpleasant body odor fall into two categories:
•
• Liver cirrhosis, impaired hepatocellular function, or the existence of portosystemic shunts may affect clearance of TMA absorbed from the gut. The resulting trimethylaminuria may contribute to the development of hepatic encephalopathy and coma and associated foetor hepaticus [
• In uremia, increased release of TMA from dietary precursors as a consequence of bacterial overgrowth in the small intestine, coupled with reduced renal clearance of TMA, can result in trimethylaminuria [
• Liver cirrhosis, impaired hepatocellular function, or the existence of portosystemic shunts may affect clearance of TMA absorbed from the gut. The resulting trimethylaminuria may contribute to the development of hepatic encephalopathy and coma and associated foetor hepaticus [
• In uremia, increased release of TMA from dietary precursors as a consequence of bacterial overgrowth in the small intestine, coupled with reduced renal clearance of TMA, can result in trimethylaminuria [
• Liver cirrhosis, impaired hepatocellular function, or the existence of portosystemic shunts may affect clearance of TMA absorbed from the gut. The resulting trimethylaminuria may contribute to the development of hepatic encephalopathy and coma and associated foetor hepaticus [
• In uremia, increased release of TMA from dietary precursors as a consequence of bacterial overgrowth in the small intestine, coupled with reduced renal clearance of TMA, can result in trimethylaminuria [
## Management
No clinical practice guidelines for primary trimethylaminuria have been published.
To establish the extent of disease and needs in an individual diagnosed with primary trimethylaminuria, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Determine the urinary ratio of trimethylamine (TMA)
Ratios of 70%-89% are classified as mild.
Ratios lower than 70% are classified as severe.
Assess social issues associated with body odor. These may include harassment, bullying, discrimination, negative self-image, social isolation, and relationship problems [
Consult 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 primary trimethylaminuria in order to facilitate medical and personal decision making.
Strategies for the treatment of primary trimethylaminuria summarized in this section are reviewed by
Dietary regimens should be planned and monitored to ensure that the daily intake of choline and folate meet recommendations for the age and sex of the individual [
Foods rich in choline include eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas (Brussels sprouts, broccoli, cabbage, cauliflower) as well as rapeseed products such as oil and flour.
Nutritionally balanced, choline-restricted diets suitable for the treatment of trimethylaminuria have been developed [
Because choline is essential in the fetus and in young infants for nerve and brain development, it should not be over-restricted in infants, children, and pregnant or lactating women. Large amounts of choline are transferred to the fetus via the placenta and to the newborn infant via the mother's milk, thus potentially depleting maternal choline reserves. Dietary restriction of choline increases the requirement for folate, a methyl donor.
Note: Freshwater fish have a lower content of trimethylamine
Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements.
In addition to being a source of trimethylamine precursors, brassicas (Brussels sprouts, broccoli, cabbage, and cauliflower) contain indoles, which may inhibit FMO3 enzyme activity and thus increase urinary excretion of trimethylamine [
The following should be avoided:
Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity, including seafood (fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products. Avoid or eat in moderation.
Food supplements and "health" foods that contain high doses of the trimethylamine precursors choline and lecithin
Drugs that are metabolized by the FMO3 enzyme; for example, the antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac [
Factors that promote sweating (e.g., exercise, stress, emotional upsets)
See
Choline, which is essential for nerve and brain development in the fetus, should not be over-restricted in pregnant women with primary trimethylaminuria.
Search
• Determine the urinary ratio of trimethylamine (TMA)
• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.
• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.
• Assess social issues associated with body odor. These may include harassment, bullying, discrimination, negative self-image, social isolation, and relationship problems [
• Consult 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 primary trimethylaminuria in order to facilitate medical and personal decision making.
• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.
• Foods rich in choline include eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas (Brussels sprouts, broccoli, cabbage, cauliflower) as well as rapeseed products such as oil and flour.
• Nutritionally balanced, choline-restricted diets suitable for the treatment of trimethylaminuria have been developed [
• Because choline is essential in the fetus and in young infants for nerve and brain development, it should not be over-restricted in infants, children, and pregnant or lactating women. Large amounts of choline are transferred to the fetus via the placenta and to the newborn infant via the mother's milk, thus potentially depleting maternal choline reserves. Dietary restriction of choline increases the requirement for folate, a methyl donor.
• Note: Freshwater fish have a lower content of trimethylamine
• Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements.
• In addition to being a source of trimethylamine precursors, brassicas (Brussels sprouts, broccoli, cabbage, and cauliflower) contain indoles, which may inhibit FMO3 enzyme activity and thus increase urinary excretion of trimethylamine [
• Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity, including seafood (fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products. Avoid or eat in moderation.
• Food supplements and "health" foods that contain high doses of the trimethylamine precursors choline and lecithin
• Drugs that are metabolized by the FMO3 enzyme; for example, the antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac [
• Factors that promote sweating (e.g., exercise, stress, emotional upsets)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with primary trimethylaminuria, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Determine the urinary ratio of trimethylamine (TMA)
Ratios of 70%-89% are classified as mild.
Ratios lower than 70% are classified as severe.
Assess social issues associated with body odor. These may include harassment, bullying, discrimination, negative self-image, social isolation, and relationship problems [
Consult 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 primary trimethylaminuria in order to facilitate medical and personal decision making.
• Determine the urinary ratio of trimethylamine (TMA)
• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.
• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.
• Assess social issues associated with body odor. These may include harassment, bullying, discrimination, negative self-image, social isolation, and relationship problems [
• Consult 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 primary trimethylaminuria in order to facilitate medical and personal decision making.
• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.
## Treatment of Manifestations
Strategies for the treatment of primary trimethylaminuria summarized in this section are reviewed by
Dietary regimens should be planned and monitored to ensure that the daily intake of choline and folate meet recommendations for the age and sex of the individual [
Foods rich in choline include eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas (Brussels sprouts, broccoli, cabbage, cauliflower) as well as rapeseed products such as oil and flour.
Nutritionally balanced, choline-restricted diets suitable for the treatment of trimethylaminuria have been developed [
Because choline is essential in the fetus and in young infants for nerve and brain development, it should not be over-restricted in infants, children, and pregnant or lactating women. Large amounts of choline are transferred to the fetus via the placenta and to the newborn infant via the mother's milk, thus potentially depleting maternal choline reserves. Dietary restriction of choline increases the requirement for folate, a methyl donor.
Note: Freshwater fish have a lower content of trimethylamine
Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements.
In addition to being a source of trimethylamine precursors, brassicas (Brussels sprouts, broccoli, cabbage, and cauliflower) contain indoles, which may inhibit FMO3 enzyme activity and thus increase urinary excretion of trimethylamine [
• Foods rich in choline include eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas (Brussels sprouts, broccoli, cabbage, cauliflower) as well as rapeseed products such as oil and flour.
• Nutritionally balanced, choline-restricted diets suitable for the treatment of trimethylaminuria have been developed [
• Because choline is essential in the fetus and in young infants for nerve and brain development, it should not be over-restricted in infants, children, and pregnant or lactating women. Large amounts of choline are transferred to the fetus via the placenta and to the newborn infant via the mother's milk, thus potentially depleting maternal choline reserves. Dietary restriction of choline increases the requirement for folate, a methyl donor.
• Note: Freshwater fish have a lower content of trimethylamine
• Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements.
• In addition to being a source of trimethylamine precursors, brassicas (Brussels sprouts, broccoli, cabbage, and cauliflower) contain indoles, which may inhibit FMO3 enzyme activity and thus increase urinary excretion of trimethylamine [
## Agents/Circumstances to Avoid
The following should be avoided:
Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity, including seafood (fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products. Avoid or eat in moderation.
Food supplements and "health" foods that contain high doses of the trimethylamine precursors choline and lecithin
Drugs that are metabolized by the FMO3 enzyme; for example, the antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac [
Factors that promote sweating (e.g., exercise, stress, emotional upsets)
• Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity, including seafood (fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products. Avoid or eat in moderation.
• Food supplements and "health" foods that contain high doses of the trimethylamine precursors choline and lecithin
• Drugs that are metabolized by the FMO3 enzyme; for example, the antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac [
• Factors that promote sweating (e.g., exercise, stress, emotional upsets)
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Choline, which is essential for nerve and brain development in the fetus, should not be over-restricted in pregnant women with primary trimethylaminuria.
## Therapies Under Investigation
Search
## Genetic Counseling
Primary trimethylaminuria 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 each parent is heterozygous for an
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 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.
• 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 each parent is heterozygous for an
• 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 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 trimethylaminuria 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 each parent is heterozygous for an
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 each parent is heterozygous for an
• 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.
## Carrier Detection
## 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
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 Trimethylaminuria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Primary Trimethylaminuria (
Metabolism of trimethylamine is primarily via
Trimethylamine is derived from dietary precursors, such as choline and trimethylamine
Two types of trimethylaminuria exist, resulting from one of the following:
The two types of trimethylaminuria are intimately interrelated: a combination of genetic, physiologic, and environmental factors may interact to give rise to the disorder. For instance, a substrate load that is handled by one individual may represent a substrate overload for a person whose FMO3 enzyme activity is decreased.
Notable
Variants listed in the table have been provided by the authors.
Denotes two
## Molecular Pathogenesis
Metabolism of trimethylamine is primarily via
Trimethylamine is derived from dietary precursors, such as choline and trimethylamine
Two types of trimethylaminuria exist, resulting from one of the following:
The two types of trimethylaminuria are intimately interrelated: a combination of genetic, physiologic, and environmental factors may interact to give rise to the disorder. For instance, a substrate load that is handled by one individual may represent a substrate overload for a person whose FMO3 enzyme activity is decreased.
Notable
Variants listed in the table have been provided by the authors.
Denotes two
## Chapter Notes
5 November 2020 (bp) Comprehensive update posted live
1 October 2015 (me) Comprehensive update posted live
19 April 2011 (me) Comprehensive update posted live
8 October 2007 (me) Review posted live
30 July 2007 (eas) Original submission
• 5 November 2020 (bp) Comprehensive update posted live
• 1 October 2015 (me) Comprehensive update posted live
• 19 April 2011 (me) Comprehensive update posted live
• 8 October 2007 (me) Review posted live
• 30 July 2007 (eas) Original submission
## Revision History
5 November 2020 (bp) Comprehensive update posted live
1 October 2015 (me) Comprehensive update posted live
19 April 2011 (me) Comprehensive update posted live
8 October 2007 (me) Review posted live
30 July 2007 (eas) Original submission
• 5 November 2020 (bp) Comprehensive update posted live
• 1 October 2015 (me) Comprehensive update posted live
• 19 April 2011 (me) Comprehensive update posted live
• 8 October 2007 (me) Review posted live
• 30 July 2007 (eas) Original submission
## References
Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. 2006;29:162–72.
• Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. 2006;29:162–72.
## Published Guidelines / Consensus Statements
Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. 2006;29:162–72.
• Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. 2006;29:162–72.
## Literature Cited
|
[] |
8/10/2007
|
5/11/2020
|
18/3/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
trio-id
|
trio-id
|
[
"Triple functional domain protein",
"TRIO",
"TRIO-Related Neurodevelopmental Disorder"
] |
Konstantinos Varvagiannis, Lisenka ELM Vissers, Diana Baralle, Bert BA de Vries, Gabriella Gazdagh
|
Summary The diagnosis of
|
## Diagnosis
Early feeding issues with poor weight gain
Delayed motor and speech development
Variable intellectual functioning ranging from borderline cognitive function (IQ: 70-85) to severe intellectual disability
Neurobehavioral manifestations including stereotypies, obsessive-compulsive behavior, autistic findings or autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, and/or sleep disorder
Abnormal head circumference, either macrocephaly or microcephaly
Minor digit anomalies including short and/or tapering fingers, broad proximal interphalangeal joints, clinodactyly of the fifth finger, and/or 2-3 toe syndactyly
Dental anomalies, including dental crowding and delayed or failed tooth eruption
Scoliosis and/or kyphosis
The diagnosis of
Note: (1) As 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
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels 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.
• Early feeding issues with poor weight gain
• Delayed motor and speech development
• Variable intellectual functioning ranging from borderline cognitive function (IQ: 70-85) to severe intellectual disability
• Neurobehavioral manifestations including stereotypies, obsessive-compulsive behavior, autistic findings or autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, and/or sleep disorder
• Abnormal head circumference, either macrocephaly or microcephaly
• Minor digit anomalies including short and/or tapering fingers, broad proximal interphalangeal joints, clinodactyly of the fifth finger, and/or 2-3 toe syndactyly
• Dental anomalies, including dental crowding and delayed or failed tooth eruption
• Scoliosis and/or kyphosis
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Early feeding issues with poor weight gain
Delayed motor and speech development
Variable intellectual functioning ranging from borderline cognitive function (IQ: 70-85) to severe intellectual disability
Neurobehavioral manifestations including stereotypies, obsessive-compulsive behavior, autistic findings or autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, and/or sleep disorder
Abnormal head circumference, either macrocephaly or microcephaly
Minor digit anomalies including short and/or tapering fingers, broad proximal interphalangeal joints, clinodactyly of the fifth finger, and/or 2-3 toe syndactyly
Dental anomalies, including dental crowding and delayed or failed tooth eruption
Scoliosis and/or kyphosis
• Early feeding issues with poor weight gain
• Delayed motor and speech development
• Variable intellectual functioning ranging from borderline cognitive function (IQ: 70-85) to severe intellectual disability
• Neurobehavioral manifestations including stereotypies, obsessive-compulsive behavior, autistic findings or autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, and/or sleep disorder
• Abnormal head circumference, either macrocephaly or microcephaly
• Minor digit anomalies including short and/or tapering fingers, broad proximal interphalangeal joints, clinodactyly of the fifth finger, and/or 2-3 toe syndactyly
• Dental anomalies, including dental crowding and delayed or failed tooth eruption
• Scoliosis and/or kyphosis
## Establishing the Diagnosis
The diagnosis of
Note: (1) As 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
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels 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.
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
Select Features of
– = feature is not reported as part of this phenotype; GOF = gain-of-function; LOF = loss-of-function
Among all individuals for whom information on independent sitting was available, approximately one third (6/17) achieved sitting by age 14 months. Seventy-five percent (13/17) achieved sitting by 36 months. For one affected individual, independent sitting occurred after age six years [
Information on use of first words was available for 16 individuals, seven of whom were verbal. Earliest use of first words was at age 12 to 15 months [Gazdagh et al, unpublished data], and oldest age at first words was 5.5 years [
Presence of a tall forehead and prominent ears appear to be common [Gazdagh, personal communication]. In the cohort of 20 individuals, the following features were described in more than one individual:
Prominent or tall forehead in six individuals, with frontal bossing in six additional individuals
Highly arched eyebrows reported in three individuals. with synophrys reported in two
Hypertelorism in two individuals, and downslanted palpebral fissures in two individuals
Low-set ears in three individuals, and large ear lobes in two individuals
Wide mouth, everted vermilion of the upper lip, and high palate in two individuals each
Micro-/retrognathia in two individuals
Supernumerary or inverted nipples (each reported in a single individual) [Gazdagh et al, unpublished data]
Multiple hyperpigmented nevi (one individual) [
Frequent airway infections (one individual) [
Independent sitting was achieved in 19 individuals, in 80% of these by the age of 14 months. Two individuals were not sitting independently at their last assessment (ages 21 months and 16 years, respectively) [
First words occurred by the age of 48 months in 80% of the 20 individuals who were verbal. Four individuals were nonverbal at last assessment (ages 21 months, 3.5 years, 14 years, and 16 years, respectively) [
Note: Macrocephaly was reported in two individuals with a
Upslanted palpebral fissures, tubular nose, and bulbous nose appear to be common in individuals with a
Recurrent infections (three individuals) [
Urinary incontinence (two individuals), although one had syringomyelia [
Brisk reflexes (two individuals) [
Fatigue (two individuals) [
Bilateral accessory nipples (one individual) [Gazdagh et al, unpublished data]
Unilateral cleft lip (one individual) [Gazdagh et al, unpublished data]
Profound neonatal anemia (one individual) [Gazdagh et al, unpublished data]
Cutis aplasia (one individual) [
A summary of major developmental milestones in individuals with a
The developmental phenotype of nonsense, frameshift, and splicing variants was often less severe compared to missense variants within the GEFD1 domain. A similar conclusion might be indirectly inferred by the fact that missense variants within the GEFD1 domain are
Loss-of-function truncating variants are associated with a higher risk of seizures (30%-35%) than missense variants in the GEFD1 domain (likely 10%).
Delayed dental eruption and dental crowding are more common in individuals with missense variants within the GEFD1 domain and truncating variants [
Toe syndactyly (2-3) was only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
Broad (or swelling of) proximal interphalangeal joints and fifth finger clinodactyly were only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
Penetrance appears to be complete. Based on the seven individuals (from five families) in whom the
• Prominent or tall forehead in six individuals, with frontal bossing in six additional individuals
• Highly arched eyebrows reported in three individuals. with synophrys reported in two
• Hypertelorism in two individuals, and downslanted palpebral fissures in two individuals
• Low-set ears in three individuals, and large ear lobes in two individuals
• Wide mouth, everted vermilion of the upper lip, and high palate in two individuals each
• Micro-/retrognathia in two individuals
• Supernumerary or inverted nipples (each reported in a single individual) [Gazdagh et al, unpublished data]
• Multiple hyperpigmented nevi (one individual) [
• Frequent airway infections (one individual) [
• Recurrent infections (three individuals) [
• Urinary incontinence (two individuals), although one had syringomyelia [
• Brisk reflexes (two individuals) [
• Fatigue (two individuals) [
• Bilateral accessory nipples (one individual) [Gazdagh et al, unpublished data]
• Unilateral cleft lip (one individual) [Gazdagh et al, unpublished data]
• Profound neonatal anemia (one individual) [Gazdagh et al, unpublished data]
• Cutis aplasia (one individual) [
• The developmental phenotype of nonsense, frameshift, and splicing variants was often less severe compared to missense variants within the GEFD1 domain. A similar conclusion might be indirectly inferred by the fact that missense variants within the GEFD1 domain are
• Loss-of-function truncating variants are associated with a higher risk of seizures (30%-35%) than missense variants in the GEFD1 domain (likely 10%).
• Delayed dental eruption and dental crowding are more common in individuals with missense variants within the GEFD1 domain and truncating variants [
• Toe syndactyly (2-3) was only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
• Broad (or swelling of) proximal interphalangeal joints and fifth finger clinodactyly were only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
## Clinical Description
Select Features of
– = feature is not reported as part of this phenotype; GOF = gain-of-function; LOF = loss-of-function
Among all individuals for whom information on independent sitting was available, approximately one third (6/17) achieved sitting by age 14 months. Seventy-five percent (13/17) achieved sitting by 36 months. For one affected individual, independent sitting occurred after age six years [
Information on use of first words was available for 16 individuals, seven of whom were verbal. Earliest use of first words was at age 12 to 15 months [Gazdagh et al, unpublished data], and oldest age at first words was 5.5 years [
Presence of a tall forehead and prominent ears appear to be common [Gazdagh, personal communication]. In the cohort of 20 individuals, the following features were described in more than one individual:
Prominent or tall forehead in six individuals, with frontal bossing in six additional individuals
Highly arched eyebrows reported in three individuals. with synophrys reported in two
Hypertelorism in two individuals, and downslanted palpebral fissures in two individuals
Low-set ears in three individuals, and large ear lobes in two individuals
Wide mouth, everted vermilion of the upper lip, and high palate in two individuals each
Micro-/retrognathia in two individuals
Supernumerary or inverted nipples (each reported in a single individual) [Gazdagh et al, unpublished data]
Multiple hyperpigmented nevi (one individual) [
Frequent airway infections (one individual) [
Independent sitting was achieved in 19 individuals, in 80% of these by the age of 14 months. Two individuals were not sitting independently at their last assessment (ages 21 months and 16 years, respectively) [
First words occurred by the age of 48 months in 80% of the 20 individuals who were verbal. Four individuals were nonverbal at last assessment (ages 21 months, 3.5 years, 14 years, and 16 years, respectively) [
Note: Macrocephaly was reported in two individuals with a
Upslanted palpebral fissures, tubular nose, and bulbous nose appear to be common in individuals with a
Recurrent infections (three individuals) [
Urinary incontinence (two individuals), although one had syringomyelia [
Brisk reflexes (two individuals) [
Fatigue (two individuals) [
Bilateral accessory nipples (one individual) [Gazdagh et al, unpublished data]
Unilateral cleft lip (one individual) [Gazdagh et al, unpublished data]
Profound neonatal anemia (one individual) [Gazdagh et al, unpublished data]
Cutis aplasia (one individual) [
• Prominent or tall forehead in six individuals, with frontal bossing in six additional individuals
• Highly arched eyebrows reported in three individuals. with synophrys reported in two
• Hypertelorism in two individuals, and downslanted palpebral fissures in two individuals
• Low-set ears in three individuals, and large ear lobes in two individuals
• Wide mouth, everted vermilion of the upper lip, and high palate in two individuals each
• Micro-/retrognathia in two individuals
• Supernumerary or inverted nipples (each reported in a single individual) [Gazdagh et al, unpublished data]
• Multiple hyperpigmented nevi (one individual) [
• Frequent airway infections (one individual) [
• Recurrent infections (three individuals) [
• Urinary incontinence (two individuals), although one had syringomyelia [
• Brisk reflexes (two individuals) [
• Fatigue (two individuals) [
• Bilateral accessory nipples (one individual) [Gazdagh et al, unpublished data]
• Unilateral cleft lip (one individual) [Gazdagh et al, unpublished data]
• Profound neonatal anemia (one individual) [Gazdagh et al, unpublished data]
• Cutis aplasia (one individual) [
Among all individuals for whom information on independent sitting was available, approximately one third (6/17) achieved sitting by age 14 months. Seventy-five percent (13/17) achieved sitting by 36 months. For one affected individual, independent sitting occurred after age six years [
Information on use of first words was available for 16 individuals, seven of whom were verbal. Earliest use of first words was at age 12 to 15 months [Gazdagh et al, unpublished data], and oldest age at first words was 5.5 years [
Presence of a tall forehead and prominent ears appear to be common [Gazdagh, personal communication]. In the cohort of 20 individuals, the following features were described in more than one individual:
Prominent or tall forehead in six individuals, with frontal bossing in six additional individuals
Highly arched eyebrows reported in three individuals. with synophrys reported in two
Hypertelorism in two individuals, and downslanted palpebral fissures in two individuals
Low-set ears in three individuals, and large ear lobes in two individuals
Wide mouth, everted vermilion of the upper lip, and high palate in two individuals each
Micro-/retrognathia in two individuals
Supernumerary or inverted nipples (each reported in a single individual) [Gazdagh et al, unpublished data]
Multiple hyperpigmented nevi (one individual) [
Frequent airway infections (one individual) [
• Prominent or tall forehead in six individuals, with frontal bossing in six additional individuals
• Highly arched eyebrows reported in three individuals. with synophrys reported in two
• Hypertelorism in two individuals, and downslanted palpebral fissures in two individuals
• Low-set ears in three individuals, and large ear lobes in two individuals
• Wide mouth, everted vermilion of the upper lip, and high palate in two individuals each
• Micro-/retrognathia in two individuals
• Supernumerary or inverted nipples (each reported in a single individual) [Gazdagh et al, unpublished data]
• Multiple hyperpigmented nevi (one individual) [
• Frequent airway infections (one individual) [
Independent sitting was achieved in 19 individuals, in 80% of these by the age of 14 months. Two individuals were not sitting independently at their last assessment (ages 21 months and 16 years, respectively) [
First words occurred by the age of 48 months in 80% of the 20 individuals who were verbal. Four individuals were nonverbal at last assessment (ages 21 months, 3.5 years, 14 years, and 16 years, respectively) [
Note: Macrocephaly was reported in two individuals with a
Upslanted palpebral fissures, tubular nose, and bulbous nose appear to be common in individuals with a
Recurrent infections (three individuals) [
Urinary incontinence (two individuals), although one had syringomyelia [
Brisk reflexes (two individuals) [
Fatigue (two individuals) [
Bilateral accessory nipples (one individual) [Gazdagh et al, unpublished data]
Unilateral cleft lip (one individual) [Gazdagh et al, unpublished data]
Profound neonatal anemia (one individual) [Gazdagh et al, unpublished data]
Cutis aplasia (one individual) [
• Recurrent infections (three individuals) [
• Urinary incontinence (two individuals), although one had syringomyelia [
• Brisk reflexes (two individuals) [
• Fatigue (two individuals) [
• Bilateral accessory nipples (one individual) [Gazdagh et al, unpublished data]
• Unilateral cleft lip (one individual) [Gazdagh et al, unpublished data]
• Profound neonatal anemia (one individual) [Gazdagh et al, unpublished data]
• Cutis aplasia (one individual) [
## Genotype-Phenotype Correlations
A summary of major developmental milestones in individuals with a
The developmental phenotype of nonsense, frameshift, and splicing variants was often less severe compared to missense variants within the GEFD1 domain. A similar conclusion might be indirectly inferred by the fact that missense variants within the GEFD1 domain are
Loss-of-function truncating variants are associated with a higher risk of seizures (30%-35%) than missense variants in the GEFD1 domain (likely 10%).
Delayed dental eruption and dental crowding are more common in individuals with missense variants within the GEFD1 domain and truncating variants [
Toe syndactyly (2-3) was only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
Broad (or swelling of) proximal interphalangeal joints and fifth finger clinodactyly were only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
• The developmental phenotype of nonsense, frameshift, and splicing variants was often less severe compared to missense variants within the GEFD1 domain. A similar conclusion might be indirectly inferred by the fact that missense variants within the GEFD1 domain are
• Loss-of-function truncating variants are associated with a higher risk of seizures (30%-35%) than missense variants in the GEFD1 domain (likely 10%).
• Delayed dental eruption and dental crowding are more common in individuals with missense variants within the GEFD1 domain and truncating variants [
• Toe syndactyly (2-3) was only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
• Broad (or swelling of) proximal interphalangeal joints and fifth finger clinodactyly were only reported in individuals with missense variants within the GEFD1 domain and truncating variants.
## Penetrance
Penetrance appears to be complete. Based on the seven individuals (from five families) in whom the
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Developmental delay, intellectual disability, and/or neurobehavioral manifestations and abnormal head circumference are among the major features in
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI, as clinically indicated
Consider EEG if seizures are a concern & in those who have LOF or truncating variant.
Radiographic scoliosis survey (spinal x-rays) based on clinical suspicion
Consider referral to orthopedic surgeon if scoliosis is present.
Consider referral based on clinical judgement.
Echocardiography & EKG as indicated
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; LOF = loss-of-function; 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 multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
GERD = gastroesophageal reflux disease
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 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).
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.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
GERD = gastroesophageal reflux disease
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl brain MRI, as clinically indicated
• Consider EEG if seizures are a concern & in those who have LOF or truncating variant.
• Radiographic scoliosis survey (spinal x-rays) based on clinical suspicion
• Consider referral to orthopedic surgeon if scoliosis is present.
• Consider referral based on clinical judgement.
• Echocardiography & EKG as indicated
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• 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 complications (e.g., scoliosis).
• 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
## Evaluations and Referrals Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl brain MRI, as clinically indicated
Consider EEG if seizures are a concern & in those who have LOF or truncating variant.
Radiographic scoliosis survey (spinal x-rays) based on clinical suspicion
Consider referral to orthopedic surgeon if scoliosis is present.
Consider referral based on clinical judgement.
Echocardiography & EKG as indicated
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; LOF = loss-of-function; 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 brain MRI, as clinically indicated
• Consider EEG if seizures are a concern & in those who have LOF or truncating variant.
• Radiographic scoliosis survey (spinal x-rays) based on clinical suspicion
• Consider referral to orthopedic surgeon if scoliosis is present.
• Consider referral based on clinical judgement.
• Echocardiography & EKG as indicated
• 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 multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
GERD = gastroesophageal reflux disease
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 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).
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.
• 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 complications (e.g., scoliosis).
• 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 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 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 complications (e.g., scoliosis).
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).
• 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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
GERD = gastroesophageal reflux disease
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The majority of individuals diagnosed with
Some individuals diagnosed with
Because
Molecular 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 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 has the
Clinical variability has been observed among affected family members with the same
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.
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
• Some individuals diagnosed with
• Because
• Molecular 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 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 has the
• Clinical variability has been observed among affected family members with the same
• 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
The majority of individuals diagnosed with
Some individuals diagnosed with
Because
Molecular 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 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 has the
Clinical variability has been observed among affected family members with the same
If the
• The majority of individuals diagnosed with
• Some individuals diagnosed with
• Because
• Molecular 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 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 has the
• Clinical variability has been observed among affected family members with the same
• 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 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
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
## Molecular Genetics
TRIO-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TRIO-Related Neurodevelopmental Disorder (
TRIO is a major regulator of different processes, including cytokinesis, cell migration, axon guidance, and dendritic arborization, and is involved in synaptogenesis by modulating excitatory synaptic transmission [
Pathogenic missense variants occur in two hot spots: missense variants in the spectrin repeat domain increase Rac1 activation, and missense variants in the first GEF domain (GEFD1) decrease Rac1 activation (see
Missense variants in the GEFD1 domain as well as truncating variants throughout the gene result in loss of function (decreased Rac1 activation).
Loss-of-function (truncating) variants have been observed in large-scale reference population data sets (e.g., the Exome Aggregation Consortium [ExAC] data set) [
## Molecular Pathogenesis
TRIO is a major regulator of different processes, including cytokinesis, cell migration, axon guidance, and dendritic arborization, and is involved in synaptogenesis by modulating excitatory synaptic transmission [
Pathogenic missense variants occur in two hot spots: missense variants in the spectrin repeat domain increase Rac1 activation, and missense variants in the first GEF domain (GEFD1) decrease Rac1 activation (see
Missense variants in the GEFD1 domain as well as truncating variants throughout the gene result in loss of function (decreased Rac1 activation).
Loss-of-function (truncating) variants have been observed in large-scale reference population data sets (e.g., the Exome Aggregation Consortium [ExAC] data set) [
## Chapter Notes
Dr Gazdagh (
Contact Dr Gazdagh and Dr Varvagiannis to inquire about review of
The authors are grateful to the patients and families who participated in these research projects, as well as the clinicians and scientists contributing to understanding of the clinical and molecular aspects of
23 March 2023 (sw) Comprehensive updated posted live
10 August 2017 (bp) Review posted live
23 December 2016 (kv) Original submission
• 23 March 2023 (sw) Comprehensive updated posted live
• 10 August 2017 (bp) Review posted live
• 23 December 2016 (kv) Original submission
## Author Notes
Dr Gazdagh (
Contact Dr Gazdagh and Dr Varvagiannis to inquire about review of
## Acknowledgments
The authors are grateful to the patients and families who participated in these research projects, as well as the clinicians and scientists contributing to understanding of the clinical and molecular aspects of
## Revision History
23 March 2023 (sw) Comprehensive updated posted live
10 August 2017 (bp) Review posted live
23 December 2016 (kv) Original submission
• 23 March 2023 (sw) Comprehensive updated posted live
• 10 August 2017 (bp) Review posted live
• 23 December 2016 (kv) Original submission
## References
## Literature Cited
Two clusters of pathogenic missense variants are observed, one within the spectrin repeat domain and another within the GEFD1 domain (see
Generated with MutationMapper [
|
[
"W Ba, Y Yan, MR Reijnders, JH Schuurs-Hoeijmakers, I Feenstra, EM Bongers, DG Bosch, N De Leeuw, R Pfundt, C Gilissen, PF De Vries, JA Veltman, A Hoischen, HC Mefford, EE Eichler, LE Vissers, N Nadif Kasri, BB De Vries. TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function.. Hum Mol Genet. 2016;25:892-902",
"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",
"E Cerami, J Gao, U Dogrusoz, BE Gross, SO Sumer, BA Aksoy, A Jacobsen, CJ Byrne, ML Heuer, E Larsson, Y Antipin, B Reva, AP Goldberg, C Sander, N Schultz. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.. Cancer Discov. 2012;2:401-4",
"K Kloth, L Graul-Neumann, K Hermann, J Johannsen, T Bierhals, F. Kortüm. More evidence on TRIO missense mutations in the spectrin repeat domain causing severe developmental delay and recognizable facial dysmorphism with macrocephaly.. Neurogenetics. 2021;22:221-4",
"S Kolbjer, DA Martin, M Pettersson, M Dahlin, BM Anderlid. Lissencephaly in an epilepsy cohort: Molecular, radiological and clinical aspects.. Eur J Paediatr Neurol. 2021;30:71-81",
"M Lek, KJ Karczewski, EV Minikel, KE Samocha, E Banks, T Fennell, AH O'Donnell-Luria, JS Ware, AJ Hill, BB Cummings, T Tukiainen, DP Birnbaum, JA Kosmicki, LE Duncan, K Estrada, F Zhao, J Zou, E Pierce-Hoffman, J Berghout, DN Cooper, N Deflaux, M DePristo, R Do, J Flannick, M Fromer, L Gauthier, J Goldstein, N Gupta, D Howrigan, A Kiezun, MI Kurki, AL Moonshine, P Natarajan, L Orozco, GM Peloso, R Poplin, MA Rivas, V Ruano-Rubio, SA Rose, DM Ruderfer, K Shakir, PD Stenson, C Stevens, BP Thomas, G Tiao, MT Tusie-Luna, B Weisburd, HH Won, D Yu, DM Altshuler, D Ardissino, M Boehnke, J Danesh, S Donnelly, R Elosua, JC Florez, SB Gabriel, G Getz, SJ Glatt, CM Hultman, S Kathiresan, M Laakso, S McCarroll, MI McCarthy, D McGovern, R McPherson, BM Neale, A Palotie, SM Purcell, D Saleheen, JM Scharf, P Sklar, PF Sullivan, J Tuomilehto, MT Tsuang, HC Watkins, JG Wilson, MJ Daly, DG MacArthur. Analysis of protein-coding genetic variation in 60,706 humans.. Nature. 2016;536:285-91",
"RJ Pengelly, S Greville-Heygate, S Schmidt, EG Seaby, MR Jabalameli, SG Mehta, MJ Parker, D Goudie, C Fagotto-Kaufmann, C Mercer, A Debant, S Ennis, D Baralle. Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly.. J Med Genet. 2016;53:735-42",
"R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, S Al 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",
"L Schultz-Rogers, K Muthusamy, E Pinto, F Vairo, EW Klee, B Lanpher. Novel loss-of-function variants in TRIO are associated with neurodevelopmental disorder: case report.. BMC Med Genet. 2020;21:219",
"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"
] |
10/8/2017
|
23/3/2023
|
GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
trma
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trma
|
[
"Rogers Syndrome",
"TRMA",
"Rogers Syndrome",
"TRMA",
"Thiamine transporter 1",
"SLC19A2",
"Thiamine-Responsive Megaloblastic Anemia Syndrome"
] |
Thiamine-Responsive Megaloblastic Anemia Syndrome
|
Shuhei Sako, Toshiki Tsunogai, Kimihiko Oishi
|
Summary Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. Onset of megaloblastic anemia occurs between infancy and adolescence. The anemia is corrected with thiamine treatment, but the red cells remain macrocytic and anemia can recur if treatment is withdrawn. Progressive sensorineural hearing loss often occurs early and can be detected in toddlers; hearing loss is irreversible and may not be prevented by thiamine treatment. The diabetes mellitus is non-type I in nature, with age of onset from infancy to adolescence. Thiamine treatment may reduce insulin requirement and delay onset of diabetes in some individuals. The diagnosis of TRMA is established in a proband with: megaloblastic anemia with normal vitamin B TRMA 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 a pregnancy at increased risk are possible for families in which the
|
## Diagnosis
Thiamine-responsive megaloblastic anemia syndrome (TRMA)
Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
Vitamin B
The anemia is corrected with pharmacologic doses of thiamine (vitamin B
Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
The diagnosis of TRMA
Note: Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
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 Thiamine-Responsive Megaloblastic Anemia 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.
• Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
• Vitamin B
• The anemia is corrected with pharmacologic doses of thiamine (vitamin B
• Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
• Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
• Vitamin B
• The anemia is corrected with pharmacologic doses of thiamine (vitamin B
• Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
• Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
• Vitamin B
• The anemia is corrected with pharmacologic doses of thiamine (vitamin B
• Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
## Suggestive Findings
Thiamine-responsive megaloblastic anemia syndrome (TRMA)
Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
Vitamin B
The anemia is corrected with pharmacologic doses of thiamine (vitamin B
Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
• Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
• Vitamin B
• The anemia is corrected with pharmacologic doses of thiamine (vitamin B
• Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
• Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
• Vitamin B
• The anemia is corrected with pharmacologic doses of thiamine (vitamin B
• Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
• Examination of the bone marrow reveals megaloblastic changes with erythroblasts often containing iron-filled mitochondria (ringed sideroblasts).
• Vitamin B
• The anemia is corrected with pharmacologic doses of thiamine (vitamin B
• Even without thiamine supplementation, serum thiamine concentrations are normal; there is no evidence of acidosis or aciduria.
## Establishing the Diagnosis
The diagnosis of TRMA
Note: Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
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 Thiamine-Responsive Megaloblastic Anemia 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.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Thiamine-Responsive Megaloblastic Anemia 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.
## Clinical Characteristics
Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by the triad of megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. To date, more than 183 individuals from more than 138 families have been identified [
Thiamine-Responsive Megaloblastic Anemia Syndrome: Frequency of Select Features
No genotype-phenotype correlations have been identified.
The synonym "Rogers syndrome" derives from the first report of the disease in a child with diabetes mellitus, sensorineural deafness, and megaloblastic anemia who responded to thiamine (vitamin B
Approximately 130 pedigrees are known. TRMA is exceedingly rare outside of consanguineous families or isolated populations. Affected individuals have been observed in various ethnicities including Israeli Arab and Lebanese populations, an Alaskan kindred of native and ethnic Russian descent, and kindreds from Brazil, Japan, Oman, Tunisia, Italy (Venetian and other), Iran, India, and Pakistan, as well as Kashmiri families in Great Britain, ethnic Kurds, persons of northern European heritage, and African Americans [
## Clinical Description
Thiamine-responsive megaloblastic anemia syndrome (TRMA) is characterized by the triad of megaloblastic anemia, progressive sensorineural hearing loss, and diabetes mellitus. To date, more than 183 individuals from more than 138 families have been identified [
Thiamine-Responsive Megaloblastic Anemia Syndrome: Frequency of Select Features
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
The synonym "Rogers syndrome" derives from the first report of the disease in a child with diabetes mellitus, sensorineural deafness, and megaloblastic anemia who responded to thiamine (vitamin B
## Prevalence
Approximately 130 pedigrees are known. TRMA is exceedingly rare outside of consanguineous families or isolated populations. Affected individuals have been observed in various ethnicities including Israeli Arab and Lebanese populations, an Alaskan kindred of native and ethnic Russian descent, and kindreds from Brazil, Japan, Oman, Tunisia, Italy (Venetian and other), Iran, India, and Pakistan, as well as Kashmiri families in Great Britain, ethnic Kurds, persons of northern European heritage, and African Americans [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Disorders with Hearing Loss and Diabetes Mellitus in the Differential Diagnosis of Thiamine-Responsive Megaloblastic Anemia Syndrome
AD = autosomal dominant; AR = autosomal recessive; DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; DM = diabetes mellitus; GI = gastrointestinal; Mat = maternal; MOI = mode of inheritance; TRMA = thiamine-responsive megaloblastic anemia syndrome; XL = X-linked
Non-classic (autosomal dominant)
## Management
To establish the extent of disease and needs in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome
Peripheral blood count
Bone marrow analysis for evidence of megaloblastic anemia
Cardiac eval, incl echocardiography
EKG
Neuroimaging, incl brain MRI if clinically indicated
Assess for seizures.
DM = diabetes mellitus; MOI = mode of inheritance; OGTT = oral glucose tolerance test
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome
Red blood cell transfusion for severe anemia
High-dose thiamine supplementation invariably improves hematologic picture.
There is no addl clinical benefit w/thiamine dose >150mg/day.
DM = diabetes mellitus; TRMA = thiamine-responsive megaloblastic anemia syndrome
Recommended Surveillance for Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome
Assess for glucose intolerance (fasting serum glucose concentration, OGTT, urinalysis).
Assess for clinical manifestations of poor glycemic control.
CBC = complete blood count; OGTT = oral glucose tolerance test
It is appropriate to clarify the genetic status of sibs of an affected individual by molecular genetic testing for the
Supplementation with pharmacologic doses of thiamine (vitamin B
See
While there are no published studies evaluating pregnancy outcome in affected women, good diabetic control prior to and during pregnancy is recommended.
Search
• Peripheral blood count
• Bone marrow analysis for evidence of megaloblastic anemia
• Cardiac eval, incl echocardiography
• EKG
• Neuroimaging, incl brain MRI if clinically indicated
• Assess for seizures.
• Red blood cell transfusion for severe anemia
• High-dose thiamine supplementation invariably improves hematologic picture.
• There is no addl clinical benefit w/thiamine dose >150mg/day.
• Assess for glucose intolerance (fasting serum glucose concentration, OGTT, urinalysis).
• Assess for clinical manifestations of poor glycemic control.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with thiamine-responsive megaloblastic anemia syndrome (TRMA), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome
Peripheral blood count
Bone marrow analysis for evidence of megaloblastic anemia
Cardiac eval, incl echocardiography
EKG
Neuroimaging, incl brain MRI if clinically indicated
Assess for seizures.
DM = diabetes mellitus; MOI = mode of inheritance; OGTT = oral glucose tolerance test
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Peripheral blood count
• Bone marrow analysis for evidence of megaloblastic anemia
• Cardiac eval, incl echocardiography
• EKG
• Neuroimaging, incl brain MRI if clinically indicated
• Assess for seizures.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome
Red blood cell transfusion for severe anemia
High-dose thiamine supplementation invariably improves hematologic picture.
There is no addl clinical benefit w/thiamine dose >150mg/day.
DM = diabetes mellitus; TRMA = thiamine-responsive megaloblastic anemia syndrome
• Red blood cell transfusion for severe anemia
• High-dose thiamine supplementation invariably improves hematologic picture.
• There is no addl clinical benefit w/thiamine dose >150mg/day.
## Surveillance
Recommended Surveillance for Individuals with Thiamine-Responsive Megaloblastic Anemia Syndrome
Assess for glucose intolerance (fasting serum glucose concentration, OGTT, urinalysis).
Assess for clinical manifestations of poor glycemic control.
CBC = complete blood count; OGTT = oral glucose tolerance test
• Assess for glucose intolerance (fasting serum glucose concentration, OGTT, urinalysis).
• Assess for clinical manifestations of poor glycemic control.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of sibs of an affected individual by molecular genetic testing for the
Supplementation with pharmacologic doses of thiamine (vitamin B
See
## Pregnancy Management
While there are no published studies evaluating pregnancy outcome in affected women, good diabetic control prior to and during pregnancy is recommended.
## Therapies Under Investigation
Search
## Genetic Counseling
Thiamine-responsive megaloblastic anemia syndrome (TRMA) 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
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.
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 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Thiamine-responsive megaloblastic anemia syndrome (TRMA) 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
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.
• 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.
## 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 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
Thiamine-Responsive Megaloblastic Anemia Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Thiamine-Responsive Megaloblastic Anemia Syndrome (
Defect of a high-affinity thiamine transporter, SLC19A2, causes thiamine-responsive megaloblastic anemia syndrome (TRMA); however, it is still unclear how the absence of
Studies to demonstrate
Reduction of protein expression caused by impaired RNA translation;
Protein retained within an intracellular segment such as the endoplasmic reticulum;
Proteins that are able to reach the cell membrane but are functionally impaired.
Questions regarding TRMA disease pathogenesis that still require explanation include why individuals with TRMA do not have manifestations seen in dietary thiamine deficiency [
Studies have shown that a second high-affinity thiamine transporter, encoded by
• Reduction of protein expression caused by impaired RNA translation;
• Protein retained within an intracellular segment such as the endoplasmic reticulum;
• Proteins that are able to reach the cell membrane but are functionally impaired.
## Molecular Pathogenesis
Defect of a high-affinity thiamine transporter, SLC19A2, causes thiamine-responsive megaloblastic anemia syndrome (TRMA); however, it is still unclear how the absence of
Studies to demonstrate
Reduction of protein expression caused by impaired RNA translation;
Protein retained within an intracellular segment such as the endoplasmic reticulum;
Proteins that are able to reach the cell membrane but are functionally impaired.
Questions regarding TRMA disease pathogenesis that still require explanation include why individuals with TRMA do not have manifestations seen in dietary thiamine deficiency [
Studies have shown that a second high-affinity thiamine transporter, encoded by
• Reduction of protein expression caused by impaired RNA translation;
• Protein retained within an intracellular segment such as the endoplasmic reticulum;
• Proteins that are able to reach the cell membrane but are functionally impaired.
## Chapter Notes
George A Diaz, MD, PhD; Icahn School of Medicine at Mount Sinai (2006-2022) Judith C Fleming, PhD; Children's Hospital and Harvard Medical School (2003-2006) Ellis J Neufeld, MD, PhD; Children's Hospital and Harvard Medical School (2003-2006) Kimihiko Oishi, MD (2006-present)Shuhei Sako, MD (2022-present)Toshiki Tsunogai, MD (2022-present)
28 July 2022 (sw) Comprehensive update posted live
4 May 2017 (ha) Comprehensive update posted live
20 November 2014 (me) Comprehensive update posted live
20 September 2012 (me) Comprehensive update posted live
8 April 2010 (me) Comprehensive update posted live
19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for
22 June 2006 (ca) Comprehensive update posted live
24 October 2003 (me) Review posted live
25 August 2003 (ejn) Original submission
• 28 July 2022 (sw) Comprehensive update posted live
• 4 May 2017 (ha) Comprehensive update posted live
• 20 November 2014 (me) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 8 April 2010 (me) Comprehensive update posted live
• 19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for
• 22 June 2006 (ca) Comprehensive update posted live
• 24 October 2003 (me) Review posted live
• 25 August 2003 (ejn) Original submission
## Author History
George A Diaz, MD, PhD; Icahn School of Medicine at Mount Sinai (2006-2022) Judith C Fleming, PhD; Children's Hospital and Harvard Medical School (2003-2006) Ellis J Neufeld, MD, PhD; Children's Hospital and Harvard Medical School (2003-2006) Kimihiko Oishi, MD (2006-present)Shuhei Sako, MD (2022-present)Toshiki Tsunogai, MD (2022-present)
## Revision History
28 July 2022 (sw) Comprehensive update posted live
4 May 2017 (ha) Comprehensive update posted live
20 November 2014 (me) Comprehensive update posted live
20 September 2012 (me) Comprehensive update posted live
8 April 2010 (me) Comprehensive update posted live
19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for
22 June 2006 (ca) Comprehensive update posted live
24 October 2003 (me) Review posted live
25 August 2003 (ejn) Original submission
• 28 July 2022 (sw) Comprehensive update posted live
• 4 May 2017 (ha) Comprehensive update posted live
• 20 November 2014 (me) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 8 April 2010 (me) Comprehensive update posted live
• 19 November 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for
• 22 June 2006 (ca) Comprehensive update posted live
• 24 October 2003 (me) Review posted live
• 25 August 2003 (ejn) Original submission
## References
## Literature Cited
|
[
"MR Abboud, D Alexander, SS Najjar. Diabetes mellitus, thiamine-dependent megaloblastic anemia, and sensorineural deafness associated with deficient alpha-ketoglutarate dehydrogenase activity.. J Pediatr 1985;107:537-41",
"L Akın, S Kurtoğlu, M Kendirci, MA Akın, M Karakükçü. Does early treatment prevent deafness in thiamine-responsive megaloblastic anaemia syndrome?. J Clin Res Pediatr Endocrinol 2011;3:36-9",
"AK Bergmann, I Sahai, JF Falcone, J Fleming, A Bagg, C Borgna-Pignati, R Casey, L Fabris, E Hexner, L Mathews, ML Ribeiro, KJ Wierenga, EJ Neufeld. Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update.. J Pediatr 2009;155:888-92.e1",
"I Beshlawi, S Al Zadjali, W Bashir, M Elshinawy, A Alrawas, Y Wali. Thiamine responsive megaloblastic anemia: the puzzling phenotype.. Pediatr Blood Cancer. 2014;61:528-31",
"C Borgna-Pignatti, M Azzalli, S Pedretti. Thiamine-responsive megaloblastic anemia syndrome: long term follow-up.. J Pediatr 2009;155:295-7",
"C Borgna-Pignatti, P Marradi, L Pinelli, N Monetti, C Patrini. Thiamine-responsive anemia in DIDMOAD syndrome.. J Pediatr 1989;114:405-10",
"LG Boros, MP Steinkamp, JC Fleming, WN Lee, M Cascante, EJ Neufeld. Defective RNA ribose synthesis in fibroblasts from patients with thiamine-responsive megaloblastic anemia (TRMA).. Blood 2003;102:3556-61",
"GA Diaz, M Banikazemi, K Oishi, RJ Desnick, BD Gelb. Mutations in a new gene encoding a thiamine transporter cause thiamine-responsive megaloblastic anaemia syndrome.. Nat Genet 1999;22:309-12",
"JD Eudy, O Spiegelstein, RC Barber, BJ Wlodarczyk, J Talbot, RH Finnell. Identification and characterization of the human and mouse SLC19A3 gene: a novel member of the reduced folate family of micronutrient transporter genes.. Mol Genet Metab 2000;71:581-90",
"JC Fleming, E Tartaglini, R Kawatsuji, D Yao, Y Fujiwara, JJ Bednarski, MD Fleming, EJ Neufeld. Male infertility and thiamine-dependent erythroid hypoplasia in mice lacking thiamine transporter Slc19a2.. Mol Genet Metab 2003;80:234-41",
"S Gritli, S Omar, E Tartaglini, S Guannouni, JC Fleming, MP Steinkamp, CI Berul, R Hafsia, SB Jilani, A Belhani, M Hamdi, EJ Neufeld. A novel mutation in the SLC19A2 gene in a Tunisian family with thiamine-responsive megaloblastic anaemia, diabetes and deafness syndrome.. Br J Haematol 2001;113:508-13",
"AM Habeb, SE Flanagan, MA Zulali, MA Abdullah, R Pomahačová, V Boyadzhiev, LE Colindres, GV Godoy, T Vasanthi, R Al Saif, A Setoodeh, A Haghighi, A Haghighi, Y Shaalan, AT Hattersley, S Ellard, E De Franco. Pharmacogenomics in diabetes: outcomes of thiamine therapy in TRMA syndrome.. Diabetologia. 2018;61:1027-36",
"AA Hagr. Cochlear implant and thiamine-responsive megaloblastic anemia syndrome.. Ann Saudi Med 2014;34:78-80",
"C Haworth, DI Evans, J Mitra, SN Wickramasinghe. Thiamine responsive anaemia: a study of two further cases.. Br J Haematol 1982;50:549-61",
"P Kang, W Zhang, J Wen, J Zhang, F Li, W. Sun. Case report: genetic and clinical features of maternal uniparental isodisomy-induced thiamine-responsive megaloblastic anemia syndrome.. Front Pediatr. 2021;9",
"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",
"P Jungtrakoon, J Shirakawa, P Buranasupkajorn, MK Gupta, M De Jesus, M Pezzolesi, A Panya, T Hastings, C Chanprasert, C Mendonca, R Kulkarni, A Doria. Loss-of-function mutation in thiamine transporter 1 in a family with autosomal dominant diabetes.. Diabetes 2019;68:1084-93",
"A Kipioti, ND George, AV Hoffbrand, E Sheridan. Cone-rod dystrophy in thiamine-responsive megaloblastic anemia.. J Pediatr Ophthalmol Strabismus 2003;40:105-7",
"S Kono, H Miyajima, K Yoshida, A Togawa, K Shirakawa, H Suzuki. Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy.. N Engl J Med. 2009;360:1792-4",
"WH Lagarde, LE Underwood, BM Moats-Staats, AS Calikoglu. Novel mutation in the SLC19A2 gene in an African-American female with thiamine-responsive megaloblastic anemia syndrome.. Am J Med Genet A. 2004;125A:299-305",
"MC Liberman, E Tartaglini, JC Fleming, EJ Neufeld. Deletion of SLC19A2, the high affinity thiamine transporter, causes selective inner hair cell loss and an auditory neuropathy phenotype.. J Assoc Res Otolaryngol. 2006;7:211-7",
"H Mandel, M Berant, A Hazani, Y Naveh. Thiamine-dependent beriberi in the \"thiamine-responsive anemia syndrome.\". N Engl J Med 1984;311:836-8",
"A Marcé-Grau, L Martí-Sánchez, H Baide-Mairena, J Ortigoza-Escobar, B Pérez-Dueñas. Genetic defects of thiamine transport and metabolism: a review of clinical phenotypes, genetics, and functional studies.. J Inherit Metab Dis 2019;42:581-97",
"L Mee, SM Nabokina, VT Sekar, VS Subramanian, K Maedler, HM Said. Pancreatic beta cells and islets take up thiamin by a regulated carrier-mediated process: studies using mice and human pancreatic preparations.. Am J Physiol Gastrointest Liver Physiol 2009;297:G197-206",
"FM Meire, MM Van Genderen, K Lemmens, MH Ens-Dokkum. Thiamine-responsive megaloblastic anemia syndrome (TRMA) with cone-rod dystrophy.. Ophthalmic Genet 2000;21:243-50",
"EJ Neufeld, JC Fleming, E Tartaglini, MP Steinkamp. Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport.. Blood Cells Mol Dis 2001;27:135-8",
"EJ Neufeld, H Mandel, T Raz, R Szargel, CN Yandava, A Stagg, S Faure, T Barrett, N Buist, N Cohen. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping.. Am J Hum Genet 1997;61:1335-41",
"K Oishi, S Hofmann, GA Diaz, T Brown, D Manwani, L Ng, R Young, H Vlassara, YA Ioannou, D Forrest, BD Gelb. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice.. Hum Mol Genet 2002;11:2951-60",
"H Onal, S Bariş, M Ozdil, G Yeşil, G Altun, I Ozyilmaz, A Aydin, T Celkan. Thiamine-responsive megaloblastic anemia: early diagnosis may be effective in preventing deafness.. Turk J Pediatr. 2009;51:301-4",
"J Ortigoza-Escobar, M Molero-Luis, A Arias, M Martí-Sánchez, P Rodriguez-Pombo, R Artuch, B Pérez-Dueñas. Treatment of genetic defects of thiamine transport and metabolism.. Expert Rev Neurother. 2016;16:755-63",
"MA Ozdemir, M Akcakus, S Kurtoglu, T Gunes, YA Torun. TRMA syndrome (thiamine-responsive megaloblastic anemia): a case report and review of the literature.. Pediatr Diabetes 2002;3:205-9",
"H Pichler, P Zeitlhofer, MN Dworzak, C Diakos, OA Haas, L Kager. Thiamine-responsive megaloblastic anemia (TRMA) in an Austrian boy with compound heterozygous SLC19A2 mutations.. Eur J Pediatr. 2012;171:1711-5",
"V Poggi, G Longo, B DeVizia, G Andria, G Rindi, C Patrini, E Cassandro. Thiamin-responsive megaloblastic anaemia: a disorder of thiamin transport?. J Inherit Metab Dis. 1984;7:153-4",
"A Rajgopal, A Edmondnson, ID Goldman, R Zhao. SLC19A3 encodes a second thiamine transporter ThTr2.. Biochim Biophys Acta 2001;1537:175-8",
"T Raz, V Labay, D Baron, R Szargel, Y Anbinder, T Barrett, W Rabl, MB Viana, H Mandel, A Baruchel, JM Cayuela, N Cohen. The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families.. Hum Mutat 2000;16:37-42",
"JC Reidling, N Lambrecht, M Kassir, HM Said. Impaired intestinal vitamin B(1) (thiamin) uptake in thiamin transporter-2-deficient mice.. Gastroenterology 2010;138:1802-9",
"CJ Ricketts, JA Minton, J Samuel, I Ariyawansa, JK Wales, IF Lo, TG Barrett. Thiamine-responsive megaloblastic anaemia syndrome: long-term follow-up and mutation analysis of seven families.. Acta Paediatr 2006;95:99-104",
"G Rindi, D Casirola, V Poggi, B De Vizia, C Patrini, U Laforenza. Thiamine transport by erythrocytes and ghosts in thiamine-responsive megaloblastic anaemia.. J Inherit Metab Dis 1992;15:231-42",
"C Scharfe, M Hauschild, T Klopstock, AJ Janssen, PH Heidemann, T Meitinger, M Jaksch. A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I.. J Med Genet 2000;37:669-73",
"A Setoodeh, A Haghighi, N Saleh-Gohari, S Ellard, A Haghighi. Identification of a SLC19A2 nonsense mutation in Persian families with thiamine-responsive megaloblastic anemia.. Gene 2013;519:295-7",
"C Shaw-Smith, SE Flanagan, AM Patch, J Grulich-Henn, AM Habeb, K Hussain, R Pomahacova, K Matyka, M Abdullah, AT Hattersley, S Ellard. Recessive SLC19A2 mutations are a cause of neonatal diabetes mellitus in thiamine-responsive megaloblastic anaemia.. Pediatr Diabetes. 2012;13:314-21",
"AR Stagg, JC Fleming, MA Baker, M Sakamoto, N Cohen, EJ Neufeld. Defective high-affinity thiamine transporter leads to cell death in thiamine-responsive megaloblastic anemia syndrome fibroblasts.. J Clin Invest 1999;103:723-9",
"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",
"G Valerio, A Franzese, V Poggi, A Tenore. Long-term follow-up of diabetes in two patients with thiamine-responsive megaloblastic anemia syndrome.. Diabetes Care. 1998;21:38-41",
"S Wu, Z Yuan, Z Sun, F Yao, R Sui. Lever congenital amaurosis as an initial manifestation in a Chinese patient with thiamine-responsive megaloblastic anemia syndrome.. Am J Med Genet A 2022;188:948-52",
"S Yilmaz Agladioglu, Z Aycan, VN Bas, HN Peltek Kendirci, A Onder. Thiamine-responsive megaloblastic anemia syndrome: a novel mutation.. Genet Couns. 2012;23:149-56",
"S Zhang, Y Qiao, Z Wang, Z Zhuang, Y Sun, Y Shang, G Li. Identification of novel compound heterozygous variants in SLC19A2 and the genotype-phenotype associations in thiamine-responsive megaloblastic anemia.. Clin Chim Acta 2021;516:157-68"
] |
24/10/2003
|
28/7/2022
|
19/11/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
trmu-def
|
trmu-def
|
[
"TRMU-Related Reversible Infantile Respiratory Chain Deficiency",
"TRMU-Related Mitochondrial Hepatopathy",
"TRMU-Related Reversible Infantile Liver Failure",
"TRMU-Related Reversible Infantile Respiratory Chain Deficiency",
"TRMU-Related Mitochondrial Hepatopathy",
"TRMU-Related Reversible Infantile Liver Failure",
"Mitochondrial tRNA-specific 2-thiouridylase 1",
"TRMU",
"TRMU Deficiency"
] |
TRMU Deficiency
|
Michaela Reinhart, Colleen Muraresku, Rebecca Ganetzky
|
Summary Infants with untreated TRMU deficiency, a mitochondrial disorder, typically become symptomatic between ages two and four months with transient acute liver dysfunction (including elevated transaminases, abnormal synthetic functions, and/or hepatomegaly), metabolic derangements (severe persistent lactic acidosis, hypoglycemia, hyperammonemia), and poor weight gain. With proper supportive treatment (but not disease-targeted therapy), abnormal liver findings (including coagulopathy) improve or normalize. Likewise, metabolic derangements improve. However, other manifestations typical of a mitochondrial disorder such as persistent lactic acidosis, neurologic dysfunction (including developmental delay / intellectual disability and seizures), cardiomyopathy, and respiratory failure may persist or develop or over time. The diagnosis of TRMU deficiency TRMU 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 TRMU deficiency have been published.
TRMU deficiency
Acute liver dysfunction with elevated liver enzymes (gamma-glutamyl transferase and transaminases), hyperammonemia, and jaundice due to conjugated hyperbilirubinemia
Severe persistent lactic acidosis in the acute setting, likely as a result of disease onset and progression for some time prior to initial diagnostic evaluation
Persistent hypoglycemia
Poor feeding with failure to gain weight
Leigh-like syndrome
Cardiomyopathy
Hepatomegaly
Poor weight gain
Lactic acidosis
TRMU Deficiency: Frequency of Select Features in Children who were Untreated and Symptomatic at the time of Diagnosis
Based on
Enlargement and hyperechogenicity of the liver
Diffuse hepatic steatosis and persistent hepatic nodules
Note: Brain imaging may be normal in some children; in others, repeat imaging after clinical recovery (including resolution of acute liver failure, growth restriction, and motor delay) shows normalization of MRI findings [
While not required to either suspect or establish the diagnosis of TRMU deficiency, liver and/or muscle biopsies were often obtained in the past prior to the availability of molecular genetic testing or may have been obtained pending results of molecular genetic testing.
Histologic findings in TRMU deficiency include bridging fibrosis, portal and perisinusoidal fibrosis, focal eosinophilic ground-glass appearance, micronodular cirrhosis, necrosis, mitochondrial proliferation, micro- and macrovesicular steatosis, canalicular cholestasis, bile duct proliferation, ballooning degeneration, and increased hepatic iron and oncocytic hepatocytes [
One individual showed periportal hepatocyte copper loading thought to be secondary cholestasis resulting from severe mitochondrial dysfunction [
Electron transport chain enzymology is variable but uniformly shows lower complex IV activity.
Blue native gel electrophoresis also showed the nonspecific findings of abnormal complex assembly particularly affecting complexes I and IV.
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.
Medical intervention recommended pending confirmation of the definitive diagnosis of TRMU deficiency is supplementation with exogenous cysteine as L-cysteine, N-acetylcysteine, or both. See Management,
The diagnosis of TRMU 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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TRMU 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.
• Acute liver dysfunction with elevated liver enzymes (gamma-glutamyl transferase and transaminases), hyperammonemia, and jaundice due to conjugated hyperbilirubinemia
• Severe persistent lactic acidosis in the acute setting, likely as a result of disease onset and progression for some time prior to initial diagnostic evaluation
• Persistent hypoglycemia
• Poor feeding with failure to gain weight
• Leigh-like syndrome
• Cardiomyopathy
• Hepatomegaly
• Poor weight gain
• Lactic acidosis
• Enlargement and hyperechogenicity of the liver
• Diffuse hepatic steatosis and persistent hepatic nodules
## Suggestive Findings
TRMU deficiency
Acute liver dysfunction with elevated liver enzymes (gamma-glutamyl transferase and transaminases), hyperammonemia, and jaundice due to conjugated hyperbilirubinemia
Severe persistent lactic acidosis in the acute setting, likely as a result of disease onset and progression for some time prior to initial diagnostic evaluation
Persistent hypoglycemia
Poor feeding with failure to gain weight
Leigh-like syndrome
Cardiomyopathy
Hepatomegaly
Poor weight gain
Lactic acidosis
TRMU Deficiency: Frequency of Select Features in Children who were Untreated and Symptomatic at the time of Diagnosis
Based on
Enlargement and hyperechogenicity of the liver
Diffuse hepatic steatosis and persistent hepatic nodules
Note: Brain imaging may be normal in some children; in others, repeat imaging after clinical recovery (including resolution of acute liver failure, growth restriction, and motor delay) shows normalization of MRI findings [
While not required to either suspect or establish the diagnosis of TRMU deficiency, liver and/or muscle biopsies were often obtained in the past prior to the availability of molecular genetic testing or may have been obtained pending results of molecular genetic testing.
Histologic findings in TRMU deficiency include bridging fibrosis, portal and perisinusoidal fibrosis, focal eosinophilic ground-glass appearance, micronodular cirrhosis, necrosis, mitochondrial proliferation, micro- and macrovesicular steatosis, canalicular cholestasis, bile duct proliferation, ballooning degeneration, and increased hepatic iron and oncocytic hepatocytes [
One individual showed periportal hepatocyte copper loading thought to be secondary cholestasis resulting from severe mitochondrial dysfunction [
Electron transport chain enzymology is variable but uniformly shows lower complex IV activity.
Blue native gel electrophoresis also showed the nonspecific findings of abnormal complex assembly particularly affecting complexes I and IV.
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.
Medical intervention recommended pending confirmation of the definitive diagnosis of TRMU deficiency is supplementation with exogenous cysteine as L-cysteine, N-acetylcysteine, or both. See Management,
• Acute liver dysfunction with elevated liver enzymes (gamma-glutamyl transferase and transaminases), hyperammonemia, and jaundice due to conjugated hyperbilirubinemia
• Severe persistent lactic acidosis in the acute setting, likely as a result of disease onset and progression for some time prior to initial diagnostic evaluation
• Persistent hypoglycemia
• Poor feeding with failure to gain weight
• Leigh-like syndrome
• Cardiomyopathy
• Hepatomegaly
• Poor weight gain
• Lactic acidosis
• Enlargement and hyperechogenicity of the liver
• Diffuse hepatic steatosis and persistent hepatic nodules
## Clinical Findings
Acute liver dysfunction with elevated liver enzymes (gamma-glutamyl transferase and transaminases), hyperammonemia, and jaundice due to conjugated hyperbilirubinemia
Severe persistent lactic acidosis in the acute setting, likely as a result of disease onset and progression for some time prior to initial diagnostic evaluation
Persistent hypoglycemia
Poor feeding with failure to gain weight
Leigh-like syndrome
Cardiomyopathy
Hepatomegaly
Poor weight gain
Lactic acidosis
TRMU Deficiency: Frequency of Select Features in Children who were Untreated and Symptomatic at the time of Diagnosis
Based on
• Acute liver dysfunction with elevated liver enzymes (gamma-glutamyl transferase and transaminases), hyperammonemia, and jaundice due to conjugated hyperbilirubinemia
• Severe persistent lactic acidosis in the acute setting, likely as a result of disease onset and progression for some time prior to initial diagnostic evaluation
• Persistent hypoglycemia
• Poor feeding with failure to gain weight
• Leigh-like syndrome
• Cardiomyopathy
• Hepatomegaly
• Poor weight gain
• Lactic acidosis
## Imaging Findings
Enlargement and hyperechogenicity of the liver
Diffuse hepatic steatosis and persistent hepatic nodules
Note: Brain imaging may be normal in some children; in others, repeat imaging after clinical recovery (including resolution of acute liver failure, growth restriction, and motor delay) shows normalization of MRI findings [
• Enlargement and hyperechogenicity of the liver
• Diffuse hepatic steatosis and persistent hepatic nodules
## Tissue Biopsies
While not required to either suspect or establish the diagnosis of TRMU deficiency, liver and/or muscle biopsies were often obtained in the past prior to the availability of molecular genetic testing or may have been obtained pending results of molecular genetic testing.
Histologic findings in TRMU deficiency include bridging fibrosis, portal and perisinusoidal fibrosis, focal eosinophilic ground-glass appearance, micronodular cirrhosis, necrosis, mitochondrial proliferation, micro- and macrovesicular steatosis, canalicular cholestasis, bile duct proliferation, ballooning degeneration, and increased hepatic iron and oncocytic hepatocytes [
One individual showed periportal hepatocyte copper loading thought to be secondary cholestasis resulting from severe mitochondrial dysfunction [
Electron transport chain enzymology is variable but uniformly shows lower complex IV activity.
Blue native gel electrophoresis also showed the nonspecific findings of abnormal complex assembly particularly affecting complexes I and IV.
## 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.
## Medical Intervention
Medical intervention recommended pending confirmation of the definitive diagnosis of TRMU deficiency is supplementation with exogenous cysteine as L-cysteine, N-acetylcysteine, or both. See Management,
## Establishing the Diagnosis
The diagnosis of TRMU 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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TRMU 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.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in TRMU 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.
## Clinical Characteristics
Infants with untreated TRMU deficiency, a mitochondrial disorder, typically become symptomatic between ages two and four months with transient acute liver dysfunction (including elevated transaminases, abnormal synthetic functions, and/or hepatomegaly), metabolic derangements (severe persistent lactic acidosis, hypoglycemia, hyperammonemia), and poor weight gain.
With proper supportive treatment (but not disease-targeted therapy), abnormal liver findings (including coagulopathy) improve or normalize, as do metabolic derangements. Lactic acidemia typically improves, but typically does not fully normalize. Neurologic dysfunction may persist or evolve over time [
Early targeted therapy (i.e., L-cysteine and N-acetylcysteine [NAC] supplementation) may significantly alter the disease course based on the limited experience to date with two unrelated at-risk sibs who were diagnosed prenatally or shortly after birth. These two children, who were treated presymptomatically, had a milder disease course with less severe acidosis and liver dysfunction and fewer hospitalizations than their affected sibs [
To date, 62 individuals (60 probands and two at-risk sibs) have been identified with biallelic pathogenic variants in
The following is a description of the features associated with TRMU deficiency in 60 untreated symptomatic children at the time of diagnosis (see
TRMU Deficiency: Frequency of Select Features in Untreated Symptomatic Children at the Time of Diagnosis
Can incl hepatitis, cholestasis, steatosis, &/or cirrhosis.
Synthetic liver failure & hyperammonemia are common.
Hepatomegaly may or may not be present & may persist beyond the acute episode.
In the setting of liver dysfunction or cholestasis, jaundice often – but not always – results from direct hyperbilirubinemia.
Abnormal liver findings during the acute phase improve or normalize with proper supportive symptomatic treatment. Twenty-three percent of children have recurrent episodes of liver failure in the first year of life, which most frequently occur in the first five months of life. The largest number of episodes of acute liver failure reported per child was five, which occurred in two unrelated children. One of these children underwent orthotopic liver transplantation and was last followed up at age 13 years; the other had spontaneous resolution of liver disease and is living with their native liver at age 17 years [
Hepatomegaly, which may or may not develop, does not correlate with the presence of acute liver failure. Variceal bleeding may also occur.
Progression of liver disease can result in fibrosis and/or cirrhosis, as well as macro- and microvesicular steatosis and cholestatic changes.
Although lactic acidosis is a predominant finding in the acute setting, it likely begins some time prior to manifestations of other liver dysfunction. The presence of both hyperalaninemia and lactic aciduria help distinguish chronic lactic acidosis from the acute lactic acidemia that is secondary to acute liver failure.
Hypoglycemia is often persistent and may require dextrose-containing fluids in the acute setting (see Management,
Unpublished experience suggests that even infants who are neurologically nearly typical may have brain MRI findings suggestive of Leigh syndrome. Given limited evaluation for neurologic involvement of other affected infants, the prevalence of a Leigh syndrome phenotype may be underestimated [
In a retrospective study of 25 individuals, nine had resolution of developmental delays at least several months following recovery of liver function, whereas five had persistent delays. The remaining 11 individuals were either lost to follow up or deceased. The cause of persistent neurodevelopmental delay may be either secondary to acute liver failure or the underlying mitochondrial disorder causing TRMU deficiency [
Liver dysfunction and metabolic derangements were more easily managed in the at-risk infants treated presymptomatically than in their older sibs; however, it should be noted that one child was listed for liver transplantation in the setting of severe hyperammonemia prior to becoming stabilized [
TRMU Deficiency: Frequency of Select Features in Children who were Treated Presymptomatically
Based on
Patient 6 was previously described by
Severity of metabolic findings were milder than those of sibs who were symptomatic at the time of initial diagnosis (i.e., Patient 1 and Patient 5, respectively).
One sib (Patient 2 in
The other sib (Patient 6 in
There is no consensus on genotype-phenotype correlations for TRMU deficiency at this time.
The Yemenite Jewish founder variant
Mortality in individuals with the p.Tyr77His variant may be lower than the mortality rate in individuals without this variant (6/23). No deaths were reported in p.Tyr77His homozygotes; one individual who was a compound heterozygote for this variant died at age four months [
The recurrent
Sixty-two individuals from 56 families with biallelic
TRMU deficiency is particularly common in persons of Yemenite Jewish ancestry due to the founder variant
• Can incl hepatitis, cholestasis, steatosis, &/or cirrhosis.
• Synthetic liver failure & hyperammonemia are common.
• Hepatomegaly may or may not be present & may persist beyond the acute episode.
• The Yemenite Jewish founder variant
• Mortality in individuals with the p.Tyr77His variant may be lower than the mortality rate in individuals without this variant (6/23). No deaths were reported in p.Tyr77His homozygotes; one individual who was a compound heterozygote for this variant died at age four months [
• The recurrent
## Clinical Description
Infants with untreated TRMU deficiency, a mitochondrial disorder, typically become symptomatic between ages two and four months with transient acute liver dysfunction (including elevated transaminases, abnormal synthetic functions, and/or hepatomegaly), metabolic derangements (severe persistent lactic acidosis, hypoglycemia, hyperammonemia), and poor weight gain.
With proper supportive treatment (but not disease-targeted therapy), abnormal liver findings (including coagulopathy) improve or normalize, as do metabolic derangements. Lactic acidemia typically improves, but typically does not fully normalize. Neurologic dysfunction may persist or evolve over time [
Early targeted therapy (i.e., L-cysteine and N-acetylcysteine [NAC] supplementation) may significantly alter the disease course based on the limited experience to date with two unrelated at-risk sibs who were diagnosed prenatally or shortly after birth. These two children, who were treated presymptomatically, had a milder disease course with less severe acidosis and liver dysfunction and fewer hospitalizations than their affected sibs [
To date, 62 individuals (60 probands and two at-risk sibs) have been identified with biallelic pathogenic variants in
The following is a description of the features associated with TRMU deficiency in 60 untreated symptomatic children at the time of diagnosis (see
TRMU Deficiency: Frequency of Select Features in Untreated Symptomatic Children at the Time of Diagnosis
Can incl hepatitis, cholestasis, steatosis, &/or cirrhosis.
Synthetic liver failure & hyperammonemia are common.
Hepatomegaly may or may not be present & may persist beyond the acute episode.
In the setting of liver dysfunction or cholestasis, jaundice often – but not always – results from direct hyperbilirubinemia.
Abnormal liver findings during the acute phase improve or normalize with proper supportive symptomatic treatment. Twenty-three percent of children have recurrent episodes of liver failure in the first year of life, which most frequently occur in the first five months of life. The largest number of episodes of acute liver failure reported per child was five, which occurred in two unrelated children. One of these children underwent orthotopic liver transplantation and was last followed up at age 13 years; the other had spontaneous resolution of liver disease and is living with their native liver at age 17 years [
Hepatomegaly, which may or may not develop, does not correlate with the presence of acute liver failure. Variceal bleeding may also occur.
Progression of liver disease can result in fibrosis and/or cirrhosis, as well as macro- and microvesicular steatosis and cholestatic changes.
Although lactic acidosis is a predominant finding in the acute setting, it likely begins some time prior to manifestations of other liver dysfunction. The presence of both hyperalaninemia and lactic aciduria help distinguish chronic lactic acidosis from the acute lactic acidemia that is secondary to acute liver failure.
Hypoglycemia is often persistent and may require dextrose-containing fluids in the acute setting (see Management,
Unpublished experience suggests that even infants who are neurologically nearly typical may have brain MRI findings suggestive of Leigh syndrome. Given limited evaluation for neurologic involvement of other affected infants, the prevalence of a Leigh syndrome phenotype may be underestimated [
In a retrospective study of 25 individuals, nine had resolution of developmental delays at least several months following recovery of liver function, whereas five had persistent delays. The remaining 11 individuals were either lost to follow up or deceased. The cause of persistent neurodevelopmental delay may be either secondary to acute liver failure or the underlying mitochondrial disorder causing TRMU deficiency [
Liver dysfunction and metabolic derangements were more easily managed in the at-risk infants treated presymptomatically than in their older sibs; however, it should be noted that one child was listed for liver transplantation in the setting of severe hyperammonemia prior to becoming stabilized [
TRMU Deficiency: Frequency of Select Features in Children who were Treated Presymptomatically
Based on
Patient 6 was previously described by
Severity of metabolic findings were milder than those of sibs who were symptomatic at the time of initial diagnosis (i.e., Patient 1 and Patient 5, respectively).
One sib (Patient 2 in
The other sib (Patient 6 in
• Can incl hepatitis, cholestasis, steatosis, &/or cirrhosis.
• Synthetic liver failure & hyperammonemia are common.
• Hepatomegaly may or may not be present & may persist beyond the acute episode.
## Untreated Symptomatic Children at the Time of Diagnosis
The following is a description of the features associated with TRMU deficiency in 60 untreated symptomatic children at the time of diagnosis (see
TRMU Deficiency: Frequency of Select Features in Untreated Symptomatic Children at the Time of Diagnosis
Can incl hepatitis, cholestasis, steatosis, &/or cirrhosis.
Synthetic liver failure & hyperammonemia are common.
Hepatomegaly may or may not be present & may persist beyond the acute episode.
In the setting of liver dysfunction or cholestasis, jaundice often – but not always – results from direct hyperbilirubinemia.
Abnormal liver findings during the acute phase improve or normalize with proper supportive symptomatic treatment. Twenty-three percent of children have recurrent episodes of liver failure in the first year of life, which most frequently occur in the first five months of life. The largest number of episodes of acute liver failure reported per child was five, which occurred in two unrelated children. One of these children underwent orthotopic liver transplantation and was last followed up at age 13 years; the other had spontaneous resolution of liver disease and is living with their native liver at age 17 years [
Hepatomegaly, which may or may not develop, does not correlate with the presence of acute liver failure. Variceal bleeding may also occur.
Progression of liver disease can result in fibrosis and/or cirrhosis, as well as macro- and microvesicular steatosis and cholestatic changes.
Although lactic acidosis is a predominant finding in the acute setting, it likely begins some time prior to manifestations of other liver dysfunction. The presence of both hyperalaninemia and lactic aciduria help distinguish chronic lactic acidosis from the acute lactic acidemia that is secondary to acute liver failure.
Hypoglycemia is often persistent and may require dextrose-containing fluids in the acute setting (see Management,
Unpublished experience suggests that even infants who are neurologically nearly typical may have brain MRI findings suggestive of Leigh syndrome. Given limited evaluation for neurologic involvement of other affected infants, the prevalence of a Leigh syndrome phenotype may be underestimated [
In a retrospective study of 25 individuals, nine had resolution of developmental delays at least several months following recovery of liver function, whereas five had persistent delays. The remaining 11 individuals were either lost to follow up or deceased. The cause of persistent neurodevelopmental delay may be either secondary to acute liver failure or the underlying mitochondrial disorder causing TRMU deficiency [
• Can incl hepatitis, cholestasis, steatosis, &/or cirrhosis.
• Synthetic liver failure & hyperammonemia are common.
• Hepatomegaly may or may not be present & may persist beyond the acute episode.
## Presymptomatically Treated At-Risk Sibs
Liver dysfunction and metabolic derangements were more easily managed in the at-risk infants treated presymptomatically than in their older sibs; however, it should be noted that one child was listed for liver transplantation in the setting of severe hyperammonemia prior to becoming stabilized [
TRMU Deficiency: Frequency of Select Features in Children who were Treated Presymptomatically
Based on
Patient 6 was previously described by
Severity of metabolic findings were milder than those of sibs who were symptomatic at the time of initial diagnosis (i.e., Patient 1 and Patient 5, respectively).
One sib (Patient 2 in
The other sib (Patient 6 in
## Genotype-Phenotype Correlations
There is no consensus on genotype-phenotype correlations for TRMU deficiency at this time.
The Yemenite Jewish founder variant
Mortality in individuals with the p.Tyr77His variant may be lower than the mortality rate in individuals without this variant (6/23). No deaths were reported in p.Tyr77His homozygotes; one individual who was a compound heterozygote for this variant died at age four months [
The recurrent
• The Yemenite Jewish founder variant
• Mortality in individuals with the p.Tyr77His variant may be lower than the mortality rate in individuals without this variant (6/23). No deaths were reported in p.Tyr77His homozygotes; one individual who was a compound heterozygote for this variant died at age four months [
• The recurrent
## Prevalence
Sixty-two individuals from 56 families with biallelic
TRMU deficiency is particularly common in persons of Yemenite Jewish ancestry due to the founder variant
## Genetically Related (Allelic) Disorders
The
## Differential Diagnosis
The differential diagnosis of TRMU deficiency includes
Selected Disorders in the Differential Diagnosis of TRMU Deficiency
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; XL = X-linked
## Management
No clinical practice guidelines for TRMU deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with TRMU deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with TRMU Deficiency
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in infants w/↑ risk of dysphagia &/or aspiration.
To incl motor, adaptive, & cognitive eval
Speech-language eval by speech-language pathologist
Eval for early intervention / special education
Assessment of neurologic status by primary care provider
Referral to neurologist if there are persistent neurodevelopmental delays or seizures develop
Gross motor & fine motor skills
Mobility, ADL, & need for durable equipment &/or 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
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for TRMU deficiency.
There is no consensus regarding the best method to provide sufficient exogenous cysteine in TRMU deficiency. Because N-acetylcysteine (NAC) also improves redox potential in mitochondrial disease and thus supports mitochondrial function, it is recommended along with cysteine. The limited evidence available suggest that NAC is best used in conjunction with L-cysteine to ameliorate TRMU deficiency, especially in the first year of life.
Treatment with L-cysteine and NAC should be initiated as soon as a diagnosis of TRMU deficiency is suspected.
Previous studies have used doses of L-cysteine ranging from 85 to 300 mg/kg per day (with a goal of 300 mg/kg per day total) and doses of NAC ranging from 70 to 150 mg/kg per day [
Infant formulas enriched with L-cysteine may also be considered to reach this supplementation goal. Given the recovery of liver function over time as physiologic compensatory mechanisms may take effect, supplementation should continue for at least the first year of life [
In one study the survival rate beyond the acute decompensation phase in children supplemented with L-cysteine and/or NAC was 84% compared to 61% in those not supplemented [
Although a small number of infants treated presymptomatically overall had a milder clinical course than affected relatives [
Note: Although the direct substrate of TRMU for thiouridylation is taurine and taurine supplementation may theoretically be of benefit [
Orthotopic liver transplantation, reported in 11 children with TRMU deficiency, was indicated when the hepatopathy did not respond to medical interventions [
Liver transplantation did not influence overall survival. Two individuals died following transplantation (one from variceal bleeding and one from multiorgan failure) [
Liver transplantation may also be considered before a trial of targeted therapy in individuals with the
Note: The underlying
Supportive care by a multidisciplinary team including a hepatologist, neurologist, and medical geneticist is recommended (see
Supportive Treatment in Individuals with TRMU Deficiency
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
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.
Routine follow up is recommended to monitor response to L-cysteine and NAC supplementation, to evaluate response to supportive interventions, and to identify emergence of new findings or concerns regarding developmental/educational progress such as persistent neurodevelopmental delay or new onset of seizures that may develop over time (see
Recommended Surveillance for Individuals with TRMU Deficiency
Annual alpha-fetoprotein & abdominal ultrasounds beginning at age 1 yr
Screening is most important in children who have had advanced fibrosis or cirrhosis.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as type or frequency of seizures, changes in tone, & movement disorders.
Agents to avoid:
Those that increase metabolic demand, such as corticosteroids (see below), or inhibit mitochondrial activity, such as valproic acid and prolonged propofol infusion
Fasting, as it increases metabolic demand and may exacerbate hypoglycemia
Agents to be used with caution:
Corticosteroids may raise the lactate level because of increased glycogenolysis and gluconeogenesis. If they are indicated they should be given under guidance of a clinician / metabolic specialist who can aid in monitoring metabolic acidosis.
Because of limited liver oxidative metabolism in the acute period, administration of high concentrations of dextrose will increase lactic acid concentration, which may cause or worsen metabolic acidosis. Therefore, dextrose must be given with care to balance euglycemia with acid-base status.
See
In one instance of prenatally identified TRMU deficiency, the mother received 500 mg of L-cysteine twice daily during the third trimester of the pregnancy with the intent of providing sufficient cysteine to the fetus in the postnatal period when cysteine is an essential amino acid (see Management,
Search
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in infants w/↑ risk of dysphagia &/or aspiration.
• To incl motor, adaptive, & cognitive eval
• Speech-language eval by speech-language pathologist
• Eval for early intervention / special education
• Assessment of neurologic status by primary care provider
• Referral to neurologist if there are persistent neurodevelopmental delays or seizures develop
• Gross motor & fine motor skills
• Mobility, ADL, & need for durable equipment &/or 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.
• Previous studies have used doses of L-cysteine ranging from 85 to 300 mg/kg per day (with a goal of 300 mg/kg per day total) and doses of NAC ranging from 70 to 150 mg/kg per day [
• Infant formulas enriched with L-cysteine may also be considered to reach this supplementation goal. Given the recovery of liver function over time as physiologic compensatory mechanisms may take effect, supplementation should continue for at least the first year of life [
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Annual alpha-fetoprotein & abdominal ultrasounds beginning at age 1 yr
• Screening is most important in children who have had advanced fibrosis or cirrhosis.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as type or frequency of seizures, changes in tone, & movement disorders.
• Those that increase metabolic demand, such as corticosteroids (see below), or inhibit mitochondrial activity, such as valproic acid and prolonged propofol infusion
• Fasting, as it increases metabolic demand and may exacerbate hypoglycemia
• Corticosteroids may raise the lactate level because of increased glycogenolysis and gluconeogenesis. If they are indicated they should be given under guidance of a clinician / metabolic specialist who can aid in monitoring metabolic acidosis.
• Because of limited liver oxidative metabolism in the acute period, administration of high concentrations of dextrose will increase lactic acid concentration, which may cause or worsen metabolic acidosis. Therefore, dextrose must be given with care to balance euglycemia with acid-base status.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TRMU deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with TRMU Deficiency
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in infants w/↑ risk of dysphagia &/or aspiration.
To incl motor, adaptive, & cognitive eval
Speech-language eval by speech-language pathologist
Eval for early intervention / special education
Assessment of neurologic status by primary care provider
Referral to neurologist if there are persistent neurodevelopmental delays or seizures develop
Gross motor & fine motor skills
Mobility, ADL, & need for durable equipment &/or 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
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in infants w/↑ risk of dysphagia &/or aspiration.
• To incl motor, adaptive, & cognitive eval
• Speech-language eval by speech-language pathologist
• Eval for early intervention / special education
• Assessment of neurologic status by primary care provider
• Referral to neurologist if there are persistent neurodevelopmental delays or seizures develop
• Gross motor & fine motor skills
• Mobility, ADL, & need for durable equipment &/or 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 TRMU deficiency.
There is no consensus regarding the best method to provide sufficient exogenous cysteine in TRMU deficiency. Because N-acetylcysteine (NAC) also improves redox potential in mitochondrial disease and thus supports mitochondrial function, it is recommended along with cysteine. The limited evidence available suggest that NAC is best used in conjunction with L-cysteine to ameliorate TRMU deficiency, especially in the first year of life.
Treatment with L-cysteine and NAC should be initiated as soon as a diagnosis of TRMU deficiency is suspected.
Previous studies have used doses of L-cysteine ranging from 85 to 300 mg/kg per day (with a goal of 300 mg/kg per day total) and doses of NAC ranging from 70 to 150 mg/kg per day [
Infant formulas enriched with L-cysteine may also be considered to reach this supplementation goal. Given the recovery of liver function over time as physiologic compensatory mechanisms may take effect, supplementation should continue for at least the first year of life [
In one study the survival rate beyond the acute decompensation phase in children supplemented with L-cysteine and/or NAC was 84% compared to 61% in those not supplemented [
Although a small number of infants treated presymptomatically overall had a milder clinical course than affected relatives [
Note: Although the direct substrate of TRMU for thiouridylation is taurine and taurine supplementation may theoretically be of benefit [
Orthotopic liver transplantation, reported in 11 children with TRMU deficiency, was indicated when the hepatopathy did not respond to medical interventions [
Liver transplantation did not influence overall survival. Two individuals died following transplantation (one from variceal bleeding and one from multiorgan failure) [
Liver transplantation may also be considered before a trial of targeted therapy in individuals with the
Note: The underlying
Supportive care by a multidisciplinary team including a hepatologist, neurologist, and medical geneticist is recommended (see
Supportive Treatment in Individuals with TRMU Deficiency
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
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.
• Previous studies have used doses of L-cysteine ranging from 85 to 300 mg/kg per day (with a goal of 300 mg/kg per day total) and doses of NAC ranging from 70 to 150 mg/kg per day [
• Infant formulas enriched with L-cysteine may also be considered to reach this supplementation goal. Given the recovery of liver function over time as physiologic compensatory mechanisms may take effect, supplementation should continue for at least the first year of life [
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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 consensus regarding the best method to provide sufficient exogenous cysteine in TRMU deficiency. Because N-acetylcysteine (NAC) also improves redox potential in mitochondrial disease and thus supports mitochondrial function, it is recommended along with cysteine. The limited evidence available suggest that NAC is best used in conjunction with L-cysteine to ameliorate TRMU deficiency, especially in the first year of life.
Treatment with L-cysteine and NAC should be initiated as soon as a diagnosis of TRMU deficiency is suspected.
Previous studies have used doses of L-cysteine ranging from 85 to 300 mg/kg per day (with a goal of 300 mg/kg per day total) and doses of NAC ranging from 70 to 150 mg/kg per day [
Infant formulas enriched with L-cysteine may also be considered to reach this supplementation goal. Given the recovery of liver function over time as physiologic compensatory mechanisms may take effect, supplementation should continue for at least the first year of life [
In one study the survival rate beyond the acute decompensation phase in children supplemented with L-cysteine and/or NAC was 84% compared to 61% in those not supplemented [
Although a small number of infants treated presymptomatically overall had a milder clinical course than affected relatives [
Note: Although the direct substrate of TRMU for thiouridylation is taurine and taurine supplementation may theoretically be of benefit [
• Previous studies have used doses of L-cysteine ranging from 85 to 300 mg/kg per day (with a goal of 300 mg/kg per day total) and doses of NAC ranging from 70 to 150 mg/kg per day [
• Infant formulas enriched with L-cysteine may also be considered to reach this supplementation goal. Given the recovery of liver function over time as physiologic compensatory mechanisms may take effect, supplementation should continue for at least the first year of life [
## Liver Transplantation
Orthotopic liver transplantation, reported in 11 children with TRMU deficiency, was indicated when the hepatopathy did not respond to medical interventions [
Liver transplantation did not influence overall survival. Two individuals died following transplantation (one from variceal bleeding and one from multiorgan failure) [
Liver transplantation may also be considered before a trial of targeted therapy in individuals with the
Note: The underlying
## Supportive Care
Supportive care by a multidisciplinary team including a hepatologist, neurologist, and medical geneticist is recommended (see
Supportive Treatment in Individuals with TRMU Deficiency
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
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.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
## Surveillance
Routine follow up is recommended to monitor response to L-cysteine and NAC supplementation, to evaluate response to supportive interventions, and to identify emergence of new findings or concerns regarding developmental/educational progress such as persistent neurodevelopmental delay or new onset of seizures that may develop over time (see
Recommended Surveillance for Individuals with TRMU Deficiency
Annual alpha-fetoprotein & abdominal ultrasounds beginning at age 1 yr
Screening is most important in children who have had advanced fibrosis or cirrhosis.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as type or frequency of seizures, changes in tone, & movement disorders.
• Annual alpha-fetoprotein & abdominal ultrasounds beginning at age 1 yr
• Screening is most important in children who have had advanced fibrosis or cirrhosis.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as type or frequency of seizures, changes in tone, & movement disorders.
## Agents/Circumstances to Avoid
Agents to avoid:
Those that increase metabolic demand, such as corticosteroids (see below), or inhibit mitochondrial activity, such as valproic acid and prolonged propofol infusion
Fasting, as it increases metabolic demand and may exacerbate hypoglycemia
Agents to be used with caution:
Corticosteroids may raise the lactate level because of increased glycogenolysis and gluconeogenesis. If they are indicated they should be given under guidance of a clinician / metabolic specialist who can aid in monitoring metabolic acidosis.
Because of limited liver oxidative metabolism in the acute period, administration of high concentrations of dextrose will increase lactic acid concentration, which may cause or worsen metabolic acidosis. Therefore, dextrose must be given with care to balance euglycemia with acid-base status.
• Those that increase metabolic demand, such as corticosteroids (see below), or inhibit mitochondrial activity, such as valproic acid and prolonged propofol infusion
• Fasting, as it increases metabolic demand and may exacerbate hypoglycemia
• Corticosteroids may raise the lactate level because of increased glycogenolysis and gluconeogenesis. If they are indicated they should be given under guidance of a clinician / metabolic specialist who can aid in monitoring metabolic acidosis.
• Because of limited liver oxidative metabolism in the acute period, administration of high concentrations of dextrose will increase lactic acid concentration, which may cause or worsen metabolic acidosis. Therefore, dextrose must be given with care to balance euglycemia with acid-base status.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In one instance of prenatally identified TRMU deficiency, the mother received 500 mg of L-cysteine twice daily during the third trimester of the pregnancy with the intent of providing sufficient cysteine to the fetus in the postnatal period when cysteine is an essential amino acid (see Management,
## Therapies Under Investigation
Search
## Genetic Counseling
TRMU 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 TRMU deficiency.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing TRMU deficiency.
Unless an affected individual's reproductive partner also has TRMU deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
Given the young age of the identified cohort, individuals with TRMU deficiency have not been reported to reproduce (long-term data on individuals with TRMU deficiency are limited).
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 should be considered. TRMU deficiency is particularly common in persons of Yemenite Jewish ancestry due to a 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 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 TRMU deficiency.
• 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 TRMU deficiency.
• Unless an affected individual's reproductive partner also has TRMU deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• Given the young age of the identified cohort, individuals with TRMU deficiency have not been reported to reproduce (long-term data on individuals with TRMU deficiency are limited).
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 should be considered. TRMU deficiency is particularly common in persons of Yemenite Jewish ancestry due to a founder variant (see
## Mode of Inheritance
TRMU 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 TRMU deficiency.
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing TRMU deficiency.
Unless an affected individual's reproductive partner also has TRMU deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
Given the young age of the identified cohort, individuals with TRMU deficiency have not been reported to reproduce (long-term data on individuals with TRMU deficiency are limited).
• 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 TRMU deficiency.
• 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 TRMU deficiency.
• Unless an affected individual's reproductive partner also has TRMU deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• Given the young age of the identified cohort, individuals with TRMU deficiency have not been reported to reproduce (long-term data on individuals with TRMU deficiency are limited).
## 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 should be considered. TRMU deficiency is particularly common in persons of Yemenite Jewish ancestry due to a 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.
• Carrier testing for the reproductive partners of known carriers should be considered. TRMU deficiency is particularly common in persons of Yemenite Jewish ancestry due to a 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
Canada
United Kingdom
•
•
•
• Canada
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
TRMU Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TRMU Deficiency (
Because cystathionase, the enzyme responsible for the endogenous cysteine supply, has a physiologic nadir in the first few months of life, cysteine is an essential amino acid during that period. In combination with low cysteine levels in the body in the first few months of life, the severe reduction of thiolated mt-tRNAs leads to the decompensation (primarily hepatic failure) observed in TRMU deficiency [
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
## Molecular Pathogenesis
Because cystathionase, the enzyme responsible for the endogenous cysteine supply, has a physiologic nadir in the first few months of life, cysteine is an essential amino acid during that period. In combination with low cysteine levels in the body in the first few months of life, the severe reduction of thiolated mt-tRNAs leads to the decompensation (primarily hepatic failure) observed in TRMU deficiency [
Notable
Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (
## Chapter Notes
The authors work in the
The authors would like to acknowledge the patients and families with TRMU deficiency and the many physicians who have referred their patients with TRMU deficiency.
11 May 2023 (bp) Review posted live
29 April 2022 (rg) Original submission
• 11 May 2023 (bp) Review posted live
• 29 April 2022 (rg) Original submission
## Author Notes
The authors work in the
## Acknowledgments
The authors would like to acknowledge the patients and families with TRMU deficiency and the many physicians who have referred their patients with TRMU deficiency.
## Revision History
11 May 2023 (bp) Review posted live
29 April 2022 (rg) Original submission
• 11 May 2023 (bp) Review posted live
• 29 April 2022 (rg) Original submission
## Key Sections in this
## References
## Literature Cited
|
[] |
11/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
trpm3-ndd
|
trpm3-ndd
|
[
"Transient receptor potential cation channel subfamily M member 3",
"TRPM3",
"TRPM3-Related Neurodevelopmental Disorder"
] |
David Dyment, Matthew Lines, A Micheil Innes
|
Summary The diagnosis of
|
## Diagnosis
Congenital hypotonia
Developmental delay (DD)
Intellectual disability (ID) of varying degrees of severity (mild to severe)
Seizures (febrile, absence, generalized tonic-clonic, infantile spasms, atonic drops)
Ophthalmologic findings (strabismus, nystagmus, refractive errors)
Musculoskeletal features (talipes equinovarus, hip dysplasia and/or subluxation, scoliosis)
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 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.
All pathogenic variants reported to date are gain-of-function
• Congenital hypotonia
• Developmental delay (DD)
• Intellectual disability (ID) of varying degrees of severity (mild to severe)
• Seizures (febrile, absence, generalized tonic-clonic, infantile spasms, atonic drops)
• Ophthalmologic findings (strabismus, nystagmus, refractive errors)
• Musculoskeletal features (talipes equinovarus, hip dysplasia and/or subluxation, scoliosis)
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Congenital hypotonia
Developmental delay (DD)
Intellectual disability (ID) of varying degrees of severity (mild to severe)
Seizures (febrile, absence, generalized tonic-clonic, infantile spasms, atonic drops)
Ophthalmologic findings (strabismus, nystagmus, refractive errors)
Musculoskeletal features (talipes equinovarus, hip dysplasia and/or subluxation, scoliosis)
• Congenital hypotonia
• Developmental delay (DD)
• Intellectual disability (ID) of varying degrees of severity (mild to severe)
• Seizures (febrile, absence, generalized tonic-clonic, infantile spasms, atonic drops)
• Ophthalmologic findings (strabismus, nystagmus, refractive errors)
• Musculoskeletal features (talipes equinovarus, hip dysplasia and/or subluxation, scoliosis)
## 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 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.
All pathogenic variants reported to date are gain-of-function
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Select Features of
Infant feeding difficulties have been reported (four individuals) that included dysphagia and gastroesophageal reflux.
A significant proportion of individuals assessed at age two years and older had not attained independent steps (11/26; this includes two adults older than age 18 years). For those that are able to walk independently, the average age of first steps is three years (range: age 1-5 years).
Speech is often severely affected and approximately half of affected individuals do not have single words (13/24). For those using at least single words, first words were used at an average age of three years (range: age 1-5 years). Some individuals can use signs or aids to help with communication, and a minority of individuals can speak in short sentences.
ID is also common. When the extent of disability was assessed and reported, the majority had ID in the severe or moderate-to-severe range. Moderate and mild ID was reported in 4/22 and 1/22 individuals, respectively. Two individuals were reported to have cognitive ability in the "low-normal" range.
No genotype-phenotype correlations have been identified.
Penetrance is complete though clinical expression is variable.
There is no known prevalence estimate to date; 28 individuals with
## Clinical Description
Select Features of
Infant feeding difficulties have been reported (four individuals) that included dysphagia and gastroesophageal reflux.
A significant proportion of individuals assessed at age two years and older had not attained independent steps (11/26; this includes two adults older than age 18 years). For those that are able to walk independently, the average age of first steps is three years (range: age 1-5 years).
Speech is often severely affected and approximately half of affected individuals do not have single words (13/24). For those using at least single words, first words were used at an average age of three years (range: age 1-5 years). Some individuals can use signs or aids to help with communication, and a minority of individuals can speak in short sentences.
ID is also common. When the extent of disability was assessed and reported, the majority had ID in the severe or moderate-to-severe range. Moderate and mild ID was reported in 4/22 and 1/22 individuals, respectively. Two individuals were reported to have cognitive ability in the "low-normal" range.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance is complete though clinical expression is variable.
## Prevalence
There is no known prevalence estimate to date; 28 individuals with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Pathogenic variant c.195A>G (p.Ile65Met) in
## Differential Diagnosis
Because the phenotypic features associated with
## Management
No clinical practice guidelines for
To establish the extent of disease and the needs of an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider EEG if seizures are a concern.
Consider MRI if ataxia or other movement disorder is present.
Gross motor & fine motor skills
Talipes equinovarus, hip dysplasia, & 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.
ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Treatment of Manifestations in Individuals with
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: 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; OT = occupational therapy; PT = physical therapy
A well-known anti-seizure medication, primidone, has been tried in several affected individuals [D Dyment, personal communication]. The use of primidone has not been associated with any formal scientific study and no outcomes in individuals with
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.
Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, 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 in
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, ataxia, &/or movement disorders.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
See
Search
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider EEG if seizures are a concern.
• Consider MRI if ataxia or other movement disorder is present.
• Gross motor & fine motor skills
• Talipes equinovarus, hip dysplasia, & 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.
• Education of parents/caregivers
• 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, ataxia, &/or movement disorders.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluations Following Initial Diagnosis
To establish the extent of disease and the needs of an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider EEG if seizures are a concern.
Consider MRI if ataxia or other movement disorder is present.
Gross motor & fine motor skills
Talipes equinovarus, hip dysplasia, & 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.
ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider EEG if seizures are a concern.
• Consider MRI if ataxia or other movement disorder is present.
• Gross motor & fine motor skills
• Talipes equinovarus, hip dysplasia, & 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
There is no cure for
Treatment of Manifestations in Individuals with
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: 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; OT = occupational therapy; PT = physical therapy
A well-known anti-seizure medication, primidone, has been tried in several affected individuals [D Dyment, personal communication]. The use of primidone has not been associated with any formal scientific study and no outcomes in individuals with
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.
Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, 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
• 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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 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.
Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Occupational therapy, physical therapy, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, 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 in
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, ataxia, &/or movement disorders.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, ataxia, &/or movement disorders.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals reported to date with
Vertical transmission 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. To date, this has not been reported.
* A parent with somatic and germline mosaicism for a
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 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 reported to date with
• Vertical transmission 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. To date, this has not been reported.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only. To date, this has not been reported.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only. To date, this has not been reported.
• * A parent with somatic and germline mosaicism for a
• 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
## Risk to Family Members
Most individuals reported to date with
Vertical transmission 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. To date, this has not been reported.
* A parent with somatic and germline mosaicism for a
If a parent of the proband is known to have the
If the
• Most individuals reported to date with
• Vertical transmission 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. To date, this has not been reported.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only. To date, this has not been reported.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only. To date, this has not been reported.
• * A parent with somatic and germline mosaicism for a
• 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 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
TRPM3-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TRPM3-Related Neurodevelopmental Disorder (
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 David Dyment's research interests are the identification of the molecular causes of rare syndromic and neurogenetic diseases.
Dr Matthew Lines's research focus is on the clinical description and gene identification of rare metabolic diseases.
Dr A Micheil Innes's research is focused on both the clinical delineation and the identification of the molecular basis of rare genetic conditions.
Drs Dyment and Innes are investigators with Care for Rare – SOLVE, a pan Canadian collaboration to investigate the causes of rare genetic diseases and improve the clinical care for patients and families affected by them.
Dr David Dyment would like to acknowledge the helpful discussion, expertise, and advice from Drs Joris Vriens and Thomas Voets of the University of Leuven, Leuven, Belgium.
There is an active Facebook family support group for families of children with
23 February 2023 (sw) Review posted live
2 November 2022 (dd) Original submission
• 23 February 2023 (sw) Review posted live
• 2 November 2022 (dd) Original submission
## Author Notes
Dr David Dyment's research interests are the identification of the molecular causes of rare syndromic and neurogenetic diseases.
Dr Matthew Lines's research focus is on the clinical description and gene identification of rare metabolic diseases.
Dr A Micheil Innes's research is focused on both the clinical delineation and the identification of the molecular basis of rare genetic conditions.
Drs Dyment and Innes are investigators with Care for Rare – SOLVE, a pan Canadian collaboration to investigate the causes of rare genetic diseases and improve the clinical care for patients and families affected by them.
## Acknowledgments
Dr David Dyment would like to acknowledge the helpful discussion, expertise, and advice from Drs Joris Vriens and Thomas Voets of the University of Leuven, Leuven, Belgium.
There is an active Facebook family support group for families of children with
## Revision History
23 February 2023 (sw) Review posted live
2 November 2022 (dd) Original submission
• 23 February 2023 (sw) Review posted live
• 2 November 2022 (dd) Original submission
## References
## Literature Cited
|
[] |
23/2/2023
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GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
tubb4a-leuk
|
tubb4a-leuk
|
[
"TUBB4A-Related Hypomyelinating Leukodystrophy",
"TUBB4A-Related Isolated Hypomyelination",
"Hypomyelination with Atrophy of Basal Ganglia and Cerebellum (H-ABC)",
"Tubulin beta-4A chain",
"TUBB4A",
"TUBB4A-Related Leukodystrophy"
] |
Norah Nahhas, Alex Conant, Eline Hamilton, Julian Curiel, Cas Simons, Marjo van der Knaap, Adeline Vanderver
|
Summary The diagnosis is established in a proband with characteristic clinical and MRI findings and a heterozygous
|
Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC)
Isolated hypomyelination
For other genetic causes of these phenotypes see
• Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC)
• Isolated hypomyelination
## Diagnosis
Onset during infancy or childhood
Motor developmental delay
Presence of pyramidal and extrapyramidal signs
Gait ataxia and cerebellar dysfunction
Dysarthria, aphonia, or "whispering" dysphonia
Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
Diffuse cerebral hypomyelination manifest as mild T
Cerebellar findings of white matter T
The diagnosis of a
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
When the phenotypic findings, such as hypomyelination with basal ganglia atrophy, suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders with leukodystrophy or with atypical white matter changes on 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 during infancy or childhood
• Motor developmental delay
• Presence of pyramidal and extrapyramidal signs
• Gait ataxia and cerebellar dysfunction
• Dysarthria, aphonia, or "whispering" dysphonia
• Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
• Diffuse cerebral hypomyelination manifest as mild T
• Cerebellar findings of white matter T
• Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
• Diffuse cerebral hypomyelination manifest as mild T
• Cerebellar findings of white matter T
• Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
• Diffuse cerebral hypomyelination manifest as mild T
• Cerebellar findings of white matter T
• For an introduction to multigene panels click
## Suggestive Findings
Onset during infancy or childhood
Motor developmental delay
Presence of pyramidal and extrapyramidal signs
Gait ataxia and cerebellar dysfunction
Dysarthria, aphonia, or "whispering" dysphonia
Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
Diffuse cerebral hypomyelination manifest as mild T
Cerebellar findings of white matter T
• Onset during infancy or childhood
• Motor developmental delay
• Presence of pyramidal and extrapyramidal signs
• Gait ataxia and cerebellar dysfunction
• Dysarthria, aphonia, or "whispering" dysphonia
• Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
• Diffuse cerebral hypomyelination manifest as mild T
• Cerebellar findings of white matter T
• Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
• Diffuse cerebral hypomyelination manifest as mild T
• Cerebellar findings of white matter T
• Progressive atrophy of the basal ganglia involving the neostriatum (i.e., the putamen and caudate nucleus) predominantly, often with a significant decrease in size of the putamen (which can disappear over time) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared. Note that although changes in the putamen are evident in many children with the H-ABC phenotype by age two years, in some children the changes may not be evident until later childhood.
• Diffuse cerebral hypomyelination manifest as mild T
• Cerebellar findings of white matter T
## Establishing the Diagnosis
The diagnosis of a
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
When the phenotypic findings, such as hypomyelination with basal ganglia atrophy, suggest the diagnosis of
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders with leukodystrophy or with atypical white matter changes on 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.
• For an introduction to multigene panels click
## Option 1. Gene-Targeted Testing
When the phenotypic findings, such as hypomyelination with basal ganglia atrophy, suggest the diagnosis of
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2. Genomic Testing
When the phenotype is indistinguishable from many other inherited disorders with leukodystrophy or with atypical white matter changes on 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
The disorder is progressive; rate of progression varies with disease severity. Males and females are similarly affected.
Manifestations can include the following.
Of note, some individuals with a heterozygous
Microcephaly
Short stature
Seizures
Poor vision
Hearing loss
Scoliosis and joint dislocation resulting from a combination of motor dysfunction and improper positioning
Hypogonadotropic hypogonadism (in 1 individual) [
Electroencephalogram is usually normal or demonstrates slow background activity.
Electromyogram and nerve conduction studies are normal.
Brain stem evoked potentials are usually delayed.
Visual evoked potentials are usually normal.
Somatosensory evoked potentials in some instances show delayed conduction [
Four
The penetrance is not known but appears to be 100%.
Of note, a few parents of individuals with
The exact prevalence is unknown; 71 affected individuals have been reported to date.
• Microcephaly
• Short stature
• Seizures
• Poor vision
• Hearing loss
• Scoliosis and joint dislocation resulting from a combination of motor dysfunction and improper positioning
• Hypogonadotropic hypogonadism (in 1 individual) [
• Electroencephalogram is usually normal or demonstrates slow background activity.
• Electromyogram and nerve conduction studies are normal.
• Brain stem evoked potentials are usually delayed.
• Visual evoked potentials are usually normal.
• Somatosensory evoked potentials in some instances show delayed conduction [
## Clinical Description
The disorder is progressive; rate of progression varies with disease severity. Males and females are similarly affected.
Manifestations can include the following.
Of note, some individuals with a heterozygous
Microcephaly
Short stature
Seizures
Poor vision
Hearing loss
Scoliosis and joint dislocation resulting from a combination of motor dysfunction and improper positioning
Hypogonadotropic hypogonadism (in 1 individual) [
Electroencephalogram is usually normal or demonstrates slow background activity.
Electromyogram and nerve conduction studies are normal.
Brain stem evoked potentials are usually delayed.
Visual evoked potentials are usually normal.
Somatosensory evoked potentials in some instances show delayed conduction [
• Microcephaly
• Short stature
• Seizures
• Poor vision
• Hearing loss
• Scoliosis and joint dislocation resulting from a combination of motor dysfunction and improper positioning
• Hypogonadotropic hypogonadism (in 1 individual) [
• Electroencephalogram is usually normal or demonstrates slow background activity.
• Electromyogram and nerve conduction studies are normal.
• Brain stem evoked potentials are usually delayed.
• Visual evoked potentials are usually normal.
• Somatosensory evoked potentials in some instances show delayed conduction [
## Genotype-Phenotype Correlations
Four
## Penetrance
The penetrance is not known but appears to be 100%.
Of note, a few parents of individuals with
## Prevalence
The exact prevalence is unknown; 71 affected individuals have been reported to date.
## Genetically Related (Allelic) Disorders
In addition to the leukodystrophies caused by a heterozygous
While Erro et al have hypothesized that the two
## Differential Diagnosis
Hypomyelinating leukodystrophies with early childhood onset and/or extrapyramidal signs should be considered in the differential diagnosis.
Involvement of the peripheral nervous system (sensory loss)
Waardenburg syndrome (skin and hair pigmentation changes, heterochromia iridis, and hearing loss) and Hirschsprung disease [
• Involvement of the peripheral nervous system (sensory loss)
• Waardenburg syndrome (skin and hair pigmentation changes, heterochromia iridis, and hearing loss) and Hirschsprung disease [
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Evaluation by a pediatric neurologist for evidence of developmental delay, spasticity, and extrapyramidal movement disorders
Assessment of developmental milestones and cognitive function
Assessment of functional disability and equipment needs by a physiotherapist
Assessment of speech (communication) and feeding (swallowing)
Audiologic assessment
Orthopedic evaluation for evidence of scoliosis and/or joint deformity, particularly in individuals with significant dystonia
Consultation with a clinical geneticist and/or genetic counselor
Although there is no curative treatment for
Spasticity that is functionally disabling can lead to joint contractures and scoliosis; both require physical therapy (stretching and positioning) and medical management. Oral GABA agonists such as baclofen and diazepam can be used. In some instances intrathecal baclofen pumps can be considered. For focal spasticity, intramuscular botulinum toxin may be helpful.
Dystonia can be managed with:
Baclofen or intramuscular botulinum toxin when associated with spasticity;
Trihexyphenidyl or tetrabenazine;
High doses of levodopa and carbidopa [
When dystonia is refractory to medical management, a baclofen pump may be considered. Of note, to date deep brain stimulation has not been studied in
Swallowing dysfunction may result in use of a gastrostomy tube for feeding to reduce the risk of aspiration.
Dysarthria may warrant augmentative communication tools.
Anticonvulsant medications should be used when seizures are present.
Constipation, commonly due to neurologic dysfunction and poor intestinal motility, can be treated with diet, laxatives, and stool softeners.
Gastroesophageal reflux disease is common and should be considered in the evaluation of pain.
Functional ability can be improved by use of walkers or wheeled mobility devices and other necessary equipment.
Accommodations in school such as an individual educational plan are often needed. With such accommodations many children with the classic H-ABC phenotype perform at or near grade level for many years, although cognitive decline may be seen later.
Family support and advocacy groups can provide needed psychosocial support for affected individuals.
The following recommendations – based on consensus – have been developed for all leukodystrophies [
Calcium and vitamin D supplementation as required to prevent osteoporosis
Skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility
Annual flu vaccination
Fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy (to increase strength) to help prevent secondary injury
The following are appropriate:
Routine evaluations of swallowing and feeding to reduce the risk of aspiration, and nutrition to prevent malnutrition
At least yearly:
Medical evaluation including physical examination to assess weight and medications
Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
Evaluation by orthopedists to assess for scoliosis and joint dislocation
Annual neurologic evaluation to assess symptoms and any emerging complications
See
Search
• Evaluation by a pediatric neurologist for evidence of developmental delay, spasticity, and extrapyramidal movement disorders
• Assessment of developmental milestones and cognitive function
• Assessment of functional disability and equipment needs by a physiotherapist
• Assessment of speech (communication) and feeding (swallowing)
• Audiologic assessment
• Orthopedic evaluation for evidence of scoliosis and/or joint deformity, particularly in individuals with significant dystonia
• Consultation with a clinical geneticist and/or genetic counselor
• Spasticity that is functionally disabling can lead to joint contractures and scoliosis; both require physical therapy (stretching and positioning) and medical management. Oral GABA agonists such as baclofen and diazepam can be used. In some instances intrathecal baclofen pumps can be considered. For focal spasticity, intramuscular botulinum toxin may be helpful.
• Dystonia can be managed with:
• Baclofen or intramuscular botulinum toxin when associated with spasticity;
• Trihexyphenidyl or tetrabenazine;
• High doses of levodopa and carbidopa [
• Baclofen or intramuscular botulinum toxin when associated with spasticity;
• Trihexyphenidyl or tetrabenazine;
• High doses of levodopa and carbidopa [
• When dystonia is refractory to medical management, a baclofen pump may be considered. Of note, to date deep brain stimulation has not been studied in
• Swallowing dysfunction may result in use of a gastrostomy tube for feeding to reduce the risk of aspiration.
• Dysarthria may warrant augmentative communication tools.
• Anticonvulsant medications should be used when seizures are present.
• Constipation, commonly due to neurologic dysfunction and poor intestinal motility, can be treated with diet, laxatives, and stool softeners.
• Gastroesophageal reflux disease is common and should be considered in the evaluation of pain.
• Functional ability can be improved by use of walkers or wheeled mobility devices and other necessary equipment.
• Accommodations in school such as an individual educational plan are often needed. With such accommodations many children with the classic H-ABC phenotype perform at or near grade level for many years, although cognitive decline may be seen later.
• Family support and advocacy groups can provide needed psychosocial support for affected individuals.
• Baclofen or intramuscular botulinum toxin when associated with spasticity;
• Trihexyphenidyl or tetrabenazine;
• High doses of levodopa and carbidopa [
• Calcium and vitamin D supplementation as required to prevent osteoporosis
• Skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility
• Annual flu vaccination
• Fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy (to increase strength) to help prevent secondary injury
• Routine evaluations of swallowing and feeding to reduce the risk of aspiration, and nutrition to prevent malnutrition
• At least yearly:
• Medical evaluation including physical examination to assess weight and medications
• Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
• Evaluation by orthopedists to assess for scoliosis and joint dislocation
• Medical evaluation including physical examination to assess weight and medications
• Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
• Evaluation by orthopedists to assess for scoliosis and joint dislocation
• Annual neurologic evaluation to assess symptoms and any emerging complications
• Medical evaluation including physical examination to assess weight and medications
• Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
• Evaluation by orthopedists to assess for scoliosis and joint dislocation
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Evaluation by a pediatric neurologist for evidence of developmental delay, spasticity, and extrapyramidal movement disorders
Assessment of developmental milestones and cognitive function
Assessment of functional disability and equipment needs by a physiotherapist
Assessment of speech (communication) and feeding (swallowing)
Audiologic assessment
Orthopedic evaluation for evidence of scoliosis and/or joint deformity, particularly in individuals with significant dystonia
Consultation with a clinical geneticist and/or genetic counselor
• Evaluation by a pediatric neurologist for evidence of developmental delay, spasticity, and extrapyramidal movement disorders
• Assessment of developmental milestones and cognitive function
• Assessment of functional disability and equipment needs by a physiotherapist
• Assessment of speech (communication) and feeding (swallowing)
• Audiologic assessment
• Orthopedic evaluation for evidence of scoliosis and/or joint deformity, particularly in individuals with significant dystonia
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Although there is no curative treatment for
Spasticity that is functionally disabling can lead to joint contractures and scoliosis; both require physical therapy (stretching and positioning) and medical management. Oral GABA agonists such as baclofen and diazepam can be used. In some instances intrathecal baclofen pumps can be considered. For focal spasticity, intramuscular botulinum toxin may be helpful.
Dystonia can be managed with:
Baclofen or intramuscular botulinum toxin when associated with spasticity;
Trihexyphenidyl or tetrabenazine;
High doses of levodopa and carbidopa [
When dystonia is refractory to medical management, a baclofen pump may be considered. Of note, to date deep brain stimulation has not been studied in
Swallowing dysfunction may result in use of a gastrostomy tube for feeding to reduce the risk of aspiration.
Dysarthria may warrant augmentative communication tools.
Anticonvulsant medications should be used when seizures are present.
Constipation, commonly due to neurologic dysfunction and poor intestinal motility, can be treated with diet, laxatives, and stool softeners.
Gastroesophageal reflux disease is common and should be considered in the evaluation of pain.
Functional ability can be improved by use of walkers or wheeled mobility devices and other necessary equipment.
Accommodations in school such as an individual educational plan are often needed. With such accommodations many children with the classic H-ABC phenotype perform at or near grade level for many years, although cognitive decline may be seen later.
Family support and advocacy groups can provide needed psychosocial support for affected individuals.
• Spasticity that is functionally disabling can lead to joint contractures and scoliosis; both require physical therapy (stretching and positioning) and medical management. Oral GABA agonists such as baclofen and diazepam can be used. In some instances intrathecal baclofen pumps can be considered. For focal spasticity, intramuscular botulinum toxin may be helpful.
• Dystonia can be managed with:
• Baclofen or intramuscular botulinum toxin when associated with spasticity;
• Trihexyphenidyl or tetrabenazine;
• High doses of levodopa and carbidopa [
• Baclofen or intramuscular botulinum toxin when associated with spasticity;
• Trihexyphenidyl or tetrabenazine;
• High doses of levodopa and carbidopa [
• When dystonia is refractory to medical management, a baclofen pump may be considered. Of note, to date deep brain stimulation has not been studied in
• Swallowing dysfunction may result in use of a gastrostomy tube for feeding to reduce the risk of aspiration.
• Dysarthria may warrant augmentative communication tools.
• Anticonvulsant medications should be used when seizures are present.
• Constipation, commonly due to neurologic dysfunction and poor intestinal motility, can be treated with diet, laxatives, and stool softeners.
• Gastroesophageal reflux disease is common and should be considered in the evaluation of pain.
• Functional ability can be improved by use of walkers or wheeled mobility devices and other necessary equipment.
• Accommodations in school such as an individual educational plan are often needed. With such accommodations many children with the classic H-ABC phenotype perform at or near grade level for many years, although cognitive decline may be seen later.
• Family support and advocacy groups can provide needed psychosocial support for affected individuals.
• Baclofen or intramuscular botulinum toxin when associated with spasticity;
• Trihexyphenidyl or tetrabenazine;
• High doses of levodopa and carbidopa [
## Prevention of Secondary Complications
The following recommendations – based on consensus – have been developed for all leukodystrophies [
Calcium and vitamin D supplementation as required to prevent osteoporosis
Skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility
Annual flu vaccination
Fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy (to increase strength) to help prevent secondary injury
• Calcium and vitamin D supplementation as required to prevent osteoporosis
• Skin care and frequent repositioning to help prevent pressure sores in individuals with decreased mobility
• Annual flu vaccination
• Fall prevention strategies, adaptive equipment (e.g., wheelchairs and walkers), and physical therapy (to increase strength) to help prevent secondary injury
## Surveillance
The following are appropriate:
Routine evaluations of swallowing and feeding to reduce the risk of aspiration, and nutrition to prevent malnutrition
At least yearly:
Medical evaluation including physical examination to assess weight and medications
Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
Evaluation by orthopedists to assess for scoliosis and joint dislocation
Annual neurologic evaluation to assess symptoms and any emerging complications
• Routine evaluations of swallowing and feeding to reduce the risk of aspiration, and nutrition to prevent malnutrition
• At least yearly:
• Medical evaluation including physical examination to assess weight and medications
• Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
• Evaluation by orthopedists to assess for scoliosis and joint dislocation
• Medical evaluation including physical examination to assess weight and medications
• Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
• Evaluation by orthopedists to assess for scoliosis and joint dislocation
• Annual neurologic evaluation to assess symptoms and any emerging complications
• Medical evaluation including physical examination to assess weight and medications
• Evaluations by specialists in occupational therapy, physical therapy, speech therapy, and rehabilitation medicine
• Evaluation by orthopedists to assess for scoliosis and joint dislocation
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most probands with
Recommendations for the evaluation of parents of a proband with an apparent
If the
If the parent is the individual in whom the
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
Because
Sib recurrence was reported in a family in which the asymptomatic mother was found to be mosaic 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 parents of affected individuals.
Once the
• Most probands with
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• If the parent is the individual in whom the
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• Because
• Sib recurrence was reported in a family in which the asymptomatic mother was found to be mosaic 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 parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Most probands with
Recommendations for the evaluation of parents of a proband with an apparent
If the
If the parent is the individual in whom the
The risk to the sibs of the proband depends on the genetic status of the proband's parents.
Because
Sib recurrence was reported in a family in which the asymptomatic mother was found to be mosaic for a
• Most probands with
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• If the parent is the individual in whom the
• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• Because
• Sib recurrence was reported in a family in which the asymptomatic mother was found to be mosaic for 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 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
## Resources
Australia
•
•
•
• Australia
•
•
•
•
•
## Molecular Genetics
TUBB4A-Related Leukodystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TUBB4A-Related Leukodystrophy (
Variant c.745G>A is the most common
Variant c.4C>G is not associated with a leukodystrophy but with DYT4 ("hereditary whispering dysphonia") [
Variants listed in the table have been provided by the authors.
See
To view information on additional variants, see
TUBB4A is predominantly expressed in the CNS, especially in the cerebellum and putamen and white matter [
## Chapter Notes
3 November 2016 (bp) Review posted live
2 January 2016 (av) Original submission
• 3 November 2016 (bp) Review posted live
• 2 January 2016 (av) Original submission
## Revision History
3 November 2016 (bp) Review posted live
2 January 2016 (av) Original submission
• 3 November 2016 (bp) Review posted live
• 2 January 2016 (av) Original submission
## References
## Literature Cited
MRI findings
A. Cerebellar white matter T
B. Progressive atrophy of the basal ganglia predominantly involving the neostriatum (i.e., the putamen and caudate nucleus), often with a significant decrease in size of the putamen (thin white arrow) and to a lesser degree the head of the caudate. The thalamus and globus pallidus are typically spared.
C. Diffuse cerebral hypomyelination manifesting as mild T
D. Diffuse cerebral hypomyelination typically manifesting as isointense or mild T
E. Cerebellar white matter T
|
[
"L Blumkin, A Halevy, D Ben-Ami-Raichman, D Dahari, A Haviv, C Sarit, D Lev, MS van der Knaap, T Lerman-Sagie, E Leshinsky-Silver. Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene.. Neurogenetics. 2014;15:107-13",
"N Bondurand, F Dastot-Le Moal, L Stanchina, N Collot, V Baral, S Marlin, T Attie-Bitach, I Giurgea, L Skopinski, W Reardon, A Toutain, P Sarda, A Echaieb, M Lackmy-Port-Lis, R Touraine, J Amiel, M Goossens, V. Pingault. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4.. Am J Hum Genet. 2007;81:1169-85",
"D Carvalho, S Santos, B Martins, FP Marques. TUBB4A novel mutation reinforces the genotype-phenotype correlation of hypomyelination with atrophy of the basal ganglia and cerebellum.. Brain. 2015;138",
"R Erro, J Hersheson, C Ganos, NE Mencacci, M Stamelou, A Batla, SC Thust, JM Bras, RJ Guerreiro, J Hardy, NP Quinn, H Houlden, KP Bhatia. H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?. Mov Disord. 2015a;30:828-33",
"R Erro, J Hersheson, H Houlden, KP Bhatia. A novel TUBB4A mutation suggests that genotype-phenotype correlation of H-ABC syndrome needs to be revisited.. Brain. 2015b;138",
"C Ferreira, A Poretti, J Cohen, A Hamosh, S. Naidu. Novel TUBB4A mutations and expansion of the neuroimaging phenotype of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC).. Am J Med Genet A. 2014;164A:1802-7",
"EM Hamilton, E Polder, A Vanderver, S Naidu, R Schiffmann, K Fisher, AB Raguž, L Blumkin. H-ABC Research Group, van Berkel CG, Waisfisz Q, Simons C, Taft RJ, Abbink TE, Wolf NI, van der Knaap MS. Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype-phenotype correlation.. Brain. 2014;137:1921-30",
"EM Hamilton, NI Wolf, MS van der Knaap. Reply: A novel TUBB4A mutation suggests that genotype-phenotype correlation of H-ABC syndrome needs to be revisited.. Brain. 2015;138",
"J Hersheson, NE Mencacci, M Davis, N MacDonald, D Trabzuni, M Ryten, A Pittman, R Paudel, E Kara, K Fawcett, V Plagnol, KP Bhatia, AJ Medlar, HC Stanescu, J Hardy, R Kleta, NW Wood, H Houlden. Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.. Ann Neurol. 2013;73:546-53",
"K Inoue, K Shilo, CF Boerkoel, C Crowe, J Sawady, JR Lupski, DP Agamanolis. Congenital hypomyelinating neuropathy, central dysmyelination, and Waardenburg-Hirschsprung disease: phenotypes linked by SOX10 mutation.. Ann Neurol. 2002;52:836-42",
"D Kancheva, T Chamova, V Guergueltcheva, V Mitev, DN Azmanov, L Kalaydjieva, I Tournev, A Jordanova. Mosaic dominant TUBB4A mutation in an inbred family with complicated hereditary spastic paraplegia.. Mov Disord. 2015;30:854-8",
"KR Kumar, F Vulinovic, K Lohmann, JS Park, S Schaake, CM Sue, C Klein. Mutations in TUBB4A and spastic paraplegia.. Mov Disord. 2015;30:1857-8",
"MG Lee, C Loomis, NJ Cowan. Sequence of an expressed human beta-tubulin gene containing ten Alu family members.. Nucleic Acids Res. 1984;12:5823-36",
"S Mercimek-Mahmutoglu, S Stockler-Ipsiroglu. Cerebral folate deficiency and folinic acid treatment in hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome.. Tohoku J Exp Med. 2007;211:95-6",
"S Mercimek-Mahmutoglu, MS van der Knaap, I Baric, D Prayer, S Stoeckler-Ipsiroglu. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). Report of a new case.. Neuropediatrics. 2005;36:223-6",
"S Miyatake, H Osaka, M Shiina, M Sasaki, J Takanashi, K Haginoya, T Wada, M Morimoto, N Ando, Y Ikuta, M Nakashima, Y Tsurusaki, N Miyake, K Ogata, N Matsumoto, H. Saitsu. Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies.. Neurology. 2014;82:2230-7",
"E. Nogales. Structural insight into microtubule function.. Annu Rev Biophys Biomol Struct. 2001;30:397-420",
"A Pizzino, TM Pierson, Y Guo, G Helman, S Fortini, K Guerrero, S Saitta, JL Murphy, Q Padiath, Y Xie, H Hakonarson, X Xu, T Funari, M Fox, RJ Taft, MS van der Knaap, G Bernard, R Schiffmann, C Simons, A Vanderver. TUBB4A de novo mutations cause isolated hypomyelination.. Neurology. 2014;83:898-902",
"SM Purnell, SB Bleyl, JL Bonkowsky. Clinical exome sequencing identifies a novel TUBB4A mutation in a child with static hypomyelinating leukodystrophy.. Pediatr Neurol. 2014;50:608-11",
"A Sagnelli, S Magri, L Farina, L Chiapparini, G Marotta, D Tonduti, M Consonni, GM Scigliuolo, R Benti, D Pareyson, F Taroni, E Salsano, D Di Bella. Early-onset progressive spastic paraplegia caused by a novel TUBB4A mutation: brain MRI and FDG-PET findings.. J Neurol. 2016;263:591-3",
"M Sasaki, J Takanashi, H Tada, H Sakuma, W Furushima, N Sato. Diffuse cerebral hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum.. Brain Dev. 2009;31:582-7",
"C Savage, Y Xue, S Mitani, D Hall, R Zakhary, M. Chalfie. Mutations in the Caenorhabditis elegans beta-tubulin gene mec-7: effects on microtubule assembly and stability and on tubulin autoregulation.. J Cell Sci. 1994;107:2165-75",
"K Shimojima, A Okumura, M Ikeno, A Nishimura, A Saito, H Saitsu, N Matsumoto, T. Yamamoto. A de novo TUBB4A mutation in a patient with hypomyelination mimicking Pelizaeus-Merzbacher disease.. Brain Dev. 2015;37:281-5",
"C Simons, NI Wolf, N McNeil, L Caldovic, JM Devaney, A Takanohashi, J Crawford, K Ru, SM Grimmond, D Miller, D Tonduti, JL Schmidt, RS Chudnow, R van Coster, L Lagae, J Kisler, J Sperner, MS van der Knaap, R Schiffmann, RJ Taft, A Vanderver. A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum.. Am J Hum Genet. 2013;92:767-73",
"M Tomás-Vila, F Menor, M Ley-Martos, MJ Jumillas-Luján, AV Marco-Hernández, P Barbero. Hypomyelination with atrophy of the basal ganglia and cerebellum. Contribution of two new cases to a recently reported entity. Rev Neurol. 2014;58:161-5",
"D Tonduti, C Aiello, F Renaldo, I Dorboz, S Saaman, D Rodriguez, H Fettah, M Elmaleh, R Biancheri, S Barresi, L Boccone, S Orcesi, A Pichiecchio, R Zangaglia, H Maurey, A Rossi, O Boespflug-Tanguy, E. Bertini. TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients.. Eur J Paediatr Neurol. 2016;20:323-30",
"B Uhlenberg, M Schuelke, F Rüschendorf, N Ruf, AM Kaindl, M Henneke, H Thiele, G Stoltenburg-Didinger, F Aksu, H Topaloğlu, P Nürnberg, C Hübner, B Weschke, J Gärtner. Mutations in the gene encoding gap junction protein alpha 12 (connexin 46.6) cause Pelizaeus-Merzbacher-like disease.. Am J Hum Genet. 2004;75:251-60",
"MS van der Knaap, S Naidu, PJ Pouwels, S Bonavita, R van Coster, L Lagae, J Sperner, R Surtees, R Schiffmann, J Valk. New syndrome characterized by hypomyelination with atrophy of the basal ganglia and cerebellum.. AJNR Am J Neuroradiol. 2002;23:1466-74",
"K Van Haren, JL Bonkowsky, G Bernard, JL Murphy, A Pizzino, G Helman, D Suhr, J Waggoner, D Hobson, A Vanderver, MC Patterson. GLIA Consortium. Consensus statement on preventive and symptomatic care of leukodystrophy patients.. Mol Genet Metab. 2015;114:516-26",
"K Wakusawa, K Haginoya, T Kitamura, N Togashi, M Ishitobi, H Yokoyama, S Higano, A Onuma, T Nara, K Iinuma. Effective treatment with levodopa and carbidopa for hypomyelination with atrophy of the basal ganglia and cerebellum.. Tohoku J Exp Med. 2006;209:163-7"
] |
3/11/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
tuberous-sclerosis
|
tuberous-sclerosis
|
[
"Bourneville Disease",
"Bourneville Disease",
"Hamartin",
"Tuberin",
"TSC1",
"TSC2",
"Tuberous Sclerosis Complex"
] |
Tuberous Sclerosis Complex
|
Hope Northrup, Mary Kay Koenig, Deborah A Pearson, Kit Sing Au
|
Summary Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, confetti skin lesions, facial angiofibromas, shagreen patches, fibrous cephalic plaques, ungual fibromas); brain (subependymal nodules, cortical tubers, and subependymal giant cell astrocytomas [SEGAs], seizures, TSC-associated neuropsychiatric disorder [TAND]); kidneys (benign renal angiomyolipomas, epithelial cysts, oncocytoma, renal cell carcinoma); heart (rhabdomyomas, arrhythmias); and lungs (lymphangioleiomyomatosis [LAM], multifocal micronodular pneumonocyte hyperplasia). Central nervous system-related problems (including TAND) are the leading cause of morbidity, whereas kidney disease is the leading cause of mortality. The clinical diagnosis of TSC can be established in a proband based on clinical diagnostic criteria (presence of two major clinical features or one major clinical feature and two or more minor features). The molecular diagnosis can be established in a proband with a heterozygous pathogenic variant in TSC is inherited in an autosomal dominant manner. About one third of individuals diagnosed with TSC have an affected parent; two thirds of individuals with TSC have the disorder as the result of a
|
## Diagnosis
Consensus clinical diagnostic criteria for tuberous sclerosis complex (TSC) have been published [
TSC
Hypomelanotic macules (≥3 macules that are at least 5 mm in diameter)
Angiofibromas (≥3) or fibrous cephalic plaque
Shagreen patch
Ungual fibromas (≥2)
Subependymal nodules (SENs) (≥2)
Multiple cortical tubers and/or radial migration lines
Subependymal giant cell astrocytoma (SEGA)
Renal angiomyolipomas (≥2) (See
Cardiac rhabdomyoma
Lymphangioleiomyomatosis (LAM) (See
Multiple retinal nodular hamartomas
"Confetti" skin lesions (numerous 1- to 3-mm hypopigmented macules scattered across regions of the body such as the arms and legs)
Sclerotic bone lesions
Dental enamel pits (>3)
Intraoral fibromas (≥2)
Multiple renal cysts (≥2)
Extrarenal hamartomas
Retinal achromic patch
The clinical diagnosis of TSC
A
* Note: The combination of LAM and renal angiomyolipomas without additional features does not meet the clinical diagnostic criteria for a definite diagnosis.
The molecular diagnosis of TSC
Note: (1) Clinical manifestations of TSC develop over time; therefore, identification of a
Molecular genetic testing approaches can include
Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Tuberous Sclerosis Complex
TSC = tuberous sclerosis complex
Genes are listed in alphabetic order.
See
See
Simplex case = single occurrence in a family
Of the more than 10,000 individuals with TSC in whom pathogenic variants have been identified, ~26% of probands had a pathogenic variant in
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.
Inferring from the 5% detection rate for somatic mosaicism [
• Hypomelanotic macules (≥3 macules that are at least 5 mm in diameter)
• Angiofibromas (≥3) or fibrous cephalic plaque
• Shagreen patch
• Ungual fibromas (≥2)
• Subependymal nodules (SENs) (≥2)
• Multiple cortical tubers and/or radial migration lines
• Subependymal giant cell astrocytoma (SEGA)
• Renal angiomyolipomas (≥2) (See
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis (LAM) (See
• Multiple retinal nodular hamartomas
• "Confetti" skin lesions (numerous 1- to 3-mm hypopigmented macules scattered across regions of the body such as the arms and legs)
• Sclerotic bone lesions
• Dental enamel pits (>3)
• Intraoral fibromas (≥2)
• Multiple renal cysts (≥2)
• Extrarenal hamartomas
• Retinal achromic patch
• Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [
• For an introduction to multigene panels click
## Suggestive Findings
TSC
Hypomelanotic macules (≥3 macules that are at least 5 mm in diameter)
Angiofibromas (≥3) or fibrous cephalic plaque
Shagreen patch
Ungual fibromas (≥2)
Subependymal nodules (SENs) (≥2)
Multiple cortical tubers and/or radial migration lines
Subependymal giant cell astrocytoma (SEGA)
Renal angiomyolipomas (≥2) (See
Cardiac rhabdomyoma
Lymphangioleiomyomatosis (LAM) (See
Multiple retinal nodular hamartomas
"Confetti" skin lesions (numerous 1- to 3-mm hypopigmented macules scattered across regions of the body such as the arms and legs)
Sclerotic bone lesions
Dental enamel pits (>3)
Intraoral fibromas (≥2)
Multiple renal cysts (≥2)
Extrarenal hamartomas
Retinal achromic patch
• Hypomelanotic macules (≥3 macules that are at least 5 mm in diameter)
• Angiofibromas (≥3) or fibrous cephalic plaque
• Shagreen patch
• Ungual fibromas (≥2)
• Subependymal nodules (SENs) (≥2)
• Multiple cortical tubers and/or radial migration lines
• Subependymal giant cell astrocytoma (SEGA)
• Renal angiomyolipomas (≥2) (See
• Cardiac rhabdomyoma
• Lymphangioleiomyomatosis (LAM) (See
• Multiple retinal nodular hamartomas
• "Confetti" skin lesions (numerous 1- to 3-mm hypopigmented macules scattered across regions of the body such as the arms and legs)
• Sclerotic bone lesions
• Dental enamel pits (>3)
• Intraoral fibromas (≥2)
• Multiple renal cysts (≥2)
• Extrarenal hamartomas
• Retinal achromic patch
## Establishing the Diagnosis
The clinical diagnosis of TSC
A
* Note: The combination of LAM and renal angiomyolipomas without additional features does not meet the clinical diagnostic criteria for a definite diagnosis.
The molecular diagnosis of TSC
Note: (1) Clinical manifestations of TSC develop over time; therefore, identification of a
Molecular genetic testing approaches can include
Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Tuberous Sclerosis Complex
TSC = tuberous sclerosis complex
Genes are listed in alphabetic order.
See
See
Simplex case = single occurrence in a family
Of the more than 10,000 individuals with TSC in whom pathogenic variants have been identified, ~26% of probands had a pathogenic variant in
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.
Inferring from the 5% detection rate for somatic mosaicism [
• Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [
• For an introduction to multigene panels click
## Clinical Diagnosis
A
* Note: The combination of LAM and renal angiomyolipomas without additional features does not meet the clinical diagnostic criteria for a definite diagnosis.
## Molecular Diagnosis
The molecular diagnosis of TSC
Note: (1) Clinical manifestations of TSC develop over time; therefore, identification of a
Molecular genetic testing approaches can include
Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Tuberous Sclerosis Complex
TSC = tuberous sclerosis complex
Genes are listed in alphabetic order.
See
See
Simplex case = single occurrence in a family
Of the more than 10,000 individuals with TSC in whom pathogenic variants have been identified, ~26% of probands had a pathogenic variant in
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.
Inferring from the 5% detection rate for somatic mosaicism [
• Note: If no pathogenic variant is identified, somatic mosaicism for a pathogenic variant should be considered [
• For an introduction to multigene panels click
## Clinical Characteristics
Tuberous sclerosis complex (TSC) involves abnormalities primarily of the skin, brain, kidneys, heart, and lungs (see
Tuberous Sclerosis Complex: Frequency of Select Features
CNS = central nervous system; TSC = tuberous sclerosis complex
The skin is affected in virtually 100% of individuals with TSC. Skin lesions include hypomelanotic macules (~90% of individuals), "confetti" skin lesions (frequency varies widely from 3% of children to ≤58% overall), facial angiofibromas (~75%), shagreen patches (~50%), fibrous cephalic plaques, and ungual fibromas (20% overall but ≤80% in older affected adults). Among the skin lesions, facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems [
The brain lesions of TSC, including subependymal nodules (SENs) and cortical tubers, occur in approximately 80% of affected individuals, and subependymal giant cell astrocytomas (SEGAs) develop in up to 25% of all individuals with TSC [
More than 80% of individuals with TSC have seizures, with most displaying features of focal or partial-onset seizures. Up to 75% of affected individuals develop seizures prior to age two years; caregivers should be educated to recognize seizures, especially when they are not present at the time of diagnosis. Two thirds of individuals with TSC experience drug-resistant epilepsy. Developmental delays, autism spectrum disorder, and psychiatric disorders demonstrate a strong association with early-onset and drug-resistant epilepsy.
Early recognition and control of seizures is highly correlated with improved developmental and neurologic outcomes in infants with TSC. Epileptiform activity on EEG can predict the eventual development of epilepsy; pre-emptive treatment with vigabatrin, before the onset of clinical seizures, may prevent infantile spasms and/or delay seizure onset. Pre-emptive treatment with vigabatrin has not, however, been shown to improve developmental or neurologic outcomes over that achieved by early recognition and control of clinical seizures alone.
TAND refers to the interrelated functional and clinical manifestations of brain dysfunction common in individuals with TSC, including behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties [
The risk of learning and cognitive impairment increases significantly if seizure activity is not controlled. A number of investigations have demonstrated that a history of infantile spasms and/or poor seizure control in general is associated with lower intellectual ability [
Given that neuropsychiatric concerns are more frequent in individuals with TSC and that many children and adults with TSC have multiple neuropsychiatric concerns [
Kidney disease is the leading cause of early death (50%) in individuals with TSC [
Five different kidney lesions occur in TSC: benign renal angiomyolipoma (AMLs; 70% of affected individuals); epithelial cysts (20%-30%) [
Cardiac rhabdomyomas are present in ~50% of individuals with TSC [
The mean age of diagnosis for LAM in those with TSC is 28 years. Individuals with TSC-associated LAM may present with shortness of breath or hemoptysis [
The retinal lesions of TSC include hamartomas (elevated mulberry lesions or plaque-like lesions), observed in 34% of individuals with TSC [
Extrarenal AMLs, including hepatic and pancreatic, have been reported. Hepatic AMLs are reported in 10%-15% of individuals with TSC and are most often observed in individuals who also have renal AMLs [
Functional and non-functional pancreatic NETs have been increasingly identified in individuals with TSC due to recommended abdominal MRI surveillance in individuals with TSC [
Sclerotic bone lesions are common in individuals with TSC. In one study, 51/70 (73%) children with TSC who underwent abdominal imaging had sclerotic bone lesions. These lesions were discovered much more frequently after surveillance imaging of the abdomen and lungs became standard of care in individuals with TSC. Sclerotic bone lesions in TSC are commonly observed in the posterior vertebral elements and increase in size and number over time [
Multiple dental findings are observed in individuals with TSC; the two most common are dental pitting and intraoral fibromas. Dental pitting (small depressions in the dental enamel) results in increased susceptibility to formation of dental caries. Intraoral fibromas are usually observed on the gingival surfaces. Intraoral fibromas typically occur after oral trauma or as a side effect of some anti-seizure medications [
Individuals with a
Increased number of renal AMLs (>4) (P=0.044) [
Significant developmental delays by age 24 months [
Cardiac rhabdomyomas (P=0.004) [
Facial angiofibromas (P=0.026) [
Females with pathogenic variants in the carboxy terminus of tuberin, the
Some pathogenic
Renal cystic disease may be more severe in individuals with small
The penetrance of TSC appears to be 100%. Rare instances of apparent non-penetrance have been reported; however, molecular studies revealed the presence of two different pathogenic variants in the family and gonadal mosaicism in others [
Terms used in the past to describe findings in TSC that are now outdated or inappropriate but have not yet been eliminated from the medical literature include the following:
The incidence of TSC may be as high as 1:5,800 live births [
• Increased number of renal AMLs (>4) (P=0.044) [
• Significant developmental delays by age 24 months [
• Cardiac rhabdomyomas (P=0.004) [
• Facial angiofibromas (P=0.026) [
• Females with pathogenic variants in the carboxy terminus of tuberin, the
• Some pathogenic
• Renal cystic disease may be more severe in individuals with small
## Clinical Description
Tuberous sclerosis complex (TSC) involves abnormalities primarily of the skin, brain, kidneys, heart, and lungs (see
Tuberous Sclerosis Complex: Frequency of Select Features
CNS = central nervous system; TSC = tuberous sclerosis complex
The skin is affected in virtually 100% of individuals with TSC. Skin lesions include hypomelanotic macules (~90% of individuals), "confetti" skin lesions (frequency varies widely from 3% of children to ≤58% overall), facial angiofibromas (~75%), shagreen patches (~50%), fibrous cephalic plaques, and ungual fibromas (20% overall but ≤80% in older affected adults). Among the skin lesions, facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems [
The brain lesions of TSC, including subependymal nodules (SENs) and cortical tubers, occur in approximately 80% of affected individuals, and subependymal giant cell astrocytomas (SEGAs) develop in up to 25% of all individuals with TSC [
More than 80% of individuals with TSC have seizures, with most displaying features of focal or partial-onset seizures. Up to 75% of affected individuals develop seizures prior to age two years; caregivers should be educated to recognize seizures, especially when they are not present at the time of diagnosis. Two thirds of individuals with TSC experience drug-resistant epilepsy. Developmental delays, autism spectrum disorder, and psychiatric disorders demonstrate a strong association with early-onset and drug-resistant epilepsy.
Early recognition and control of seizures is highly correlated with improved developmental and neurologic outcomes in infants with TSC. Epileptiform activity on EEG can predict the eventual development of epilepsy; pre-emptive treatment with vigabatrin, before the onset of clinical seizures, may prevent infantile spasms and/or delay seizure onset. Pre-emptive treatment with vigabatrin has not, however, been shown to improve developmental or neurologic outcomes over that achieved by early recognition and control of clinical seizures alone.
TAND refers to the interrelated functional and clinical manifestations of brain dysfunction common in individuals with TSC, including behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties [
The risk of learning and cognitive impairment increases significantly if seizure activity is not controlled. A number of investigations have demonstrated that a history of infantile spasms and/or poor seizure control in general is associated with lower intellectual ability [
Given that neuropsychiatric concerns are more frequent in individuals with TSC and that many children and adults with TSC have multiple neuropsychiatric concerns [
Kidney disease is the leading cause of early death (50%) in individuals with TSC [
Five different kidney lesions occur in TSC: benign renal angiomyolipoma (AMLs; 70% of affected individuals); epithelial cysts (20%-30%) [
Cardiac rhabdomyomas are present in ~50% of individuals with TSC [
The mean age of diagnosis for LAM in those with TSC is 28 years. Individuals with TSC-associated LAM may present with shortness of breath or hemoptysis [
The retinal lesions of TSC include hamartomas (elevated mulberry lesions or plaque-like lesions), observed in 34% of individuals with TSC [
Extrarenal AMLs, including hepatic and pancreatic, have been reported. Hepatic AMLs are reported in 10%-15% of individuals with TSC and are most often observed in individuals who also have renal AMLs [
Functional and non-functional pancreatic NETs have been increasingly identified in individuals with TSC due to recommended abdominal MRI surveillance in individuals with TSC [
Sclerotic bone lesions are common in individuals with TSC. In one study, 51/70 (73%) children with TSC who underwent abdominal imaging had sclerotic bone lesions. These lesions were discovered much more frequently after surveillance imaging of the abdomen and lungs became standard of care in individuals with TSC. Sclerotic bone lesions in TSC are commonly observed in the posterior vertebral elements and increase in size and number over time [
Multiple dental findings are observed in individuals with TSC; the two most common are dental pitting and intraoral fibromas. Dental pitting (small depressions in the dental enamel) results in increased susceptibility to formation of dental caries. Intraoral fibromas are usually observed on the gingival surfaces. Intraoral fibromas typically occur after oral trauma or as a side effect of some anti-seizure medications [
## Skin
The skin is affected in virtually 100% of individuals with TSC. Skin lesions include hypomelanotic macules (~90% of individuals), "confetti" skin lesions (frequency varies widely from 3% of children to ≤58% overall), facial angiofibromas (~75%), shagreen patches (~50%), fibrous cephalic plaques, and ungual fibromas (20% overall but ≤80% in older affected adults). Among the skin lesions, facial angiofibromas cause the most disfigurement. None of the skin lesions results in serious medical problems [
## Central Nervous System (CNS)
The brain lesions of TSC, including subependymal nodules (SENs) and cortical tubers, occur in approximately 80% of affected individuals, and subependymal giant cell astrocytomas (SEGAs) develop in up to 25% of all individuals with TSC [
## Seizures
More than 80% of individuals with TSC have seizures, with most displaying features of focal or partial-onset seizures. Up to 75% of affected individuals develop seizures prior to age two years; caregivers should be educated to recognize seizures, especially when they are not present at the time of diagnosis. Two thirds of individuals with TSC experience drug-resistant epilepsy. Developmental delays, autism spectrum disorder, and psychiatric disorders demonstrate a strong association with early-onset and drug-resistant epilepsy.
Early recognition and control of seizures is highly correlated with improved developmental and neurologic outcomes in infants with TSC. Epileptiform activity on EEG can predict the eventual development of epilepsy; pre-emptive treatment with vigabatrin, before the onset of clinical seizures, may prevent infantile spasms and/or delay seizure onset. Pre-emptive treatment with vigabatrin has not, however, been shown to improve developmental or neurologic outcomes over that achieved by early recognition and control of clinical seizures alone.
## TSC-Associated Neuropsychiatric Disorder (TAND)
TAND refers to the interrelated functional and clinical manifestations of brain dysfunction common in individuals with TSC, including behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties [
The risk of learning and cognitive impairment increases significantly if seizure activity is not controlled. A number of investigations have demonstrated that a history of infantile spasms and/or poor seizure control in general is associated with lower intellectual ability [
Given that neuropsychiatric concerns are more frequent in individuals with TSC and that many children and adults with TSC have multiple neuropsychiatric concerns [
## Kidneys
Kidney disease is the leading cause of early death (50%) in individuals with TSC [
Five different kidney lesions occur in TSC: benign renal angiomyolipoma (AMLs; 70% of affected individuals); epithelial cysts (20%-30%) [
## Heart
Cardiac rhabdomyomas are present in ~50% of individuals with TSC [
## Lung
The mean age of diagnosis for LAM in those with TSC is 28 years. Individuals with TSC-associated LAM may present with shortness of breath or hemoptysis [
## Eyes
The retinal lesions of TSC include hamartomas (elevated mulberry lesions or plaque-like lesions), observed in 34% of individuals with TSC [
## Extrarenal AMLs
Extrarenal AMLs, including hepatic and pancreatic, have been reported. Hepatic AMLs are reported in 10%-15% of individuals with TSC and are most often observed in individuals who also have renal AMLs [
## Neuroendocrine Tumors (NETs)
Functional and non-functional pancreatic NETs have been increasingly identified in individuals with TSC due to recommended abdominal MRI surveillance in individuals with TSC [
## Sclerotic Bone Lesions
Sclerotic bone lesions are common in individuals with TSC. In one study, 51/70 (73%) children with TSC who underwent abdominal imaging had sclerotic bone lesions. These lesions were discovered much more frequently after surveillance imaging of the abdomen and lungs became standard of care in individuals with TSC. Sclerotic bone lesions in TSC are commonly observed in the posterior vertebral elements and increase in size and number over time [
## Oral and Dental Manifestations
Multiple dental findings are observed in individuals with TSC; the two most common are dental pitting and intraoral fibromas. Dental pitting (small depressions in the dental enamel) results in increased susceptibility to formation of dental caries. Intraoral fibromas are usually observed on the gingival surfaces. Intraoral fibromas typically occur after oral trauma or as a side effect of some anti-seizure medications [
## Phenotype Correlations by Gene
Individuals with a
Increased number of renal AMLs (>4) (P=0.044) [
Significant developmental delays by age 24 months [
Cardiac rhabdomyomas (P=0.004) [
Facial angiofibromas (P=0.026) [
• Increased number of renal AMLs (>4) (P=0.044) [
• Significant developmental delays by age 24 months [
• Cardiac rhabdomyomas (P=0.004) [
• Facial angiofibromas (P=0.026) [
## Genotype-Phenotype Correlations
Females with pathogenic variants in the carboxy terminus of tuberin, the
Some pathogenic
Renal cystic disease may be more severe in individuals with small
• Females with pathogenic variants in the carboxy terminus of tuberin, the
• Some pathogenic
• Renal cystic disease may be more severe in individuals with small
## Penetrance
The penetrance of TSC appears to be 100%. Rare instances of apparent non-penetrance have been reported; however, molecular studies revealed the presence of two different pathogenic variants in the family and gonadal mosaicism in others [
## Nomenclature
Terms used in the past to describe findings in TSC that are now outdated or inappropriate but have not yet been eliminated from the medical literature include the following:
## Prevalence
The incidence of TSC may be as high as 1:5,800 live births [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Many of the features of tuberous sclerosis complex (TSC) are nonspecific and can be seen as isolated findings or as a feature of another condition.
The
Genes of Interest in the Differential Diagnosis of Tuberous Sclerosis Complex
Characteristic skin lesions in BHDS incl fibrofolliculomas, acrochordons, oral papules, cutaneous collagenomas, & epidermal cysts. Facial angiofibromas have been reported in persons w/BHDS but are more common in persons w/TSC.
Multisystem disorder involving brain, kidney, & eye
Focal neurologic symptoms
Seizures
Mass lesions on brain imaging
AD = autosomal dominant; AMLs = angiomyolipomas; LAM = lymphangioleiomyomatosis; MOI = mode of inheritance; SENs = subependymal nodules; TSC = tuberous sclerosis complex; XL = X-linked
See also
• The
• Characteristic skin lesions in BHDS incl fibrofolliculomas, acrochordons, oral papules, cutaneous collagenomas, & epidermal cysts. Facial angiofibromas have been reported in persons w/BHDS but are more common in persons w/TSC.
• Multisystem disorder involving brain, kidney, & eye
• Focal neurologic symptoms
• Seizures
• Mass lesions on brain imaging
## Genes of Interest in the Differential Diagnosis of Tuberous Sclerosis Complex
Genes of Interest in the Differential Diagnosis of Tuberous Sclerosis Complex
Characteristic skin lesions in BHDS incl fibrofolliculomas, acrochordons, oral papules, cutaneous collagenomas, & epidermal cysts. Facial angiofibromas have been reported in persons w/BHDS but are more common in persons w/TSC.
Multisystem disorder involving brain, kidney, & eye
Focal neurologic symptoms
Seizures
Mass lesions on brain imaging
AD = autosomal dominant; AMLs = angiomyolipomas; LAM = lymphangioleiomyomatosis; MOI = mode of inheritance; SENs = subependymal nodules; TSC = tuberous sclerosis complex; XL = X-linked
See also
• Characteristic skin lesions in BHDS incl fibrofolliculomas, acrochordons, oral papules, cutaneous collagenomas, & epidermal cysts. Facial angiofibromas have been reported in persons w/BHDS but are more common in persons w/TSC.
• Multisystem disorder involving brain, kidney, & eye
• Focal neurologic symptoms
• Seizures
• Mass lesions on brain imaging
## Management
Consensus clinical management and surveillance recommendations for individuals with tuberous sclerosis complex (TSC) have been published [
To establish the extent of disease and needs in an individual diagnosed with TSC, the evaluations summarized in
Tuberous Sclerosis Complex: Recommended Evaluations Following Initial Diagnosis
Neurologic eval for manifestations of seizures
Baseline EEG while awake & asleep
During infancy, educate parents to recognize infantile spasms as well as other seizure types even if none have occurred at time of diagnosis.
Infantile spasms are a neurologic emergency in infants w/TSC requiring immediate eval & treatment.
If baseline EEG is abnormal or if TAND is present: 24-hr video EEG to assess for subclinical seizure activity
Earlier recognition & treatment of epilepsy in infancy is assoc w/better long-term neurologic outcome.
Parent/caregiver education & training re TAND manifestations (e.g., ASD, ADHD, language & anxiety disorders)
Comprehensive eval for all manifestations using
To ensure families are monitoring for emerging TAND manifestations
Unaddressed TAND manifestations contribute significantly to poor outcome.
ADHD = attention-deficit/hyperactivity disorder; AML = angiomyolipomas; ASD = autism spectrum disorder; c/w = consistent with; GFR = glomerular filtration rate; LAM = lymphangioleiomyomatosis; MOI = mode of inheritance; PFT = pulmonary function testing; SEGAs = subependymal giant cell astrocytomas; SENs = subependymal nodules; TAND = TSC-associated neuropsychiatric disorder; TSC = tuberous sclerosis complex
A simple screening questionnaire available at no cost to address the significant gap between clinical need associated with TAND and those receiving intervention for these needs [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Tuberous Sclerosis Complex: Targeted Therapies
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
Tuberous Sclerosis Complex: Treatment of Manifestations
mTOR inhibitor (See
Resection by neurosurgeon if size of SEGA causes life-threatening neurologic symptoms
Vigabatrin
Standard ASMs
mTOR inhibitors for intractable epilepsy (See
Dietary therapy
Epilepsy surgery
If sharp or poly-spike waves develop on presymptomatic EEG, treatment w/vigabatrin should be considered to prevent infantile spams & delay onset of focal seizures.
Early seizure control is correlated w/improved developmental & neurologic outcomes.
Other than for infantile spasms, seizure treatment should generally follow that of other epilepsies. Everolimus & a specific formulation of cannabidiol have been evaluated in randomized controlled clinical trials to treat TSC-related seizures & were effective; however, no comparative efficacy data exists to recommend any specific ASM, everolimus, or cannabidiol over another.
Up to two thirds of seizures in persons w/TSC may be resistant to polydrug therapy w/ASMs & mTOR inhibitors; epilepsy surgery should be considered for persons w/refractory epilepsy & TSC.
Refer to neurodevelopmental specialist &/or psychiatry based on features.
ABA therapy for ASD
Consider medication for ADHD.
Consider use of an mTOR inhibitor (see
Alternative treatment is open heart surgery.
Treatment per ophthalmologist
Monitor for signs of rapid growth or effects on vision.
Consider use of mTOR inhibitor if rapid growth or local issues w/compression to potentially avoid surgery.
Surgery if indicated
ABA = applied behavior analysis; ACTH = adrenocorticotropic hormone; ADHD = attention-deficit/hyperactivity disorder; AML = angiomyolipoma; ASD = autism spectrum disorder; ASM = anti-seizure medication; LAM = lymphangioleiomyomatosis; NETs = neuroendocrine tumors; SEGAs = subependymal giant cell astrocytomas; TAND = TSC-associated neuropsychiatric disorder
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Tuberous Sclerosis Complex: Recommended Surveillance
Continue imaging periodically throughout adulthood to monitor for SEGA growth.
For large or growing SEGAs causing ventricular enlargement w/o symptoms, brain MRI should be performed more frequently; these persons & their families should be educated re potential for new symptoms.
In asymptomatic infants: every 6 wks up to age 12 mos; every 3 mos up to age 24 mos
In those w/known or suspected seizures: as clinically indicated
If infantile spams or focal seizures are suspected but cannot be confirmed clinically or on routine EEG, prolonged video EEG that includes sleep should be performed.
Every 1-3 yrs in asymptomatic infants & children w/cardiac rhabdomyomas until regression of lesions begins
Frequency per cardiologist in those w/symptomatic cardiac rhabdomyomas
Clinical screening (targeted history) for LAM symptoms (e.g., exertional dyspnea & shortness of breath)
Counseling regarding ↑ risk of LAM assoc w/smoking & estrogen use
Every 5-7 yrs through menopause in asymptomatic persons at risk for LAM who have no evidence of lung cysts on baseline high-resolution CT
For persons w/cystic lung disease consistent w/LAM on CT, follow-up imaging should be determined on an individual basis (e.g., presence of symptoms, ability to perform reliable PFTs, pre-existing use of mTOR inhibitor, response to treatment, & development of other pulmonary complications).
AML = angiomyolipoma; CNS = central nervous system; GFR = glomerular filtration rate; LAM = lymphangioleiomyomatosis; NETs = neuroendocrine tumors; PFTs = pulmonary function tests; SEGAs = subependymal giant cell astrocytomas; TAND = TSC-associated neuropsychiatric disorder; TSC = tuberous sclerosis complex
Abnormal EEG frequently precedes onset of clinical seizures.
Avoid the following:
Smoking
Estrogen use in adolescent and adult females
Nephrectomy (See
It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (including children) of an affected individual in order to identify as early as possible those who would benefit from
Molecular genetic testing if the pathogenic variant in the family is known;
If the pathogenic variant in the family is not known, physical examination and imaging studies (skin examination, retinal examination, brain imaging, and renal MRI examination) to assess for the clinical features of TSC (see
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 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
Many clinical trials are assessing the effect of drug therapy on the manifestations of TSC (see
• Neurologic eval for manifestations of seizures
• Baseline EEG while awake & asleep
• During infancy, educate parents to recognize infantile spasms as well as other seizure types even if none have occurred at time of diagnosis.
• Infantile spasms are a neurologic emergency in infants w/TSC requiring immediate eval & treatment.
• If baseline EEG is abnormal or if TAND is present: 24-hr video EEG to assess for subclinical seizure activity
• Earlier recognition & treatment of epilepsy in infancy is assoc w/better long-term neurologic outcome.
• Parent/caregiver education & training re TAND manifestations (e.g., ASD, ADHD, language & anxiety disorders)
• Comprehensive eval for all manifestations using
• To ensure families are monitoring for emerging TAND manifestations
• Unaddressed TAND manifestations contribute significantly to poor outcome.
• mTOR inhibitor (See
• Resection by neurosurgeon if size of SEGA causes life-threatening neurologic symptoms
• Vigabatrin
• Standard ASMs
• mTOR inhibitors for intractable epilepsy (See
• Dietary therapy
• Epilepsy surgery
• If sharp or poly-spike waves develop on presymptomatic EEG, treatment w/vigabatrin should be considered to prevent infantile spams & delay onset of focal seizures.
• Early seizure control is correlated w/improved developmental & neurologic outcomes.
• Other than for infantile spasms, seizure treatment should generally follow that of other epilepsies. Everolimus & a specific formulation of cannabidiol have been evaluated in randomized controlled clinical trials to treat TSC-related seizures & were effective; however, no comparative efficacy data exists to recommend any specific ASM, everolimus, or cannabidiol over another.
• Up to two thirds of seizures in persons w/TSC may be resistant to polydrug therapy w/ASMs & mTOR inhibitors; epilepsy surgery should be considered for persons w/refractory epilepsy & TSC.
• Refer to neurodevelopmental specialist &/or psychiatry based on features.
• ABA therapy for ASD
• Consider medication for ADHD.
• Consider use of an mTOR inhibitor (see
• Alternative treatment is open heart surgery.
• Treatment per ophthalmologist
• Monitor for signs of rapid growth or effects on vision.
• Consider use of mTOR inhibitor if rapid growth or local issues w/compression to potentially avoid surgery.
• Surgery if indicated
• Continue imaging periodically throughout adulthood to monitor for SEGA growth.
• For large or growing SEGAs causing ventricular enlargement w/o symptoms, brain MRI should be performed more frequently; these persons & their families should be educated re potential for new symptoms.
• In asymptomatic infants: every 6 wks up to age 12 mos; every 3 mos up to age 24 mos
• In those w/known or suspected seizures: as clinically indicated
• If infantile spams or focal seizures are suspected but cannot be confirmed clinically or on routine EEG, prolonged video EEG that includes sleep should be performed.
• Every 1-3 yrs in asymptomatic infants & children w/cardiac rhabdomyomas until regression of lesions begins
• Frequency per cardiologist in those w/symptomatic cardiac rhabdomyomas
• Clinical screening (targeted history) for LAM symptoms (e.g., exertional dyspnea & shortness of breath)
• Counseling regarding ↑ risk of LAM assoc w/smoking & estrogen use
• Every 5-7 yrs through menopause in asymptomatic persons at risk for LAM who have no evidence of lung cysts on baseline high-resolution CT
• For persons w/cystic lung disease consistent w/LAM on CT, follow-up imaging should be determined on an individual basis (e.g., presence of symptoms, ability to perform reliable PFTs, pre-existing use of mTOR inhibitor, response to treatment, & development of other pulmonary complications).
• Smoking
• Estrogen use in adolescent and adult females
• Nephrectomy (See
• Molecular genetic testing if the pathogenic variant in the family is known;
• If the pathogenic variant in the family is not known, physical examination and imaging studies (skin examination, retinal examination, brain imaging, and renal MRI examination) to assess for the clinical features of TSC (see
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with TSC, the evaluations summarized in
Tuberous Sclerosis Complex: Recommended Evaluations Following Initial Diagnosis
Neurologic eval for manifestations of seizures
Baseline EEG while awake & asleep
During infancy, educate parents to recognize infantile spasms as well as other seizure types even if none have occurred at time of diagnosis.
Infantile spasms are a neurologic emergency in infants w/TSC requiring immediate eval & treatment.
If baseline EEG is abnormal or if TAND is present: 24-hr video EEG to assess for subclinical seizure activity
Earlier recognition & treatment of epilepsy in infancy is assoc w/better long-term neurologic outcome.
Parent/caregiver education & training re TAND manifestations (e.g., ASD, ADHD, language & anxiety disorders)
Comprehensive eval for all manifestations using
To ensure families are monitoring for emerging TAND manifestations
Unaddressed TAND manifestations contribute significantly to poor outcome.
ADHD = attention-deficit/hyperactivity disorder; AML = angiomyolipomas; ASD = autism spectrum disorder; c/w = consistent with; GFR = glomerular filtration rate; LAM = lymphangioleiomyomatosis; MOI = mode of inheritance; PFT = pulmonary function testing; SEGAs = subependymal giant cell astrocytomas; SENs = subependymal nodules; TAND = TSC-associated neuropsychiatric disorder; TSC = tuberous sclerosis complex
A simple screening questionnaire available at no cost to address the significant gap between clinical need associated with TAND and those receiving intervention for these needs [
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Neurologic eval for manifestations of seizures
• Baseline EEG while awake & asleep
• During infancy, educate parents to recognize infantile spasms as well as other seizure types even if none have occurred at time of diagnosis.
• Infantile spasms are a neurologic emergency in infants w/TSC requiring immediate eval & treatment.
• If baseline EEG is abnormal or if TAND is present: 24-hr video EEG to assess for subclinical seizure activity
• Earlier recognition & treatment of epilepsy in infancy is assoc w/better long-term neurologic outcome.
• Parent/caregiver education & training re TAND manifestations (e.g., ASD, ADHD, language & anxiety disorders)
• Comprehensive eval for all manifestations using
• To ensure families are monitoring for emerging TAND manifestations
• Unaddressed TAND manifestations contribute significantly to poor outcome.
## Treatment of Manifestations
Tuberous Sclerosis Complex: Targeted Therapies
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
Tuberous Sclerosis Complex: Treatment of Manifestations
mTOR inhibitor (See
Resection by neurosurgeon if size of SEGA causes life-threatening neurologic symptoms
Vigabatrin
Standard ASMs
mTOR inhibitors for intractable epilepsy (See
Dietary therapy
Epilepsy surgery
If sharp or poly-spike waves develop on presymptomatic EEG, treatment w/vigabatrin should be considered to prevent infantile spams & delay onset of focal seizures.
Early seizure control is correlated w/improved developmental & neurologic outcomes.
Other than for infantile spasms, seizure treatment should generally follow that of other epilepsies. Everolimus & a specific formulation of cannabidiol have been evaluated in randomized controlled clinical trials to treat TSC-related seizures & were effective; however, no comparative efficacy data exists to recommend any specific ASM, everolimus, or cannabidiol over another.
Up to two thirds of seizures in persons w/TSC may be resistant to polydrug therapy w/ASMs & mTOR inhibitors; epilepsy surgery should be considered for persons w/refractory epilepsy & TSC.
Refer to neurodevelopmental specialist &/or psychiatry based on features.
ABA therapy for ASD
Consider medication for ADHD.
Consider use of an mTOR inhibitor (see
Alternative treatment is open heart surgery.
Treatment per ophthalmologist
Monitor for signs of rapid growth or effects on vision.
Consider use of mTOR inhibitor if rapid growth or local issues w/compression to potentially avoid surgery.
Surgery if indicated
ABA = applied behavior analysis; ACTH = adrenocorticotropic hormone; ADHD = attention-deficit/hyperactivity disorder; AML = angiomyolipoma; ASD = autism spectrum disorder; ASM = anti-seizure medication; LAM = lymphangioleiomyomatosis; NETs = neuroendocrine tumors; SEGAs = subependymal giant cell astrocytomas; TAND = TSC-associated neuropsychiatric disorder
• mTOR inhibitor (See
• Resection by neurosurgeon if size of SEGA causes life-threatening neurologic symptoms
• Vigabatrin
• Standard ASMs
• mTOR inhibitors for intractable epilepsy (See
• Dietary therapy
• Epilepsy surgery
• If sharp or poly-spike waves develop on presymptomatic EEG, treatment w/vigabatrin should be considered to prevent infantile spams & delay onset of focal seizures.
• Early seizure control is correlated w/improved developmental & neurologic outcomes.
• Other than for infantile spasms, seizure treatment should generally follow that of other epilepsies. Everolimus & a specific formulation of cannabidiol have been evaluated in randomized controlled clinical trials to treat TSC-related seizures & were effective; however, no comparative efficacy data exists to recommend any specific ASM, everolimus, or cannabidiol over another.
• Up to two thirds of seizures in persons w/TSC may be resistant to polydrug therapy w/ASMs & mTOR inhibitors; epilepsy surgery should be considered for persons w/refractory epilepsy & TSC.
• Refer to neurodevelopmental specialist &/or psychiatry based on features.
• ABA therapy for ASD
• Consider medication for ADHD.
• Consider use of an mTOR inhibitor (see
• Alternative treatment is open heart surgery.
• Treatment per ophthalmologist
• Monitor for signs of rapid growth or effects on vision.
• Consider use of mTOR inhibitor if rapid growth or local issues w/compression to potentially avoid surgery.
• Surgery if indicated
## Targeted Therapies
Tuberous Sclerosis Complex: Targeted Therapies
## 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
Tuberous Sclerosis Complex: Treatment of Manifestations
mTOR inhibitor (See
Resection by neurosurgeon if size of SEGA causes life-threatening neurologic symptoms
Vigabatrin
Standard ASMs
mTOR inhibitors for intractable epilepsy (See
Dietary therapy
Epilepsy surgery
If sharp or poly-spike waves develop on presymptomatic EEG, treatment w/vigabatrin should be considered to prevent infantile spams & delay onset of focal seizures.
Early seizure control is correlated w/improved developmental & neurologic outcomes.
Other than for infantile spasms, seizure treatment should generally follow that of other epilepsies. Everolimus & a specific formulation of cannabidiol have been evaluated in randomized controlled clinical trials to treat TSC-related seizures & were effective; however, no comparative efficacy data exists to recommend any specific ASM, everolimus, or cannabidiol over another.
Up to two thirds of seizures in persons w/TSC may be resistant to polydrug therapy w/ASMs & mTOR inhibitors; epilepsy surgery should be considered for persons w/refractory epilepsy & TSC.
Refer to neurodevelopmental specialist &/or psychiatry based on features.
ABA therapy for ASD
Consider medication for ADHD.
Consider use of an mTOR inhibitor (see
Alternative treatment is open heart surgery.
Treatment per ophthalmologist
Monitor for signs of rapid growth or effects on vision.
Consider use of mTOR inhibitor if rapid growth or local issues w/compression to potentially avoid surgery.
Surgery if indicated
ABA = applied behavior analysis; ACTH = adrenocorticotropic hormone; ADHD = attention-deficit/hyperactivity disorder; AML = angiomyolipoma; ASD = autism spectrum disorder; ASM = anti-seizure medication; LAM = lymphangioleiomyomatosis; NETs = neuroendocrine tumors; SEGAs = subependymal giant cell astrocytomas; TAND = TSC-associated neuropsychiatric disorder
• mTOR inhibitor (See
• Resection by neurosurgeon if size of SEGA causes life-threatening neurologic symptoms
• Vigabatrin
• Standard ASMs
• mTOR inhibitors for intractable epilepsy (See
• Dietary therapy
• Epilepsy surgery
• If sharp or poly-spike waves develop on presymptomatic EEG, treatment w/vigabatrin should be considered to prevent infantile spams & delay onset of focal seizures.
• Early seizure control is correlated w/improved developmental & neurologic outcomes.
• Other than for infantile spasms, seizure treatment should generally follow that of other epilepsies. Everolimus & a specific formulation of cannabidiol have been evaluated in randomized controlled clinical trials to treat TSC-related seizures & were effective; however, no comparative efficacy data exists to recommend any specific ASM, everolimus, or cannabidiol over another.
• Up to two thirds of seizures in persons w/TSC may be resistant to polydrug therapy w/ASMs & mTOR inhibitors; epilepsy surgery should be considered for persons w/refractory epilepsy & TSC.
• Refer to neurodevelopmental specialist &/or psychiatry based on features.
• ABA therapy for ASD
• Consider medication for ADHD.
• Consider use of an mTOR inhibitor (see
• Alternative treatment is open heart surgery.
• Treatment per ophthalmologist
• Monitor for signs of rapid growth or effects on vision.
• Consider use of mTOR inhibitor if rapid growth or local issues w/compression to potentially avoid surgery.
• Surgery if indicated
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Tuberous Sclerosis Complex: Recommended Surveillance
Continue imaging periodically throughout adulthood to monitor for SEGA growth.
For large or growing SEGAs causing ventricular enlargement w/o symptoms, brain MRI should be performed more frequently; these persons & their families should be educated re potential for new symptoms.
In asymptomatic infants: every 6 wks up to age 12 mos; every 3 mos up to age 24 mos
In those w/known or suspected seizures: as clinically indicated
If infantile spams or focal seizures are suspected but cannot be confirmed clinically or on routine EEG, prolonged video EEG that includes sleep should be performed.
Every 1-3 yrs in asymptomatic infants & children w/cardiac rhabdomyomas until regression of lesions begins
Frequency per cardiologist in those w/symptomatic cardiac rhabdomyomas
Clinical screening (targeted history) for LAM symptoms (e.g., exertional dyspnea & shortness of breath)
Counseling regarding ↑ risk of LAM assoc w/smoking & estrogen use
Every 5-7 yrs through menopause in asymptomatic persons at risk for LAM who have no evidence of lung cysts on baseline high-resolution CT
For persons w/cystic lung disease consistent w/LAM on CT, follow-up imaging should be determined on an individual basis (e.g., presence of symptoms, ability to perform reliable PFTs, pre-existing use of mTOR inhibitor, response to treatment, & development of other pulmonary complications).
AML = angiomyolipoma; CNS = central nervous system; GFR = glomerular filtration rate; LAM = lymphangioleiomyomatosis; NETs = neuroendocrine tumors; PFTs = pulmonary function tests; SEGAs = subependymal giant cell astrocytomas; TAND = TSC-associated neuropsychiatric disorder; TSC = tuberous sclerosis complex
Abnormal EEG frequently precedes onset of clinical seizures.
• Continue imaging periodically throughout adulthood to monitor for SEGA growth.
• For large or growing SEGAs causing ventricular enlargement w/o symptoms, brain MRI should be performed more frequently; these persons & their families should be educated re potential for new symptoms.
• In asymptomatic infants: every 6 wks up to age 12 mos; every 3 mos up to age 24 mos
• In those w/known or suspected seizures: as clinically indicated
• If infantile spams or focal seizures are suspected but cannot be confirmed clinically or on routine EEG, prolonged video EEG that includes sleep should be performed.
• Every 1-3 yrs in asymptomatic infants & children w/cardiac rhabdomyomas until regression of lesions begins
• Frequency per cardiologist in those w/symptomatic cardiac rhabdomyomas
• Clinical screening (targeted history) for LAM symptoms (e.g., exertional dyspnea & shortness of breath)
• Counseling regarding ↑ risk of LAM assoc w/smoking & estrogen use
• Every 5-7 yrs through menopause in asymptomatic persons at risk for LAM who have no evidence of lung cysts on baseline high-resolution CT
• For persons w/cystic lung disease consistent w/LAM on CT, follow-up imaging should be determined on an individual basis (e.g., presence of symptoms, ability to perform reliable PFTs, pre-existing use of mTOR inhibitor, response to treatment, & development of other pulmonary complications).
## Agents/Circumstances to Avoid
Avoid the following:
Smoking
Estrogen use in adolescent and adult females
Nephrectomy (See
• Smoking
• Estrogen use in adolescent and adult females
• Nephrectomy (See
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (including children) of an affected individual in order to identify as early as possible those who would benefit from
Molecular genetic testing if the pathogenic variant in the family is known;
If the pathogenic variant in the family is not known, physical examination and imaging studies (skin examination, retinal examination, brain imaging, and renal MRI examination) to assess for the clinical features of TSC (see
See
• Molecular genetic testing if the pathogenic variant in the family is known;
• If the pathogenic variant in the family is not known, physical examination and imaging studies (skin examination, retinal examination, brain imaging, and renal MRI examination) to assess for the clinical features of TSC (see
## 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 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
Many clinical trials are assessing the effect of drug therapy on the manifestations of TSC (see
## Genetic Counseling
Tuberous sclerosis complex (TSC) is inherited in an autosomal dominant manner.
About one third of individuals diagnosed with TSC have an affected parent.
Two thirds of individuals with TSC have the disorder as the result of a
If the proband appears to be the only affected family member, recommended evaluations for the parents of the proband include:
Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
If a molecular diagnosis has been established in the proband, 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.* Parental gonadal mosaicism has been reported in several families [
* A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
The family history of some individuals diagnosed with TSC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the recognition of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation or (if a molecular diagnosis has been established in the proband) molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent is affected and/or known to have a
Although the penetrance of TSC is thought to be 100% (see
If the proband represents a simplex case and has a known TSC-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (~1%-2%) but greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the TSC-related pathogenic variant identified in the proband is known to have occurred as a postzygotic event (i.e., the proband has somatic mosaicism for the pathogenic variant) (see
If the proband represents a simplex case and the parents are clinically unaffected (based on skin examination, retinal examination, brain imaging, and renal imaging) 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,
Predictive testing for at-risk asymptomatic family members requires prior identification of the
Predictive testing of at-risk family members (including children) is recommended in order to guide medical management [
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.
Note: The cardiac tumors are generally not detected until the third trimester.
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.
• About one third of individuals diagnosed with TSC have an affected parent.
• Two thirds of individuals with TSC have the disorder as the result of a
• If the proband appears to be the only affected family member, recommended evaluations for the parents of the proband include:
• Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
• Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
• Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• If a molecular diagnosis has been established in the proband, 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.* Parental gonadal mosaicism has been reported in several families [
• * A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental gonadal mosaicism has been reported in several families [
• * A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
• The family history of some individuals diagnosed with TSC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the recognition of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation or (if a molecular diagnosis has been established in the proband) molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
• Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental gonadal mosaicism has been reported in several families [
• * A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
• If a parent is affected and/or known to have a
• Although the penetrance of TSC is thought to be 100% (see
• Although the penetrance of TSC is thought to be 100% (see
• If the proband represents a simplex case and has a known TSC-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (~1%-2%) but greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the TSC-related pathogenic variant identified in the proband is known to have occurred as a postzygotic event (i.e., the proband has somatic mosaicism for the pathogenic variant) (see
• If the proband represents a simplex case and the parents are clinically unaffected (based on skin examination, retinal examination, brain imaging, and renal imaging) 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 [
• Although the penetrance of TSC is thought to be 100% (see
• Predictive testing for at-risk asymptomatic family members requires prior identification of the
• Predictive testing of at-risk family members (including children) is recommended in order to guide medical management [
• 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.
• Note: The cardiac tumors are generally not detected until the third trimester.
## Mode of Inheritance
Tuberous sclerosis complex (TSC) is inherited in an autosomal dominant manner.
## Risk to Family Members
About one third of individuals diagnosed with TSC have an affected parent.
Two thirds of individuals with TSC have the disorder as the result of a
If the proband appears to be the only affected family member, recommended evaluations for the parents of the proband include:
Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
If a molecular diagnosis has been established in the proband, 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.* Parental gonadal mosaicism has been reported in several families [
* A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
The family history of some individuals diagnosed with TSC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the recognition of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation or (if a molecular diagnosis has been established in the proband) molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent is affected and/or known to have a
Although the penetrance of TSC is thought to be 100% (see
If the proband represents a simplex case and has a known TSC-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (~1%-2%) but greater than that of the general population because of the possibility of parental gonadal mosaicism [
If the TSC-related pathogenic variant identified in the proband is known to have occurred as a postzygotic event (i.e., the proband has somatic mosaicism for the pathogenic variant) (see
If the proband represents a simplex case and the parents are clinically unaffected (based on skin examination, retinal examination, brain imaging, and renal imaging) 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 [
• About one third of individuals diagnosed with TSC have an affected parent.
• Two thirds of individuals with TSC have the disorder as the result of a
• If the proband appears to be the only affected family member, recommended evaluations for the parents of the proband include:
• Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
• Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
• Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• If a molecular diagnosis has been established in the proband, 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.* Parental gonadal mosaicism has been reported in several families [
• * A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental gonadal mosaicism has been reported in several families [
• * A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
• The family history of some individuals diagnosed with TSC may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the recognition of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation or (if a molecular diagnosis has been established in the proband) molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• Molecular genetic testing if the TSC-related pathogenic variant has been identified in the proband;
• Skin examination, retinal examination, brain imaging, and renal MRI if the TSC-related pathogenic variant has not been identified in the proband. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation.
• The proband has a
• The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Parental gonadal mosaicism has been reported in several families [
• * A parent with somatic and gonadal mosaicism for a TSC-related pathogenic variant may be mildly/minimally affected [
• If a parent is affected and/or known to have a
• Although the penetrance of TSC is thought to be 100% (see
• Although the penetrance of TSC is thought to be 100% (see
• If the proband represents a simplex case and has a known TSC-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (~1%-2%) but greater than that of the general population because of the possibility of parental gonadal mosaicism [
• If the TSC-related pathogenic variant identified in the proband is known to have occurred as a postzygotic event (i.e., the proband has somatic mosaicism for the pathogenic variant) (see
• If the proband represents a simplex case and the parents are clinically unaffected (based on skin examination, retinal examination, brain imaging, and renal imaging) 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 [
• Although the penetrance of TSC is thought to be 100% (see
## Related Genetic Counseling Issues
See Management,
Predictive testing for at-risk asymptomatic family members requires prior identification of the
Predictive testing of at-risk family members (including children) is recommended in order to guide medical management [
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.
• Predictive testing for at-risk asymptomatic family members requires prior identification of the
• Predictive testing of at-risk family members (including children) is recommended in order to guide medical management [
• 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
Note: The cardiac tumors are generally not detected until the third trimester.
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.
• Note: The cardiac tumors are generally not detected until the third trimester.
## Resources
•
•
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Tuberous Sclerosis Complex: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tuberous Sclerosis Complex (
Hamartin (protein encoded by
Additionally, because tuberin and hamartin are subjected to regulation by multiple cell signaling pathways, somatic pathogenic variants and environmental factors affecting these pathways are expected to modify disease severity in individuals with only one normal germline copy of
A pathogenic variant is defined as a variant that clearly inactivates the function of hamartin or tuberin (i.e., out-of-frame indel or nonsense variant), prevents protein synthesis (i.e., large genomic deletion), or whose effect on protein function has been established by functional assessment (see
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
This DNA nucleotide change results in creation of a cryptic splice donor site that gives rise to the inframe deletion p.Gln1419_Ser1449del rather than the predicted nonsense variant p.Gly1419ValfsTer104 [
## Molecular Pathogenesis
Hamartin (protein encoded by
Additionally, because tuberin and hamartin are subjected to regulation by multiple cell signaling pathways, somatic pathogenic variants and environmental factors affecting these pathways are expected to modify disease severity in individuals with only one normal germline copy of
A pathogenic variant is defined as a variant that clearly inactivates the function of hamartin or tuberin (i.e., out-of-frame indel or nonsense variant), prevents protein synthesis (i.e., large genomic deletion), or whose effect on protein function has been established by functional assessment (see
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
This DNA nucleotide change results in creation of a cryptic splice donor site that gives rise to the inframe deletion p.Gln1419_Ser1449del rather than the predicted nonsense variant p.Gly1419ValfsTer104 [
## Chapter Notes
1 August 2024 (sw) Comprehensive update posted live
12 July 2018 (sw) Comprehensive update posted live
3 September 2015 (me) Comprehensive update posted live
23 November 2011 (me) Comprehensive update posted live
7 May 2009 (me) Comprehensive update posted live
5 December 2005 (me) Comprehensive update posted live
29 August 2003 (me) Comprehensive update posted live
18 April 2001 (me) Comprehensive update posted live
13 July 1999 (pb) Review posted live
5 February 1999 (hn) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 12 July 2018 (sw) Comprehensive update posted live
• 3 September 2015 (me) Comprehensive update posted live
• 23 November 2011 (me) Comprehensive update posted live
• 7 May 2009 (me) Comprehensive update posted live
• 5 December 2005 (me) Comprehensive update posted live
• 29 August 2003 (me) Comprehensive update posted live
• 18 April 2001 (me) Comprehensive update posted live
• 13 July 1999 (pb) Review posted live
• 5 February 1999 (hn) Original submission
## Revision History
1 August 2024 (sw) Comprehensive update posted live
12 July 2018 (sw) Comprehensive update posted live
3 September 2015 (me) Comprehensive update posted live
23 November 2011 (me) Comprehensive update posted live
7 May 2009 (me) Comprehensive update posted live
5 December 2005 (me) Comprehensive update posted live
29 August 2003 (me) Comprehensive update posted live
18 April 2001 (me) Comprehensive update posted live
13 July 1999 (pb) Review posted live
5 February 1999 (hn) Original submission
• 1 August 2024 (sw) Comprehensive update posted live
• 12 July 2018 (sw) Comprehensive update posted live
• 3 September 2015 (me) Comprehensive update posted live
• 23 November 2011 (me) Comprehensive update posted live
• 7 May 2009 (me) Comprehensive update posted live
• 5 December 2005 (me) Comprehensive update posted live
• 29 August 2003 (me) Comprehensive update posted live
• 18 April 2001 (me) Comprehensive update posted live
• 13 July 1999 (pb) Review posted live
• 5 February 1999 (hn) Original submission
## Key Sections in This
## References
Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. An official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017;196:1337-48. [
McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194:748-61. [
Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, Weiner HL, Wheless JW, Towbin AJ, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. [
• Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. An official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017;196:1337-48. [
• McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194:748-61. [
• Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, Weiner HL, Wheless JW, Towbin AJ, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. [
## Published Guidelines / Consensus Statements
Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. An official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017;196:1337-48. [
McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194:748-61. [
Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, Weiner HL, Wheless JW, Towbin AJ, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. [
• Gupta N, Finlay GA, Kotloff RM, Strange C, Wilson KC, Young LR, Taveira-DaSilva AM, Johnson SR, Cottin V, Sahn SA, Ryu JH, Seyama K, Inoue Y, Downey GP, Han MK, Colby TV, Wikenheiser-Brokamp KA, Meyer CA, Smith K, Moss J, McCormack FX; ATS Assembly on Clinical Problems. Lymphangioleiomyomatosis diagnosis and management: high-resolution chest computed tomography, transbronchial lung biopsy, and pleural disease management. An official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med. 2017;196:1337-48. [
• McCormack FX, Gupta N, Finlay GR, Young LR, Taveira-DaSilva AM, Glasgow CG, Steagall WK, Johnson SR, Sahn SA, Ryu JH, Strange C, Seyama K, Sullivan EJ, Kotloff RM, Downey GP, Chapman JT, Han MK, D'Armiento JM, Inoue Y, Henske EP, Bissler JJ, Colby TV, Kinder BW, Wikenheiser-Brokamp KA, Brown KK, Cordier JF, Meyer C, Cottin V, Brozek JL, Smith K, Wilson KC, Moss J; ATS/JRS Committee on Lymphangioleiomyomatosis. Official American Thoracic Society/Japanese Respiratory Society clinical practice guidelines: lymphangioleiomyomatosis diagnosis and management. Am J Respir Crit Care Med. 2016;194:748-61. [
• Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, Frost MD, Fuchs Z, Gosnell ES, Gupta N, Jansen AC, Jóźwiak S, Kingswood JC, Knilans TK, McCormack FX, Pounders A, Roberds SL, Rodriguez-Buritica DF, Roth J, Sampson JR, Sparagana S, Thiele EA, Weiner HL, Wheless JW, Towbin AJ, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66. [
## Literature Cited
|
[] |
13/7/1999
|
1/8/2024
|
9/12/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
tubulin-ov
|
tubulin-ov
|
[
"Tubulin-Related Cortical Dysgenesis",
"Tubulin alpha-1A chain",
"Tubulin beta chain",
"Tubulin beta-2A chain",
"Tubulin beta-2B chain",
"Tubulin beta-3 chain",
"Tubulin gamma-1 chain",
"TUBA1A",
"TUBB",
"TUBB2A",
"TUBB2B",
"TUBB3",
"TUBG1",
"Tubulinopathies",
"Overview"
] |
Tubulinopathies Overview
|
Nadia Bahi-Buisson, Camille Maillard
|
Summary The purpose of this overview is to: Describe the Review the genetic Review the Provide an Review general medical Inform
|
## Clinical Characteristics of Tubulinopathies
Tubulinopathies (or tubulin-related cortical dysgenesis) comprise a wide and overlapping range of brain malformations as well as other clinical features caused by pathogenic variants in genes encoding different isotypes of tubulin [
MRI reveals a "coarse" appearance with a thick cortex and irregular surfaces on both the pial and grey-white junction sides (
Note: Dysgyria was previously referred to as "simplified gyral pattern" or "polymicrogyria-like cortical dysplasia"; these terms are potentially confusing.
The corpus callosum is variably affected, ranging from almost complete agenesis to normal.
A large majority of affected individuals show brain stem hypoplasia that is usually asymmetric with a midline ventral indentation and asymmetric inferior and middle cerebellar peduncles [
The clinical features of the tubulinopathies include motor and intellectual disabilities and epilepsy.
Lissencephaly, microlissencephaly, and generalized severe dysgyria: spastic tetraplegia and virtually no voluntary motor control and absent eye contact
Mild-to-moderate dysgyria: mild motor disability and intellectual disabilities
While most affected individuals have severe-to-profound intellectual disability, a minority have less extensive cortical malformations that result in only moderate intellectual disability, and a few have limited malformations that allow near-normal cognitive abilities. In the latter instance, the cortical malformation is typically less severe and less extensive on MRI.
Early epileptic encephalopathy (with or without infantile spasms) is common in lissencephaly and generalized severe dysgyria.
Seizures are usually present in fewer than 30% of individuals with a simplified gyral pattern with the exception of the two individuals with
• Lissencephaly, microlissencephaly, and generalized severe dysgyria: spastic tetraplegia and virtually no voluntary motor control and absent eye contact
• Mild-to-moderate dysgyria: mild motor disability and intellectual disabilities
• Early epileptic encephalopathy (with or without infantile spasms) is common in lissencephaly and generalized severe dysgyria.
• Seizures are usually present in fewer than 30% of individuals with a simplified gyral pattern with the exception of the two individuals with
## Brain Malformations
MRI reveals a "coarse" appearance with a thick cortex and irregular surfaces on both the pial and grey-white junction sides (
Note: Dysgyria was previously referred to as "simplified gyral pattern" or "polymicrogyria-like cortical dysplasia"; these terms are potentially confusing.
The corpus callosum is variably affected, ranging from almost complete agenesis to normal.
A large majority of affected individuals show brain stem hypoplasia that is usually asymmetric with a midline ventral indentation and asymmetric inferior and middle cerebellar peduncles [
## Clinical Features of the Tubulinopathies
The clinical features of the tubulinopathies include motor and intellectual disabilities and epilepsy.
Lissencephaly, microlissencephaly, and generalized severe dysgyria: spastic tetraplegia and virtually no voluntary motor control and absent eye contact
Mild-to-moderate dysgyria: mild motor disability and intellectual disabilities
While most affected individuals have severe-to-profound intellectual disability, a minority have less extensive cortical malformations that result in only moderate intellectual disability, and a few have limited malformations that allow near-normal cognitive abilities. In the latter instance, the cortical malformation is typically less severe and less extensive on MRI.
Early epileptic encephalopathy (with or without infantile spasms) is common in lissencephaly and generalized severe dysgyria.
Seizures are usually present in fewer than 30% of individuals with a simplified gyral pattern with the exception of the two individuals with
• Lissencephaly, microlissencephaly, and generalized severe dysgyria: spastic tetraplegia and virtually no voluntary motor control and absent eye contact
• Mild-to-moderate dysgyria: mild motor disability and intellectual disabilities
• Early epileptic encephalopathy (with or without infantile spasms) is common in lissencephaly and generalized severe dysgyria.
• Seizures are usually present in fewer than 30% of individuals with a simplified gyral pattern with the exception of the two individuals with
## Genetic Causes of Tubulinopathies
The genetic causes of tubulinopathies and their associated complex cortical malformations are summarized in
Tubulinopathies: Molecular Genetics and Complex Cortical Malformations
AD = autosomal dominant; AR = autosomal recessive; CC = corpus callosum; CFEOM =
Genes are in alphabetic order.
Dysgyria or cortical dysplasia resembling polymicrogyria [
At the extreme severe end of the spectrum, only one fetus was reported with microlissencephaly and corpus callosum agenesis, severe brain stem and cerebellar hypoplasia, and dysmorphic basal ganglia [
## Differential Diagnosis of Tubulinopathies
Tubulinopathies need to be distinguished clinically from other brain malformations that may resemble them (
Differential Diagnosis of Tubulinopathies
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Mutation of
As currently defined, Miller-Dieker syndrome is associated with deletions that include both
See Fukuyama Congenital Muscular Dystrophy:
## Evaluation Strategies to Identify the Genetic Cause of Tubulinopathy in a Proband
Establishing a specific genetic cause of a tubulinopathy:
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
## General Medical Management of Tubulinopathies
A pediatric neurologist with expertise in the management of children with multiple disabilities and medically refractory epilepsy is recommended for long-term management.
Supportive management, including an individualized therapy plan that includes physical therapy to manage the complications of spasticity, occupational therapy, speech therapy, and vision therapy for oculomotor deficits and/or strabismus should begin at the time of diagnosis to ensure the best possible functionality and developmental outcome. Of note, it is appropriate to institute measures early on to manage potential complications of spasticity (e.g., joint contractures or reduced range of motion), which can increase the risk for decubitus ulcers as well as affect mobility and hygiene.
Those with congenital fibrosis of the extraocular muscles may require nonsurgical and/or surgical treatment.
Nutritional needs in infants with the more severe brain malformations (e.g., lissencephaly, generalized polymicrogyria) are usually managed by nasogastric tube feedings, followed by gastrostomy tube placement as needed.
Seizures are treated with anti-seizure medications based on the specific seizure type. In general, seizures should be treated promptly by specialists, as poor seizure control frequently worsens feeding and increases both the likelihood that a gastrostomy tube will be needed and the risk for aspiration.
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
For individuals with severe cortical malformations (lissencephalies, polymicrogyria-like cortical dysplasia, microlissencephaly), it is usually appropriate to discuss the level of care to be provided in the event of a severe intercurrent illness.
## Genetic Counseling of Family Members of an Individual with a Tubulinopathy
Tubulinopathies caused by pathogenic variants in
More than 95% of individuals diagnosed with a tubulinopathy have a
Rarely, an individual diagnosed with a tubulinopathy has an affected parent. These individuals generally have either 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 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.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
* A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
The family history of some individuals diagnosed with a tubulinopathy may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. 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 of inheriting the pathogenic variant is 50%.
If the proband has a known tubulinopathy-related 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 [
If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a tubulinopathy because of the possibility of the possibility of parental germline mosaicism.
The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.
The risk to other family members appears to be low given that most probands with an autosomal dominant tubulinopathy have the disorder as a result of a
Once the tubulinopathy-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 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.
• More than 95% of individuals diagnosed with a tubulinopathy have a
• Rarely, an individual diagnosed with a tubulinopathy has an affected parent. These individuals generally have either 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 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.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
• * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
• * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
• The family history of some individuals diagnosed with a tubulinopathy may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. 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.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
• * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
• 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 proband has a known tubulinopathy-related 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 [
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a tubulinopathy because of the possibility of the possibility of parental germline mosaicism.
• The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.
• The risk to other family members appears to be low given that most probands with an autosomal dominant tubulinopathy have the disorder as a result of a
## Mode of Inheritance
Tubulinopathies caused by pathogenic variants in
## Risk to Family Members
More than 95% of individuals diagnosed with a tubulinopathy have a
Rarely, an individual diagnosed with a tubulinopathy has an affected parent. These individuals generally have either 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 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.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
* A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
The family history of some individuals diagnosed with a tubulinopathy may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. 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 of inheriting the pathogenic variant is 50%.
If the proband has a known tubulinopathy-related 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 [
If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a tubulinopathy because of the possibility of the possibility of parental germline mosaicism.
The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.
The risk to other family members appears to be low given that most probands with an autosomal dominant tubulinopathy have the disorder as a result of a
• More than 95% of individuals diagnosed with a tubulinopathy have a
• Rarely, an individual diagnosed with a tubulinopathy has an affected parent. These individuals generally have either 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 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.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
• * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
• * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
• The family history of some individuals diagnosed with a tubulinopathy may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. 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.* Maternal germline mosaicism has been reported in two families with multiple affected offspring [
• * A parent with somatic and germline mosaicism for a pathogenic variant may be mildly/minimally affected. While this situation is unusual, several groups have reported somatic mosaic pathogenic variants in genes encoding tubulin [
• 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 proband has a known tubulinopathy-related 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 [
• If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of the proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for a tubulinopathy because of the possibility of the possibility of parental germline mosaicism.
• The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.
• The risk to other family members appears to be low given that most probands with an autosomal dominant tubulinopathy have the disorder as a result of a
## Prenatal Testing and Preimplantation Genetic Testing
Once the tubulinopathy-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 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
PO Box 5801
Bethesda MD 20824
•
•
•
•
•
•
•
•
•
• PO Box 5801
• Bethesda MD 20824
•
## Chapter Notes
Nadia Bahi-Buisson is a pediatric neurologist specializing in cortical malformations and fetal neurology. Her research at
Catherine Fallet Bianco and Annie Laquerriere, for sharing their fetal cases and for their helpful discussion of fetal brain tubulinopathies
Chérif Beldjord, Aurelie Toussaint, and Nathalie Carion, for their help in the screening of tubulin genes for diagnosis – from Sanger sequencing to the recent development of NGS panel screening
Jamel Chelly and Karine Poirier, who allowed the first author to collaborate on the identification of tubulin genes and to define/refine the associated phenotypes; and who have contributed through constructive discussion to the understanding of the pathophysiology of tubulinopathies
Sophie Thomas and Stanislas Lyonnet (Imagine Institute), for welcoming the authors to the Laboratory of Embryology and Genetics of Congenital Malformations and supporting their continued work in the identification of genes associated with cortical malformations
Nadia Bahi-Buisson, MD, PhD (2016-present)Mara Cavallin, MD; Paris Descartes University (2016-2021)Camille Maillard, PhD (2021-present)
16 September 2021 (bp) Comprehensive update posted live
24 March 2016 (bp) Review posted live
7 July 2015 (nbb) Original submission
• Catherine Fallet Bianco and Annie Laquerriere, for sharing their fetal cases and for their helpful discussion of fetal brain tubulinopathies
• Chérif Beldjord, Aurelie Toussaint, and Nathalie Carion, for their help in the screening of tubulin genes for diagnosis – from Sanger sequencing to the recent development of NGS panel screening
• Jamel Chelly and Karine Poirier, who allowed the first author to collaborate on the identification of tubulin genes and to define/refine the associated phenotypes; and who have contributed through constructive discussion to the understanding of the pathophysiology of tubulinopathies
• Sophie Thomas and Stanislas Lyonnet (Imagine Institute), for welcoming the authors to the Laboratory of Embryology and Genetics of Congenital Malformations and supporting their continued work in the identification of genes associated with cortical malformations
• 16 September 2021 (bp) Comprehensive update posted live
• 24 March 2016 (bp) Review posted live
• 7 July 2015 (nbb) Original submission
## Author Notes
Nadia Bahi-Buisson is a pediatric neurologist specializing in cortical malformations and fetal neurology. Her research at
## Acknowledgments
Catherine Fallet Bianco and Annie Laquerriere, for sharing their fetal cases and for their helpful discussion of fetal brain tubulinopathies
Chérif Beldjord, Aurelie Toussaint, and Nathalie Carion, for their help in the screening of tubulin genes for diagnosis – from Sanger sequencing to the recent development of NGS panel screening
Jamel Chelly and Karine Poirier, who allowed the first author to collaborate on the identification of tubulin genes and to define/refine the associated phenotypes; and who have contributed through constructive discussion to the understanding of the pathophysiology of tubulinopathies
Sophie Thomas and Stanislas Lyonnet (Imagine Institute), for welcoming the authors to the Laboratory of Embryology and Genetics of Congenital Malformations and supporting their continued work in the identification of genes associated with cortical malformations
• Catherine Fallet Bianco and Annie Laquerriere, for sharing their fetal cases and for their helpful discussion of fetal brain tubulinopathies
• Chérif Beldjord, Aurelie Toussaint, and Nathalie Carion, for their help in the screening of tubulin genes for diagnosis – from Sanger sequencing to the recent development of NGS panel screening
• Jamel Chelly and Karine Poirier, who allowed the first author to collaborate on the identification of tubulin genes and to define/refine the associated phenotypes; and who have contributed through constructive discussion to the understanding of the pathophysiology of tubulinopathies
• Sophie Thomas and Stanislas Lyonnet (Imagine Institute), for welcoming the authors to the Laboratory of Embryology and Genetics of Congenital Malformations and supporting their continued work in the identification of genes associated with cortical malformations
## Author History
Nadia Bahi-Buisson, MD, PhD (2016-present)Mara Cavallin, MD; Paris Descartes University (2016-2021)Camille Maillard, PhD (2021-present)
## Revision History
16 September 2021 (bp) Comprehensive update posted live
24 March 2016 (bp) Review posted live
7 July 2015 (nbb) Original submission
• 16 September 2021 (bp) Comprehensive update posted live
• 24 March 2016 (bp) Review posted live
• 7 July 2015 (nbb) Original submission
## References
## Literature Cited
Representative images of
A-C. Infant age four months with classic lissencephaly. Other features include dysmorphic corpus callosum, dysmorphic/dysplastic internal capsules, and hypoplasia of the cerebellar vermis.
D-F. Fetus at 32 weeks' gestation with complete agyria, virtually no sulci, and complete corpus callosum agenesis
G-I. Child age six years with central pachygyria that appears mildly asymmetric and most severe over the central regions rather than over the posterior pole (H). The basal ganglia are malformed, appearing as large round structures in which the caudate, putamen, and globus pallidus cannot be distinguished (H). Associated malformations include partial agenesis of the rostrum and the splenium (G), hypoplastic brain stem, and dysplasia of the cerebellar vermis (I).
J-L. Child age six years. Dysgyria appears typical with an irregular or overfolded cortical surface and irregularity at the grey-white matter interface (K). Dysgyria appears mildly asymmetric and most severe over the central (mid- and posterior frontal, perisylvian, and anterior parietal) regions rather than over the frontal and the posterior pole. The frontal horns of both lateral ventricles are dysmorphic with malformed basal ganglia (mostly in K). The corpus callosum is hypoplastic (J).The superior vermis is dysplastic (arrow in L).
Representative images of
A-C. Child age three years with cortical dysgyria resembling polymicrogyria. The cortex has a coarse appearance with excessively folded gyri (arrowheads in B). Cortical dysgyria resembling polymicrogyria is associated with complete agenesis of the corpus callosum (A). The basal ganglia are hypertrophic and fused; the lateral ventricles are dysmorphic (B). The cerebellar vermis is dysplastic (arrow in C).
D-F. Individual age 15 years with cortical dysgyria resembling polymicrogyria that appears to be typical with an irregular cortical surface or overfolded cortex aspect and irregularity at the grey-white interface (E). Cortical dysgyria resembling polymicrogyria appears mildly asymmetric and most severe over the central (mid- and posterior frontal, perisylvian, and anterior parietal) regions rather than over the posterior and frontal poles. The superior vermis is dysplastic (F).
G-I. Fetus at 27 weeks' gestation with microlissencephaly. Macroscopic view of the left hemisphere shows agyria with absent sylvian fissure and absent olfactory bulbs (G). Coronal section passing through the hemispheres shows a thin mantle with absence of the corpus callosum, internal capsule, and basal ganglia; enlarged ventricles; and voluminous germinal zones (H). There is diffuse disorganization of the cortical plate with massive overmigration of cells within the meningeal spaces (I).
Representatives images of
A-C. Child age three years with diffuse cortical dysgyria. The cortex shows a coarse appearance, with excessively folded gyri (arrowhead in B). Associated malformations include complete agenesis of corpus callosum (A), pontocerebellar hypoplasia (A), and dysplasia of the cerebellar vermis (arrowhead in C). The basal ganglia are hypertrophic and fused (asterisks in B); the lateral ventricles are dysmorphic (B).
D-F. Child age 11 years; G-I. Child age three years. Both show gyral disorganization with multifocal dysplasia. In both individuals, the cortex has an abnormal appearance with poorly folded gyri, generalized undersulcation (mostly the ternary sulci) (D-F). The basal ganglia are malformed and the lateral ventricles are dysmorphic (E-H). The corpus callosum is hypoplastic (G). The cerebellar vermis is dysplastic (F-I).
|
[] |
24/3/2016
|
16/9/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
tyrosinemia-2
|
tyrosinemia-2
|
[
"Oculocutaneous Tyrosinemia",
"Richner-Hanhart Syndrome",
"TAT Deficiency",
"Tyrosine Aminotransferase Deficiency",
"Oculocutaneous Tyrosinemia",
"Richner-Hanhart Syndrome",
"Tyrosine Aminotransferase Deficiency",
"TAT Deficiency",
"Tyrosine aminotransferase",
"TAT",
"Tyrosinemia Type II"
] |
Tyrosinemia Type II
|
Zahra Bayzaei, Seyed Mohsen Dehghani, Bita Geramizadeh
|
Summary Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability. Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations. Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations. The diagnosis of tyrosinemia type II is established in a proband by identification of biallelic pathogenic variants in Tyrosinemia type II is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for tyrosinemia type II have been published.
Tyrosinemia type II is caused by deficiency of the enzyme tyrosine aminotransferase (TAT) (see
NBS for hepatorenal tyrosinemia (tyrosinemia type I) is typically based on quantification of tyrosine in dried blood spots. Elevated tyrosine above the cutoff reported by the screening laboratory is considered positive and requires follow-up biochemical testing. The identification of an infant with elevated tyrosine without the presence of succinylacetone (which is seen in tyrosinemia type I) should prompt investigation of other defects in tyrosine metabolism, including tyrosinemia type II.
Additional supportive laboratory findings of tyrosinemia type II include the following:
Markedly elevated plasma tyrosine concentration
Note: Elevated plasma tyrosine concentration can be a nonspecific indicator of liver damage or immaturity.
Normal succinylacetone measured directly from the newborn blood spot by tandem mass spectroscopy
Absence of succinylacetone in the blood and urine
Elevated urinary concentration of tyrosine metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, N-acetyltyrosine, and 4-tyramine)
If the follow-up biochemical testing supports the likelihood of tyrosinemia type II, additional testing is required to confirm the diagnosis (see
Upon identification of high tyrosine levels on NBS (typically >500 µmol/L and may exceed 1,000 µmol/L), consultation with a metabolic physician / biochemical geneticist and specialist metabolic dietitian should be obtained while additional testing is performed to determine whether the result is a true positive NBS and to definitively establish the diagnosis of tyrosinemia type II.
A symptomatic individual who has either (1) atypical findings associated with later-onset tyrosinemia type II or (2) untreated infantile-onset tyrosinemia type II may present with the following supportive clinical findings, preliminary laboratory findings, and family history.
Ocular manifestations such as increased tearing, photophobia, pain, redness, and bilateral keratitis
Skin manifestations such as progressive, painful, nonpruritic, and hyperkeratotic plaques on soles and palms, often associated with hyperhidrosis; usually begin after first year of life
Developmental delay, particularly in those with high blood tyrosine concentration
Variable intellectual disability
Elevated plasma tyrosine concentration
Elevated 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis.
Serum transaminase levels are usually normal.
Note: Because these laboratory findings are not specific to tyrosinemia type II, additional testing is required to
The diagnosis of tyrosinemia type II
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 Tyrosinemia Type II
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.
• Markedly elevated plasma tyrosine concentration
• Note: Elevated plasma tyrosine concentration can be a nonspecific indicator of liver damage or immaturity.
• Normal succinylacetone measured directly from the newborn blood spot by tandem mass spectroscopy
• Absence of succinylacetone in the blood and urine
• Elevated urinary concentration of tyrosine metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, N-acetyltyrosine, and 4-tyramine)
• Ocular manifestations such as increased tearing, photophobia, pain, redness, and bilateral keratitis
• Skin manifestations such as progressive, painful, nonpruritic, and hyperkeratotic plaques on soles and palms, often associated with hyperhidrosis; usually begin after first year of life
• Developmental delay, particularly in those with high blood tyrosine concentration
• Variable intellectual disability
• Elevated plasma tyrosine concentration
• Elevated 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis.
• Serum transaminase levels are usually normal.
• For an introduction to multigene panels click
## Suggestive Findings
Tyrosinemia type II is caused by deficiency of the enzyme tyrosine aminotransferase (TAT) (see
NBS for hepatorenal tyrosinemia (tyrosinemia type I) is typically based on quantification of tyrosine in dried blood spots. Elevated tyrosine above the cutoff reported by the screening laboratory is considered positive and requires follow-up biochemical testing. The identification of an infant with elevated tyrosine without the presence of succinylacetone (which is seen in tyrosinemia type I) should prompt investigation of other defects in tyrosine metabolism, including tyrosinemia type II.
Additional supportive laboratory findings of tyrosinemia type II include the following:
Markedly elevated plasma tyrosine concentration
Note: Elevated plasma tyrosine concentration can be a nonspecific indicator of liver damage or immaturity.
Normal succinylacetone measured directly from the newborn blood spot by tandem mass spectroscopy
Absence of succinylacetone in the blood and urine
Elevated urinary concentration of tyrosine metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, N-acetyltyrosine, and 4-tyramine)
If the follow-up biochemical testing supports the likelihood of tyrosinemia type II, additional testing is required to confirm the diagnosis (see
Upon identification of high tyrosine levels on NBS (typically >500 µmol/L and may exceed 1,000 µmol/L), consultation with a metabolic physician / biochemical geneticist and specialist metabolic dietitian should be obtained while additional testing is performed to determine whether the result is a true positive NBS and to definitively establish the diagnosis of tyrosinemia type II.
A symptomatic individual who has either (1) atypical findings associated with later-onset tyrosinemia type II or (2) untreated infantile-onset tyrosinemia type II may present with the following supportive clinical findings, preliminary laboratory findings, and family history.
Ocular manifestations such as increased tearing, photophobia, pain, redness, and bilateral keratitis
Skin manifestations such as progressive, painful, nonpruritic, and hyperkeratotic plaques on soles and palms, often associated with hyperhidrosis; usually begin after first year of life
Developmental delay, particularly in those with high blood tyrosine concentration
Variable intellectual disability
Elevated plasma tyrosine concentration
Elevated 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis.
Serum transaminase levels are usually normal.
Note: Because these laboratory findings are not specific to tyrosinemia type II, additional testing is required to
• Markedly elevated plasma tyrosine concentration
• Note: Elevated plasma tyrosine concentration can be a nonspecific indicator of liver damage or immaturity.
• Normal succinylacetone measured directly from the newborn blood spot by tandem mass spectroscopy
• Absence of succinylacetone in the blood and urine
• Elevated urinary concentration of tyrosine metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, N-acetyltyrosine, and 4-tyramine)
• Ocular manifestations such as increased tearing, photophobia, pain, redness, and bilateral keratitis
• Skin manifestations such as progressive, painful, nonpruritic, and hyperkeratotic plaques on soles and palms, often associated with hyperhidrosis; usually begin after first year of life
• Developmental delay, particularly in those with high blood tyrosine concentration
• Variable intellectual disability
• Elevated plasma tyrosine concentration
• Elevated 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis.
• Serum transaminase levels are usually normal.
## Scenario 1: Abnormal NBS Result
NBS for hepatorenal tyrosinemia (tyrosinemia type I) is typically based on quantification of tyrosine in dried blood spots. Elevated tyrosine above the cutoff reported by the screening laboratory is considered positive and requires follow-up biochemical testing. The identification of an infant with elevated tyrosine without the presence of succinylacetone (which is seen in tyrosinemia type I) should prompt investigation of other defects in tyrosine metabolism, including tyrosinemia type II.
Additional supportive laboratory findings of tyrosinemia type II include the following:
Markedly elevated plasma tyrosine concentration
Note: Elevated plasma tyrosine concentration can be a nonspecific indicator of liver damage or immaturity.
Normal succinylacetone measured directly from the newborn blood spot by tandem mass spectroscopy
Absence of succinylacetone in the blood and urine
Elevated urinary concentration of tyrosine metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, N-acetyltyrosine, and 4-tyramine)
If the follow-up biochemical testing supports the likelihood of tyrosinemia type II, additional testing is required to confirm the diagnosis (see
Upon identification of high tyrosine levels on NBS (typically >500 µmol/L and may exceed 1,000 µmol/L), consultation with a metabolic physician / biochemical geneticist and specialist metabolic dietitian should be obtained while additional testing is performed to determine whether the result is a true positive NBS and to definitively establish the diagnosis of tyrosinemia type II.
• Markedly elevated plasma tyrosine concentration
• Note: Elevated plasma tyrosine concentration can be a nonspecific indicator of liver damage or immaturity.
• Normal succinylacetone measured directly from the newborn blood spot by tandem mass spectroscopy
• Absence of succinylacetone in the blood and urine
• Elevated urinary concentration of tyrosine metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate, N-acetyltyrosine, and 4-tyramine)
## Scenario 2: Symptomatic Individual
A symptomatic individual who has either (1) atypical findings associated with later-onset tyrosinemia type II or (2) untreated infantile-onset tyrosinemia type II may present with the following supportive clinical findings, preliminary laboratory findings, and family history.
Ocular manifestations such as increased tearing, photophobia, pain, redness, and bilateral keratitis
Skin manifestations such as progressive, painful, nonpruritic, and hyperkeratotic plaques on soles and palms, often associated with hyperhidrosis; usually begin after first year of life
Developmental delay, particularly in those with high blood tyrosine concentration
Variable intellectual disability
Elevated plasma tyrosine concentration
Elevated 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis.
Serum transaminase levels are usually normal.
Note: Because these laboratory findings are not specific to tyrosinemia type II, additional testing is required to
• Ocular manifestations such as increased tearing, photophobia, pain, redness, and bilateral keratitis
• Skin manifestations such as progressive, painful, nonpruritic, and hyperkeratotic plaques on soles and palms, often associated with hyperhidrosis; usually begin after first year of life
• Developmental delay, particularly in those with high blood tyrosine concentration
• Variable intellectual disability
• Elevated plasma tyrosine concentration
• Elevated 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, and 4-hydroxyphenylacetate and presence of small quantities of N-acetyltyrosine and 4-tyramine on urine organic acid analysis.
• Serum transaminase levels are usually normal.
## Establishing the Diagnosis
The diagnosis of tyrosinemia type II
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 Tyrosinemia Type II
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.
• For an introduction to multigene panels click
## Clinical Characteristics
Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability. Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations. Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations [
Select Features of Tyrosinemia Type II
Based on
Bacterial, viral, and fungal cultures are typically negative.
Ocular manifestations may undergo spontaneous remission and/or recurrence and may occur independently of other clinical manifestations.
Individuals are often misdiagnosed with herpes simplex keratitis [
Bilateral corneal lesions unresponsive to antiviral therapies should alert the clinician to the possible diagnosis of tyrosinemia type II, even in the absence of skin lesions [
Some individuals with tyrosinemia type II report isolated burning and redness of the eyes since childhood [
Asynchronous bilateral eye disease was the sole clinical feature reported in one child age 15 months with negative NBS for tyrosinemia type II [
Dietary treatment (see Management,
Corneal lesions recurred in one individual after discontinuation of dietary restrictions [
One individual had vesicular lesions on the fingertips [
Skin manifestations rarely resolve spontaneously and often recur.
The pain experienced with palmoplantar keratoderma is a key diagnostic feature, and it can be severe enough to hinder walking [
A skin biopsy from a plantar callus showed hyperkeratosis, hypergranulosis, and acanthosis [
Dietary restriction of tyrosine and phenylalanine is a highly effective treatment; significant improvement of skin manifestations in most individuals occurs within the first week of treatment [
In one individual, the toenails showed subungual hyperkeratosis and secondary nail dystrophy [
Mild developmental delay with hemiparesis and seizures has been reported in one individual [
Isolated geographic tongue with otherwise normal clinical findings (1 individual) [
Self-harm (agitation with paroxysms of head banging and hand and tongue biting) and diffuse plantar keratoderma (1 individual) [
Precise genotype-phenotype correlations are difficult to determine, as most
The most common variant reported to date,
Tyrosinemia type II was previously referred to as keratosis palmoplantaris with corneal dystrophy.
Tyrosinemia type II is rare, with an incidence of less than one in 250,000 [
Founder pathogenic variants have been reported in populations from northern Italy (Lombardy and Tuscany;
• Bacterial, viral, and fungal cultures are typically negative.
• Ocular manifestations may undergo spontaneous remission and/or recurrence and may occur independently of other clinical manifestations.
• Individuals are often misdiagnosed with herpes simplex keratitis [
• Bilateral corneal lesions unresponsive to antiviral therapies should alert the clinician to the possible diagnosis of tyrosinemia type II, even in the absence of skin lesions [
• Some individuals with tyrosinemia type II report isolated burning and redness of the eyes since childhood [
• Asynchronous bilateral eye disease was the sole clinical feature reported in one child age 15 months with negative NBS for tyrosinemia type II [
• Dietary treatment (see Management,
• Corneal lesions recurred in one individual after discontinuation of dietary restrictions [
• One individual had vesicular lesions on the fingertips [
• Skin manifestations rarely resolve spontaneously and often recur.
• The pain experienced with palmoplantar keratoderma is a key diagnostic feature, and it can be severe enough to hinder walking [
• A skin biopsy from a plantar callus showed hyperkeratosis, hypergranulosis, and acanthosis [
• Dietary restriction of tyrosine and phenylalanine is a highly effective treatment; significant improvement of skin manifestations in most individuals occurs within the first week of treatment [
• In one individual, the toenails showed subungual hyperkeratosis and secondary nail dystrophy [
• Isolated geographic tongue with otherwise normal clinical findings (1 individual) [
• Self-harm (agitation with paroxysms of head banging and hand and tongue biting) and diffuse plantar keratoderma (1 individual) [
## Clinical Description
Tyrosinemia type II is characterized by corneal dystrophy, painful palmoplantar hyperkeratosis, and variable intellectual disability. Individuals diagnosed and treated from early infancy may be asymptomatic or have only mild ocular and skin manifestations. Individuals with delayed diagnosis or lack of treatment present with ocular, skin, and variable cognitive manifestations [
Select Features of Tyrosinemia Type II
Based on
Bacterial, viral, and fungal cultures are typically negative.
Ocular manifestations may undergo spontaneous remission and/or recurrence and may occur independently of other clinical manifestations.
Individuals are often misdiagnosed with herpes simplex keratitis [
Bilateral corneal lesions unresponsive to antiviral therapies should alert the clinician to the possible diagnosis of tyrosinemia type II, even in the absence of skin lesions [
Some individuals with tyrosinemia type II report isolated burning and redness of the eyes since childhood [
Asynchronous bilateral eye disease was the sole clinical feature reported in one child age 15 months with negative NBS for tyrosinemia type II [
Dietary treatment (see Management,
Corneal lesions recurred in one individual after discontinuation of dietary restrictions [
One individual had vesicular lesions on the fingertips [
Skin manifestations rarely resolve spontaneously and often recur.
The pain experienced with palmoplantar keratoderma is a key diagnostic feature, and it can be severe enough to hinder walking [
A skin biopsy from a plantar callus showed hyperkeratosis, hypergranulosis, and acanthosis [
Dietary restriction of tyrosine and phenylalanine is a highly effective treatment; significant improvement of skin manifestations in most individuals occurs within the first week of treatment [
In one individual, the toenails showed subungual hyperkeratosis and secondary nail dystrophy [
Mild developmental delay with hemiparesis and seizures has been reported in one individual [
Isolated geographic tongue with otherwise normal clinical findings (1 individual) [
Self-harm (agitation with paroxysms of head banging and hand and tongue biting) and diffuse plantar keratoderma (1 individual) [
• Bacterial, viral, and fungal cultures are typically negative.
• Ocular manifestations may undergo spontaneous remission and/or recurrence and may occur independently of other clinical manifestations.
• Individuals are often misdiagnosed with herpes simplex keratitis [
• Bilateral corneal lesions unresponsive to antiviral therapies should alert the clinician to the possible diagnosis of tyrosinemia type II, even in the absence of skin lesions [
• Some individuals with tyrosinemia type II report isolated burning and redness of the eyes since childhood [
• Asynchronous bilateral eye disease was the sole clinical feature reported in one child age 15 months with negative NBS for tyrosinemia type II [
• Dietary treatment (see Management,
• Corneal lesions recurred in one individual after discontinuation of dietary restrictions [
• One individual had vesicular lesions on the fingertips [
• Skin manifestations rarely resolve spontaneously and often recur.
• The pain experienced with palmoplantar keratoderma is a key diagnostic feature, and it can be severe enough to hinder walking [
• A skin biopsy from a plantar callus showed hyperkeratosis, hypergranulosis, and acanthosis [
• Dietary restriction of tyrosine and phenylalanine is a highly effective treatment; significant improvement of skin manifestations in most individuals occurs within the first week of treatment [
• In one individual, the toenails showed subungual hyperkeratosis and secondary nail dystrophy [
• Isolated geographic tongue with otherwise normal clinical findings (1 individual) [
• Self-harm (agitation with paroxysms of head banging and hand and tongue biting) and diffuse plantar keratoderma (1 individual) [
## Genotype-Phenotype Correlations
Precise genotype-phenotype correlations are difficult to determine, as most
The most common variant reported to date,
## Nomenclature
Tyrosinemia type II was previously referred to as keratosis palmoplantaris with corneal dystrophy.
## Prevalence
Tyrosinemia type II is rare, with an incidence of less than one in 250,000 [
Founder pathogenic variants have been reported in populations from northern Italy (Lombardy and Tuscany;
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Transient tyrosinemia of the newborn
Immature liver
Hypertyrosinemia due to liver disease
Genetic disorders of interest in the differential diagnosis of tyrosinemia type II are listed in
Genes of Interest in the Differential Diagnosis of Tyrosinemia Type II
Liver & kidney dysfunction
↑ succinylacetone concentration in blood & urine
Hypoglycemia
High alkaline phosphatase
Moderately ↑ plasma concentration of tyrosine, phenylalanine, & other amino acids, esp methionine (due to secondary inhibition of methionine adenosyltransferase)
Moderately ↑ plasma concentration of tyrosine
Low activity of enzyme HPD in liver biopsy
Ataxia & seizures
Absence of skin & ocular lesions
Sparse hair & onychodystrophy
Joint abnormalities
Hypotrichosis
AD = autosomal dominant; AR = autosomal recessive; HPD = 4-hydroxyphenylpyruvic acid dioxygenase; MOI = mode of inheritance; XL = X-linked
• Transient tyrosinemia of the newborn
• Immature liver
• Hypertyrosinemia due to liver disease
• Liver & kidney dysfunction
• ↑ succinylacetone concentration in blood & urine
• Hypoglycemia
• High alkaline phosphatase
• Moderately ↑ plasma concentration of tyrosine, phenylalanine, & other amino acids, esp methionine (due to secondary inhibition of methionine adenosyltransferase)
• Moderately ↑ plasma concentration of tyrosine
• Low activity of enzyme HPD in liver biopsy
• Ataxia & seizures
• Absence of skin & ocular lesions
• Sparse hair & onychodystrophy
• Joint abnormalities
• Hypotrichosis
## Management
No clinical practice guidelines for tyrosinemia type II have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
When tyrosinemia type II is suspected during the diagnostic evaluation due to high levels of tyrosine (typically >500 µmol/L and may exceed 1,000 µmol/L), metabolic treatment should be initiated immediately (see
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 and the involvement of a dietitian with specialized training.
To establish the extent of disease and needs in an individual diagnosed with tyrosinemia type II, the evaluations summarized
Tyrosinemia Type II: Recommended Evaluations Following Initial Diagnosis
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
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is a lifelong tyrosine- and phenylalanine-restricted diet. Initially this is in the form of a prescribed infant formula. After weaning, a low-protein diet is prescribed and age-appropriate amino acid (tyrosine- and phenylalanine-free), vitamin, and mineral supplements are given.
A diet that is low in tyrosine and phenylalanine can help correct chemical abnormalities and lead to significant improvement in skin and eye lesions.
Early dietary restriction of tyrosine can help prevent intellectual disability [
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
Tyrosinemia Type II: Treatment of Manifestations
Lubricating eye drops & ointment
Ocular surgery to treat bilateral corneal ulcers
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Tyrosinemia Type II: Recommended Surveillance
Monitoring of developmental milestones
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
Avoid increased dietary protein.
Testing of at-risk sibs of any age is warranted to allow for early diagnosis and treatment of tyrosinemia type II.
See
Infants born to women with untreated tyrosinemia type II may have an increased risk of intrauterine growth deficiency and developmental delay [
Search
• 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 is a lifelong tyrosine- and phenylalanine-restricted diet. Initially this is in the form of a prescribed infant formula. After weaning, a low-protein diet is prescribed and age-appropriate amino acid (tyrosine- and phenylalanine-free), vitamin, and mineral supplements are given.
• A diet that is low in tyrosine and phenylalanine can help correct chemical abnormalities and lead to significant improvement in skin and eye lesions.
• Early dietary restriction of tyrosine can help prevent intellectual disability [
• Lubricating eye drops & ointment
• Ocular surgery to treat bilateral corneal ulcers
• Monitoring of developmental milestones
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with tyrosinemia type II, the evaluations summarized
Tyrosinemia Type II: Recommended Evaluations Following Initial Diagnosis
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
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
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Treatment is a lifelong tyrosine- and phenylalanine-restricted diet. Initially this is in the form of a prescribed infant formula. After weaning, a low-protein diet is prescribed and age-appropriate amino acid (tyrosine- and phenylalanine-free), vitamin, and mineral supplements are given.
A diet that is low in tyrosine and phenylalanine can help correct chemical abnormalities and lead to significant improvement in skin and eye lesions.
Early dietary restriction of tyrosine can help prevent intellectual disability [
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
Tyrosinemia Type II: Treatment of Manifestations
Lubricating eye drops & ointment
Ocular surgery to treat bilateral corneal ulcers
• Treatment is a lifelong tyrosine- and phenylalanine-restricted diet. Initially this is in the form of a prescribed infant formula. After weaning, a low-protein diet is prescribed and age-appropriate amino acid (tyrosine- and phenylalanine-free), vitamin, and mineral supplements are given.
• A diet that is low in tyrosine and phenylalanine can help correct chemical abnormalities and lead to significant improvement in skin and eye lesions.
• Early dietary restriction of tyrosine can help prevent intellectual disability [
• Lubricating eye drops & ointment
• Ocular surgery to treat bilateral corneal ulcers
## Targeted Therapy
Treatment is a lifelong tyrosine- and phenylalanine-restricted diet. Initially this is in the form of a prescribed infant formula. After weaning, a low-protein diet is prescribed and age-appropriate amino acid (tyrosine- and phenylalanine-free), vitamin, and mineral supplements are given.
A diet that is low in tyrosine and phenylalanine can help correct chemical abnormalities and lead to significant improvement in skin and eye lesions.
Early dietary restriction of tyrosine can help prevent intellectual disability [
• Treatment is a lifelong tyrosine- and phenylalanine-restricted diet. Initially this is in the form of a prescribed infant formula. After weaning, a low-protein diet is prescribed and age-appropriate amino acid (tyrosine- and phenylalanine-free), vitamin, and mineral supplements are given.
• A diet that is low in tyrosine and phenylalanine can help correct chemical abnormalities and lead to significant improvement in skin and eye lesions.
• Early dietary restriction of tyrosine can help prevent intellectual disability [
## 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
Tyrosinemia Type II: Treatment of Manifestations
Lubricating eye drops & ointment
Ocular surgery to treat bilateral corneal ulcers
• Lubricating eye drops & ointment
• Ocular surgery to treat bilateral corneal ulcers
## Surveillance
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Tyrosinemia Type II: Recommended Surveillance
Monitoring of developmental milestones
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
• Monitoring of developmental milestones
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
## Agents/Circumstances to Avoid
Avoid increased dietary protein.
## Evaluation of Relatives at Risk
Testing of at-risk sibs of any age is warranted to allow for early diagnosis and treatment of tyrosinemia type II.
See
## Pregnancy Management
Infants born to women with untreated tyrosinemia type II may have an increased risk of intrauterine growth deficiency and developmental delay [
## Therapies Under Investigation
Search
## Genetic Counseling
Tyrosinemia type II 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 the 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
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 should be considered for the reproductive partners of individuals affected with tyrosinemia type II and individuals known to be carriers of a
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 the 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
• 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 individuals affected with tyrosinemia type II and individuals known to be carriers of a
## Mode of Inheritance
Tyrosinemia type II 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 the 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
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 the 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
• 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 should be considered for the reproductive partners of individuals affected with tyrosinemia type II and individuals known to be carriers of 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 individuals affected with tyrosinemia type II and individuals known to be carriers of a
## 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
Health Resources & Services Administration
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Tyrosinemia Type II: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tyrosinemia Type II (
TAT is a homodimer and is composed of two identical polypeptide chains. It is expressed in the liver, kidneys, and brain. The enzyme has the highest activity in the liver. In TAT, the first 38 amino acids may not be involved in enzyme dimerization and are not required in the active site stability and enzyme-substrate interactions. This N-terminal fragment, however, is required for targeting by the ubiquitin-proteasome pathway, which degrades proteins to small peptides.
Founder variant identified in northern Italy (Lombardy & Tuscany)
Most common variant reported to date (10 affected persons from 3 families) [
Variants listed in the table have been provided by the authors.
• Founder variant identified in northern Italy (Lombardy & Tuscany)
• Most common variant reported to date (10 affected persons from 3 families) [
## Molecular Pathogenesis
TAT is a homodimer and is composed of two identical polypeptide chains. It is expressed in the liver, kidneys, and brain. The enzyme has the highest activity in the liver. In TAT, the first 38 amino acids may not be involved in enzyme dimerization and are not required in the active site stability and enzyme-substrate interactions. This N-terminal fragment, however, is required for targeting by the ubiquitin-proteasome pathway, which degrades proteins to small peptides.
Founder variant identified in northern Italy (Lombardy & Tuscany)
Most common variant reported to date (10 affected persons from 3 families) [
Variants listed in the table have been provided by the authors.
• Founder variant identified in northern Italy (Lombardy & Tuscany)
• Most common variant reported to date (10 affected persons from 3 families) [
## Chapter Notes
Dr Bita Geramizadeh is a molecular pathologist. Her clinical and research interests include transplant hepatology, acute liver failure, and inherited metabolic disorders of the liver. She is the author of numerous (more than 450) original manuscripts and reviews on the subject. Her research has been in both the clinical and basic science spheres. Dr Geramizadeh has launched and established a transplant research center and national registry trial for inherited metabolic disorders with a data coordinating center at the Shiraz University of Medical Sciences. She is the vice president of the Association for Inherited Metabolic Disorders (Ibn Sina).
Dr Seyed Mohsen Dehghani is a professor of pediatric gastroenterology and hepatology with experience in inherited disorders and more than 200 highly cited published papers.
Dr Zahra Beyzaei is a molecular and biochemical geneticist. She is a staff scientist in the transplant research center at the Shiraz University of Medical Sciences. She would be happy to communicate with persons who have any questions regarding tyrosinemia type II disease. Contact Dr Beyzaei to inquire about review of
We extend our gratitude to the individuals with tyrosinemia type II and their families, our institutions, laboratory personnel, and researchers, as well as the Association for Inherited Metabolic Disorders (Ibn Sina), for their dedicated efforts and collaborative work.
24 October 2024 (sw) Review posted live
17 June 2024 (bg) Original submission
• 24 October 2024 (sw) Review posted live
• 17 June 2024 (bg) Original submission
## Author Notes
Dr Bita Geramizadeh is a molecular pathologist. Her clinical and research interests include transplant hepatology, acute liver failure, and inherited metabolic disorders of the liver. She is the author of numerous (more than 450) original manuscripts and reviews on the subject. Her research has been in both the clinical and basic science spheres. Dr Geramizadeh has launched and established a transplant research center and national registry trial for inherited metabolic disorders with a data coordinating center at the Shiraz University of Medical Sciences. She is the vice president of the Association for Inherited Metabolic Disorders (Ibn Sina).
Dr Seyed Mohsen Dehghani is a professor of pediatric gastroenterology and hepatology with experience in inherited disorders and more than 200 highly cited published papers.
Dr Zahra Beyzaei is a molecular and biochemical geneticist. She is a staff scientist in the transplant research center at the Shiraz University of Medical Sciences. She would be happy to communicate with persons who have any questions regarding tyrosinemia type II disease. Contact Dr Beyzaei to inquire about review of
## Acknowledgments
We extend our gratitude to the individuals with tyrosinemia type II and their families, our institutions, laboratory personnel, and researchers, as well as the Association for Inherited Metabolic Disorders (Ibn Sina), for their dedicated efforts and collaborative work.
## Revision History
24 October 2024 (sw) Review posted live
17 June 2024 (bg) Original submission
• 24 October 2024 (sw) Review posted live
• 17 June 2024 (bg) Original submission
## Key Sections in This
## References
## Literature Cited
The tyrosine catabolic pathway
FAH = fumarylacetoacetate hydrolase; HGD = homogentisate 1,2-dioxygenase; HPD = 4-hydroxyphenylpyruvic acid dioxygenase; MAI = 4-maleylacetoacetate cis-trans-isomerase; PAH = phenylalanine hydroxylase; TAT = tyrosine aminotransferase
|
[] |
24/10/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
tyrosinemia
|
tyrosinemia
|
[
"FAH Deficiency",
"Fumarylacetoacetase Deficiency",
"Fumarylacetoacetate Hydrolase Deficiency",
"Hepatorenal Tyrosinemia",
"FAH Deficiency",
"Hepatorenal Tyrosinemia",
"Hereditary Tyrosinemia Type I",
"Fumarylacetoacetase Deficiency",
"Fumarylacetoacetate Hydrolase Deficiency",
"Fumarylacetoacetase",
"FAH",
"Tyrosinemia Type I"
] |
Tyrosinemia Type I
|
Lisa Sniderman King, Cristine Trahms, C Ronald Scott
|
Summary Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets. Tyrosinemia type I results from deficiency of the enzyme fumarylacetoacetase (FAH). The diagnosis is established in a proband with typical biochemical findings (increased succinylacetone concentration in the blood and urine; elevated plasma concentrations of tyrosine, methionine, and phenylalanine; and elevated urinary concentration of tyrosine metabolites and the compound δ-ALA) and/or by the identification of biallelic pathogenic variants in Tyrosinemia type I 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 a pregnancy at increased risk are possible if both pathogenic variants in a family are known.
|
## Diagnosis
Tyrosinemia type I is caused by deficiency of the enzyme fumarylacetoacetase (FAH) (
Tyrosinemia type I
Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
Severe liver disease in young infants
Signs of kidney disease, rickets, and/or neurologic crises in children older than age six months
Untreated children may have repeated neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.
Note: (1) Increased excretion of succinylacetone in the urine of a child with liver failure or severe kidney disease is a pathognomonic sign of tyrosinemia type I. (2) Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.
Note: (1) Plasma tyrosine concentration in affected infants can be normal in cord blood and during the newborn period. (2) Elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity; for example, in infants taking a high-protein formula [
Prolonged prothrombin and partial thromboplastin times
Note: (1) Changes in serum concentration of alpha-fetoprotein (AFP) and prothrombin time / partial thromboplastin time (PT/PTT) are more severe in tyrosinemia type I than in nonspecific liver disease and are often the presenting findings in tyrosinemia type I. (2) Transaminases and bilirubin are only modestly elevated, if at all. (3) An individual with liver disease and normal serum concentration of AFP and normal PT/PTT has a low probability of having tyrosinemia type I.
The diagnosis of tyrosinemia type I
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 [
Targeted analysis for the
The pathogenic variant
The four common
Molecular Genetic Testing Used in Tyrosinemia Type I
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.
• Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
• Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
• Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
• Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
• Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
• Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
• Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
• Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
• Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
• Severe liver disease in young infants
• Signs of kidney disease, rickets, and/or neurologic crises in children older than age six months
• Untreated children may have repeated neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.
•
• Note: (1) Increased excretion of succinylacetone in the urine of a child with liver failure or severe kidney disease is a pathognomonic sign of tyrosinemia type I. (2) Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.
•
• Note: (1) Plasma tyrosine concentration in affected infants can be normal in cord blood and during the newborn period. (2) Elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity; for example, in infants taking a high-protein formula [
•
• Prolonged prothrombin and partial thromboplastin times
• Prolonged prothrombin and partial thromboplastin times
• Prolonged prothrombin and partial thromboplastin times
• Targeted analysis for the
• The pathogenic variant
• The four common
## Suggestive Findings
Tyrosinemia type I
Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
Severe liver disease in young infants
Signs of kidney disease, rickets, and/or neurologic crises in children older than age six months
Untreated children may have repeated neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.
Note: (1) Increased excretion of succinylacetone in the urine of a child with liver failure or severe kidney disease is a pathognomonic sign of tyrosinemia type I. (2) Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.
Note: (1) Plasma tyrosine concentration in affected infants can be normal in cord blood and during the newborn period. (2) Elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity; for example, in infants taking a high-protein formula [
Prolonged prothrombin and partial thromboplastin times
Note: (1) Changes in serum concentration of alpha-fetoprotein (AFP) and prothrombin time / partial thromboplastin time (PT/PTT) are more severe in tyrosinemia type I than in nonspecific liver disease and are often the presenting findings in tyrosinemia type I. (2) Transaminases and bilirubin are only modestly elevated, if at all. (3) An individual with liver disease and normal serum concentration of AFP and normal PT/PTT has a low probability of having tyrosinemia type I.
• Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
• Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
• Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
• Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
• Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
• Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
• Infants with tyrosinemia type I may have only modestly elevated or normal blood concentrations of tyrosine and methionine when the first newborn screening sample is collected.
• Elevated tyrosine concentration on newborn screening can be the result of transient tyrosinemia of the newborn,
• Elevated methionine concentration can indicate liver dysfunction, defects in methionine metabolism, or homocystinuria (see
• Severe liver disease in young infants
• Signs of kidney disease, rickets, and/or neurologic crises in children older than age six months
• Untreated children may have repeated neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation.
•
• Note: (1) Increased excretion of succinylacetone in the urine of a child with liver failure or severe kidney disease is a pathognomonic sign of tyrosinemia type I. (2) Many laboratories require that measurement of succinylacetone be specifically requested when ordering urine organic acids.
•
• Note: (1) Plasma tyrosine concentration in affected infants can be normal in cord blood and during the newborn period. (2) Elevated plasma tyrosine concentration can also be a nonspecific indicator of liver damage or immaturity; for example, in infants taking a high-protein formula [
•
• Prolonged prothrombin and partial thromboplastin times
• Prolonged prothrombin and partial thromboplastin times
• Prolonged prothrombin and partial thromboplastin times
## Establishing the Diagnosis
The diagnosis of tyrosinemia type I
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 [
Targeted analysis for the
The pathogenic variant
The four common
Molecular Genetic Testing Used in Tyrosinemia Type I
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.
• Targeted analysis for the
• The pathogenic variant
• The four common
## Molecular Genetic Testing
Targeted analysis for the
The pathogenic variant
The four common
Molecular Genetic Testing Used in Tyrosinemia Type I
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.
• Targeted analysis for the
• The pathogenic variant
• The four common
## Clinical Characteristics
This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [
In an international survey,
Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
Children with
In Quebec, where tyrosinemia type I is included in the newborn screening program, no affected individuals have been hospitalized for manifestations of tyrosinemia type I, and hepatocellular carcinoma has not been reported in individuals who were placed on nitisinone therapy prior to age 30 days. The longest period of treatment reported in this group is 12 years [
Fumarylacetoacetase (FAH) is the terminal enzyme in the tyrosine catabolic pathway (
Appears to accumulate in hepatocytes, causing cellular damage and apoptosis (identified in an animal model by
Is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the following hepatic enzymes:
Parahydroxyphenylpyruvic acid dioxygenase
PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
In general, no correlation is observed between clinical presentation and genotype. Acute and chronic forms have been seen in the same families, as well as in unrelated individuals with the same genotype [
One mechanism that explains this clinical variation is gene reversion. Hepatic nodules removed from livers of individuals with the chronic form of tyrosinemia type I have been shown to have cells that are immunologically positive for FAH protein and to have enzymatic activity for FAH [
Spontaneous somatic variants that suppress the effects of the pathogenic variants and allow for normal or near-normal gene expression in these cells have also been reported [
A rare and atypical form of tyrosinemia type I has been reported in a four-month-old Belgian infant with severe liver disease. Liver function studies were abnormal with markedly elevated alpha-fetoprotein, prolonged PT and PTT, and undetectable succinylacetone in urine. Fumarylacetoacetase (FAH) protein and activity was decreased, but not absent. Homozygosity for a unique pathogenic variant,
Similarly, three sibs who developed chronic liver disease and HCC without detectable blood or urine succinylacetone had deficient FAH activity. The family was of Middle Eastern background and each child was homozygous for
The term " tyrosinosis" was previously used to refer to tyrosinemia type I include tyrosinosis.
In geographic areas without newborn screening, tyrosinemia type I affects approximately one in 100,000 to 120,000 births [
In the general US population, the carrier frequency is estimated at 1:150 to 1:100.
Two regions of the world have a higher than expected frequency of tyrosinemia type I due to the increased frequency of certain pathogenic variants resulting from a founder effect:
In the Scandanavian countries (
A founder effect from colonization by French settlers is present in the province of Quebec, Canada. The c.1062+5G>A (IVS12+5 G>A) pathogenic variant accounts for 87% of allelic variants in this population. The birth prevalence in the province of Quebec is 1:16,000. In the Saguenay-Lac Saint-Jean region of Quebec, it is 1:1,846 live births. The overall carrier frequency in Quebec is 1:66 based on newborn screening data. The carrier frequency in the Saguenay-Lac St-Jean region is 1:16-1:20.
• This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [
• In an international survey,
• In an international survey,
• Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
• After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
• Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
• After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
• In an international survey,
• Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
• After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
• Children with
• In Quebec, where tyrosinemia type I is included in the newborn screening program, no affected individuals have been hospitalized for manifestations of tyrosinemia type I, and hepatocellular carcinoma has not been reported in individuals who were placed on nitisinone therapy prior to age 30 days. The longest period of treatment reported in this group is 12 years [
• Appears to accumulate in hepatocytes, causing cellular damage and apoptosis (identified in an animal model by
• Is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the following hepatic enzymes:
• Parahydroxyphenylpyruvic acid dioxygenase
• PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
• Parahydroxyphenylpyruvic acid dioxygenase
• PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
• Parahydroxyphenylpyruvic acid dioxygenase
• PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
• In the Scandanavian countries (
• A founder effect from colonization by French settlers is present in the province of Quebec, Canada. The c.1062+5G>A (IVS12+5 G>A) pathogenic variant accounts for 87% of allelic variants in this population. The birth prevalence in the province of Quebec is 1:16,000. In the Saguenay-Lac Saint-Jean region of Quebec, it is 1:1,846 live births. The overall carrier frequency in Quebec is 1:66 based on newborn screening data. The carrier frequency in the Saguenay-Lac St-Jean region is 1:16-1:20.
## Clinical Description
This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [
In an international survey,
Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
Children with
In Quebec, where tyrosinemia type I is included in the newborn screening program, no affected individuals have been hospitalized for manifestations of tyrosinemia type I, and hepatocellular carcinoma has not been reported in individuals who were placed on nitisinone therapy prior to age 30 days. The longest period of treatment reported in this group is 12 years [
• This early phase can progress to liver failure with ascites, jaundice, and gastrointestinal bleeding. Children may have a characteristic odor of "boiled cabbage" or "rotten mushrooms." Infants occasionally have persistent hypoglycemia; some have hyperinsulinism [
• In an international survey,
• In an international survey,
• Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
• After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
• Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
• After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
• In an international survey,
• Those diagnosed between ages two and six months had a 74% two-year survival rate; those diagnosed after age six months had a 96% two-year survival rate.
• After more than five years the survival rate of the group diagnosed between ages two and six months dropped to approximately 30% and that of the group diagnosed after age six months dropped to approximately 60% (
• Children with
• In Quebec, where tyrosinemia type I is included in the newborn screening program, no affected individuals have been hospitalized for manifestations of tyrosinemia type I, and hepatocellular carcinoma has not been reported in individuals who were placed on nitisinone therapy prior to age 30 days. The longest period of treatment reported in this group is 12 years [
## Pathophysiology
Fumarylacetoacetase (FAH) is the terminal enzyme in the tyrosine catabolic pathway (
Appears to accumulate in hepatocytes, causing cellular damage and apoptosis (identified in an animal model by
Is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the following hepatic enzymes:
Parahydroxyphenylpyruvic acid dioxygenase
PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
• Appears to accumulate in hepatocytes, causing cellular damage and apoptosis (identified in an animal model by
• Is diverted into succinylacetoacetate and succinylacetone. Succinylacetone interferes with the activity of the following hepatic enzymes:
• Parahydroxyphenylpyruvic acid dioxygenase
• PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
• Parahydroxyphenylpyruvic acid dioxygenase
• PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
• Parahydroxyphenylpyruvic acid dioxygenase
• PBG synthase, resulting in (1) reduced activity of the enzyme δ-ALA dehydratase in liver and circulating red blood cells; (2) reduced heme synthesis; (3) increased δ-aminolevulinic acid (δ-ALA), which may induce acute neurologic episodes; and (4) increased urinary excretion of δ-ALA.
## Genotype-Phenotype Correlations
In general, no correlation is observed between clinical presentation and genotype. Acute and chronic forms have been seen in the same families, as well as in unrelated individuals with the same genotype [
One mechanism that explains this clinical variation is gene reversion. Hepatic nodules removed from livers of individuals with the chronic form of tyrosinemia type I have been shown to have cells that are immunologically positive for FAH protein and to have enzymatic activity for FAH [
Spontaneous somatic variants that suppress the effects of the pathogenic variants and allow for normal or near-normal gene expression in these cells have also been reported [
A rare and atypical form of tyrosinemia type I has been reported in a four-month-old Belgian infant with severe liver disease. Liver function studies were abnormal with markedly elevated alpha-fetoprotein, prolonged PT and PTT, and undetectable succinylacetone in urine. Fumarylacetoacetase (FAH) protein and activity was decreased, but not absent. Homozygosity for a unique pathogenic variant,
Similarly, three sibs who developed chronic liver disease and HCC without detectable blood or urine succinylacetone had deficient FAH activity. The family was of Middle Eastern background and each child was homozygous for
## Nomenclature
The term " tyrosinosis" was previously used to refer to tyrosinemia type I include tyrosinosis.
## Prevalence
In geographic areas without newborn screening, tyrosinemia type I affects approximately one in 100,000 to 120,000 births [
In the general US population, the carrier frequency is estimated at 1:150 to 1:100.
Two regions of the world have a higher than expected frequency of tyrosinemia type I due to the increased frequency of certain pathogenic variants resulting from a founder effect:
In the Scandanavian countries (
A founder effect from colonization by French settlers is present in the province of Quebec, Canada. The c.1062+5G>A (IVS12+5 G>A) pathogenic variant accounts for 87% of allelic variants in this population. The birth prevalence in the province of Quebec is 1:16,000. In the Saguenay-Lac Saint-Jean region of Quebec, it is 1:1,846 live births. The overall carrier frequency in Quebec is 1:66 based on newborn screening data. The carrier frequency in the Saguenay-Lac St-Jean region is 1:16-1:20.
• In the Scandanavian countries (
• A founder effect from colonization by French settlers is present in the province of Quebec, Canada. The c.1062+5G>A (IVS12+5 G>A) pathogenic variant accounts for 87% of allelic variants in this population. The birth prevalence in the province of Quebec is 1:16,000. In the Saguenay-Lac Saint-Jean region of Quebec, it is 1:1,846 live births. The overall carrier frequency in Quebec is 1:66 based on newborn screening data. The carrier frequency in the Saguenay-Lac St-Jean region is 1:16-1:20.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Children with any of the following presenting findings (see
Differential Diagnosis of Tyrosinemia Type I in Infants by Presenting Finding
Immature liver
High-protein diet
Tyrosinemia type III (OMIM
Other liver disease
Disorders of methionine metabolism
Other liver disease
Fructose 1, 6 biphosphatase deficiency (OMIM
Neonatal hemochromatosis (OMIM
Transaldolase deficiency (OMIM
Acetaminophen toxicity
Bacterial infections (sepsis, salmonella, TB)
Viral infections (e.g., CMV, hepatitis A/B, herpes)
Mushroom poisoning
Herbal medicines
Idiosyncratic drug reaction, toxin, vascular/ischemic or infiltrative process
Renal tubular acidosis
Fanconi syndrome
Vitamin D deficiency (nutritional/genetic)
Vitamin D-dependent rickets
Fanconi syndrome
Cerebral hemorrhage/edema
Bacterial/viral meningitis
Hypernatremic dehydration
Undiluted goat's milk [
Plasma tyrosine concentration typically greater than 500 µmol/L that may exceed 1,000 µmol/L (The concentration of other amino acids is normal.)
Increased excretion of
Affected individuals have painful, nonpruritic, and hyperkeratotic plaques on the soles and palms. The plantar surface of the digits may show marked yellowish thickening associated with the hyperkeratosis. Ophthalmologic involvement is recalcitrant pseudodendritic keratitis [
Findings improve on a diet restricted in tyrosine and phenylalanine [
Few individuals with the disorder have been identified, and the clinical phenotype remains ill defined. The first affected individuals came to medical attention because of intellectual disability or ataxia; another was detected on routine screening [
A diet low in phenylalanine and tyrosine can lower plasma tyrosine concentration.
• Immature liver
• High-protein diet
• Tyrosinemia type III (OMIM
• Other liver disease
• Disorders of methionine metabolism
• Other liver disease
• Fructose 1, 6 biphosphatase deficiency (OMIM
• Neonatal hemochromatosis (OMIM
• Transaldolase deficiency (OMIM
• Acetaminophen toxicity
• Bacterial infections (sepsis, salmonella, TB)
• Viral infections (e.g., CMV, hepatitis A/B, herpes)
• Mushroom poisoning
• Herbal medicines
• Idiosyncratic drug reaction, toxin, vascular/ischemic or infiltrative process
• Renal tubular acidosis
• Fanconi syndrome
• Vitamin D deficiency (nutritional/genetic)
• Vitamin D-dependent rickets
• Fanconi syndrome
• Cerebral hemorrhage/edema
• Bacterial/viral meningitis
• Hypernatremic dehydration
• Plasma tyrosine concentration typically greater than 500 µmol/L that may exceed 1,000 µmol/L (The concentration of other amino acids is normal.)
• Increased excretion of
## Management
To establish the extent of disease and needs of a child diagnosed with tyrosinemia type I
CBC with platelet count
Serum concentration of electrolytes
Assessment of liver function (PT, PTT, AST, ALT, GGT, serum bilirubin concentration, alkaline phosphatase, and serum AFP).
For children ascertained
Baseline abdominal imagining by CT or MRI (with contrast) to evaluate for liver adenomas or nodules (see
X-ray of wrist to document presence or absence of rickets.
Clinical genetics consultation is indicated for all affected individuals.
Management guidelines have been published. US recommendations include
Nitisinone should be prescribed as soon as the diagnosis of tyrosinemia type I is confirmed.
Nitisinone is generally prescribed at 1.0 mg/kg/day; individual requirements may vary. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, which theoretically blocks more than 99% of
Nitisinone is typically given in two divided doses; however, because of the long half-life (50-60 hours), affected individuals who are older than one year and stable may maintain adequate therapy with 1x/day dosing [
Rare side effects of nitisinone have included: transient low platelet count and transient low neutrophil count that resolved without intervention; and photophobia that resolved with stricter dietary control and subsequent lowering of blood tyrosine concentrations.
Dietary management should be started immediately upon diagnosis and should provide a nutritionally complete diet with controlled intakes of phenylalanine and tyrosine using a vegetarian diet with low-protein foods and a medical formula such as Tyrex
Phenylalanine and tyrosine requirements are interdependent and vary from individual to individual and within the same individual depending on growth rate, adequacy of energy and protein intakes, and state of health. With appropriate dietary management, plasma tyrosine concentration should be 300-600 µmol/L, regardless of age; plasma phenylalanine concentration should be 20-80 µmol/L (0.3-1.3 mg/dL). If the blood concentration of phenylalanine is too low (<20 µmol/L), additional protein should be added to the diet from milk or foods.
Liver transplantation should be reserved for those children who (1) have severe liver failure at clinical presentation and fail to respond to nitisinone therapy or (2) have documented evidence of malignant changes in hepatic tissue [
Transplant recipients require long-term immunosuppression. Mortality associated with liver transplantation in young children is approximately 10%.
Transplant recipients may also benefit from low-dose (0.1mg/kg/day) nitisinone therapy to prevent continued renal tubular and glomerular dysfunction resulting from persistence of succinylacetone in the plasma and urine [
Treatment with nitisinone (Orfadin
Because carnitine deficiency secondary to the renal tubular Fanconi syndrome can cause skeletal muscle weakness, serum concentration of carnitine should be measured so that carnitine deficiency, if identified, can be treated [
Osteoporosis and rickets resulting from renal tubular damage are treated by correction of acidosis, restoring of calcium and phosphate balance, and administration of 25-hydroxy-vitamin D.
Frequent evaluation of the following parameters is typical in the management of individuals with tyrosinemia type I (
Suggested Guidelines for Monitoring in Individuals with Tyrosinemia Type I Diagnosed by Newborn Screening
AFP = alpha-fetoprotein; ALT/AST = alanine transaminase/aspartate transaminase; BUN = blood urea nitrogen; CBC = complete blood count; GGT = gamma-glutamyl transferase; nl = normal; PT/PTT = prothrombin time/partial thromboplastin time
MRI with contrast to evaluate for liver adenomas or nodules and for kidney size
For monitoring children diagnosed based on clinical presention, see
For alternative management recommendations, see
Avoid inappropriate protein intake.
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 preventive measures. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known. Prenatal testing can be used to clarify the genetic status of at-risk sibs before birth.
Blood or urine succinylacetone analysis as soon as possible after birth if prenatal testing was not performed. This allows prompt initiation of treatment, as postnatal genetic testing results may not be available in a timely fashion.
If the pathogenic variants in the family are not known, consideration of analysis for urine succinylacetone in healthy older sibs
See
Little data exist on the use of nitisinone during human pregnancy. Speculation would assume that the pregnant woman remains safe from untoward events; however, the developing fetus may be at risk because of alterations in tyrosine metabolism.
At least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone [
In one instance the affected mother gave birth to an unaffected infant who is reported to be healthy and developing normally at age 2.5 years [
In another instance, an affected woman gave birth to an affected child. The child is reported to have normal growth and development at age seven months [
See
Search
Prior to the availability of nitisinone, the only available non-transplant therapy was a diet limiting the availability of phenylalorine and tyrosine. Although the diet was modestly helpful, recurrent episodes of neurologic crises and progression of liver disease occurred. Average survival was less than age ten years.
• CBC with platelet count
• Serum concentration of electrolytes
• Assessment of liver function (PT, PTT, AST, ALT, GGT, serum bilirubin concentration, alkaline phosphatase, and serum AFP).
• Baseline abdominal imagining by CT or MRI (with contrast) to evaluate for liver adenomas or nodules (see
• X-ray of wrist to document presence or absence of rickets.
• Nitisinone should be prescribed as soon as the diagnosis of tyrosinemia type I is confirmed.
• Nitisinone is generally prescribed at 1.0 mg/kg/day; individual requirements may vary. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, which theoretically blocks more than 99% of
• Nitisinone is typically given in two divided doses; however, because of the long half-life (50-60 hours), affected individuals who are older than one year and stable may maintain adequate therapy with 1x/day dosing [
• Rare side effects of nitisinone have included: transient low platelet count and transient low neutrophil count that resolved without intervention; and photophobia that resolved with stricter dietary control and subsequent lowering of blood tyrosine concentrations.
• Dietary management should be started immediately upon diagnosis and should provide a nutritionally complete diet with controlled intakes of phenylalanine and tyrosine using a vegetarian diet with low-protein foods and a medical formula such as Tyrex
• Phenylalanine and tyrosine requirements are interdependent and vary from individual to individual and within the same individual depending on growth rate, adequacy of energy and protein intakes, and state of health. With appropriate dietary management, plasma tyrosine concentration should be 300-600 µmol/L, regardless of age; plasma phenylalanine concentration should be 20-80 µmol/L (0.3-1.3 mg/dL). If the blood concentration of phenylalanine is too low (<20 µmol/L), additional protein should be added to the diet from milk or foods.
• Liver transplantation should be reserved for those children who (1) have severe liver failure at clinical presentation and fail to respond to nitisinone therapy or (2) have documented evidence of malignant changes in hepatic tissue [
• Transplant recipients require long-term immunosuppression. Mortality associated with liver transplantation in young children is approximately 10%.
• Transplant recipients may also benefit from low-dose (0.1mg/kg/day) nitisinone therapy to prevent continued renal tubular and glomerular dysfunction resulting from persistence of succinylacetone in the plasma and urine [
• Molecular genetic testing if the pathogenic variants in the family are known. Prenatal testing can be used to clarify the genetic status of at-risk sibs before birth.
• Blood or urine succinylacetone analysis as soon as possible after birth if prenatal testing was not performed. This allows prompt initiation of treatment, as postnatal genetic testing results may not be available in a timely fashion.
• If the pathogenic variants in the family are not known, consideration of analysis for urine succinylacetone in healthy older sibs
• In one instance the affected mother gave birth to an unaffected infant who is reported to be healthy and developing normally at age 2.5 years [
• In another instance, an affected woman gave birth to an affected child. The child is reported to have normal growth and development at age seven months [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of a child diagnosed with tyrosinemia type I
CBC with platelet count
Serum concentration of electrolytes
Assessment of liver function (PT, PTT, AST, ALT, GGT, serum bilirubin concentration, alkaline phosphatase, and serum AFP).
For children ascertained
Baseline abdominal imagining by CT or MRI (with contrast) to evaluate for liver adenomas or nodules (see
X-ray of wrist to document presence or absence of rickets.
Clinical genetics consultation is indicated for all affected individuals.
• CBC with platelet count
• Serum concentration of electrolytes
• Assessment of liver function (PT, PTT, AST, ALT, GGT, serum bilirubin concentration, alkaline phosphatase, and serum AFP).
• Baseline abdominal imagining by CT or MRI (with contrast) to evaluate for liver adenomas or nodules (see
• X-ray of wrist to document presence or absence of rickets.
## Treatment of Manifestations
Management guidelines have been published. US recommendations include
Nitisinone should be prescribed as soon as the diagnosis of tyrosinemia type I is confirmed.
Nitisinone is generally prescribed at 1.0 mg/kg/day; individual requirements may vary. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, which theoretically blocks more than 99% of
Nitisinone is typically given in two divided doses; however, because of the long half-life (50-60 hours), affected individuals who are older than one year and stable may maintain adequate therapy with 1x/day dosing [
Rare side effects of nitisinone have included: transient low platelet count and transient low neutrophil count that resolved without intervention; and photophobia that resolved with stricter dietary control and subsequent lowering of blood tyrosine concentrations.
Dietary management should be started immediately upon diagnosis and should provide a nutritionally complete diet with controlled intakes of phenylalanine and tyrosine using a vegetarian diet with low-protein foods and a medical formula such as Tyrex
Phenylalanine and tyrosine requirements are interdependent and vary from individual to individual and within the same individual depending on growth rate, adequacy of energy and protein intakes, and state of health. With appropriate dietary management, plasma tyrosine concentration should be 300-600 µmol/L, regardless of age; plasma phenylalanine concentration should be 20-80 µmol/L (0.3-1.3 mg/dL). If the blood concentration of phenylalanine is too low (<20 µmol/L), additional protein should be added to the diet from milk or foods.
Liver transplantation should be reserved for those children who (1) have severe liver failure at clinical presentation and fail to respond to nitisinone therapy or (2) have documented evidence of malignant changes in hepatic tissue [
Transplant recipients require long-term immunosuppression. Mortality associated with liver transplantation in young children is approximately 10%.
Transplant recipients may also benefit from low-dose (0.1mg/kg/day) nitisinone therapy to prevent continued renal tubular and glomerular dysfunction resulting from persistence of succinylacetone in the plasma and urine [
• Nitisinone should be prescribed as soon as the diagnosis of tyrosinemia type I is confirmed.
• Nitisinone is generally prescribed at 1.0 mg/kg/day; individual requirements may vary. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, which theoretically blocks more than 99% of
• Nitisinone is typically given in two divided doses; however, because of the long half-life (50-60 hours), affected individuals who are older than one year and stable may maintain adequate therapy with 1x/day dosing [
• Rare side effects of nitisinone have included: transient low platelet count and transient low neutrophil count that resolved without intervention; and photophobia that resolved with stricter dietary control and subsequent lowering of blood tyrosine concentrations.
• Dietary management should be started immediately upon diagnosis and should provide a nutritionally complete diet with controlled intakes of phenylalanine and tyrosine using a vegetarian diet with low-protein foods and a medical formula such as Tyrex
• Phenylalanine and tyrosine requirements are interdependent and vary from individual to individual and within the same individual depending on growth rate, adequacy of energy and protein intakes, and state of health. With appropriate dietary management, plasma tyrosine concentration should be 300-600 µmol/L, regardless of age; plasma phenylalanine concentration should be 20-80 µmol/L (0.3-1.3 mg/dL). If the blood concentration of phenylalanine is too low (<20 µmol/L), additional protein should be added to the diet from milk or foods.
• Liver transplantation should be reserved for those children who (1) have severe liver failure at clinical presentation and fail to respond to nitisinone therapy or (2) have documented evidence of malignant changes in hepatic tissue [
• Transplant recipients require long-term immunosuppression. Mortality associated with liver transplantation in young children is approximately 10%.
• Transplant recipients may also benefit from low-dose (0.1mg/kg/day) nitisinone therapy to prevent continued renal tubular and glomerular dysfunction resulting from persistence of succinylacetone in the plasma and urine [
## Prevention of Primary Manifestations
Treatment with nitisinone (Orfadin
## Prevention of Secondary Complications
Because carnitine deficiency secondary to the renal tubular Fanconi syndrome can cause skeletal muscle weakness, serum concentration of carnitine should be measured so that carnitine deficiency, if identified, can be treated [
Osteoporosis and rickets resulting from renal tubular damage are treated by correction of acidosis, restoring of calcium and phosphate balance, and administration of 25-hydroxy-vitamin D.
## Surveillance
Frequent evaluation of the following parameters is typical in the management of individuals with tyrosinemia type I (
Suggested Guidelines for Monitoring in Individuals with Tyrosinemia Type I Diagnosed by Newborn Screening
AFP = alpha-fetoprotein; ALT/AST = alanine transaminase/aspartate transaminase; BUN = blood urea nitrogen; CBC = complete blood count; GGT = gamma-glutamyl transferase; nl = normal; PT/PTT = prothrombin time/partial thromboplastin time
MRI with contrast to evaluate for liver adenomas or nodules and for kidney size
For monitoring children diagnosed based on clinical presention, see
For alternative management recommendations, see
## Agents/Circumstances to Avoid
Avoid inappropriate protein intake.
## 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 preventive measures. Evaluations can include:
Molecular genetic testing if the pathogenic variants in the family are known. Prenatal testing can be used to clarify the genetic status of at-risk sibs before birth.
Blood or urine succinylacetone analysis as soon as possible after birth if prenatal testing was not performed. This allows prompt initiation of treatment, as postnatal genetic testing results may not be available in a timely fashion.
If the pathogenic variants in the family are not known, consideration of analysis for urine succinylacetone in healthy older sibs
See
• Molecular genetic testing if the pathogenic variants in the family are known. Prenatal testing can be used to clarify the genetic status of at-risk sibs before birth.
• Blood or urine succinylacetone analysis as soon as possible after birth if prenatal testing was not performed. This allows prompt initiation of treatment, as postnatal genetic testing results may not be available in a timely fashion.
• If the pathogenic variants in the family are not known, consideration of analysis for urine succinylacetone in healthy older sibs
## Pregnancy Management
Little data exist on the use of nitisinone during human pregnancy. Speculation would assume that the pregnant woman remains safe from untoward events; however, the developing fetus may be at risk because of alterations in tyrosine metabolism.
At least two women have given birth to healthy infants while receiving therapeutic doses of nitisinone [
In one instance the affected mother gave birth to an unaffected infant who is reported to be healthy and developing normally at age 2.5 years [
In another instance, an affected woman gave birth to an affected child. The child is reported to have normal growth and development at age seven months [
See
• In one instance the affected mother gave birth to an unaffected infant who is reported to be healthy and developing normally at age 2.5 years [
• In another instance, an affected woman gave birth to an affected child. The child is reported to have normal growth and development at age seven months [
## Therapies Under Investigation
Search
## Other
Prior to the availability of nitisinone, the only available non-transplant therapy was a diet limiting the availability of phenylalorine and tyrosine. Although the diet was modestly helpful, recurrent episodes of neurologic crises and progression of liver disease occurred. Average survival was less than age ten years.
## Genetic Counseling
Tyrosinemia type I 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.
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.
• 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 affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Tyrosinemia type I 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.
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
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
## Resources
United Kingdom
Health Resources & Services Administration
•
•
•
•
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
## Molecular Genetics
Tyrosinemia Type I: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Tyrosinemia Type I (
The following population-specific pathogenic variants result from founder effects or genetic drift [
Ashkenazi Jewish: p.Pro261Leu
Finnish: p.Trp262Ter
French Canadian: c.1062+5G>A
Pakistani: p.Gln64His
Scandinavian: p.Gly337Ser
Turkish: p.Asp233Val
Northern European: c.1062+5G>A
Southern European: c.554-1G>T
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
For additional pathogenic variants identified in North American patients, see
• Ashkenazi Jewish: p.Pro261Leu
• Finnish: p.Trp262Ter
• French Canadian: c.1062+5G>A
• Pakistani: p.Gln64His
• Scandinavian: p.Gly337Ser
• Turkish: p.Asp233Val
• Northern European: c.1062+5G>A
• Southern European: c.554-1G>T
## Chapter Notes
Supported by grants from the Food and Drug Administration (FD-4-001445) and Rare Disease Therapeutics. The authors are appreciative of the collaboration and discussions with Dr Grant Mitchell of Montreal, Canada, and Dr Sven Lindstedt and Dr Elisabeth Holme of Gothenburg, Sweden.
25 May 2017 (ma) Comprehensive update posted live
17 July 2014 (me) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
21 October 2008 (cg) Comprehensive update posted live
24 July 2006 (me) Review posted live
29 June 2005 (crs) Original submission
• 25 May 2017 (ma) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 21 October 2008 (cg) Comprehensive update posted live
• 24 July 2006 (me) Review posted live
• 29 June 2005 (crs) Original submission
## Author Notes
## Acknowledgments
Supported by grants from the Food and Drug Administration (FD-4-001445) and Rare Disease Therapeutics. The authors are appreciative of the collaboration and discussions with Dr Grant Mitchell of Montreal, Canada, and Dr Sven Lindstedt and Dr Elisabeth Holme of Gothenburg, Sweden.
## Revision History
25 May 2017 (ma) Comprehensive update posted live
17 July 2014 (me) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
21 October 2008 (cg) Comprehensive update posted live
24 July 2006 (me) Review posted live
29 June 2005 (crs) Original submission
• 25 May 2017 (ma) Comprehensive update posted live
• 17 July 2014 (me) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 21 October 2008 (cg) Comprehensive update posted live
• 24 July 2006 (me) Review posted live
• 29 June 2005 (crs) Original submission
## References
## Literature Cited
The tyrosine catabolic pathway
Survival of children with tyrosinemia before 1992 [
|
[] |
24/7/2006
|
25/5/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ucd-overview
|
ucd-overview
|
[
"Citrullinemia Type I",
"Carbamoylphosphate Synthetase I Deficiency",
"Ornithine Transcarbamylase Deficiency",
"Argininosuccinate Lyase Deficiency",
"Arginase Deficiency",
"N-Acetylglutamate Synthase Deficiency",
"Arginase-1",
"Argininosuccinate lyase",
"Argininosuccinate synthase",
"Carbamoyl-phosphate synthase [ammonia], mitochondrial",
"Electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial",
"Mitochondrial ornithine transporter 1",
"N-acetylglutamate synthase, mitochondrial",
"Ornithine transcarbamylase, mitochondrial",
"ARG1",
"ASL",
"ASS1",
"CPS1",
"NAGS",
"OTC",
"SLC25A13",
"SLC25A15",
"Urea Cycle Disorders",
"Overview"
] |
Urea Cycle Disorders Overview
|
Kara L Simpson, Erin L MacLeod, Aadil Kakajiwala, Andrea L Gropman, Nicholas Ah Mew
|
Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform
|
## Clinical Characteristics of Urea Cycle Disorders
The urea cycle is (1) the principal mechanism for the clearance of waste nitrogen from protein and other nitrogenous compounds and (2) the sole source of endogenous production of arginine, ornithine, and citrulline.
The urea cycle (see
Five catalytic enzymes:
Carbamoyl-phosphate synthetase I (CPS1)
Ornithine transcarbamylase (OTC)
Argininosuccinate synthetase (ASS) (also called argininosuccinic acid synthetase)
Argininosuccinate lyase (ASL) (also called argininosuccinic acid lyase)
Arginase (ARG1)
One cofactor-producing enzyme: N-acetylglutamate synthetase (NAGS)
Two amino acid transporters:
Ornithine translocase (ORNT1) (also called mitochondrial ornithine transporter 1 and solute carrier family 25 member 15)
Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial; mitochondrial aspartate glutamate carrier 2; and solute carrier family 25 member 13)
Urea cycle disorders result from inherited deficiencies in any one of the six enzymes (CPS1, OTC, ASS, ASL, ARG1, and NAGS) or two amino acid transporters (ORNT1 and citrin) of the urea cycle pathway.
Severity of a urea cycle disorder is influenced by the position of the non-functional protein in the urea cycle pathway (see
Neonates with a urea cycle disorder appear normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma due to hyperammonemia. Because neonates are often discharged from the hospital within two days after birth, the manifestations of a urea cycle disorder often develop when the newborn is at home and may not be recognized in a timely manner by the family and/or primary care physician.
Failure to feed and vomiting
Loss of thermoregulation with a low core temperature
Irritability
Somnolence
Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem.
About 50% of neonates with severe hyperammonemia may have seizures, some without overt clinical manifestations. Seizures are common in acute hyperammonemia and may result from cerebral damage. Subclinical seizures are common in acute hyperammonemic episodes, especially in neonates; their effects on cerebral metabolism in an otherwise compromised state should be addressed. These seizures may be seen during the rise of blood glutamine concentration even before blood ammonia concentrations peak [
Hyperventilation, secondary to the effects of hyperammonemia on the brain stem, is a common early finding with hyperammonemia that results in respiratory alkalosis [
Hypoventilation and respiratory arrest follow as pressure on the brain stem increases.
Manifestations of hyperammonemia may be different from those in neonates. Although clinical manifestations vary somewhat depending on the specific urea cycle disorder, hyperammonemia may result in loss of appetite, vomiting, lethargy, and neurobehavioral/psychiatric manifestations that can include sleep disorders, delusions, hallucinations, and/or psychosis.
Correct diagnosis of the manifestations of recurrent mild episodes of hyperammonemia may be delayed for months or years.
Children and adults, in whom cranial sutures are typically closed, are at a higher risk for rapid neurologic deterioration due to the cerebral edema that results from increased blood ammonia concentration.
Acute liver failure may also be a presenting feature [
Some individuals with "mild" or apparently "asymptomatic"
• Five catalytic enzymes:
• Carbamoyl-phosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinate synthetase (ASS) (also called argininosuccinic acid synthetase)
• Argininosuccinate lyase (ASL) (also called argininosuccinic acid lyase)
• Arginase (ARG1)
• Carbamoyl-phosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinate synthetase (ASS) (also called argininosuccinic acid synthetase)
• Argininosuccinate lyase (ASL) (also called argininosuccinic acid lyase)
• Arginase (ARG1)
• One cofactor-producing enzyme: N-acetylglutamate synthetase (NAGS)
• Two amino acid transporters:
• Ornithine translocase (ORNT1) (also called mitochondrial ornithine transporter 1 and solute carrier family 25 member 15)
• Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial; mitochondrial aspartate glutamate carrier 2; and solute carrier family 25 member 13)
• Ornithine translocase (ORNT1) (also called mitochondrial ornithine transporter 1 and solute carrier family 25 member 15)
• Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial; mitochondrial aspartate glutamate carrier 2; and solute carrier family 25 member 13)
• Carbamoyl-phosphate synthetase I (CPS1)
• Ornithine transcarbamylase (OTC)
• Argininosuccinate synthetase (ASS) (also called argininosuccinic acid synthetase)
• Argininosuccinate lyase (ASL) (also called argininosuccinic acid lyase)
• Arginase (ARG1)
• Ornithine translocase (ORNT1) (also called mitochondrial ornithine transporter 1 and solute carrier family 25 member 15)
• Citrin (also called electrogenic aspartate/glutamate antiporter SLC25A13, mitochondrial; mitochondrial aspartate glutamate carrier 2; and solute carrier family 25 member 13)
• Failure to feed and vomiting
• Loss of thermoregulation with a low core temperature
• Irritability
• Somnolence
• Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem.
• About 50% of neonates with severe hyperammonemia may have seizures, some without overt clinical manifestations. Seizures are common in acute hyperammonemia and may result from cerebral damage. Subclinical seizures are common in acute hyperammonemic episodes, especially in neonates; their effects on cerebral metabolism in an otherwise compromised state should be addressed. These seizures may be seen during the rise of blood glutamine concentration even before blood ammonia concentrations peak [
• Hyperventilation, secondary to the effects of hyperammonemia on the brain stem, is a common early finding with hyperammonemia that results in respiratory alkalosis [
• Hypoventilation and respiratory arrest follow as pressure on the brain stem increases.
• Manifestations of hyperammonemia may be different from those in neonates. Although clinical manifestations vary somewhat depending on the specific urea cycle disorder, hyperammonemia may result in loss of appetite, vomiting, lethargy, and neurobehavioral/psychiatric manifestations that can include sleep disorders, delusions, hallucinations, and/or psychosis.
• Correct diagnosis of the manifestations of recurrent mild episodes of hyperammonemia may be delayed for months or years.
• Children and adults, in whom cranial sutures are typically closed, are at a higher risk for rapid neurologic deterioration due to the cerebral edema that results from increased blood ammonia concentration.
• Acute liver failure may also be a presenting feature [
• Some individuals with "mild" or apparently "asymptomatic"
## Clinical Characteristics
Severity of a urea cycle disorder is influenced by the position of the non-functional protein in the urea cycle pathway (see
Neonates with a urea cycle disorder appear normal at birth but rapidly develop cerebral edema and the related signs of lethargy, anorexia, hyper- or hypoventilation, hypothermia, seizures, neurologic posturing, and coma due to hyperammonemia. Because neonates are often discharged from the hospital within two days after birth, the manifestations of a urea cycle disorder often develop when the newborn is at home and may not be recognized in a timely manner by the family and/or primary care physician.
Failure to feed and vomiting
Loss of thermoregulation with a low core temperature
Irritability
Somnolence
Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem.
About 50% of neonates with severe hyperammonemia may have seizures, some without overt clinical manifestations. Seizures are common in acute hyperammonemia and may result from cerebral damage. Subclinical seizures are common in acute hyperammonemic episodes, especially in neonates; their effects on cerebral metabolism in an otherwise compromised state should be addressed. These seizures may be seen during the rise of blood glutamine concentration even before blood ammonia concentrations peak [
Hyperventilation, secondary to the effects of hyperammonemia on the brain stem, is a common early finding with hyperammonemia that results in respiratory alkalosis [
Hypoventilation and respiratory arrest follow as pressure on the brain stem increases.
Manifestations of hyperammonemia may be different from those in neonates. Although clinical manifestations vary somewhat depending on the specific urea cycle disorder, hyperammonemia may result in loss of appetite, vomiting, lethargy, and neurobehavioral/psychiatric manifestations that can include sleep disorders, delusions, hallucinations, and/or psychosis.
Correct diagnosis of the manifestations of recurrent mild episodes of hyperammonemia may be delayed for months or years.
Children and adults, in whom cranial sutures are typically closed, are at a higher risk for rapid neurologic deterioration due to the cerebral edema that results from increased blood ammonia concentration.
Acute liver failure may also be a presenting feature [
Some individuals with "mild" or apparently "asymptomatic"
• Failure to feed and vomiting
• Loss of thermoregulation with a low core temperature
• Irritability
• Somnolence
• Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure on the brain stem.
• About 50% of neonates with severe hyperammonemia may have seizures, some without overt clinical manifestations. Seizures are common in acute hyperammonemia and may result from cerebral damage. Subclinical seizures are common in acute hyperammonemic episodes, especially in neonates; their effects on cerebral metabolism in an otherwise compromised state should be addressed. These seizures may be seen during the rise of blood glutamine concentration even before blood ammonia concentrations peak [
• Hyperventilation, secondary to the effects of hyperammonemia on the brain stem, is a common early finding with hyperammonemia that results in respiratory alkalosis [
• Hypoventilation and respiratory arrest follow as pressure on the brain stem increases.
• Manifestations of hyperammonemia may be different from those in neonates. Although clinical manifestations vary somewhat depending on the specific urea cycle disorder, hyperammonemia may result in loss of appetite, vomiting, lethargy, and neurobehavioral/psychiatric manifestations that can include sleep disorders, delusions, hallucinations, and/or psychosis.
• Correct diagnosis of the manifestations of recurrent mild episodes of hyperammonemia may be delayed for months or years.
• Children and adults, in whom cranial sutures are typically closed, are at a higher risk for rapid neurologic deterioration due to the cerebral edema that results from increased blood ammonia concentration.
• Acute liver failure may also be a presenting feature [
• Some individuals with "mild" or apparently "asymptomatic"
## Genetic Causes of Urea Cycle Disorders
Note: Disorders included in
Urea Cycle Disorders: Genes and Distinguishing Laboratory and Clinical Findings
Rarest of the urea cycle disorders
Neonatal presentations incl poor feeding or feeding intolerance, vomiting, lethargy, hypertonia &/or hypotonia, seizures, & tachypnea.
In later-onset disease, most common presenting symptoms incl vomiting, confusion or disorientation, ataxia, lethargy, ↓ level of consciousness, seizures, & hypotonia.
Most severe of the urea cycle disorders
Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
Children who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia.
Some persons w/CPS1 deficiency may benefit from therapy w/oral N-carbamylglutamate.
Most common urea cycle disorder
X-linked disorder
Can occur as severe neonatal-onset disease in males (but rarely in females) & as later-onset disease in males & females.
In all persons, typical neuropsychological complications incl DD/ID, learning disabilities, ADHD, & executive function deficits.
In newborns/infants, can manifest as neonatal intrahepatic cholestasis (NICCD), in older children as failure to thrive and dyslipidemia (FTTDCD), & in adults as recurrent hyperammonemia with neurobehavioral/psychiatric manifestations (CTLN2).
Often citrin deficiency is characterized by strong preference for protein-rich &/or lipid-rich foods & aversion to carbohydrate-rich foods.
Presents as a spectrum that includes a neonatal acute form, a milder late-onset form, a form in which women have onset of manifestations at pregnancy or post partum, & a form w/o symptoms or hyperammonemia
In the neonatal acute form, hyperammonemia can be quite severe.
Affected persons can incorporate some waste nitrogen into urea cycle intermediates, which makes treatment slightly easier than in other urea cycle disorders.
Presents as a severe neonatal-onset form or a late-onset form.
In the late-onset form, manifestations range from episodic hyperammonemia to cognitive impairment, behavioral abnormalities, &/or learning disabilities in the absence of any documented episodes of hyperammonemia.
Manifestations that appear to be unrelated to the severity or duration of hyperammonemic episodes are neurocognitive deficiencies, liver disease, trichorrhexis nodosa (coarse brittle hair that breaks easily), & systemic hypertension.
Characterized in untreated persons by episodic hyperammonemia of variable degree
Birth & early childhood are commonly normal.
Untreated persons have slowing of linear growth at age 1-3 yrs, followed by development of spasticity, plateauing of cognitive development, & subsequent loss of developmental milestones.
If untreated, usually progresses to severe spasticity, loss of ambulation, complete loss of bowel & bladder control, & severe ID.
Seizures are common.
Individuals treated from birth, either because of NBS or having an affected older sib, appear to have minimal symptoms.
Causes impaired ornithine transport across the inner mitochondrial membrane (ORNT1/SLC25A15) and consequent inadequate supply of ornithine to the urea cycle.
Variable clinical presentation & age of onset ranging from neonatal period to adulthood.
Those w/neonatal onset are normal for 1st 24-48 hrs, followed by onset of symptoms related to hyperammonemia.
Those w/later onset may present w/chronic neurocognitive deficits &/or unexplained seizures, spasticity, acute encephalopathy secondary to hyperammonemic crisis, or chronic liver dysfunction.
Neurologic findings & cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.
ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; ID = intellectual disability; NBS = newborn screening
The incidence of urea cycle disorders is estimated to be at least one in 35,000 to one in 51,946 live births [
Estimated Incidence of Individual Urea Cycle Disorders
ARG1 = arginase; ASL = argininosuccinate lyase; CPS1 = carbamoyl-phosphate synthetase I; HHH = hyperornithinemia-hyperammonemia-homocitrullinuria; NAGS = N-acetylglutamate synthetase deficiency; OTC = ornithine transcarbamylase
The incidence of citrin deficiency in East Asian or Southeast Asian populations may be between one in 17,000 and one in 230,000 [
• Rarest of the urea cycle disorders
• Neonatal presentations incl poor feeding or feeding intolerance, vomiting, lethargy, hypertonia &/or hypotonia, seizures, & tachypnea.
• In later-onset disease, most common presenting symptoms incl vomiting, confusion or disorientation, ataxia, lethargy, ↓ level of consciousness, seizures, & hypotonia.
• Most severe of the urea cycle disorders
• Persons w/complete CPS1 deficiency rapidly develop hyperammonemia in newborn period.
• Children who are successfully rescued from crisis are chronically at risk for repeated bouts of hyperammonemia.
• Some persons w/CPS1 deficiency may benefit from therapy w/oral N-carbamylglutamate.
• Most common urea cycle disorder
• X-linked disorder
• Can occur as severe neonatal-onset disease in males (but rarely in females) & as later-onset disease in males & females.
• In all persons, typical neuropsychological complications incl DD/ID, learning disabilities, ADHD, & executive function deficits.
• In newborns/infants, can manifest as neonatal intrahepatic cholestasis (NICCD), in older children as failure to thrive and dyslipidemia (FTTDCD), & in adults as recurrent hyperammonemia with neurobehavioral/psychiatric manifestations (CTLN2).
• Often citrin deficiency is characterized by strong preference for protein-rich &/or lipid-rich foods & aversion to carbohydrate-rich foods.
• Presents as a spectrum that includes a neonatal acute form, a milder late-onset form, a form in which women have onset of manifestations at pregnancy or post partum, & a form w/o symptoms or hyperammonemia
• In the neonatal acute form, hyperammonemia can be quite severe.
• Affected persons can incorporate some waste nitrogen into urea cycle intermediates, which makes treatment slightly easier than in other urea cycle disorders.
• Presents as a severe neonatal-onset form or a late-onset form.
• In the late-onset form, manifestations range from episodic hyperammonemia to cognitive impairment, behavioral abnormalities, &/or learning disabilities in the absence of any documented episodes of hyperammonemia.
• Manifestations that appear to be unrelated to the severity or duration of hyperammonemic episodes are neurocognitive deficiencies, liver disease, trichorrhexis nodosa (coarse brittle hair that breaks easily), & systemic hypertension.
• Characterized in untreated persons by episodic hyperammonemia of variable degree
• Birth & early childhood are commonly normal.
• Untreated persons have slowing of linear growth at age 1-3 yrs, followed by development of spasticity, plateauing of cognitive development, & subsequent loss of developmental milestones.
• If untreated, usually progresses to severe spasticity, loss of ambulation, complete loss of bowel & bladder control, & severe ID.
• Seizures are common.
• Individuals treated from birth, either because of NBS or having an affected older sib, appear to have minimal symptoms.
• Causes impaired ornithine transport across the inner mitochondrial membrane (ORNT1/SLC25A15) and consequent inadequate supply of ornithine to the urea cycle.
• Variable clinical presentation & age of onset ranging from neonatal period to adulthood.
• Those w/neonatal onset are normal for 1st 24-48 hrs, followed by onset of symptoms related to hyperammonemia.
• Those w/later onset may present w/chronic neurocognitive deficits &/or unexplained seizures, spasticity, acute encephalopathy secondary to hyperammonemic crisis, or chronic liver dysfunction.
• Neurologic findings & cognitive abilities can continue to deteriorate despite early metabolic control that prevents hyperammonemia.
## Differential Diagnosis of Urea Cycle Disorders
Genetic disorders that perturb liver function can result in hyperammonemia and mimic the effects of a urea cycle disorder are summarized in
Acquired conditions that can result in hyperammonemia and mimic the effects of a urea cycle disorder such as neonatal sepsis and diseases of the liver and biliary tract and the use of certain medications are not discussed here.
Genetic Disorders of Interest in the Differential Diagnosis of Urea Cycle Disorders
Ornithine may be ↓ in affected neonates who present w/hyperammonemia.
However, older persons w/OAT deficiency have markedly ↑ levels of ornithine & do not present w/hyperammonemia.
AD = autosomal dominant; AR = autosomal recessive; CPT = carnitine palmitoyltransferase; LCHAD = long-chain hydroxyacyl-coenzyme A dehydrogenase deficiency; MADD = multiple acyl-coenzyme A dehydrogenase deficiency; MCAD = medium-chain acyl-coenzyme A dehydrogenase deficiency; MOI = mode of inheritance; MT = mitochondrial; SCAD = short-chain acyl-coenzyme A dehydrogenase deficiency; VLCAD = very long-chain acyl-coenzyme A dehydrogenase deficiency; XL = X-linked
Transient hyperammonemia of the newborn (THAN), a diagnosis of uncertain (and possibly) heterogeneous etiology [
• Ornithine may be ↓ in affected neonates who present w/hyperammonemia.
• However, older persons w/OAT deficiency have markedly ↑ levels of ornithine & do not present w/hyperammonemia.
## Evaluation Strategies to Identify the Genetic Cause of a Urea Cycle Disorder in a Proband
The diagnosis of a urea cycle disorder in a symptomatic individual is based on clinical, biochemical, and molecular genetic data.
Establishing a specific genetic cause of a urea cycle disorder in a proband:
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a physical examination, family history, biochemical testing, and genomic/genetic testing.
The sensitivity and specificity of NBS panels for urea cycle disorders is based on the quantification of arginine and citrulline. Not all urea cycle disorders can be screened with those two analytes.
OTC deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, and
Even for urea cycle disorders detectable by NBS, neonates with severe disease are often symptomatic prior to reporting of the NBS results; thus, health care providers need a high level of clinical suspicion for clinical signs and symptoms and/or hyperammonemia in sick newborns.
Infants with abnormal NBS results but no clinical signs or symptoms will require follow up biochemical testing and, in some cases, DNA-based testing for definitive diagnosis. Results of biochemical testing should be utilized to determine treatment plans given that NBS will detect newborns with mild as well as severe urea cycle disorders [
An elevated blood ammonia concentration in a newborn is highly suggestive of an inherited metabolic disorder, including a urea cycle disorder.
The following may be helpful in determining the likelihood of a urea cycle disorder:
Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.
Elevated blood ammonia concentration in a newborn should also prompt consideration of additional investigations: quantitative analysis of plasma amino acids and urine organic acids and acylcarnitines.
Only the following urea cycle disorders have a specific biochemical pattern:
ARG1 deficiency: high plasma arginine concentration
ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
Normal or low in CPS1 deficiency and NAGS deficiency
Significantly elevated in OTC deficiency
Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the
Molecular genetic testing (i.e., DNA-based testing) is the primary method of diagnostic confirmation for all eight urea cycle disorders. Molecular testing has supplanted measurement of enzyme activity as the definitive diagnostic test. However, enzymatic testing remains available for ARG1 deficiency (see
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
If molecular testing is uninformative, ARG1 deficiency can be diagnosed by assay of enzyme activity in erythrocytes.
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a physical examination, family history, biochemical testing, and genomic/genetic testing.
• OTC deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, and
• Even for urea cycle disorders detectable by NBS, neonates with severe disease are often symptomatic prior to reporting of the NBS results; thus, health care providers need a high level of clinical suspicion for clinical signs and symptoms and/or hyperammonemia in sick newborns.
• Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
• Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.
• Only the following urea cycle disorders have a specific biochemical pattern:
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
• Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
## Biochemical Testing
The sensitivity and specificity of NBS panels for urea cycle disorders is based on the quantification of arginine and citrulline. Not all urea cycle disorders can be screened with those two analytes.
OTC deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, and
Even for urea cycle disorders detectable by NBS, neonates with severe disease are often symptomatic prior to reporting of the NBS results; thus, health care providers need a high level of clinical suspicion for clinical signs and symptoms and/or hyperammonemia in sick newborns.
Infants with abnormal NBS results but no clinical signs or symptoms will require follow up biochemical testing and, in some cases, DNA-based testing for definitive diagnosis. Results of biochemical testing should be utilized to determine treatment plans given that NBS will detect newborns with mild as well as severe urea cycle disorders [
An elevated blood ammonia concentration in a newborn is highly suggestive of an inherited metabolic disorder, including a urea cycle disorder.
The following may be helpful in determining the likelihood of a urea cycle disorder:
Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.
Elevated blood ammonia concentration in a newborn should also prompt consideration of additional investigations: quantitative analysis of plasma amino acids and urine organic acids and acylcarnitines.
Only the following urea cycle disorders have a specific biochemical pattern:
ARG1 deficiency: high plasma arginine concentration
ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
Normal or low in CPS1 deficiency and NAGS deficiency
Significantly elevated in OTC deficiency
Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the
• OTC deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, and
• Even for urea cycle disorders detectable by NBS, neonates with severe disease are often symptomatic prior to reporting of the NBS results; thus, health care providers need a high level of clinical suspicion for clinical signs and symptoms and/or hyperammonemia in sick newborns.
• Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
• Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.
• Only the following urea cycle disorders have a specific biochemical pattern:
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
• Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
## Abnormal Newborn Screening (NBS) Result
The sensitivity and specificity of NBS panels for urea cycle disorders is based on the quantification of arginine and citrulline. Not all urea cycle disorders can be screened with those two analytes.
OTC deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, and
Even for urea cycle disorders detectable by NBS, neonates with severe disease are often symptomatic prior to reporting of the NBS results; thus, health care providers need a high level of clinical suspicion for clinical signs and symptoms and/or hyperammonemia in sick newborns.
Infants with abnormal NBS results but no clinical signs or symptoms will require follow up biochemical testing and, in some cases, DNA-based testing for definitive diagnosis. Results of biochemical testing should be utilized to determine treatment plans given that NBS will detect newborns with mild as well as severe urea cycle disorders [
• OTC deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency, N-acetylglutamate synthetase (NAGS) deficiency, and
• Even for urea cycle disorders detectable by NBS, neonates with severe disease are often symptomatic prior to reporting of the NBS results; thus, health care providers need a high level of clinical suspicion for clinical signs and symptoms and/or hyperammonemia in sick newborns.
## Elevated Ammonia in the Newborn
An elevated blood ammonia concentration in a newborn is highly suggestive of an inherited metabolic disorder, including a urea cycle disorder.
The following may be helpful in determining the likelihood of a urea cycle disorder:
Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.
Elevated blood ammonia concentration in a newborn should also prompt consideration of additional investigations: quantitative analysis of plasma amino acids and urine organic acids and acylcarnitines.
Only the following urea cycle disorders have a specific biochemical pattern:
ARG1 deficiency: high plasma arginine concentration
ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
Normal or low in CPS1 deficiency and NAGS deficiency
Significantly elevated in OTC deficiency
Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the
• Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder.
• Metabolic acidosis with a wide anion gap often suggests a cause other than a urea cycle disorder, such as an organic acidemia. However, septic newborns who have a urea cycle disorder can present with metabolic acidosis.
• Only the following urea cycle disorders have a specific biochemical pattern:
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Note: Blood concentrations of glutamine and alanine that serve as storage forms of waste nitrogen are also frequently elevated.
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
• Note: Urinary orotic acid concentration can be increased in citrullinemia type I as well as in ARG1 deficiency or ORNT1 deficiency due to insufficient substrate for the OTC enzyme. Orotic acid is thus increased due to excess carbamoyl-phosphate entering the
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
• ARG1 deficiency: high plasma arginine concentration
• ASL deficiency: elevated plasma/urinary argininosuccinate and its anhydrides
• ASS deficiency: high plasma citrulline concentration in the absence of argininosuccinate
• Citrin deficiency: high plasma citrulline, often with high threonine, methionine, and tyrosine
• HHH syndrome (ORNT1 deficiency): high urinary homocitrulline concentration
• Normal or low in CPS1 deficiency and NAGS deficiency
• Significantly elevated in OTC deficiency
## Molecular Genetic Testing
Molecular genetic testing (i.e., DNA-based testing) is the primary method of diagnostic confirmation for all eight urea cycle disorders. Molecular testing has supplanted measurement of enzyme activity as the definitive diagnostic test. However, enzymatic testing remains available for ARG1 deficiency (see
Molecular genetic testing approaches can include a combination of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
## Enzyme Activity
If molecular testing is uninformative, ARG1 deficiency can be diagnosed by assay of enzyme activity in erythrocytes.
## Management
Clinical practice guidelines for the management of urea cycle disorders have been published [
See also
Acute care of an individual with a urea cycle disorder should be provided by a team coordinated by a metabolic specialist in a tertiary care center. It is critical to stabilize the individual before transfer to a tertiary care center.
One example of a protocol is:
Various KRT modalities have been used to treat hyperammonemia, each with their own advantages and disadvantages. As KRT is a higher-risk technical procedure, the choice of KRT modality should be primarily guided by the available institutional expertise and resources [
Intermittent hemodialysis (iHD) has been used successfully for rapid reduction of plasma ammonia concentrations [
High-dose CKRT has been shown to achieve ammonia clearance rates comparable to those seen with iHD [
Note: Because clearance with peritoneal dialysis is substantially lower than with hemodialysis, hemodialysis (if available) is typically preferred [
Another hybrid approach consisting of iHD or CKRT with extracorporeal membrane oxygenation (ECMO) presents an option for neonates with cardiorespiratory failure and severe hemodynamic instability. This combination addresses the limitations of limited catheter sizes and blood flow rates that hinder ammonia clearance in neonates. However, the method also carries an increased risk of bleeding and cerebrovascular events, particularly in low-birth-weight neonates.
Nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate) is available as an intravenous infusion for acute management and an oral preparation for long-term maintenance.
Note: Although sodium phenylacetate and sodium benzoate can be infused through a peripheral IV, central access is preferred. As both medications are sodium salts, reduction of sodium from other infused sources or at least monitoring of sodium is recommended.
Deficient urea cycle intermediates need to be replaced depending on the diagnosis; these can include arginine (IV/oral/enteral) and/or citrulline (oral/enteral).
Note: Continuous arginine hydrochloride (HCl) infusion requires central access as extravasation from a peripheral IV has on multiple occasions resulted in severe cutaneous necrosis. Infused arginine may also cause hypotension, as it is a precursor to nitric oxide [
Intravenous (IV) Ammonia Scavenger Therapy Protocols
Loading: over 90-120 mins
Maintenance: continuously over 24 hrs
Based on
ARG1 = arginase; ASL = argininosuccinate lyase; ASS = argininosuccinate synthetase; CPS1 = carbamoyl-phosphate synthetase I; HCI = hydrochloride; NAGS = N-acetylglutamate synthetase deficiency; OTC = ornithine transcarbamylase
Doses shown per the FDA-approved prescribing information.
Per the FDA-approved prescribing information, sodium phenylacetate and sodium benzoate must be diluted with sterile dextrose injection 10% before administration. While the standard concentration is 10 mg/mL, bolus and continuous dose concentrations of 20 mg/mL [
The primary acute treatment for NAGS deficiency should be N-carbamylglutamate (see
One hundred percent of estimated energy needs should be provided through non-protein sources (carbohydrate and fat) to reverse catabolism.
Initial elimination of protein from the diet should not exceed 24 hours and prolonged restriction (>48 hours) should be avoided, as depletion of essential amino acids results in protein catabolism and nitrogen release. Frequent (often daily if available) quantitative assessments of plasma amino acid concentrations can help optimize nutritional management, permitting the clinician to maintain adequate endogenous levels of essential amino acids without having to provide excess nitrogen. Maintenance of appropriate plasma concentrations of essential amino acids is necessary to reverse the typical catabolic state, because most acutely ill individuals either already present with essential amino acid deficiency or will quickly become deficient.
Reintroduction of protein depends on the individual's clinical state and age. The goal for total protein intake should be to meet the Dietary Recommended Intake for age, which may require a combination of natural protein and essential amino acid medical food. If dialysis has been utilized, reintroduction may be more rapid to prevent rebound hyperammonemia resulting from catabolism. If dialysis has not been utilized, reintroduction of protein (essential amino acids and/or natural protein) may need to start lower and be more gradual.
Although enteral nutrition is preferred, intravenous (total parenteral nutrition) is an option when the individual is so clinically unstable that adequate enteral intake is not possible.
The placement of a nasogastric/jejunal tube at admission is warranted for slow drip administration of solutions of essential amino acids and infant formulas and administration of medications and supplements such as N-carbamylglutamate (analog of N-acetylglutamate) and L-citrulline.
Multiple other strategies to address catabolism can be used, including low-dose continuous infusion of insulin with maintenance of adequate glucose delivery by providing continuous delivery of high-carbohydrate-containing fluids; however, caution is advised, since affected individuals are often exquisitely sensitive to either glucose or insulin.
Use intravenous fluids (≥10% dextrose with appropriate electrolytes) for physiologic stabilization.
Consider the use of continuous bedside EEG to detect subclinical seizures. Note: Individuals in a coma may have subclinical seizures that are non-convulsive and, therefore, not apparent.
Note: In individuals with prolonged hyperammonemic coma and evidence of severe neurologic damage, the relative risks versus benefits of all the treatments discussed above should be considered on an individual basis.
In individuals with
In some persons with
NAGS Deficiency: Targeted Therapy
Recommended maintenance dose should be titrated to target normal plasma ammonia levels.
Because the only form currently available is an oral preparation, administration by nasogastric/jejunal tube is necessary in treatment of acute manifestations.
Note: N-carbamylglutamate (carglumic acid) should be added to the treatment regimen in an individual with hyperammonemia without a clear diagnosis at initial presentation.
For specific treatments, see the
• Various KRT modalities have been used to treat hyperammonemia, each with their own advantages and disadvantages. As KRT is a higher-risk technical procedure, the choice of KRT modality should be primarily guided by the available institutional expertise and resources [
• Intermittent hemodialysis (iHD) has been used successfully for rapid reduction of plasma ammonia concentrations [
• High-dose CKRT has been shown to achieve ammonia clearance rates comparable to those seen with iHD [
• Note: Because clearance with peritoneal dialysis is substantially lower than with hemodialysis, hemodialysis (if available) is typically preferred [
• Another hybrid approach consisting of iHD or CKRT with extracorporeal membrane oxygenation (ECMO) presents an option for neonates with cardiorespiratory failure and severe hemodynamic instability. This combination addresses the limitations of limited catheter sizes and blood flow rates that hinder ammonia clearance in neonates. However, the method also carries an increased risk of bleeding and cerebrovascular events, particularly in low-birth-weight neonates.
• Nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate) is available as an intravenous infusion for acute management and an oral preparation for long-term maintenance.
• Note: Although sodium phenylacetate and sodium benzoate can be infused through a peripheral IV, central access is preferred. As both medications are sodium salts, reduction of sodium from other infused sources or at least monitoring of sodium is recommended.
• Deficient urea cycle intermediates need to be replaced depending on the diagnosis; these can include arginine (IV/oral/enteral) and/or citrulline (oral/enteral).
• Note: Continuous arginine hydrochloride (HCl) infusion requires central access as extravasation from a peripheral IV has on multiple occasions resulted in severe cutaneous necrosis. Infused arginine may also cause hypotension, as it is a precursor to nitric oxide [
• Loading: over 90-120 mins
• Maintenance: continuously over 24 hrs
• Use intravenous fluids (≥10% dextrose with appropriate electrolytes) for physiologic stabilization.
• Consider the use of continuous bedside EEG to detect subclinical seizures. Note: Individuals in a coma may have subclinical seizures that are non-convulsive and, therefore, not apparent.
• Recommended maintenance dose should be titrated to target normal plasma ammonia levels.
• Because the only form currently available is an oral preparation, administration by nasogastric/jejunal tube is necessary in treatment of acute manifestations.
•
•
•
•
## Treatment of Hyperammonemia
Acute care of an individual with a urea cycle disorder should be provided by a team coordinated by a metabolic specialist in a tertiary care center. It is critical to stabilize the individual before transfer to a tertiary care center.
One example of a protocol is:
Various KRT modalities have been used to treat hyperammonemia, each with their own advantages and disadvantages. As KRT is a higher-risk technical procedure, the choice of KRT modality should be primarily guided by the available institutional expertise and resources [
Intermittent hemodialysis (iHD) has been used successfully for rapid reduction of plasma ammonia concentrations [
High-dose CKRT has been shown to achieve ammonia clearance rates comparable to those seen with iHD [
Note: Because clearance with peritoneal dialysis is substantially lower than with hemodialysis, hemodialysis (if available) is typically preferred [
Another hybrid approach consisting of iHD or CKRT with extracorporeal membrane oxygenation (ECMO) presents an option for neonates with cardiorespiratory failure and severe hemodynamic instability. This combination addresses the limitations of limited catheter sizes and blood flow rates that hinder ammonia clearance in neonates. However, the method also carries an increased risk of bleeding and cerebrovascular events, particularly in low-birth-weight neonates.
Nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate) is available as an intravenous infusion for acute management and an oral preparation for long-term maintenance.
Note: Although sodium phenylacetate and sodium benzoate can be infused through a peripheral IV, central access is preferred. As both medications are sodium salts, reduction of sodium from other infused sources or at least monitoring of sodium is recommended.
Deficient urea cycle intermediates need to be replaced depending on the diagnosis; these can include arginine (IV/oral/enteral) and/or citrulline (oral/enteral).
Note: Continuous arginine hydrochloride (HCl) infusion requires central access as extravasation from a peripheral IV has on multiple occasions resulted in severe cutaneous necrosis. Infused arginine may also cause hypotension, as it is a precursor to nitric oxide [
Intravenous (IV) Ammonia Scavenger Therapy Protocols
Loading: over 90-120 mins
Maintenance: continuously over 24 hrs
Based on
ARG1 = arginase; ASL = argininosuccinate lyase; ASS = argininosuccinate synthetase; CPS1 = carbamoyl-phosphate synthetase I; HCI = hydrochloride; NAGS = N-acetylglutamate synthetase deficiency; OTC = ornithine transcarbamylase
Doses shown per the FDA-approved prescribing information.
Per the FDA-approved prescribing information, sodium phenylacetate and sodium benzoate must be diluted with sterile dextrose injection 10% before administration. While the standard concentration is 10 mg/mL, bolus and continuous dose concentrations of 20 mg/mL [
The primary acute treatment for NAGS deficiency should be N-carbamylglutamate (see
One hundred percent of estimated energy needs should be provided through non-protein sources (carbohydrate and fat) to reverse catabolism.
Initial elimination of protein from the diet should not exceed 24 hours and prolonged restriction (>48 hours) should be avoided, as depletion of essential amino acids results in protein catabolism and nitrogen release. Frequent (often daily if available) quantitative assessments of plasma amino acid concentrations can help optimize nutritional management, permitting the clinician to maintain adequate endogenous levels of essential amino acids without having to provide excess nitrogen. Maintenance of appropriate plasma concentrations of essential amino acids is necessary to reverse the typical catabolic state, because most acutely ill individuals either already present with essential amino acid deficiency or will quickly become deficient.
Reintroduction of protein depends on the individual's clinical state and age. The goal for total protein intake should be to meet the Dietary Recommended Intake for age, which may require a combination of natural protein and essential amino acid medical food. If dialysis has been utilized, reintroduction may be more rapid to prevent rebound hyperammonemia resulting from catabolism. If dialysis has not been utilized, reintroduction of protein (essential amino acids and/or natural protein) may need to start lower and be more gradual.
Although enteral nutrition is preferred, intravenous (total parenteral nutrition) is an option when the individual is so clinically unstable that adequate enteral intake is not possible.
The placement of a nasogastric/jejunal tube at admission is warranted for slow drip administration of solutions of essential amino acids and infant formulas and administration of medications and supplements such as N-carbamylglutamate (analog of N-acetylglutamate) and L-citrulline.
Multiple other strategies to address catabolism can be used, including low-dose continuous infusion of insulin with maintenance of adequate glucose delivery by providing continuous delivery of high-carbohydrate-containing fluids; however, caution is advised, since affected individuals are often exquisitely sensitive to either glucose or insulin.
Use intravenous fluids (≥10% dextrose with appropriate electrolytes) for physiologic stabilization.
Consider the use of continuous bedside EEG to detect subclinical seizures. Note: Individuals in a coma may have subclinical seizures that are non-convulsive and, therefore, not apparent.
Note: In individuals with prolonged hyperammonemic coma and evidence of severe neurologic damage, the relative risks versus benefits of all the treatments discussed above should be considered on an individual basis.
• Various KRT modalities have been used to treat hyperammonemia, each with their own advantages and disadvantages. As KRT is a higher-risk technical procedure, the choice of KRT modality should be primarily guided by the available institutional expertise and resources [
• Intermittent hemodialysis (iHD) has been used successfully for rapid reduction of plasma ammonia concentrations [
• High-dose CKRT has been shown to achieve ammonia clearance rates comparable to those seen with iHD [
• Note: Because clearance with peritoneal dialysis is substantially lower than with hemodialysis, hemodialysis (if available) is typically preferred [
• Another hybrid approach consisting of iHD or CKRT with extracorporeal membrane oxygenation (ECMO) presents an option for neonates with cardiorespiratory failure and severe hemodynamic instability. This combination addresses the limitations of limited catheter sizes and blood flow rates that hinder ammonia clearance in neonates. However, the method also carries an increased risk of bleeding and cerebrovascular events, particularly in low-birth-weight neonates.
• Nitrogen scavenger therapy (sodium phenylacetate and sodium benzoate) is available as an intravenous infusion for acute management and an oral preparation for long-term maintenance.
• Note: Although sodium phenylacetate and sodium benzoate can be infused through a peripheral IV, central access is preferred. As both medications are sodium salts, reduction of sodium from other infused sources or at least monitoring of sodium is recommended.
• Deficient urea cycle intermediates need to be replaced depending on the diagnosis; these can include arginine (IV/oral/enteral) and/or citrulline (oral/enteral).
• Note: Continuous arginine hydrochloride (HCl) infusion requires central access as extravasation from a peripheral IV has on multiple occasions resulted in severe cutaneous necrosis. Infused arginine may also cause hypotension, as it is a precursor to nitric oxide [
• Loading: over 90-120 mins
• Maintenance: continuously over 24 hrs
• Use intravenous fluids (≥10% dextrose with appropriate electrolytes) for physiologic stabilization.
• Consider the use of continuous bedside EEG to detect subclinical seizures. Note: Individuals in a coma may have subclinical seizures that are non-convulsive and, therefore, not apparent.
## Disorder-Specific Treatments
In individuals with
In some persons with
NAGS Deficiency: Targeted Therapy
Recommended maintenance dose should be titrated to target normal plasma ammonia levels.
Because the only form currently available is an oral preparation, administration by nasogastric/jejunal tube is necessary in treatment of acute manifestations.
Note: N-carbamylglutamate (carglumic acid) should be added to the treatment regimen in an individual with hyperammonemia without a clear diagnosis at initial presentation.
For specific treatments, see the
• Recommended maintenance dose should be titrated to target normal plasma ammonia levels.
• Because the only form currently available is an oral preparation, administration by nasogastric/jejunal tube is necessary in treatment of acute manifestations.
•
•
•
•
## Targeted Therapy
In individuals with
In some persons with
NAGS Deficiency: Targeted Therapy
Recommended maintenance dose should be titrated to target normal plasma ammonia levels.
Because the only form currently available is an oral preparation, administration by nasogastric/jejunal tube is necessary in treatment of acute manifestations.
Note: N-carbamylglutamate (carglumic acid) should be added to the treatment regimen in an individual with hyperammonemia without a clear diagnosis at initial presentation.
For specific treatments, see the
• Recommended maintenance dose should be titrated to target normal plasma ammonia levels.
• Because the only form currently available is an oral preparation, administration by nasogastric/jejunal tube is necessary in treatment of acute manifestations.
•
•
•
•
## Genetic Counseling
N-acetylglutamate synthase (NAGS) deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency,
Once the molecular and/or biochemical diagnosis of a specific urea cycle disorder has been established in an affected family member, genetic counseling for that condition is indicated.
See Ornithine Transcarbamylase Deficiency,
Note: A basic view of autosomal recessive inheritance is provided below; genetic counseling issues specific to individual urea cycle disorders are not addressed.
The parents of an affected individual are presumed to be heterozygous for a pathogenic variant in a gene associated with autosomal recessive urea cycle disorders (i.e.,
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 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 a pathogenic variant associated with an autosomal recessive urea cycle disorder, 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 and discussion of the availability of prenatal/preimplantation genetic testing is before 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 American College of Medical Genetics includes OTC deficiency and ASL deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
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 the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
Prompt evaluation of newborn screening results (if performed) and collection and rapid analysis of blood ammonia and amino acids; consider delivery at tertiary care center where such tests are available on-site.
Molecular genetic testing if a molecular diagnosis has been established in an affected family member.
If the familial causative pathogenic variant in the family is unknown, elevated ammonia level or a diagnostic pattern of abnormal plasma amino acids and urine orotic acid (see
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 the diagnosis can be ruled out.
Hospital delivery at a specialized center with rapid neonatal transfer is recommended for delivery of a fetus at risk for an early-onset urea cycle disorder. At-risk newborns should be administered intravenous glucose with electrolytes, protein-free feeds, and alternative pathway medications (e.g., sodium phenylbutyrate or sodium benzoate and L-arginine therapy) as well as either citrulline (for proximal urea cycle disorders [ASS deficiency and ASL deficiency]) or arginine (for distal urea cycle disorders [OTC deficiency, CPS1 deficiency, and NAGS deficiency]; not for ARG1 deficiency). Frequent ammonia monitoring and urgent amino acid analysis guide treatment. A detailed protocol is described in
• The parents of an affected individual are presumed to be heterozygous for a pathogenic variant in a gene associated with autosomal recessive urea cycle disorders (i.e.,
• 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 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 a pathogenic variant associated with an autosomal recessive urea cycle disorder, 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 and discussion of the availability of prenatal/preimplantation genetic testing is before 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 American College of Medical Genetics includes OTC deficiency and ASL deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
• Prompt evaluation of newborn screening results (if performed) and collection and rapid analysis of blood ammonia and amino acids; consider delivery at tertiary care center where such tests are available on-site.
• Molecular genetic testing if a molecular diagnosis has been established in an affected family member.
• If the familial causative pathogenic variant in the family is unknown, elevated ammonia level or a diagnostic pattern of abnormal plasma amino acids and urine orotic acid (see
## Mode of Inheritance
N-acetylglutamate synthase (NAGS) deficiency, carbamoyl-phosphate synthetase I (CPS1) deficiency,
Once the molecular and/or biochemical diagnosis of a specific urea cycle disorder has been established in an affected family member, genetic counseling for that condition is indicated.
## X-Linked Inheritance – Risk to Family Members
See Ornithine Transcarbamylase Deficiency,
## Autosomal Recessive Inheritance – Risk to Family Members
Note: A basic view of autosomal recessive inheritance is provided below; genetic counseling issues specific to individual urea cycle disorders are not addressed.
The parents of an affected individual are presumed to be heterozygous for a pathogenic variant in a gene associated with autosomal recessive urea cycle disorders (i.e.,
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 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 a pathogenic variant associated with an autosomal recessive urea cycle disorder, 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 a pathogenic variant in a gene associated with autosomal recessive urea cycle disorders (i.e.,
• 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 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 a pathogenic variant associated with an autosomal recessive urea cycle disorder, 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.
## 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 American College of Medical Genetics includes OTC deficiency and ASL deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 American College of Medical Genetics includes OTC deficiency and ASL deficiency among those disorders for which expanded carrier screening should be offered to all pregnant individuals and individuals planning a pregnancy [
## 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 the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Evaluation of Relatives at Risk
Prompt evaluation of newborn screening results (if performed) and collection and rapid analysis of blood ammonia and amino acids; consider delivery at tertiary care center where such tests are available on-site.
Molecular genetic testing if a molecular diagnosis has been established in an affected family member.
If the familial causative pathogenic variant in the family is unknown, elevated ammonia level or a diagnostic pattern of abnormal plasma amino acids and urine orotic acid (see
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 the diagnosis can be ruled out.
Hospital delivery at a specialized center with rapid neonatal transfer is recommended for delivery of a fetus at risk for an early-onset urea cycle disorder. At-risk newborns should be administered intravenous glucose with electrolytes, protein-free feeds, and alternative pathway medications (e.g., sodium phenylbutyrate or sodium benzoate and L-arginine therapy) as well as either citrulline (for proximal urea cycle disorders [ASS deficiency and ASL deficiency]) or arginine (for distal urea cycle disorders [OTC deficiency, CPS1 deficiency, and NAGS deficiency]; not for ARG1 deficiency). Frequent ammonia monitoring and urgent amino acid analysis guide treatment. A detailed protocol is described in
• Prompt evaluation of newborn screening results (if performed) and collection and rapid analysis of blood ammonia and amino acids; consider delivery at tertiary care center where such tests are available on-site.
• Molecular genetic testing if a molecular diagnosis has been established in an affected family member.
• If the familial causative pathogenic variant in the family is unknown, elevated ammonia level or a diagnostic pattern of abnormal plasma amino acids and urine orotic acid (see
## Resources
Singapore
United Kingdom
Health Resources & Services Administration
Children's National Medical Center
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• Singapore
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## Chapter Notes
Nicholas Ah Mew (
Additionally, contact Dr Ah Mew to inquire about review of variants of uncertain significance in urea cycle disorder-related genes.
Nicholas Ah Mew, MD (2014-present)Kimberly A Chapman, MD, PhD; Children's National Health System (2011-2025)Andrea Gropman, MD (2011-present)Aadil Kakajiwala, MD (2025-present)Brendan C Lanpher, MD; Mayo Clinic (2011-2025)Uta Lichter-Konecki, MD, PhD; Columbia University (2011-2014)Erin L MacLeod, PhD, RD (2025-present)Kara L Simpson, MS, CGC (2014-present)Marshall L Summar, MD; Children's National Health System (2003-2025)Mendel Tuchman, MD; Children's National Medical Center (2003-2005)
3 July 2025 (bp) Comprehensive update posted live
22 June 2017 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
11 August 2005 (me) Comprehensive update posted live
29 April 2003 (me) Overview posted live
29 January 2001 (mls) Original submission
• 3 July 2025 (bp) Comprehensive update posted live
• 22 June 2017 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 11 August 2005 (me) Comprehensive update posted live
• 29 April 2003 (me) Overview posted live
• 29 January 2001 (mls) Original submission
## Author Notes
Nicholas Ah Mew (
Additionally, contact Dr Ah Mew to inquire about review of variants of uncertain significance in urea cycle disorder-related genes.
## Author History
Nicholas Ah Mew, MD (2014-present)Kimberly A Chapman, MD, PhD; Children's National Health System (2011-2025)Andrea Gropman, MD (2011-present)Aadil Kakajiwala, MD (2025-present)Brendan C Lanpher, MD; Mayo Clinic (2011-2025)Uta Lichter-Konecki, MD, PhD; Columbia University (2011-2014)Erin L MacLeod, PhD, RD (2025-present)Kara L Simpson, MS, CGC (2014-present)Marshall L Summar, MD; Children's National Health System (2003-2025)Mendel Tuchman, MD; Children's National Medical Center (2003-2005)
## Revision History
3 July 2025 (bp) Comprehensive update posted live
22 June 2017 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
1 September 2011 (me) Comprehensive update posted live
11 August 2005 (me) Comprehensive update posted live
29 April 2003 (me) Overview posted live
29 January 2001 (mls) Original submission
• 3 July 2025 (bp) Comprehensive update posted live
• 22 June 2017 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 1 September 2011 (me) Comprehensive update posted live
• 11 August 2005 (me) Comprehensive update posted live
• 29 April 2003 (me) Overview posted live
• 29 January 2001 (mls) Original submission
## References
Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230.
• Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230.
## Published Guidelines
Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230.
• Häberle J, Burlina A, Chakrapani A, Dixon M, Karall D, Lindner M, Mandel H, Martinelli D, Pintos-Morell G, Santer R, Skouma A, Servais A, Tal G, Rubio V, Huemer M, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;42:1192-230.
## Literature Cited
The urea cycle
Testing used in the diagnosis of urea cycle disorders
* If DNA testing is not informative, enzymatic testing is available for these disorders (see
Modified from
|
[] |
29/4/2003
|
3/7/2025
|
9/4/2015
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
udd
|
udd
|
[
"Udd Myopathy",
"Udd Myopathy",
"Titin",
"TTN",
"Udd Distal Myopathy – Tibial Muscular Dystrophy"
] |
Udd Distal Myopathy – Tibial Muscular Dystrophy
|
Bjarne Udd, Peter Hackman
|
Summary Udd distal myopathy – tibial muscular dystrophy (UDM-TMD) is characterized by weakness of ankle dorsiflexion and inability to walk on the heels after age 30 years. Disease progression is slow and muscle weakness remains confined to the anterior compartment muscles for many years. The long toe extensors become clinically involved after ten to 20 years, leading to foot drop and clumsiness when walking. In the mildest form, UDM-TMD can remain unnoticed even in the elderly. EMG shows profound myopathic changes in the anterior tibial muscle, but preservation of the extensor brevis muscle. Muscle MRI shows selective fatty degeneration of the anterior tibial muscles and other anterior compartment muscles of the lower legs. Serum CK concentration may be normal or slightly elevated. Muscle biopsy shows progressive dystrophic changes in the tibialis anterior muscle with rimmed vacuoles at the early stages and replacement with adipose tissue at later stages of the disease. The diagnosis of UDM-TMD is established in a proband with typical clinical findings and the identification of a heterozygous pathogenic variant in the last exon of UDM-TMD is inherited in an autosomal dominant manner. Most individuals diagnosed with UDM-TMD have an affected parent. Each child of an individual with UDM-TMD has a 50% risk of inheriting the
|
## Diagnosis
Udd distal myopathy – tibial muscular dystrophy (UDM-TMD)
The diagnosis of UDM-TMD
Note: The last six exons of
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 UDM-TMD is relatively distinct but overlaps with other adult-onset distal myopathies, individuals who exhibit the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of UDM-TMD, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry [See
For an introduction to multigene panels click
When the diagnosis of UDM-TMD is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in UDM-TMD
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 Human Gene Mutation Database [
FINmaj is an 11-bp deletion/insertion observed in the last exon (364) 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.
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry [See
• For an introduction to multigene panels click
## Suggestive Findings
Udd distal myopathy – tibial muscular dystrophy (UDM-TMD)
## Establishing the Diagnosis
The diagnosis of UDM-TMD
Note: The last six exons of
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 UDM-TMD is relatively distinct but overlaps with other adult-onset distal myopathies, individuals who exhibit the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of UDM-TMD, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry [See
For an introduction to multigene panels click
When the diagnosis of UDM-TMD is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in UDM-TMD
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 Human Gene Mutation Database [
FINmaj is an 11-bp deletion/insertion observed in the last exon (364) 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.
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry [See
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of UDM-TMD, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry [See
For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Finnish ancestry [See
• For an introduction to multigene panels click
## Option 2
When the diagnosis of UDM-TMD is not considered because an individual has atypical phenotypic features,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in UDM-TMD
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 Human Gene Mutation Database [
FINmaj is an 11-bp deletion/insertion observed in the last exon (364) 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.
## Clinical Characteristics
To date, more than 500 individuals have been identified with a pathogenic variant in the last exon 364 of
Features of UDM-TMD
After age 65 weakness of hamstring muscles is present on manual testing.
At age 75 years, one third of affected individuals show moderate difficulty walking as a result of increasing proximal leg muscle weakness; some walking ability is otherwise preserved throughout life.
In the mildest form, Udd distal myopathy can remain unnoticed even in elderly individuals. Disease severity is usually consistent within a family.
Almost all individuals with UDM-TMD of Finnish heritage have the same pathogenic variant (FINmaj) in the last exon 364 (known as Mex6) of
Penetrance is close to 100% at age 65 years.
Prevalence in Finland is 15:100,000 individuals due to a founder effect. Outside of Finland UDM-TMD is rare but has been identified in other populations including descendants of immigrants from Finland.
• After age 65 weakness of hamstring muscles is present on manual testing.
• At age 75 years, one third of affected individuals show moderate difficulty walking as a result of increasing proximal leg muscle weakness; some walking ability is otherwise preserved throughout life.
• In the mildest form, Udd distal myopathy can remain unnoticed even in elderly individuals. Disease severity is usually consistent within a family.
## Clinical Description
To date, more than 500 individuals have been identified with a pathogenic variant in the last exon 364 of
Features of UDM-TMD
After age 65 weakness of hamstring muscles is present on manual testing.
At age 75 years, one third of affected individuals show moderate difficulty walking as a result of increasing proximal leg muscle weakness; some walking ability is otherwise preserved throughout life.
In the mildest form, Udd distal myopathy can remain unnoticed even in elderly individuals. Disease severity is usually consistent within a family.
• After age 65 weakness of hamstring muscles is present on manual testing.
• At age 75 years, one third of affected individuals show moderate difficulty walking as a result of increasing proximal leg muscle weakness; some walking ability is otherwise preserved throughout life.
• In the mildest form, Udd distal myopathy can remain unnoticed even in elderly individuals. Disease severity is usually consistent within a family.
## Genotype-Phenotype Correlations
Almost all individuals with UDM-TMD of Finnish heritage have the same pathogenic variant (FINmaj) in the last exon 364 (known as Mex6) of
## Penetrance
Penetrance is close to 100% at age 65 years.
## Prevalence
Prevalence in Finland is 15:100,000 individuals due to a founder effect. Outside of Finland UDM-TMD is rare but has been identified in other populations including descendants of immigrants from Finland.
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
## Differential Diagnosis
Genes and disorders in the differential diagnosis of Udd distal myopathy – tibial muscular dystrophy (UDM-TMD) are listed in
Genes of Interest in the Differential Diagnosis of UDM-TMD
May present w/similarities to Miyoshi myopathy
Calf involvement starting w/pain & hypertrophy & → weakness & atrophy
Nonspecific dystrophic myopathology w/scattered fiber necrosis
Evolves slowly; persons remain ambulant into late adulthood.
AR
Digenic
Weakness of ankle dorsiflexion followed by slow progression to calf muscles, finger & wrist extensor muscles, & intrinsic muscles of the hand
Proximal leg muscles eventually become involved.
Cardiomyopathy may occur at late stages.
Early-onset (usually age <5 yrs) weakness, 1st of dorsiflexors of the ankles & great toes & then of finger extensors
Weakness of neck flexors
After >10 yrs of distal weakness, mild proximal weakness
Life expectancy normal
Onset of ankle weakness may occur very late in 7
In contrast to the late onset, progression is not very slow & can → wheelchair dependence even 10-15 yrs after onset, incl weakness & atrophy of proximal & upper limb muscles.
May have onset in anterior compartment muscles of lower legs (rather than usual onset in index finger & wrist extensors)
Typically, weakness of extensor of index finger followed by slow progression to other finger extensors & to anterior & posterior leg muscles
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; FTD = frontotemporal dementia; IBMPFD = inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia; LGMD = limb-girdle muscular dystrophy; MOI = mode of inheritance; WDM = Welander distal myopathy
Topic of this GeneReview; included for comparison for quick reference.
Derepression and dysregulation of
Zaspopathy is also referred to as Markesbery-Griggs late-onset distal myopathy.
A cohort of more than 60 affected individuals was reported in Spain [
• May present w/similarities to Miyoshi myopathy
• Calf involvement starting w/pain & hypertrophy & → weakness & atrophy
• Nonspecific dystrophic myopathology w/scattered fiber necrosis
• Evolves slowly; persons remain ambulant into late adulthood.
• Weakness of ankle dorsiflexion followed by slow progression to calf muscles, finger & wrist extensor muscles, & intrinsic muscles of the hand
• Proximal leg muscles eventually become involved.
• Cardiomyopathy may occur at late stages.
• Early-onset (usually age <5 yrs) weakness, 1st of dorsiflexors of the ankles & great toes & then of finger extensors
• Weakness of neck flexors
• After >10 yrs of distal weakness, mild proximal weakness
• Life expectancy normal
• Onset of ankle weakness may occur very late in 7
• In contrast to the late onset, progression is not very slow & can → wheelchair dependence even 10-15 yrs after onset, incl weakness & atrophy of proximal & upper limb muscles.
• May have onset in anterior compartment muscles of lower legs (rather than usual onset in index finger & wrist extensors)
• Typically, weakness of extensor of index finger followed by slow progression to other finger extensors & to anterior & posterior leg muscles
## Management
To establish the extent of disease and needs in an individual diagnosed with Udd distal myopathy – tibial muscular dystrophy (UDM-TMD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with UDM-TMD
Treatment of Manifestations in Individuals with UDM-TMD
Recommended Surveillance for Individuals with UDM-TMD
Heavy muscle force training of weak muscles should be avoided.
See
Search
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Udd distal myopathy – tibial muscular dystrophy (UDM-TMD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with UDM-TMD
## Treatment of Manifestations
Treatment of Manifestations in Individuals with UDM-TMD
## Surveillance
Recommended Surveillance for Individuals with UDM-TMD
## Agents/Circumstances to Avoid
Heavy muscle force training of weak muscles should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Udd distal myopathy – tibial muscular dystrophy (UDM-TMD) is inherited in an autosomal dominant manner.
To date, all reported individuals diagnosed with UDM-TMD inherited 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
Note: Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history may appear to be negative because of failure to recognize the disorder in a family member(s) because of a milder phenotypic presentation, death of a parent before the onset of symptoms, or very late onset of mild disease in the affected parent. 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 is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
Each child of an individual with UDM-TMD has a 50% risk of inheriting the
If the reproductive partner of a proband is also heterozygous for a UDM-TMD
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 diagnosed with UDM-TMD inherited 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
• Note: Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history may appear to be negative because of failure to recognize the disorder in a family member(s) because of a milder phenotypic presentation, death of a parent before the onset of symptoms, or very late onset of mild disease in the affected parent. 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 is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• Each child of an individual with UDM-TMD has a 50% risk of inheriting the
• If the reproductive partner of a proband is also heterozygous for a UDM-TMD
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Udd distal myopathy – tibial muscular dystrophy (UDM-TMD) is inherited in an autosomal dominant manner.
## Risk to Family Members
To date, all reported individuals diagnosed with UDM-TMD inherited 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
Note: Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history may appear to be negative because of failure to recognize the disorder in a family member(s) because of a milder phenotypic presentation, death of a parent before the onset of symptoms, or very late onset of mild disease in the affected parent. 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 is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known
Each child of an individual with UDM-TMD has a 50% risk of inheriting the
If the reproductive partner of a proband is also heterozygous for a UDM-TMD
• To date, all reported individuals diagnosed with UDM-TMD inherited 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
• Note: Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history may appear to be negative because of failure to recognize the disorder in a family member(s) because of a milder phenotypic presentation, death of a parent before the onset of symptoms, or very late onset of mild disease in the affected parent. 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 is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known
• Each child of an individual with UDM-TMD has a 50% risk of inheriting the
• If the reproductive partner of a proband is also heterozygous for a UDM-TMD
## 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
United Kingdom
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Udd Distal Myopathy - Tibial Muscular Dystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Udd Distal Myopathy - Tibial Muscular Dystrophy (
Titin, a myofilament in the sarcomere, is expressed as several different isoforms, caused by alternative splicing, in skeletal and cardiac muscle. Titin spans more than one half the length of a sarcomere in heart and skeletal muscle. Structurally different parts of the protein perform distinct functions (mechanical, developmental, and regulatory). Titin binds and interacts with a large number of other sarcomeric proteins.
The molecular pathomechanism of UDM-TMD is not fully clarified but the normal C terminus of the protein undergoes proteolytic fragmentation, the fragments from which maintain a steady state level in the muscle fibers and are not immediately degraded. These normal fragments are lost in the FINmaj protein (see
LRG_391 (
All variants associated with UMD-TMD are located in the Mex6 (last) domain exon.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• LRG_391 (
## Molecular Pathogenesis
Titin, a myofilament in the sarcomere, is expressed as several different isoforms, caused by alternative splicing, in skeletal and cardiac muscle. Titin spans more than one half the length of a sarcomere in heart and skeletal muscle. Structurally different parts of the protein perform distinct functions (mechanical, developmental, and regulatory). Titin binds and interacts with a large number of other sarcomeric proteins.
The molecular pathomechanism of UDM-TMD is not fully clarified but the normal C terminus of the protein undergoes proteolytic fragmentation, the fragments from which maintain a steady state level in the muscle fibers and are not immediately degraded. These normal fragments are lost in the FINmaj protein (see
LRG_391 (
All variants associated with UMD-TMD are located in the Mex6 (last) domain exon.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• LRG_391 (
## Chapter Notes
Peter Hackman, PhD, Doc (2004-present)Tiina Suominen, MSc; Tampere University Hospital (2004-2019)Bjarne Udd, MD, PhD, Prof (2004-present)
2 January 2020 (ha) Comprehensive update posted live
8 August 2013 (cd/bu) Revision: pathogenic variants in
23 August 2012 (me) Comprehensive update posted live
4 March 2010 (me) Comprehensive update posted live
3 April 2007 (me) Comprehensive update posted live
17 February 2005 (me) Review posted live
27 July 2004 (bu) Original submission
• 2 January 2020 (ha) Comprehensive update posted live
• 8 August 2013 (cd/bu) Revision: pathogenic variants in
• 23 August 2012 (me) Comprehensive update posted live
• 4 March 2010 (me) Comprehensive update posted live
• 3 April 2007 (me) Comprehensive update posted live
• 17 February 2005 (me) Review posted live
• 27 July 2004 (bu) Original submission
## Author History
Peter Hackman, PhD, Doc (2004-present)Tiina Suominen, MSc; Tampere University Hospital (2004-2019)Bjarne Udd, MD, PhD, Prof (2004-present)
## Revision History
2 January 2020 (ha) Comprehensive update posted live
8 August 2013 (cd/bu) Revision: pathogenic variants in
23 August 2012 (me) Comprehensive update posted live
4 March 2010 (me) Comprehensive update posted live
3 April 2007 (me) Comprehensive update posted live
17 February 2005 (me) Review posted live
27 July 2004 (bu) Original submission
• 2 January 2020 (ha) Comprehensive update posted live
• 8 August 2013 (cd/bu) Revision: pathogenic variants in
• 23 August 2012 (me) Comprehensive update posted live
• 4 March 2010 (me) Comprehensive update posted live
• 3 April 2007 (me) Comprehensive update posted live
• 17 February 2005 (me) Review posted live
• 27 July 2004 (bu) Original submission
## References
## Literature Cited
|
[
"K Charton, J Sarparanta, A Vihola, A Milic, PH Jonson, L Sue, H Luque, I Boumela, I Richard, B Udd. CAPN3-mediated processing of C-terminal titin replaced by pathological cleavage in titinopathy.. Hum Mol Gen 2015;24:3718-31",
"A Evilä, J Palmio, A Vihola, M Savarese, G Tasca, S Penttilä, S Lehtinen, PH Jonson, J De Bleecker, M Auer-Grumbach, J Pouget, E Salort-Campana, J Vilchez, N Muelas, M Olive, P Hackman, B Udd. Targeted next-generation sequencing reveals novel TTN mutations causing recessive distal titinopathy.. Mol Neurobiol 2017;54:7212-23",
"A Evilä, A Vihola, J Sarparanta, O Raheem, J Palmio, S Sandell, B Eymard, I Illa, R Rojas-Garcia, K Hankiewicz, L Negrao, T Löppönen, P Nokelainen, M Kärppä, S Penttilä, M Screen, T Suominen, I Richard, P Hackman, B. Udd. Atypical phenotypes in titinopathies explained by second titin mutations.. Annal Neurol 2014;75:230-40",
"P Hackman, S Marchand, J Sarparanta, A Vihola, I Pénisson-Besnier, B Eymard, JM Pardal-Fernández, EH Hammouda, I Richard, I Illa, B Udd. Truncating mutations in C-terminal titin may cause more severe tibial muscular dystrophy (TMD).. Neuromuscul Disord 2008;18:922-8",
"P Hackman, A Vihola, H Haravuori, S Marchand, J Sarparanta, J De Seze, S Labeit, C Witt, L Peltonen, I Richard, B Udd. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin.. Am J Hum Genet 2002;71:492-500",
"KJ Kiiski, VM Lehtokari, A Vihola, J Laitila, S Huovinen, L Sagath, A Evilä, A Paetau, C Sewry, P Hackman, K Pelin, C Wallgren-Pettersson, B Udd. Dominantly inherited distal nemaline/cap myopathy caused by a large deletion in the nebulin gene.. Neuromusc Disord 2019;29:97-107",
"Y Lee, PH Jonson, J Sarparanta, P Palmio, M Sarkar, A Vihola, A Evilä, T Suominen, S Penttilä, M Savarese, M Johari, MC Minot, D Hilton-Jones, P Maddison, P Chinnery, J Reimann, C Kornblum, T Kraya, S Zierz, C Sue, H Goebel, A Azfer, S Ralston, P Hackman, R Bucelli, P Taylor, C Weihl, B Udd. TIA1 variant drives myodegeneration in multisystem proteinopathy with SQSTM1 mutations.. J Clin Invest 2018;128:1164-77",
"N Muelas, P Hackman, H Luque, M Garcés-Sánchez, I Inmaculada, T Suominen, T Sevilla, F Mayordomo, L Gómez, P Martí, JM Millán, B Udd, J Vílchez. MYH7 gene tail mutation causing myopathic profiles beyond Laing distal myopathy. Neurology. 2010;75:732-41",
"N Muelas, P Hackman, H Luque, T Suominen, C Espinós, M Garcés-Sánchez, T Sevilla, I Azorín, J Millán, B Udd, J. Vílchez. Spanish MYH7 founder mutation of Italian ancestry causing a large cluster of Laing myopathy patients.. Clin Genet. 2012;81:491-4",
"EC Oates, KJ Jones, S Donkervoort, A Charlton, S Brammah, JE Smith, JS Ware, KS Yau, LC Swanson, N Whiffin, AJ Peduto, A Bournazos, LB Waddell, MA Farrar, HA Sampaio, HL Teoh, PJ Lamont, D Mowat, RB Fitzsimons, AJ Corbett, MM Ryan, GL O'Grady, SA Sandaradura, R Ghaoui, H Joshi, JL Marshall, MA Nolan, S Kaur, J Punetha, A Töpf, E Harris, M Bakshi, CA Genetti, M Marttila, U Werlauff, N Streichenberger, A Pestronk, I Mazanti, JR Pinner, C Vuillerot, C Grosmann, A Camacho, P Mohassel, ME Leach, AR Foley, D Bharucha-Goebel, J Collins, AM Connolly, HR Gilbreath, ST Iannaccone, D Castro, BB Cummings, RI Webster, L Lazaro, J Vissing, S Coppens, N Deconinck, HM Luk, NH Thomas, NC Foulds, MA Illingworth, S Ellard, CA McLean, R Phadke, G Ravenscroft, N Witting, P Hackman, I Richard, ST Cooper, EJ Kamsteeg, EP Hoffman, K Bushby, V Straub, B Udd, A Ferreiro, KN North, NF Clarke, M Lek, AH Beggs, CG Bönnemann, DG MacArthur, H Granzier, MR Davis, NG Laing. Congenital titinopathy: comprehensive characterisation & pathogenic insights.. Annal Neurol 2018;83:1105-24",
"J Palmio, A Evilä, A Bashir, F Norwood, K Viitaniemi, A Vihola, S Huovinen, V Straub, P Hackman, M Hirano, K Bushby, B Udd. Re-evaluation of the phenotype caused by the common MATR3 p.Ser85Cys mutation in a new family.. J Neurol Neurosurg Psychiatry. 2016;87:448-50",
"I Pénisson-Besnier, K Talvinen, C Dumez, A Vihola, F Dubas, M Fardeau, P Hackman, O Carpen, B Udd. Myotilinopathy in a family with late onset myopathy.. Neuromuscul Disord 2006;16:427-31",
"M Pollazzon, T Suominen, S Penttilä, A Malandrini, MA Carluccio, M Mondelli, A Marozza, A Federico, A Renieri, P Hackman, MT Dotti, B Udd. The first Italian family with tibial muscular dystrophy (TMD) caused by a novel titin mutation.. J Neurol. 2010;257:575-9",
"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",
"M Savarese, J Palmio, J Poza, J Weinberg, M Olive, AM Cobo, A Vihola, PH Jonson, J Sarparanta, F García-Bragado, A Urtizberea, P Hackman, B Udd. Actininopathy – a new muscular dystrophy caused by ACTN2 dominant mutations.. Annal Neurol. 2019;85:899-906",
"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",
"B Udd, J Partanen, P Halonen, B Falck, L Hakamies, H Heikkilä, S Ingo, H Kalimo, H Kääriäinen, V Laulumaa, L Paljärvi, J Rapola, M Reunanen, V Sonninen, H. Somer. Tibial muscular dystrophy. Late adult-onset distal myopathy in 66 Finnish patients.. Arch Neurol. 1993;50:604-8",
"B Udd, A Vihola, J Sarparanta, I Richard, P Hackman. Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J.. Neurology 2005;64:636-42",
"PY Van den Bergh, O Bouquiaux, C Verellen, S Marchand, I Richard, P Hackman, B Udd. Tibial muscular dystrophy in a Belgian family.. Ann Neurol 2003;54:248-51"
] |
17/2/2005
|
2/1/2020
|
8/8/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
unc80-def
|
unc80-def
|
[
"Protein unc-80 homolog",
"UNC80",
"UNC80 Deficiency"
] |
UNC80 Deficiency
|
Nuria C Bramswig, Maha S Zaki
|
Summary UNC80 deficiency is characterized by developmental delay, neonatal hypotonia, severe intellectual disability, dysmorphic facial features, strabismus, dyskinetic limb movements, and neurobehavioral manifestations. The majority of individuals do not learn to walk. All individuals lack expressive speech; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional common features include clubfeet, joint contractures, scoliosis, postnatal growth deficiency, increased risk of infections, sleeping difficulties, and constipation. Individuals have slow acquisition of developmental skills and do not have features suggestive of neurodegeneration. The diagnosis of UNC80 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in UNC80 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
UNC80 deficiency
Developmental delay with severe motor delays and absent speech (less than five words)
Neonatal hypotonia
Severe intellectual disability
Strabismus
Dyskinesia of the limbs
Postnatal growth deficiency with postnatal microcephaly in some individuals
Sleeplessness and irritability
Constipation
Seizures in some individuals
The diagnosis of UNC80 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 [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in UNC80 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.
• Developmental delay with severe motor delays and absent speech (less than five words)
• Neonatal hypotonia
• Severe intellectual disability
• Strabismus
• Dyskinesia of the limbs
• Postnatal growth deficiency with postnatal microcephaly in some individuals
• Sleeplessness and irritability
• Constipation
• Seizures in some individuals
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
UNC80 deficiency
Developmental delay with severe motor delays and absent speech (less than five words)
Neonatal hypotonia
Severe intellectual disability
Strabismus
Dyskinesia of the limbs
Postnatal growth deficiency with postnatal microcephaly in some individuals
Sleeplessness and irritability
Constipation
Seizures in some individuals
• Developmental delay with severe motor delays and absent speech (less than five words)
• Neonatal hypotonia
• Severe intellectual disability
• Strabismus
• Dyskinesia of the limbs
• Postnatal growth deficiency with postnatal microcephaly in some individuals
• Sleeplessness and irritability
• Constipation
• Seizures in some individuals
## Establishing the Diagnosis
The diagnosis of UNC80 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 [
For an introduction to comprehensive genomic testing click
For an introduction to multigene panels click
Molecular Genetic Testing Used in UNC80 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.
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Clinical Characteristics
UNC80 deficiency is characterized by neonatal hypotonia, developmental delay, severe intellectual disability, and neurobehavioral manifestations. Additional common features include seizures, strabismus, postnatal growth deficiency, constipation, musculoskeletal manifestations, dysmorphic facial features, increased risk of infections, and sleeping difficulties. To date, fewer than 50 individuals have been described with biallelic pathogenic variants in
UNC80 Deficiency: Frequency of Select Features
Sleep difficulties are common, with difficulties initiating sleep and sleeping through the night.
Small hands and feet are common, with long thin fingers and tapering of the distal phalanges.
No clinically relevant genotype-phenotype correlations have been identified.
UNC80 deficiency is referred to as "infantile hypotonia with psychomotor retardation and characteristic facies 2" (IHPRF2) in OMIM (
The prevalence is unknown. Fewer than 50 individuals have been reported to date.
## Clinical Description
UNC80 deficiency is characterized by neonatal hypotonia, developmental delay, severe intellectual disability, and neurobehavioral manifestations. Additional common features include seizures, strabismus, postnatal growth deficiency, constipation, musculoskeletal manifestations, dysmorphic facial features, increased risk of infections, and sleeping difficulties. To date, fewer than 50 individuals have been described with biallelic pathogenic variants in
UNC80 Deficiency: Frequency of Select Features
Sleep difficulties are common, with difficulties initiating sleep and sleeping through the night.
Small hands and feet are common, with long thin fingers and tapering of the distal phalanges.
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
## Nomenclature
UNC80 deficiency is referred to as "infantile hypotonia with psychomotor retardation and characteristic facies 2" (IHPRF2) in OMIM (
## Prevalence
The prevalence is unknown. Fewer than 50 individuals have been reported to date.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to consider in the differential diagnosis are listed in
Selected Disorders in the Differential Diagnosis of UNC80 Deficiency
AD = autosomal dominant; AR = autosomal recessive; CNV = copy number variant; MOI = mode of inheritance; PWCR = Prader-Willi critical region; XL = X-linked
Affected individuals typically represent simplex cases (i.e., a single occurrence in the family).
## Management
No clinical practice guidelines for UNC80 deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with UNC80 deficiency, the evaluations and referrals summarized in
UNC80 Deficiency: Recommended Evaluations Following Initial Diagnosis
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.
MOI = mode of inheritance
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
UNC80 Deficiency: Treatment of Manifestations
Developmental services
Educational support
Treatment per psychologist &/or neuropsychiatrist
Melatonin & risperidone have been shown to be beneficial for treatment of sleep difficulties.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
UNC80 Deficiency: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Orthopedist eval of contractures & back exam for scoliosis
Physical medicine, OT/PT assessment of mobility, self-help skills
OT = occupational therapy; PT = physical therapy
See
Search
• 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.
• Developmental services
• Educational support
• Treatment per psychologist &/or neuropsychiatrist
• Melatonin & risperidone have been shown to be beneficial for treatment of sleep difficulties.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Orthopedist eval of contractures & back exam for scoliosis
• Physical medicine, OT/PT assessment of mobility, self-help skills
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with UNC80 deficiency, the evaluations and referrals summarized in
UNC80 Deficiency: Recommended Evaluations Following Initial Diagnosis
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.
MOI = mode of inheritance
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
• 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 multidisciplinary care by specialists in relevant fields (see
UNC80 Deficiency: Treatment of Manifestations
Developmental services
Educational support
Treatment per psychologist &/or neuropsychiatrist
Melatonin & risperidone have been shown to be beneficial for treatment of sleep difficulties.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
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
• Developmental services
• Educational support
• Treatment per psychologist &/or neuropsychiatrist
• Melatonin & risperidone have been shown to be beneficial for treatment of sleep difficulties.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• 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
UNC80 Deficiency: Recommended Surveillance
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Orthopedist eval of contractures & back exam for scoliosis
Physical medicine, OT/PT assessment of mobility, self-help skills
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Orthopedist eval of contractures & back exam for scoliosis
• Physical medicine, OT/PT assessment of mobility, self-help skills
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
UNC80 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 of the proband's 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 UNC80 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in
To date, individuals with UNC80 deficiency are not known to reproduce.
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.
Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder variant has been identified in the Bedouin population of southern Israel (see
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 of the proband's 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 UNC80 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in
• To date, individuals with UNC80 deficiency are not known to reproduce.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder variant has been identified in the Bedouin population of southern Israel (see
## Mode of Inheritance
UNC80 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 of the proband's 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 UNC80 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in
To date, individuals with UNC80 deficiency are not known to reproduce.
• 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 of the proband's 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 UNC80 deficiency are obligate heterozygotes (carriers) for a pathogenic variant in
• To date, individuals with UNC80 deficiency are not known to reproduce.
## 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.
Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder variant has been identified in the Bedouin population of southern Israel (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 carriers or are at risk of being carriers.
• Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A founder variant has been identified in the Bedouin population of southern Israel (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 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
UNC80 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for UNC80 Deficiency (
The UNC80 protein is part of the NALCN channelosome, a voltage-insensitive and nonselective sodium leak channel [
Notable UNC80 Pathogenic Variants
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The UNC80 protein is part of the NALCN channelosome, a voltage-insensitive and nonselective sodium leak channel [
Notable UNC80 Pathogenic Variants
Variants listed in the table have been provided by the authors.
## Chapter Notes
Nuria Bramswig (
Contact Dr Nuria Bramswig (
Cornelius Boerkoel, MD, PhD; University of British Columbia (2017-2023)Nuria C Bramswig, MD (2023-present)Christèle du Souich, MSc, CCGC, CGC; University of British Columbia (2017-2023)Maha S Zaki, MD, PhD (2023-present)
18 May 2023 (sw) Comprehensive update posted live
21 September 2017 (sw) Review posted live
17 January 2017 (cds) Original submission
• 18 May 2023 (sw) Comprehensive update posted live
• 21 September 2017 (sw) Review posted live
• 17 January 2017 (cds) Original submission
## Author Notes
Nuria Bramswig (
Contact Dr Nuria Bramswig (
## Author History
Cornelius Boerkoel, MD, PhD; University of British Columbia (2017-2023)Nuria C Bramswig, MD (2023-present)Christèle du Souich, MSc, CCGC, CGC; University of British Columbia (2017-2023)Maha S Zaki, MD, PhD (2023-present)
## Revision History
18 May 2023 (sw) Comprehensive update posted live
21 September 2017 (sw) Review posted live
17 January 2017 (cds) Original submission
• 18 May 2023 (sw) Comprehensive update posted live
• 21 September 2017 (sw) Review posted live
• 17 January 2017 (cds) Original submission
## References
## Literature Cited
|
[] |
21/9/2017
|
18/5/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
updates
|
updates
|
[] |
What's New in GeneReviews
|
[] |
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||||||
urofacial
|
urofacial
|
[
"Ochoa Syndrome",
"Ochoa Syndrome",
"Inactive heparanase-2",
"Leucine-rich repeats and immunoglobulin-like domains protein 2",
"HPSE2",
"LRIG2",
"Urofacial Syndrome"
] |
Urofacial Syndrome
|
William G Newman, Adrian S Woolf, Glenda M Beaman, Neil A Roberts
|
Summary Urofacial syndrome (UFS; also known as Ochoa syndrome) is characterized by prenatal or childhood onset of urinary bladder voiding dysfunction, abnormal facial movement with expression (resulting from abnormal co-contraction of the corners of the mouth and eyes), and often bowel dysfunction (constipation and/or encopresis). Bladder voiding dysfunction can present before birth as megacystis. In infancy and later childhood, UFS can present with a poor urinary stream and dribbling incontinence; incomplete bladder emptying can lead to urinary infection with progressive kidney failure. Investigations after birth can show abnormal bladder contractility and vesicoureteral reflux of urine into the ureter and renal pelvis. Nocturnal lagophthalmos (incomplete closing of the eyes during sleep) has also been documented. The clinical diagnosis of UFS can be established in an individual with urinary tract dysfunction and characteristic facial movement with expression, or the molecular diagnosis can be established in an individual with characteristic features and biallelic pathogenic variants in either UFS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a UFS-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. Once the UFS-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
No formal diagnostic criteria for urofacial syndrome (UFS) have been published.
UFS
Characteristic urinary tract abnormalities:
Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
Urodynamics is generally only available in specialist pediatric urology centers. If performed, typical findings are abnormally high hydrostatic pressure within the bladder that persists during cycles of incomplete voiding. This is associated with failure of the outflow tract to fully dilate during voiding, the so-called dyssynergic voiding [
The clinical diagnosis of UFS can be
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 comprehensive genomic testing click
Molecular Genetic Testing Used in Urofacial Syndrome
NA = not applicable; UFS = urofacial syndrome
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.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A large Alu insertion resulting in exon skipping in
• Characteristic urinary tract abnormalities:
• Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
• Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
• Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
• Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
• Urodynamics is generally only available in specialist pediatric urology centers. If performed, typical findings are abnormally high hydrostatic pressure within the bladder that persists during cycles of incomplete voiding. This is associated with failure of the outflow tract to fully dilate during voiding, the so-called dyssynergic voiding [
• Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
• Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
• Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
• Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
• Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
• Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
• Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
• Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
## Suggestive Findings
UFS
Characteristic urinary tract abnormalities:
Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
Urodynamics is generally only available in specialist pediatric urology centers. If performed, typical findings are abnormally high hydrostatic pressure within the bladder that persists during cycles of incomplete voiding. This is associated with failure of the outflow tract to fully dilate during voiding, the so-called dyssynergic voiding [
• Characteristic urinary tract abnormalities:
• Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
• Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
• Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
• Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
• Urodynamics is generally only available in specialist pediatric urology centers. If performed, typical findings are abnormally high hydrostatic pressure within the bladder that persists during cycles of incomplete voiding. This is associated with failure of the outflow tract to fully dilate during voiding, the so-called dyssynergic voiding [
• Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
• Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
• Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
• Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
• Prenatal ultrasonography in the second or third trimester can show an enlarged bladder (megacystis) and dilated upper urinary tracts (hydronephrosis).
• Postnatal imaging by ultrasonography and micturating cystourethrography typically shows muscular thickening and trabeculation of the urinary bladder, but appearances may also be normal [
• Hydroureteronephrosis associated with vesicoureteral reflux is common in UFS [
• Micturating cystourethrography and direct visualization by cystoscopy reveals a patent urethra, critically distinguishing UFS from conditions such as posterior urethral valves, which are characterized by an anatomic obstruction within the lumen of the urethra [
## Establishing the Diagnosis
The clinical diagnosis of UFS can be
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 comprehensive genomic testing click
Molecular Genetic Testing Used in Urofacial Syndrome
NA = not applicable; UFS = urofacial syndrome
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.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A large Alu insertion resulting in exon skipping in
## Option 1
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Urofacial Syndrome
NA = not applicable; UFS = urofacial syndrome
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.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
A large Alu insertion resulting in exon skipping in
## Clinical Characteristics
Urofacial syndrome (UFS) is characterized by urinary bladder voiding dysfunction, abnormal facial expression, and often bowel dysfunction. Significant inter- and intrafamilial phenotypic variability has been observed. To date, more than 150 individuals with UFS have been identified/reported. The following description of the phenotypic features associated with this condition is based on these reports.
Urofacial Syndrome: Frequency of Select Features
The typical complications of urinary tract dysfunction include recurrent urinary sepsis and failure to achieve urinary continence [
Symmetric partial facial paresis in the distribution of the facial nerve has been noted; however, the proportion of individuals in whom weakness is a significant feature is unknown [
There is evidence that individuals with biallelic missense variants in
UFS is rare. Its prevalence is currently unknown but is likely to be higher in certain regions with known founder variants (e.g., Colombia) [
## Clinical Description
Urofacial syndrome (UFS) is characterized by urinary bladder voiding dysfunction, abnormal facial expression, and often bowel dysfunction. Significant inter- and intrafamilial phenotypic variability has been observed. To date, more than 150 individuals with UFS have been identified/reported. The following description of the phenotypic features associated with this condition is based on these reports.
Urofacial Syndrome: Frequency of Select Features
The typical complications of urinary tract dysfunction include recurrent urinary sepsis and failure to achieve urinary continence [
Symmetric partial facial paresis in the distribution of the facial nerve has been noted; however, the proportion of individuals in whom weakness is a significant feature is unknown [
## Genotype-Phenotype Correlations
There is evidence that individuals with biallelic missense variants in
## Prevalence
UFS is rare. Its prevalence is currently unknown but is likely to be higher in certain regions with known founder variants (e.g., Colombia) [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The urinary tract features of urofacial syndrome (UFS) overlap with those seen in association with multiple other conditions [
Urethral obstruction due to posterior urethral valves or atresia
Chromosome abnormalities (e.g., megacystis in association with trisomy 21 and 13)
Prune-belly sequence (e.g., caused by biallelic pathogenic variants in
Megacystis microcolon intestinal hypoperistalsis syndrome, a heterogeneous condition resulting from smooth muscle dysfunction (See
Monogenic Disorders with Antenatal or Congenital Megacystis and/or Hydronephrosis in the Differential Diagnosis of Urofacial Syndrome
Bladder: neonatal megacystis & megaureter (incl prune-belly syndrome) to recurrent urinary tract infections & bladder dysfunction
GI: microcolon, CIPO, malrotation, functional intestinal obstruction
Overlapping features of MMIHS & prune-belly sequence (1 person)
Overlapping features of MMIHS & MSMDS (1 person)
AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidney and urinary tract; CIPO = chronic intestinal pseudo-obstruction; GI = gastrointestinal; GU = genitourinary; MMIHS = megacystis-microcolon-intestinal hypoperistalsis syndrome; MOI = mode of inheritance; MSMDS = multisystem smooth muscle dysfunction syndrome; PDA = patent ductus arteriosus
The bladder phenotype is associated specifically with the heterozygous
Sex-limited inheritance: disorder is lethal in males with heterozygous pathogenic variants, females only have manifestations of the disorder if they have biallelic pathogenic variants.
Neuropathic bladder (e.g., due to a neurologic lesion such as spina bifida)
Voiding dysfunction of unclear etiology, variably termed occult neuropathic bladder, subclinical neuropathic bladder, non-neurogenic neurogenic bladder, and Hinman-Allen syndrome
Common in the general population
May be familial and is genetically heterogeneous [
• Urethral obstruction due to posterior urethral valves or atresia
• Chromosome abnormalities (e.g., megacystis in association with trisomy 21 and 13)
• Prune-belly sequence (e.g., caused by biallelic pathogenic variants in
• Megacystis microcolon intestinal hypoperistalsis syndrome, a heterogeneous condition resulting from smooth muscle dysfunction (See
• Bladder: neonatal megacystis & megaureter (incl prune-belly syndrome) to recurrent urinary tract infections & bladder dysfunction
• GI: microcolon, CIPO, malrotation, functional intestinal obstruction
• Overlapping features of MMIHS & prune-belly sequence (1 person)
• Overlapping features of MMIHS & MSMDS (1 person)
• Neuropathic bladder (e.g., due to a neurologic lesion such as spina bifida)
• Voiding dysfunction of unclear etiology, variably termed occult neuropathic bladder, subclinical neuropathic bladder, non-neurogenic neurogenic bladder, and Hinman-Allen syndrome
• Common in the general population
• May be familial and is genetically heterogeneous [
## Management
No clinical practice guidelines for urofacial syndrome (UFS) have been published.
To establish the extent of disease and needs in an individual diagnosed with UFS, the evaluations summarized in
Urofacial Syndrome: Recommended Evaluations Following Initial Diagnosis
Urinalysis & urine culture for those w/manifestations of occult or chronic urinary tract infection
Urinary tract ultrasound
Micturating cystourethrogram
Uroflowmetry or urodynamic testing
Serum creatinine concentration &/or estimated glomerular filtration rate
Blood pressure measurement
DMSA = dimercaptosuccinic acid; MOI = mode of inheritance; UFS = urofacial syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Urofacial Syndrome: Treatment of Manifestations
Rapid & complete antibiotic therapy for acute urinary tract infections
Anticholinergic & alpha-1 adrenergic blocking medications can respectively lower raised pressure w/in the bladder & enhance voiding of urine.
Drug treatment can be complemented by intermittent catheterization per urethra or through vesicostomy to reduce residual urine volumes, achieve continence, & reduce risk of infections.
Lubricant drops during day
Eye ointments at night
UFS = urofacial syndrome
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Urofacial Syndrome: Recommended Surveillance
Nephrotoxic substances contraindicated in individuals with renal impairment should be avoided if possible.
Molecular genetic testing if the pathogenic variants in the family are known;
Physical examination and urinary tract ultrasound examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known.
See
Studies of gene therapy to correct the urinary tract manifestations in mice with mutated
Search
• Urinalysis & urine culture for those w/manifestations of occult or chronic urinary tract infection
• Urinary tract ultrasound
• Micturating cystourethrogram
• Uroflowmetry or urodynamic testing
• Serum creatinine concentration &/or estimated glomerular filtration rate
• Blood pressure measurement
• Rapid & complete antibiotic therapy for acute urinary tract infections
• Anticholinergic & alpha-1 adrenergic blocking medications can respectively lower raised pressure w/in the bladder & enhance voiding of urine.
• Drug treatment can be complemented by intermittent catheterization per urethra or through vesicostomy to reduce residual urine volumes, achieve continence, & reduce risk of infections.
• Lubricant drops during day
• Eye ointments at night
• Molecular genetic testing if the pathogenic variants in the family are known;
• Physical examination and urinary tract ultrasound examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with UFS, the evaluations summarized in
Urofacial Syndrome: Recommended Evaluations Following Initial Diagnosis
Urinalysis & urine culture for those w/manifestations of occult or chronic urinary tract infection
Urinary tract ultrasound
Micturating cystourethrogram
Uroflowmetry or urodynamic testing
Serum creatinine concentration &/or estimated glomerular filtration rate
Blood pressure measurement
DMSA = dimercaptosuccinic acid; MOI = mode of inheritance; UFS = urofacial syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Urinalysis & urine culture for those w/manifestations of occult or chronic urinary tract infection
• Urinary tract ultrasound
• Micturating cystourethrogram
• Uroflowmetry or urodynamic testing
• Serum creatinine concentration &/or estimated glomerular filtration rate
• Blood pressure measurement
## Treatment of Manifestations
Urofacial Syndrome: Treatment of Manifestations
Rapid & complete antibiotic therapy for acute urinary tract infections
Anticholinergic & alpha-1 adrenergic blocking medications can respectively lower raised pressure w/in the bladder & enhance voiding of urine.
Drug treatment can be complemented by intermittent catheterization per urethra or through vesicostomy to reduce residual urine volumes, achieve continence, & reduce risk of infections.
Lubricant drops during day
Eye ointments at night
UFS = urofacial syndrome
• Rapid & complete antibiotic therapy for acute urinary tract infections
• Anticholinergic & alpha-1 adrenergic blocking medications can respectively lower raised pressure w/in the bladder & enhance voiding of urine.
• Drug treatment can be complemented by intermittent catheterization per urethra or through vesicostomy to reduce residual urine volumes, achieve continence, & reduce risk of infections.
• Lubricant drops during day
• Eye ointments at night
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Urofacial Syndrome: Recommended Surveillance
## Agents/Circumstances to Avoid
Nephrotoxic substances contraindicated in individuals with renal impairment should be avoided if possible.
## Evaluation of Relatives at Risk
Molecular genetic testing if the pathogenic variants in the family are known;
Physical examination and urinary tract ultrasound examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Physical examination and urinary tract ultrasound examination to determine whether facial and/or urinary tract manifestations of UFS are present if the pathogenic variants in the family are not known.
## Therapies Under Investigation
Studies of gene therapy to correct the urinary tract manifestations in mice with mutated
Search
## Genetic Counseling
Urofacial syndrome (UFS) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a UFS-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 UFS-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 a UFS-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 phenotypic variability has been observed [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the UFS-related pathogenic variants in the family.
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 affected with UFS and the reproductive partners of individuals known to be carriers of UFS, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. An
Note: Ultrasound examination of a fetus at risk (in the second and third trimesters) to determine if UFS-related urinary tract involvement is present should be considered, as it may influence the timing and/or location of delivery (see
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 UFS-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 UFS-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 a UFS-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 phenotypic variability has been observed [
• 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 individuals affected with UFS and the reproductive partners of individuals known to be carriers of UFS, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. An
## Mode of Inheritance
Urofacial syndrome (UFS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for a UFS-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 UFS-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 a UFS-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 phenotypic variability has been observed [
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 UFS-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 UFS-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 a UFS-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 phenotypic variability has been observed [
• 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 UFS-related pathogenic variants in the family.
## 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 affected with UFS and the reproductive partners of individuals known to be carriers of UFS, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. 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 individuals affected with UFS and the reproductive partners of individuals known to be carriers of UFS, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. An
## Prenatal Testing and Preimplantation Genetic Testing
Note: Ultrasound examination of a fetus at risk (in the second and third trimesters) to determine if UFS-related urinary tract involvement is present should be considered, as it may influence the timing and/or location of delivery (see
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
Urofacial Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Urofacial Syndrome (
See
The molecular pathogenesis of urofacial syndrome (UFS) is not fully understood. However, there is increasing evidence that UFS represents an abnormality of peripheral neurodevelopment or function [
Both
While the functions of heparanase-2 and LRIG2 are not fully understood, current knowledge suggests that they have a role in regulating growth factor signaling [
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The molecular pathogenesis of urofacial syndrome (UFS) is not fully understood. However, there is increasing evidence that UFS represents an abnormality of peripheral neurodevelopment or function [
Both
While the functions of heparanase-2 and LRIG2 are not fully understood, current knowledge suggests that they have a role in regulating growth factor signaling [
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
## Chapter Notes
Glenda M Beaman is a postdoctoral fellow researching the causes of lower urinary tract disorders.
Neil A Roberts is a scientist developing advanced therapies for lower urinary tract disorders including urofacial syndrome.
William G Newman (
William G Newman (
Glenda M Beaman, PhD (2023-present)
William G Newman, MA, PhD (2013-present)
Neil A Roberts, PhD (2023-present)
Helen M Stuart, MD; University of Manchester (2013-2018)
Adrian S Woolf, MA, MD (2013-present)
The authors' work on UFS has been funded by Kidney Research UK (Paed_RP/002/20190925, Paed_RP/005/20190925), Newlife (15-15/03 and 15-16/06), National Institute for Health Research (NIHR203308), the Medical Research Council (MR/L002744/1, MR/T016809/1, MR/Y008340/1) and the Wellcome Trust. We have been supported by ERIC, a UK charity dedicated to improving children's bowel and bladder health. We dedicate this review to our colleague Dr Edward McKenzie, who first cloned
28 September 2023 (sw) Comprehensive update posted live
7 June 2018 (bp) Comprehensive update posted live
22 August 2013 (me) Review posted live
17 May 2013 (wgn) Original submission
• 28 September 2023 (sw) Comprehensive update posted live
• 7 June 2018 (bp) Comprehensive update posted live
• 22 August 2013 (me) Review posted live
• 17 May 2013 (wgn) Original submission
## Author Notes
Glenda M Beaman is a postdoctoral fellow researching the causes of lower urinary tract disorders.
Neil A Roberts is a scientist developing advanced therapies for lower urinary tract disorders including urofacial syndrome.
William G Newman (
William G Newman (
## Author History
Glenda M Beaman, PhD (2023-present)
William G Newman, MA, PhD (2013-present)
Neil A Roberts, PhD (2023-present)
Helen M Stuart, MD; University of Manchester (2013-2018)
Adrian S Woolf, MA, MD (2013-present)
## Acknowledgments
The authors' work on UFS has been funded by Kidney Research UK (Paed_RP/002/20190925, Paed_RP/005/20190925), Newlife (15-15/03 and 15-16/06), National Institute for Health Research (NIHR203308), the Medical Research Council (MR/L002744/1, MR/T016809/1, MR/Y008340/1) and the Wellcome Trust. We have been supported by ERIC, a UK charity dedicated to improving children's bowel and bladder health. We dedicate this review to our colleague Dr Edward McKenzie, who first cloned
## Revision History
28 September 2023 (sw) Comprehensive update posted live
7 June 2018 (bp) Comprehensive update posted live
22 August 2013 (me) Review posted live
17 May 2013 (wgn) Original submission
• 28 September 2023 (sw) Comprehensive update posted live
• 7 June 2018 (bp) Comprehensive update posted live
• 22 August 2013 (me) Review posted live
• 17 May 2013 (wgn) Original submission
## References
## Literature Cited
A video of a young man with urofacial syndrome demonstrating his facial appearance on smiling
Reproduced from
A graphic of
Adapted from
A graphic of
Adapted from
|
[] |
22/8/2013
|
28/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
usher1
|
usher1
|
[
"USH1",
"Usher 1",
"USH1",
"Usher 1",
"Cadherin-23",
"Calcium and integrin-binding family member 2",
"Harmonin",
"pre-mRNA splicing regulator USH1G",
"Protocadherin-15",
"Unconventional myosin-VIIa",
"CDH23",
"CIB2",
"MYO7A",
"PCDH15",
"USH1C",
"USH1G",
"Usher Syndrome Type I"
] |
Usher Syndrome Type I
|
Robert K Koenekoop, Moises A Arriaga, Karmen M Trzupek, Jennifer J Lentz
|
Summary Usher syndrome type I (USH1) is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa (RP). Unless fitted with a cochlear implant, individuals do not typically develop speech. RP, a progressive, bilateral, symmetric degeneration of rod and cone functions of the retina, develops in adolescence, resulting in progressively constricted visual fields and impaired visual acuity. The diagnosis of USH1 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function. Identification of biallelic pathogenic variants in one of six genes – USH1 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. Once the USH1-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible.
|
## Diagnosis
Usher syndrome type I (USH1)
Congenital (i.e., prelingual) severe-to-profound bilateral sensorineural hearing loss (see
No significant or delayed vestibular responses;
Normal general health and intellect and otherwise normal physical examination;
A family history consistent with autosomal recessive inheritance.
The diagnosis of USH1
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 phenotype of USH1 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP; therefore, the recommended molecular genetic testing approaches include use of a
Note: Single-gene testing is rarely useful and typically NOT recommended.
An
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 Usher Syndrome Type I (USH1)
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.
The majority of reported pathogenic variants are detectable by sequence analysis; however, intragenic multiexon deletions have been reported [
Almost all Usher syndrome type I in the Acadian population is caused by
Homozygous 11p15-p14 deletion syndrome (see
The majority of reported pathogenic variants are detectable by sequence analysis; however, intragenic deletions and duplications have been reported [
USH1E has been mapped to 21q21; USH1H has been mapped to 15q22-q23 [
• Congenital (i.e., prelingual) severe-to-profound bilateral sensorineural hearing loss (see
• No significant or delayed vestibular responses;
• Normal general health and intellect and otherwise normal physical examination;
• A family history consistent with autosomal recessive inheritance.
## Suggestive Findings
Usher syndrome type I (USH1)
Congenital (i.e., prelingual) severe-to-profound bilateral sensorineural hearing loss (see
No significant or delayed vestibular responses;
Normal general health and intellect and otherwise normal physical examination;
A family history consistent with autosomal recessive inheritance.
• Congenital (i.e., prelingual) severe-to-profound bilateral sensorineural hearing loss (see
• No significant or delayed vestibular responses;
• Normal general health and intellect and otherwise normal physical examination;
• A family history consistent with autosomal recessive inheritance.
## Establishing the Diagnosis
The diagnosis of USH1
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 phenotype of USH1 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP; therefore, the recommended molecular genetic testing approaches include use of a
Note: Single-gene testing is rarely useful and typically NOT recommended.
An
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 Usher Syndrome Type I (USH1)
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.
The majority of reported pathogenic variants are detectable by sequence analysis; however, intragenic multiexon deletions have been reported [
Almost all Usher syndrome type I in the Acadian population is caused by
Homozygous 11p15-p14 deletion syndrome (see
The majority of reported pathogenic variants are detectable by sequence analysis; however, intragenic deletions and duplications have been reported [
USH1E has been mapped to 21q21; USH1H has been mapped to 15q22-q23 [
## Clinical Characteristics
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH1 age 30-40 years. Visual impairment worsens significantly each year [
A genotype-phenotype correlation has been reported for pathogenic variants in the genes associated with USH1. Homozygous null (e.g., nonsense, frameshift, splicing) variants are associated with USH1, whereas homozygous missense variants that generate partially functional proteins typically cause nonsyndromic hearing impairment or atypical Usher syndrome. This genotype-phenotype correlation suggests that deaf children found to be homozygous for hypomorphic variants in an USH1 gene are unlikely to develop vision loss.
Penetrance is complete in Usher syndrome type I.
The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, presence or absence of vestibular areflexia, and age at onset of retinitis pigmentosa). The letters (e.g., USH1C, USH1B) indicate the molecular subtype with biallelic pathogenic variants in one of the related genes listed in
Note:
In older publications the prevalence of Usher syndrome has been reported to range from 3.2 to 6.2 per 100,000. Usher syndrome was estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. Many of these estimates were made prior to 1989, when
A recent study of children with hearing loss in Oregon found pathogenic variants in Usher syndrome-associated genes in 11% and estimated that the prevalence may be as high as one in 6,000 [
## Clinical Description
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH1 age 30-40 years. Visual impairment worsens significantly each year [
## Genotype-Phenotype Correlations
A genotype-phenotype correlation has been reported for pathogenic variants in the genes associated with USH1. Homozygous null (e.g., nonsense, frameshift, splicing) variants are associated with USH1, whereas homozygous missense variants that generate partially functional proteins typically cause nonsyndromic hearing impairment or atypical Usher syndrome. This genotype-phenotype correlation suggests that deaf children found to be homozygous for hypomorphic variants in an USH1 gene are unlikely to develop vision loss.
## Penetrance
Penetrance is complete in Usher syndrome type I.
## Nomenclature
The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, presence or absence of vestibular areflexia, and age at onset of retinitis pigmentosa). The letters (e.g., USH1C, USH1B) indicate the molecular subtype with biallelic pathogenic variants in one of the related genes listed in
Note:
## Prevalence
In older publications the prevalence of Usher syndrome has been reported to range from 3.2 to 6.2 per 100,000. Usher syndrome was estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. Many of these estimates were made prior to 1989, when
A recent study of children with hearing loss in Oregon found pathogenic variants in Usher syndrome-associated genes in 11% and estimated that the prevalence may be as high as one in 6,000 [
## Genetically Related (Allelic) Disorders
Allelic Disorders
AD = autosomal dominant; AR = autosomal recessive; DFNA = nonsyndromic deafness, autosomal dominant; DFNB = nonsyndromic deafness, autosomal recessive; MOI = mode of inheritance; RP = retinitis pigmentosa; USH = Usher syndrome; USH1 = Usher syndrome type I; USH2 = Usher syndrome type II
See
## Differential Diagnosis
While the timing and extent of vestibulopathy related to Usher syndrome is not fully defined, vestibular symptoms in young children thought to have NSHL may also prompt visual evaluation and subsequent genetic testing.
Hereditary disorders characterized by both sensorineural hearing impairment (SNHI) and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type I (USH1) are summarized in
Genes of Interest in the Differential Diagnosis of Usher Syndrome Type I
Congenital bilateral SNHL (predominantly in the higher frequencies); ranges from mild to severe
Adolescent- to adult-onset RP
Normal vestibular function
SNHI
Progressive cone-rod dystrophy leading to blindness
Childhood obesity associated w/hyperinsulinemia, & type 2 diabetes
Cardiomyopathy occurs in ~70% of affected persons in infancy or adolescence.
Kidney failure & pulmonary, hepatic, & urologic dysfunction are frequent.
Systemic fibrosis develops w/age.
Variable onset & severity of hearing loss
Variable onset & severity of visual loss
Late-onset hearing loss
Late-onset visual loss
Postlingual progressive SNHL
Late-onset RP
Variable impairment of vestibular function
Variable SNHL
Variable ocular anomalies
Progressive deterioration of glomerular basement membranes resulting in progressive kidney failure
SNHL
Retinal degeneration
Enamel dysplasia & nail abnormalities
SNHL
RP
Hypotonia
Deafness
OA
Polyneuropathy
Hearing impairment
OA
ID, early-onset hypotonia, ataxia, delayed motor development
Males: prelingual or postlingual SNHL in early childhood; slowly progressive ↓ visual acuity from OA beginning at age ~20 yrs; dementia beginning at age ~40 yrs; slowly progressive dystonia or ataxia in the teens
Females: mild hearing impairment & focal dystonia
AR = autosomal recessive; CMTX5 = Charcot-Marie-Tooth neuropathy X type 5; DIDMOAD = diabetes insipidus, diabetes mellitus, optic atrophy, and deafness; ID = intellectual disability; MOI = mode of inheritance; OA = optic atrophy; RP = retinitis pigmentosa; SNHI = sensorineural hearing impairment; SNHL = sensorineural hearing loss; USH = Usher syndrome; XL = X-linked; USH1 = Usher syndrome type I; USH2 = Usher syndrome type II; USH3 = Usher syndrome type III
Digenic USH2 is caused by pathogenic variants in
Nikopoulos et at [2016],
60.5% of Zellweger spectrum disorder (ZSD) is associated with biallelic pathogenic variants in
• Congenital bilateral SNHL (predominantly in the higher frequencies); ranges from mild to severe
• Adolescent- to adult-onset RP
• Normal vestibular function
• SNHI
• Progressive cone-rod dystrophy leading to blindness
• Childhood obesity associated w/hyperinsulinemia, & type 2 diabetes
• Cardiomyopathy occurs in ~70% of affected persons in infancy or adolescence.
• Kidney failure & pulmonary, hepatic, & urologic dysfunction are frequent.
• Systemic fibrosis develops w/age.
• Variable onset & severity of hearing loss
• Variable onset & severity of visual loss
• Late-onset hearing loss
• Late-onset visual loss
• Postlingual progressive SNHL
• Late-onset RP
• Variable impairment of vestibular function
• Variable SNHL
• Variable ocular anomalies
• Progressive deterioration of glomerular basement membranes resulting in progressive kidney failure
• SNHL
• Retinal degeneration
• Enamel dysplasia & nail abnormalities
• SNHL
• RP
• Hypotonia
• Deafness
• OA
• Polyneuropathy
• Hearing impairment
• OA
• ID, early-onset hypotonia, ataxia, delayed motor development
• Males: prelingual or postlingual SNHL in early childhood; slowly progressive ↓ visual acuity from OA beginning at age ~20 yrs; dementia beginning at age ~40 yrs; slowly progressive dystonia or ataxia in the teens
• Females: mild hearing impairment & focal dystonia
## Management
To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type I (USH1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type I
Fundus photography documents the extent of pigmentation & retinal/RPE atrophy.
VA is often maintained until late in the disease.
VF maps the extent of functional peripheral vision, retinal sensitivities, & functional rod & cone responses.
ERG is often nondetectable at presentation.
OCT allows the determination of "live" photoreceptors (measuring the ellipsoid zone).
FAF can measure the perifoveal hyperfluorescent ring, & lipofuscin disturbance.
ABR = auditory brain stem response; DPOAE = distortion product otoacoustic emission; ECOG = electrocochleography; ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; RPE = retinal pigment epithelium; VA = visual acuity; VF = visual field; VHIT = vestibular head impulse testing; VNG = videonystagmography
Treatment of Manifestations in Individuals with Usher Syndrome Type I
An initial trial of hearing aids even w/profound loss stimulates any residual hearing & accustoms the infant to auditory stimulation for auditory/oral language development.
Cochlear implantation should be considered as early as is medically feasible.
Recommended Surveillance for Individuals with Usher Syndrome Type I
For persons w/o profound loss, annual testing allows appropriate hearing aid adjustment.
For cochlear implant recipients, annual follow up is necessary to assure appropriate implant function & programming.
Children w/profound loss & cochlear implants can still develop fluid & chronic ear infection issues, which are less evident to the child because of hearing loss. Annual otoscopic exam w/tympanometry avoids potential serious complications of chronic otitis media.
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; VA = visual acuity; VF = visual field
Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous.
Persons with USH1 often become disoriented when submerged in water because they lack the sense of where "up" is; they should therefore exercise caution while swimming. Similarly, the vestibular dysfunction increases the risk of falls when walking on sloped or uneven surfaces.
Progressive loss of peripheral vision may eventually impair the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.
It is appropriate to evaluate the hearing of all sibs at risk for USH1 as soon after birth as possible to allow early diagnosis and treatment of hearing impairment.
Additional evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
See
Search
• Fundus photography documents the extent of pigmentation & retinal/RPE atrophy.
• VA is often maintained until late in the disease.
• VF maps the extent of functional peripheral vision, retinal sensitivities, & functional rod & cone responses.
• ERG is often nondetectable at presentation.
• OCT allows the determination of "live" photoreceptors (measuring the ellipsoid zone).
• FAF can measure the perifoveal hyperfluorescent ring, & lipofuscin disturbance.
• An initial trial of hearing aids even w/profound loss stimulates any residual hearing & accustoms the infant to auditory stimulation for auditory/oral language development.
• Cochlear implantation should be considered as early as is medically feasible.
• For persons w/o profound loss, annual testing allows appropriate hearing aid adjustment.
• For cochlear implant recipients, annual follow up is necessary to assure appropriate implant function & programming.
• Children w/profound loss & cochlear implants can still develop fluid & chronic ear infection issues, which are less evident to the child because of hearing loss. Annual otoscopic exam w/tympanometry avoids potential serious complications of chronic otitis media.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type I (USH1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type I
Fundus photography documents the extent of pigmentation & retinal/RPE atrophy.
VA is often maintained until late in the disease.
VF maps the extent of functional peripheral vision, retinal sensitivities, & functional rod & cone responses.
ERG is often nondetectable at presentation.
OCT allows the determination of "live" photoreceptors (measuring the ellipsoid zone).
FAF can measure the perifoveal hyperfluorescent ring, & lipofuscin disturbance.
ABR = auditory brain stem response; DPOAE = distortion product otoacoustic emission; ECOG = electrocochleography; ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; RPE = retinal pigment epithelium; VA = visual acuity; VF = visual field; VHIT = vestibular head impulse testing; VNG = videonystagmography
• Fundus photography documents the extent of pigmentation & retinal/RPE atrophy.
• VA is often maintained until late in the disease.
• VF maps the extent of functional peripheral vision, retinal sensitivities, & functional rod & cone responses.
• ERG is often nondetectable at presentation.
• OCT allows the determination of "live" photoreceptors (measuring the ellipsoid zone).
• FAF can measure the perifoveal hyperfluorescent ring, & lipofuscin disturbance.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Usher Syndrome Type I
An initial trial of hearing aids even w/profound loss stimulates any residual hearing & accustoms the infant to auditory stimulation for auditory/oral language development.
Cochlear implantation should be considered as early as is medically feasible.
• An initial trial of hearing aids even w/profound loss stimulates any residual hearing & accustoms the infant to auditory stimulation for auditory/oral language development.
• Cochlear implantation should be considered as early as is medically feasible.
## Surveillance
Recommended Surveillance for Individuals with Usher Syndrome Type I
For persons w/o profound loss, annual testing allows appropriate hearing aid adjustment.
For cochlear implant recipients, annual follow up is necessary to assure appropriate implant function & programming.
Children w/profound loss & cochlear implants can still develop fluid & chronic ear infection issues, which are less evident to the child because of hearing loss. Annual otoscopic exam w/tympanometry avoids potential serious complications of chronic otitis media.
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; VA = visual acuity; VF = visual field
• For persons w/o profound loss, annual testing allows appropriate hearing aid adjustment.
• For cochlear implant recipients, annual follow up is necessary to assure appropriate implant function & programming.
• Children w/profound loss & cochlear implants can still develop fluid & chronic ear infection issues, which are less evident to the child because of hearing loss. Annual otoscopic exam w/tympanometry avoids potential serious complications of chronic otitis media.
## Agents/Circumstances to Avoid
Competition in sports requiring acute vision and/or good balance may be difficult and possibly dangerous.
Persons with USH1 often become disoriented when submerged in water because they lack the sense of where "up" is; they should therefore exercise caution while swimming. Similarly, the vestibular dysfunction increases the risk of falls when walking on sloped or uneven surfaces.
Progressive loss of peripheral vision may eventually impair the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.
## Evaluation of Relatives at Risk
It is appropriate to evaluate the hearing of all sibs at risk for USH1 as soon after birth as possible to allow early diagnosis and treatment of hearing impairment.
Additional evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
## Therapies Under Investigation
Search
## Other
## Genetic Counseling
Usher syndrome type I (USH1) is typically inherited in an autosomal recessive manner.
Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
Although digenic inheritance has been proposed in Usher syndrome, particularly involving
The unaffected parents of an individual with USH1 are obligate heterozygotes (i.e., presumed to be carriers of one USH1-causing 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 USH1-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 USH1-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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has USH1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH1-related gene.
Assuming that: (1) the prevalence of Usher syndrome is one in 20,000, (2) 30% of individuals with Usher syndrome have type I, and (3) 60% of individuals with USH1 have biallelic pathogenic variants in
Carrier testing for at-risk relatives requires prior identification of the USH1-causing pathogenic variants in the family.
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 USH1-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, 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.
• Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
• Although digenic inheritance has been proposed in Usher syndrome, particularly involving
• The unaffected parents of an individual with USH1 are obligate heterozygotes (i.e., presumed to be carriers of one USH1-causing 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 USH1-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 USH1-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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has USH1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH1-related gene.
• Assuming that: (1) the prevalence of Usher syndrome is one in 20,000, (2) 30% of individuals with Usher syndrome have type I, and (3) 60% of individuals with USH1 have biallelic pathogenic variants in
• 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
Usher syndrome type I (USH1) is typically inherited in an autosomal recessive manner.
Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
Although digenic inheritance has been proposed in Usher syndrome, particularly involving
• Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
• Although digenic inheritance has been proposed in Usher syndrome, particularly involving
## Risk to Family Members (Autosomal Recessive Inheritance)
The unaffected parents of an individual with USH1 are obligate heterozygotes (i.e., presumed to be carriers of one USH1-causing 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 USH1-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 USH1-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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has USH1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH1-related gene.
Assuming that: (1) the prevalence of Usher syndrome is one in 20,000, (2) 30% of individuals with Usher syndrome have type I, and (3) 60% of individuals with USH1 have biallelic pathogenic variants in
• The unaffected parents of an individual with USH1 are obligate heterozygotes (i.e., presumed to be carriers of one USH1-causing 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 USH1-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 USH1-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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has USH1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH1-related gene.
• Assuming that: (1) the prevalence of Usher syndrome is one in 20,000, (2) 30% of individuals with Usher syndrome have type I, and (3) 60% of individuals with USH1 have biallelic pathogenic variants in
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the USH1-causing pathogenic variants in the family.
## 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 USH1-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, 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
United Kingdom
United Kingdom
101 Pentonville Road
London N1 9LG
United Kingdom
Usher Syndrome Coalition
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• Usher Syndrome Coalition
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## Molecular Genetics
Usher Syndrome Type I: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Usher Syndrome Type I (
Usher syndrome is the most frequent genetic cause of concurrent deaf-blindness. It is clinically and genetically heterogeneous. Currently, three clinical types and ten different genes (subtypes) are associated with Usher syndrome. The proteins encoded by the six known Usher syndrome type I (USH1) genes are hypothesized to interact with one another. These proteins are expressed in the eye and ear during and after development, forming a critical macromolecular complex necessary for the development of cilia structure and function. If any one protein in this "Usher interactome" is nonfunctional or absent, sensorineural degeneration occurs in the inner ear and the retina [
Note: A comprehensive set of databases (UMD-USHbases) provides information about pathogenic variants responsible for Usher syndrome [
Usher Syndrome Type I: Notable Pathogenic Variants by Gene
HL = hearing loss; RP = retinitis pigmentosa
Variants listed in the table have been provided by the authors.
Genes from
Although this variant is predicted to result in a p.Val72Glu missense change, it is known to cause abnormal splicing.
## Molecular Pathogenesis
Usher syndrome is the most frequent genetic cause of concurrent deaf-blindness. It is clinically and genetically heterogeneous. Currently, three clinical types and ten different genes (subtypes) are associated with Usher syndrome. The proteins encoded by the six known Usher syndrome type I (USH1) genes are hypothesized to interact with one another. These proteins are expressed in the eye and ear during and after development, forming a critical macromolecular complex necessary for the development of cilia structure and function. If any one protein in this "Usher interactome" is nonfunctional or absent, sensorineural degeneration occurs in the inner ear and the retina [
Note: A comprehensive set of databases (UMD-USHbases) provides information about pathogenic variants responsible for Usher syndrome [
Usher Syndrome Type I: Notable Pathogenic Variants by Gene
HL = hearing loss; RP = retinitis pigmentosa
Variants listed in the table have been provided by the authors.
Genes from
Although this variant is predicted to result in a p.Val72Glu missense change, it is known to cause abnormal splicing.
## Chapter Notes
Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital
Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden
Research supported by FFB and NIH
Moises A Arriaga, MD, MBA, FACS (2020-present)Bronya Keats, PhD; Louisiana State University Health Sciences Center (2006-2020)William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)Robert K Koenekoop, MD, PhD, FACS (2020-present)Jennifer J Lentz, PhD (2006-present)Sandra Pieke-Dahl, PhD; Ohio State University (1999-2006)Karmen M Trzupek, MS, CGC (2020-present)Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)
8 October 2020 (jjl) Revision: C-18-04 antioxidant treatment clinical trial now active (
25 June 2020 (sw) Comprehensive update posted live
19 May 2016 (sw) Comprehensive update posted live
20 June 2013 (me) Comprehensive update posted live
28 October 2010 (me) Comprehensive update posted live
28 May 2009 (me) Comprehensive update posted live
7 November 2006 (me) Comprehensive update posted live
20 November 2003 (me) Comprehensive update posted live
10 December 1999 (me) Review posted live
19 February 1999 (wk) Original submission
• 8 October 2020 (jjl) Revision: C-18-04 antioxidant treatment clinical trial now active (
• 25 June 2020 (sw) Comprehensive update posted live
• 19 May 2016 (sw) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 28 October 2010 (me) Comprehensive update posted live
• 28 May 2009 (me) Comprehensive update posted live
• 7 November 2006 (me) Comprehensive update posted live
• 20 November 2003 (me) Comprehensive update posted live
• 10 December 1999 (me) Review posted live
• 19 February 1999 (wk) Original submission
## Acknowledgments
Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital
Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden
Research supported by FFB and NIH
## Author History
Moises A Arriaga, MD, MBA, FACS (2020-present)Bronya Keats, PhD; Louisiana State University Health Sciences Center (2006-2020)William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)Robert K Koenekoop, MD, PhD, FACS (2020-present)Jennifer J Lentz, PhD (2006-present)Sandra Pieke-Dahl, PhD; Ohio State University (1999-2006)Karmen M Trzupek, MS, CGC (2020-present)Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)
## Revision History
8 October 2020 (jjl) Revision: C-18-04 antioxidant treatment clinical trial now active (
25 June 2020 (sw) Comprehensive update posted live
19 May 2016 (sw) Comprehensive update posted live
20 June 2013 (me) Comprehensive update posted live
28 October 2010 (me) Comprehensive update posted live
28 May 2009 (me) Comprehensive update posted live
7 November 2006 (me) Comprehensive update posted live
20 November 2003 (me) Comprehensive update posted live
10 December 1999 (me) Review posted live
19 February 1999 (wk) Original submission
• 8 October 2020 (jjl) Revision: C-18-04 antioxidant treatment clinical trial now active (
• 25 June 2020 (sw) Comprehensive update posted live
• 19 May 2016 (sw) Comprehensive update posted live
• 20 June 2013 (me) Comprehensive update posted live
• 28 October 2010 (me) Comprehensive update posted live
• 28 May 2009 (me) Comprehensive update posted live
• 7 November 2006 (me) Comprehensive update posted live
• 20 November 2003 (me) Comprehensive update posted live
• 10 December 1999 (me) Review posted live
• 19 February 1999 (wk) Original submission
## References
American College of Medical Genetics. Statement on universal newborn hearing screening. Available
American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available
• American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available
## Published Guidelines / Consensus Statements
American College of Medical Genetics. Statement on universal newborn hearing screening. Available
American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available
• American College of Medical Genetics Genetic Evaluation of Congenital Hearing Loss Expert Panel. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Available
## Literature Cited
|
[] |
10/12/1999
|
25/6/2020
|
8/10/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
usher2
|
usher2
|
[
"USH2",
"USH2",
"Adhesion G-protein coupled receptor V1",
"Usherin",
"Whirlin",
"ADGRV1",
"USH2A",
"WHRN",
"Usher Syndrome Type II"
] |
Usher Syndrome Type II
|
Robert Koenekoop, Moises Arriaga, Karmen M Trzupek, Jennifer Lentz
|
Summary Usher syndrome type II (USH2) is characterized by the following: Congenital, bilateral sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies Intact or variable vestibular responses Retinitis pigmentosa (RP); progressive, bilateral, symmetric retinal degeneration that begins with night blindness and constricted visual fields (tunnel vision) and eventually includes decreased central visual acuity; the rate and degree of vision loss vary within and among families. The diagnosis of USH2 is established in a proband using electrophysiologic and subjective tests of hearing and retinal function. Identification of biallelic pathogenic variants in one of three genes – USH2 is inherited in an autosomal recessive manner. Each subsequent pregnancy of a couple who have had a child with Usher syndrome type II has a 25% chance of resulting in an affected child, a 50% chance of resulting in an unaffected child who is a carrier, and a 25% chance of resulting in an unaffected child who is not a carrier. Prenatal testing and preimplantation genetic testing are possible for pregnancies at increased risk if the pathogenic variants have been identified in the family.
|
## Diagnosis
Usher syndrome type II (USH2)
Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see
Intact or variable vestibular responses;
Normal general health and intellect; otherwise normal physical examination;
A family history consistent with autosomal recessive inheritance.
The diagnosis of USH2
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 phenotype of USH2 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP, therefore the recommended molecular testing approaches can include use of
Note: Single-gene testing is rarely useful and typically NOT recommended.
An
For an introduction to multigene panels click
Note: Unlike exome sequencing, genome sequencing can identify variants outside of the coding region. Although most confirmed pathogenic variants identified by genome sequencing are within exons [
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Usher Syndrome Type II (USH2)
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.
Several deep intronic variants outside of the exon and splice junction regions typically included in standard sequencing have been observed, especially in
By screening for duplications/deletions,
A fourth locus associated with Usher syndrome type II has been provisionally mapped to 15q in a consanguineous Tunisian family [
To date,
• Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see
• Intact or variable vestibular responses;
• Normal general health and intellect; otherwise normal physical examination;
• A family history consistent with autosomal recessive inheritance.
• An
• For an introduction to multigene panels click
• Note: Unlike exome sequencing, genome sequencing can identify variants outside of the coding region. Although most confirmed pathogenic variants identified by genome sequencing are within exons [
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Usher syndrome type II (USH2)
Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see
Intact or variable vestibular responses;
Normal general health and intellect; otherwise normal physical examination;
A family history consistent with autosomal recessive inheritance.
• Congenital (i.e., prelingual) sensorineural hearing loss that is mild to moderate in the low frequencies and severe to profound in the higher frequencies (see
• Intact or variable vestibular responses;
• Normal general health and intellect; otherwise normal physical examination;
• A family history consistent with autosomal recessive inheritance.
## Establishing the Diagnosis
The diagnosis of USH2
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 phenotype of USH2 is often indistinguishable from many other inherited disorders associated with hearing loss and/or RP, therefore the recommended molecular testing approaches can include use of
Note: Single-gene testing is rarely useful and typically NOT recommended.
An
For an introduction to multigene panels click
Note: Unlike exome sequencing, genome sequencing can identify variants outside of the coding region. Although most confirmed pathogenic variants identified by genome sequencing are within exons [
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Usher Syndrome Type II (USH2)
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.
Several deep intronic variants outside of the exon and splice junction regions typically included in standard sequencing have been observed, especially in
By screening for duplications/deletions,
A fourth locus associated with Usher syndrome type II has been provisionally mapped to 15q in a consanguineous Tunisian family [
To date,
• An
• For an introduction to multigene panels click
• Note: Unlike exome sequencing, genome sequencing can identify variants outside of the coding region. Although most confirmed pathogenic variants identified by genome sequencing are within exons [
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Usher syndrome type II (USH2) is characterized by moderate-to-severe sensorineural hearing loss at birth and retinitis pigmentosa (RP) that begins in late adolescence or early adulthood. Some individuals also have vestibular loss [
Select Features of Usher Syndrome Type II
RP = retinitis pigmentosa
The hearing loss in USH2 is typically congenital and bilateral, occurring predominantly in the higher frequencies and ranging from moderate to severe. The degree of hearing loss varies within and among families; however, the "sloping" audiogram is characteristic of USH2. The hearing loss may be perceived by the affected individual as progressing over time because speech perception decreases, possibly as a result of diminished vision that interferes with subconscious lip reading. Hearing aids are usually adequate in individuals with USH2. Cochlear implants are highly effective if speech and sentence testing indicates inadequate response with hearing aids.
Clinical variability of the hearing phenotype has been observed. In particular, a few individuals with USH2 have a mild but definite progression of hearing loss that is unrelated to presbycusis. A cross-sectional study of 27 persons with
Children with USH2 are often misdiagnosed as having nonsyndromic hearing impairment until tunnel vision and night blindness (early signs of
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH2 at age 30-40 years. Visual impairment worsens significantly each year [
Vestibular loss has been identified in 40%-80% of individuals with USH2 in a small study of specialized vestibular testing [
Heterozygotes are asymptomatic; however, they may exhibit audiogram anomalies that are not sensitive or specific enough for carrier detection.
Individuals of Swedish or Dutch origin with biallelic
Penetrance is 100% in USH2.
The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, the presence or absence of vestibular areflexia, and the age of onset of retinitis pigmentosa). The letter following USH2 indicates the molecular subtype caused by biallelic variants in one of the related genes listed in
The prevalence of Usher syndrome in the general US population has been conservatively estimated at 4.4:100,000. However, a study of children with hearing loss in Oregon found that 11% had pathogenic variants in genes associated with Usher syndrome and estimated that the prevalence may be as high as 1:6,000 [
Usher syndrome has been estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. These estimates were made prior to 1989, when
The prevalence of Usher syndrome in Heidelberg, Germany and its suburbs has been calculated to be 6.2:100,000 [
## Clinical Description
Usher syndrome type II (USH2) is characterized by moderate-to-severe sensorineural hearing loss at birth and retinitis pigmentosa (RP) that begins in late adolescence or early adulthood. Some individuals also have vestibular loss [
Select Features of Usher Syndrome Type II
RP = retinitis pigmentosa
The hearing loss in USH2 is typically congenital and bilateral, occurring predominantly in the higher frequencies and ranging from moderate to severe. The degree of hearing loss varies within and among families; however, the "sloping" audiogram is characteristic of USH2. The hearing loss may be perceived by the affected individual as progressing over time because speech perception decreases, possibly as a result of diminished vision that interferes with subconscious lip reading. Hearing aids are usually adequate in individuals with USH2. Cochlear implants are highly effective if speech and sentence testing indicates inadequate response with hearing aids.
Clinical variability of the hearing phenotype has been observed. In particular, a few individuals with USH2 have a mild but definite progression of hearing loss that is unrelated to presbycusis. A cross-sectional study of 27 persons with
Children with USH2 are often misdiagnosed as having nonsyndromic hearing impairment until tunnel vision and night blindness (early signs of
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH2 at age 30-40 years. Visual impairment worsens significantly each year [
Vestibular loss has been identified in 40%-80% of individuals with USH2 in a small study of specialized vestibular testing [
Heterozygotes are asymptomatic; however, they may exhibit audiogram anomalies that are not sensitive or specific enough for carrier detection.
## Hearing Loss
The hearing loss in USH2 is typically congenital and bilateral, occurring predominantly in the higher frequencies and ranging from moderate to severe. The degree of hearing loss varies within and among families; however, the "sloping" audiogram is characteristic of USH2. The hearing loss may be perceived by the affected individual as progressing over time because speech perception decreases, possibly as a result of diminished vision that interferes with subconscious lip reading. Hearing aids are usually adequate in individuals with USH2. Cochlear implants are highly effective if speech and sentence testing indicates inadequate response with hearing aids.
Clinical variability of the hearing phenotype has been observed. In particular, a few individuals with USH2 have a mild but definite progression of hearing loss that is unrelated to presbycusis. A cross-sectional study of 27 persons with
## Visual Loss
Children with USH2 are often misdiagnosed as having nonsyndromic hearing impairment until tunnel vision and night blindness (early signs of
Visual fields become progressively constricted with time. The rate and degree of visual field loss show intra- and interfamilial variability. A visual field of 5-10 degrees ("severe tunnel") is common for a person with USH2 at age 30-40 years. Visual impairment worsens significantly each year [
## Vestibular Loss
Vestibular loss has been identified in 40%-80% of individuals with USH2 in a small study of specialized vestibular testing [
## Heterozygotes
Heterozygotes are asymptomatic; however, they may exhibit audiogram anomalies that are not sensitive or specific enough for carrier detection.
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
Individuals of Swedish or Dutch origin with biallelic
## Penetrance
Penetrance is 100% in USH2.
## Nomenclature
The numbering system used in Usher syndrome classification (USH1, USH2, and USH3) corresponds with the associated severity of the clinical presentation (i.e., degree of hearing impairment, the presence or absence of vestibular areflexia, and the age of onset of retinitis pigmentosa). The letter following USH2 indicates the molecular subtype caused by biallelic variants in one of the related genes listed in
## Prevalence
The prevalence of Usher syndrome in the general US population has been conservatively estimated at 4.4:100,000. However, a study of children with hearing loss in Oregon found that 11% had pathogenic variants in genes associated with Usher syndrome and estimated that the prevalence may be as high as 1:6,000 [
Usher syndrome has been estimated to be responsible for 3%-6% of all childhood deafness and approximately 50% of all deaf-blindness. These estimates were made prior to 1989, when
The prevalence of Usher syndrome in Heidelberg, Germany and its suburbs has been calculated to be 6.2:100,000 [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Allelic Disorders
AD = autosomal dominant; AR = autosomal recessive; DFNB = nonsyndromic deafness, autosomal recessive; MOI = mode of inheritance
## Differential Diagnosis
Often, a family with more than one affected sib is thought to have nonsyndromic hearing loss (NSHL) (see
Pathogenic variants associated with NSHL and RP can be inherited independently by a single individual whose symptoms mimic those of Usher syndrome [
Hereditary disorders characterized by both sensorineural hearing impairment and decreased visual acuity to consider in the differential diagnosis of Usher syndrome type II (USH2) are summarized in
Genes of Interest in the Differential Diagnosis of Usher Syndrome Type II
AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss; MOI = mode of inheritance; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; USH = Usher syndrome; XL = X-linked
60.5% of Zellweger spectrum disorder (ZSD) is associated with biallelic pathogenic variants in
The term "Zellweger spectrum disorder" refers to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype.
One
DDON syndrome is caused by either (1) a hemizygous
In DDON syndrome, hearing impairment appears to be constant in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs (e.g., personality change and paranoia) vary in degree of severity and rate of progression.
## Management
To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type II (USH2), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type II
To inform affected individuals & families re nature, MOI, & implications of USH2 in order to facilitate medical & personal decision making
Community or
Social work involvement for parental support.
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; RPE = retinal pigment epithelium; VA = visual acuity; VF = visual field; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Usher Syndrome Type II
See Retinitis Pigmentosa Overview,
Argus II prosthesis
Recommended Surveillance for Individuals with Usher Syndrome Type II
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; VA = visual acuity; VF = visual field
Competition in various sports requiring a full range of vision may be difficult and possibly dangerous.
Progressive loss of peripheral vision impairs the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.
It is appropriate to evaluate all sibs at risk for USH2 as soon after birth as possible to allow early support and management of the child and the family. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
See
High-dose vitamin A supplementation should not be used by affected pregnant women, as large doses of vitamin A (doses above the RDA for pregnant or lactating women) may be teratogenic to the developing fetus (see
Search
• Community or
• Social work involvement for parental support.
• See Retinitis Pigmentosa Overview,
• Argus II prosthesis
• Molecular genetic testing if the pathogenic variants in the family are known;
• Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Usher syndrome type II (USH2), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Usher Syndrome Type II
To inform affected individuals & families re nature, MOI, & implications of USH2 in order to facilitate medical & personal decision making
Community or
Social work involvement for parental support.
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; RPE = retinal pigment epithelium; VA = visual acuity; VF = visual field; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Usher Syndrome Type II
See Retinitis Pigmentosa Overview,
Argus II prosthesis
• See Retinitis Pigmentosa Overview,
• Argus II prosthesis
## Surveillance
Recommended Surveillance for Individuals with Usher Syndrome Type II
ERG = electroretinography; FAF = fundus autofluorescence; OCT = optical coherence tomography; VA = visual acuity; VF = visual field
## Agents/Circumstances to Avoid
Competition in various sports requiring a full range of vision may be difficult and possibly dangerous.
Progressive loss of peripheral vision impairs the ability to safely drive a car. An Esterman visual field test (automated Humphrey, static visual field analyzer) with both eyes open during testing is a helpful measure to assess degrees of peripheral vision along the midline. Night driving is impaired very early.
## Evaluation of Relatives at Risk
It is appropriate to evaluate all sibs at risk for USH2 as soon after birth as possible to allow early support and management of the child and the family. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Auditory brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) if the pathogenic variants in the family are not known.
## Pregnancy Management
High-dose vitamin A supplementation should not be used by affected pregnant women, as large doses of vitamin A (doses above the RDA for pregnant or lactating women) may be teratogenic to the developing fetus (see
## Therapies Under Investigation
Search
## Other
## Genetic Counseling
Usher syndrome type II (USH2) is inherited in an autosomal recessive manner.
Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
Although digenic inheritance has been proposed in Usher syndrome, particularly involving
The unaffected parents of an individual with USH2 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 USH2-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 an USH2-causing 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.
Considerable variability in the degree of hearing loss and the rate and degree of vision loss may be observed among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has USH2 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH2-related gene.
The carrier frequency of pathogenic variants in
Thus, for each pregnancy of a couple in which one partner has USH2 and the other partner has normal vision and no family history of USH2 or RP, the probability of a child having USH2 or RP due to biallelic pathogenic variants in
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 USH2-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.
• Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
• Although digenic inheritance has been proposed in Usher syndrome, particularly involving
• The unaffected parents of an individual with USH2 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 USH2-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 an USH2-causing 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.
• Considerable variability in the degree of hearing loss and the rate and degree of vision loss may be observed among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has USH2 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH2-related gene.
• The carrier frequency of pathogenic variants in
• Thus, for each pregnancy of a couple in which one partner has USH2 and the other partner has normal vision and no family history of USH2 or RP, the probability of a child having USH2 or RP due to biallelic pathogenic variants in
• 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
Usher syndrome type II (USH2) is inherited in an autosomal recessive manner.
Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
Although digenic inheritance has been proposed in Usher syndrome, particularly involving
• Multiple affected individuals have been found with two pathogenic variants in one USH1-related gene and another pathogenic variant in a second gene associated with Usher syndrome, which may modify the retinal phenotype [
• Although digenic inheritance has been proposed in Usher syndrome, particularly involving
## Risk to Family Members (Autosomal Recessive Inheritance)
The unaffected parents of an individual with USH2 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 USH2-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 an USH2-causing 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.
Considerable variability in the degree of hearing loss and the rate and degree of vision loss may be observed among affected sibs.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has USH2 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH2-related gene.
The carrier frequency of pathogenic variants in
Thus, for each pregnancy of a couple in which one partner has USH2 and the other partner has normal vision and no family history of USH2 or RP, the probability of a child having USH2 or RP due to biallelic pathogenic variants in
• The unaffected parents of an individual with USH2 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 USH2-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 an USH2-causing 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.
• Considerable variability in the degree of hearing loss and the rate and degree of vision loss may be observed among affected sibs.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has USH2 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in an USH2-related gene.
• The carrier frequency of pathogenic variants in
• Thus, for each pregnancy of a couple in which one partner has USH2 and the other partner has normal vision and no family history of USH2 or RP, the probability of a child having USH2 or RP due to biallelic pathogenic variants in
## 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 USH2-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
United Kingdom
101 Pentonville Road
London N1 9LG
United Kingdom
Usher Syndrome Coalition
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• Usher Syndrome Coalition
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## Molecular Genetics
Usher Syndrome Type II: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Usher Syndrome Type II (
The proteins associated with Usher syndrome type I (
Member of subgroup of the large N-terminal family B seven-transmembrane receptors
Contains pentaxin (PTX) domains, similar to USH2A; may share binding partners
Contains cadherin domains similar to USH1 proteins CDH23 and PCDH15
Expressed as multiple variants that comprise isoforms a, b, and c [
Expressed as two alternatively spliced isoforms that comprise a short "isoform a" (21 exons, 1546 amino acids) and a longer "isoform b" (72 exons, 5202 amino acids)
Isoform a is a secreted protein that contains 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), and 4 fibronectin III (FN3) domains [
Isoform b is a transmembrane protein. The extracellular N-terminal end contains 1 laminin globular-like (LGL), 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), 2 laminin globular (LG), and 32 firbronectin III (FN3) domains. The intracellular C-terminal end contains a PDZ-binding domain (PBD) that interacts with other USH and deafness proteins in retinal photoreceptors and inner ear hair cells [
Usherin colocalizes with and binds to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [
Expressed as multiple transcripts with two predicted promotor regions and alternative splicing that encode full-length (FL)-, N-, and C-terminal whirlin proteins [
FL-whirlin has two harmonin N-like (HNL), three PDZ, one proline-rich (PR), and one PDZ-binding domain (PBD) [
Whirlin interacts
Another PDZ domain-containing protein, PDZD7, was identified as a result of a study of a child with nonsyndromic sensorineural hearing loss and a homozygous reciprocal translocation; protein-protein interaction studies indicated that PDZD7 is a part of the Usher protein network [
Usher Syndrome Type II: Gene-Specific Laboratory Considerations
Multiple deep intronic pathogenic variants, which would not be detected by standard exome sequencing, are known to occur in
Large single- & multiexon pathogenic variants have also been identified.
Genes from
Usher Syndrome Type II:
Variants listed in the table have been provided by the authors.
• Member of subgroup of the large N-terminal family B seven-transmembrane receptors
• Contains pentaxin (PTX) domains, similar to USH2A; may share binding partners
• Contains cadherin domains similar to USH1 proteins CDH23 and PCDH15
• Expressed as multiple variants that comprise isoforms a, b, and c [
• Expressed as two alternatively spliced isoforms that comprise a short "isoform a" (21 exons, 1546 amino acids) and a longer "isoform b" (72 exons, 5202 amino acids)
• Isoform a is a secreted protein that contains 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), and 4 fibronectin III (FN3) domains [
• Isoform b is a transmembrane protein. The extracellular N-terminal end contains 1 laminin globular-like (LGL), 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), 2 laminin globular (LG), and 32 firbronectin III (FN3) domains. The intracellular C-terminal end contains a PDZ-binding domain (PBD) that interacts with other USH and deafness proteins in retinal photoreceptors and inner ear hair cells [
• Usherin colocalizes with and binds to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [
• Expressed as multiple transcripts with two predicted promotor regions and alternative splicing that encode full-length (FL)-, N-, and C-terminal whirlin proteins [
• FL-whirlin has two harmonin N-like (HNL), three PDZ, one proline-rich (PR), and one PDZ-binding domain (PBD) [
• Whirlin interacts
• Multiple deep intronic pathogenic variants, which would not be detected by standard exome sequencing, are known to occur in
• Large single- & multiexon pathogenic variants have also been identified.
## Molecular Pathogenesis
The proteins associated with Usher syndrome type I (
Member of subgroup of the large N-terminal family B seven-transmembrane receptors
Contains pentaxin (PTX) domains, similar to USH2A; may share binding partners
Contains cadherin domains similar to USH1 proteins CDH23 and PCDH15
Expressed as multiple variants that comprise isoforms a, b, and c [
Expressed as two alternatively spliced isoforms that comprise a short "isoform a" (21 exons, 1546 amino acids) and a longer "isoform b" (72 exons, 5202 amino acids)
Isoform a is a secreted protein that contains 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), and 4 fibronectin III (FN3) domains [
Isoform b is a transmembrane protein. The extracellular N-terminal end contains 1 laminin globular-like (LGL), 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), 2 laminin globular (LG), and 32 firbronectin III (FN3) domains. The intracellular C-terminal end contains a PDZ-binding domain (PBD) that interacts with other USH and deafness proteins in retinal photoreceptors and inner ear hair cells [
Usherin colocalizes with and binds to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [
Expressed as multiple transcripts with two predicted promotor regions and alternative splicing that encode full-length (FL)-, N-, and C-terminal whirlin proteins [
FL-whirlin has two harmonin N-like (HNL), three PDZ, one proline-rich (PR), and one PDZ-binding domain (PBD) [
Whirlin interacts
Another PDZ domain-containing protein, PDZD7, was identified as a result of a study of a child with nonsyndromic sensorineural hearing loss and a homozygous reciprocal translocation; protein-protein interaction studies indicated that PDZD7 is a part of the Usher protein network [
Usher Syndrome Type II: Gene-Specific Laboratory Considerations
Multiple deep intronic pathogenic variants, which would not be detected by standard exome sequencing, are known to occur in
Large single- & multiexon pathogenic variants have also been identified.
Genes from
Usher Syndrome Type II:
Variants listed in the table have been provided by the authors.
• Member of subgroup of the large N-terminal family B seven-transmembrane receptors
• Contains pentaxin (PTX) domains, similar to USH2A; may share binding partners
• Contains cadherin domains similar to USH1 proteins CDH23 and PCDH15
• Expressed as multiple variants that comprise isoforms a, b, and c [
• Expressed as two alternatively spliced isoforms that comprise a short "isoform a" (21 exons, 1546 amino acids) and a longer "isoform b" (72 exons, 5202 amino acids)
• Isoform a is a secreted protein that contains 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), and 4 fibronectin III (FN3) domains [
• Isoform b is a transmembrane protein. The extracellular N-terminal end contains 1 laminin globular-like (LGL), 1 laminin N-terminal (LN), 10 laminin epidermal growth factor (LE), 2 laminin globular (LG), and 32 firbronectin III (FN3) domains. The intracellular C-terminal end contains a PDZ-binding domain (PBD) that interacts with other USH and deafness proteins in retinal photoreceptors and inner ear hair cells [
• Usherin colocalizes with and binds to the extracellular basement membrane protein, type IV collagen, with a relatively broad tissue distribution [
• Expressed as multiple transcripts with two predicted promotor regions and alternative splicing that encode full-length (FL)-, N-, and C-terminal whirlin proteins [
• FL-whirlin has two harmonin N-like (HNL), three PDZ, one proline-rich (PR), and one PDZ-binding domain (PBD) [
• Whirlin interacts
• Multiple deep intronic pathogenic variants, which would not be detected by standard exome sequencing, are known to occur in
• Large single- & multiexon pathogenic variants have also been identified.
## Chapter Notes
Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital
Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden
Research supported by FFB and NIH
Moises Arriaga, MD, MBA, FACS (2020-present)Bronya Keats, PhD; Louisiana State University Health Sciences Center (2006-2020)William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)Robert Koenekoop, MD, PhD, FARVO (2020-present)Jennifer Lentz, PhD (2006-present)Dana J Orten, PhD; Boys Town National Research Hospital (2003-2006)Sandra Pieke-Dahl, PhD; Ohio State University (1999-2003)Karmen M Trzupek, MS, CGC (2020-present)Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)
23 March 2023 (aa/gm) Revision: references (
22 October 2020 (sw) Comprehensive update posted live
21 July 2016 (sw) Comprehensive update posted live
29 August 2013 (me) Comprehensive update posted live
23 December 2010 (me) Comprehensive update posted live
14 April 2009 (me) Comprehensive update posted live
14 November 2006 (me) Comprehensive update posted live
20 November 2003 (me) Comprehensive update posted live
10 December 1999 (me) Review posted live
19 February 1999 (wk) Original submission
• 23 March 2023 (aa/gm) Revision: references (
• 22 October 2020 (sw) Comprehensive update posted live
• 21 July 2016 (sw) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 23 December 2010 (me) Comprehensive update posted live
• 14 April 2009 (me) Comprehensive update posted live
• 14 November 2006 (me) Comprehensive update posted live
• 20 November 2003 (me) Comprehensive update posted live
• 10 December 1999 (me) Review posted live
• 19 February 1999 (wk) Original submission
## Acknowledgments
Edward Cohn, MD, Department of Otolaryngology, Boys Town National Research Hospital
Janos Sumegi, PhD, Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha
Claes Möller, MD, PhD, Department of Otorhinolaryngology, Sahlgrenska University Hospital, Göteborg, Sweden
Research supported by FFB and NIH
## Author History
Moises Arriaga, MD, MBA, FACS (2020-present)Bronya Keats, PhD; Louisiana State University Health Sciences Center (2006-2020)William J Kimberling, PhD, FACMG; Boys Town National Research Hospital (1999-2006)Robert Koenekoop, MD, PhD, FARVO (2020-present)Jennifer Lentz, PhD (2006-present)Dana J Orten, PhD; Boys Town National Research Hospital (2003-2006)Sandra Pieke-Dahl, PhD; Ohio State University (1999-2003)Karmen M Trzupek, MS, CGC (2020-present)Michael D Weston, MA; Boys Town National Research Hospital (1999-2006)
## Revision History
23 March 2023 (aa/gm) Revision: references (
22 October 2020 (sw) Comprehensive update posted live
21 July 2016 (sw) Comprehensive update posted live
29 August 2013 (me) Comprehensive update posted live
23 December 2010 (me) Comprehensive update posted live
14 April 2009 (me) Comprehensive update posted live
14 November 2006 (me) Comprehensive update posted live
20 November 2003 (me) Comprehensive update posted live
10 December 1999 (me) Review posted live
19 February 1999 (wk) Original submission
• 23 March 2023 (aa/gm) Revision: references (
• 22 October 2020 (sw) Comprehensive update posted live
• 21 July 2016 (sw) Comprehensive update posted live
• 29 August 2013 (me) Comprehensive update posted live
• 23 December 2010 (me) Comprehensive update posted live
• 14 April 2009 (me) Comprehensive update posted live
• 14 November 2006 (me) Comprehensive update posted live
• 20 November 2003 (me) Comprehensive update posted live
• 10 December 1999 (me) Review posted live
• 19 February 1999 (wk) Original submission
## References
American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available
American College of Medical Genetics. Statement on universal newborn hearing screening. Available
• American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available
## Published Guidelines / Consensus Statements
American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available
American College of Medical Genetics. Statement on universal newborn hearing screening. Available
• American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available
• American College of Medical Genetics. Statement on universal newborn hearing screening. Available
## Literature Cited
|
[] |
10/12/1999
|
22/10/2020
|
23/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
vexas
|
vexas
|
[
"Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic Syndrome",
"Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic Syndrome",
"Ubiquitin-like modifier-activating enzyme 1",
"UBA1",
"VEXAS Syndrome"
] |
VEXAS Syndrome
|
Jerome Hadjadj, David Beck
|
Summary VEXAS syndrome is an autoinflammatory syndrome caused by a somatic The diagnosis of VEXAS syndrome is established in an individual with suggestive findings and a VEXAS syndrome is an X-linked disorder caused by somatic pathogenic variants in
|
## Diagnosis
For the purposes of this
Formal diagnostic criteria for VEXAS syndrome have not been established.
VEXAS syndrome
Recurrent episodes of fever
Weight loss
Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
Lung involvement (pulmonary infiltrates, pleural effusion)
Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
Relapsing polychondritis
Unprovoked thrombosis
Lymph node enlargement
Arthralgias and arthritis
Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
Elevated C-reactive protein during flare episodes
Macrocytosis
Macrocytic anemia
Thrombocytopenia
Monocytopenia
Lymphopenia
Myelodysplastic syndrome (MDS)
Clonal hematopoiesis
Monoclonal gammopathy of unknown significance and multiple myeloma
Presence of vacuoles in myeloid and erythroid progenitor cells in bone marrow aspirates is a key feature of VEXAS syndrome, found in more than 80% of affected individuals and observed by May-Giesma smear rather than bone marrow biopsy. However, it lacks specificity, as they can also be observed in other conditions such as copper deficiency, chronic inflammation, zinc toxicity, liver disease/alcoholism, acute myeloid leukemia MDS, and other hematologic disorders [
While bone marrow hypercellularity is a common feature in VEXAS syndrome, both normocellularity and hypocellularity can also be seen.
Acute kidney injury, with plasma cell-rich interstitial nephritis being the most common histopathologic finding [
Autoantibodies (antineutrophil cytoplasmic antibodies or antinuclear antibodies)
The diagnosis of VEXAS syndrome
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
Molecular genetic testing approaches can include a combination of
Note: (1) Because all reported
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in VEXAS 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
To date, all reported pathogenic variants 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. 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.
•
• Recurrent episodes of fever
• Weight loss
• Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
• Lung involvement (pulmonary infiltrates, pleural effusion)
• Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
• Relapsing polychondritis
• Unprovoked thrombosis
• Lymph node enlargement
• Arthralgias and arthritis
• Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
• Elevated C-reactive protein during flare episodes
• Recurrent episodes of fever
• Weight loss
• Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
• Lung involvement (pulmonary infiltrates, pleural effusion)
• Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
• Relapsing polychondritis
• Unprovoked thrombosis
• Lymph node enlargement
• Arthralgias and arthritis
• Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
• Elevated C-reactive protein during flare episodes
• Macrocytosis
• Macrocytic anemia
• Thrombocytopenia
• Monocytopenia
• Lymphopenia
• Myelodysplastic syndrome (MDS)
• Clonal hematopoiesis
• Monoclonal gammopathy of unknown significance and multiple myeloma
• Presence of vacuoles in myeloid and erythroid progenitor cells in bone marrow aspirates is a key feature of VEXAS syndrome, found in more than 80% of affected individuals and observed by May-Giesma smear rather than bone marrow biopsy. However, it lacks specificity, as they can also be observed in other conditions such as copper deficiency, chronic inflammation, zinc toxicity, liver disease/alcoholism, acute myeloid leukemia MDS, and other hematologic disorders [
• While bone marrow hypercellularity is a common feature in VEXAS syndrome, both normocellularity and hypocellularity can also be seen.
• Macrocytosis
• Macrocytic anemia
• Thrombocytopenia
• Monocytopenia
• Lymphopenia
• Myelodysplastic syndrome (MDS)
• Clonal hematopoiesis
• Monoclonal gammopathy of unknown significance and multiple myeloma
• Recurrent episodes of fever
• Weight loss
• Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
• Lung involvement (pulmonary infiltrates, pleural effusion)
• Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
• Relapsing polychondritis
• Unprovoked thrombosis
• Lymph node enlargement
• Arthralgias and arthritis
• Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
• Elevated C-reactive protein during flare episodes
• Macrocytosis
• Macrocytic anemia
• Thrombocytopenia
• Monocytopenia
• Lymphopenia
• Myelodysplastic syndrome (MDS)
• Clonal hematopoiesis
• Monoclonal gammopathy of unknown significance and multiple myeloma
• Acute kidney injury, with plasma cell-rich interstitial nephritis being the most common histopathologic finding [
• Autoantibodies (antineutrophil cytoplasmic antibodies or antinuclear antibodies)
## Suggestive Findings
VEXAS syndrome
Recurrent episodes of fever
Weight loss
Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
Lung involvement (pulmonary infiltrates, pleural effusion)
Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
Relapsing polychondritis
Unprovoked thrombosis
Lymph node enlargement
Arthralgias and arthritis
Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
Elevated C-reactive protein during flare episodes
Macrocytosis
Macrocytic anemia
Thrombocytopenia
Monocytopenia
Lymphopenia
Myelodysplastic syndrome (MDS)
Clonal hematopoiesis
Monoclonal gammopathy of unknown significance and multiple myeloma
Presence of vacuoles in myeloid and erythroid progenitor cells in bone marrow aspirates is a key feature of VEXAS syndrome, found in more than 80% of affected individuals and observed by May-Giesma smear rather than bone marrow biopsy. However, it lacks specificity, as they can also be observed in other conditions such as copper deficiency, chronic inflammation, zinc toxicity, liver disease/alcoholism, acute myeloid leukemia MDS, and other hematologic disorders [
While bone marrow hypercellularity is a common feature in VEXAS syndrome, both normocellularity and hypocellularity can also be seen.
Acute kidney injury, with plasma cell-rich interstitial nephritis being the most common histopathologic finding [
Autoantibodies (antineutrophil cytoplasmic antibodies or antinuclear antibodies)
•
• Recurrent episodes of fever
• Weight loss
• Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
• Lung involvement (pulmonary infiltrates, pleural effusion)
• Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
• Relapsing polychondritis
• Unprovoked thrombosis
• Lymph node enlargement
• Arthralgias and arthritis
• Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
• Elevated C-reactive protein during flare episodes
• Recurrent episodes of fever
• Weight loss
• Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
• Lung involvement (pulmonary infiltrates, pleural effusion)
• Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
• Relapsing polychondritis
• Unprovoked thrombosis
• Lymph node enlargement
• Arthralgias and arthritis
• Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
• Elevated C-reactive protein during flare episodes
• Macrocytosis
• Macrocytic anemia
• Thrombocytopenia
• Monocytopenia
• Lymphopenia
• Myelodysplastic syndrome (MDS)
• Clonal hematopoiesis
• Monoclonal gammopathy of unknown significance and multiple myeloma
• Presence of vacuoles in myeloid and erythroid progenitor cells in bone marrow aspirates is a key feature of VEXAS syndrome, found in more than 80% of affected individuals and observed by May-Giesma smear rather than bone marrow biopsy. However, it lacks specificity, as they can also be observed in other conditions such as copper deficiency, chronic inflammation, zinc toxicity, liver disease/alcoholism, acute myeloid leukemia MDS, and other hematologic disorders [
• While bone marrow hypercellularity is a common feature in VEXAS syndrome, both normocellularity and hypocellularity can also be seen.
• Macrocytosis
• Macrocytic anemia
• Thrombocytopenia
• Monocytopenia
• Lymphopenia
• Myelodysplastic syndrome (MDS)
• Clonal hematopoiesis
• Monoclonal gammopathy of unknown significance and multiple myeloma
• Recurrent episodes of fever
• Weight loss
• Skin lesions. Skin biopsy is needed to document neutrophilic dermatosis including Sweet syndrome, leukocytoclastic vasculitis, or other atypical rashes suggesting VEXAS syndrome (urticaria-like lesions, pustular lesions, livedo).
• Lung involvement (pulmonary infiltrates, pleural effusion)
• Ocular inflammation (episcleritis, scleritis, uveitis, periorbital edema)
• Relapsing polychondritis
• Unprovoked thrombosis
• Lymph node enlargement
• Arthralgias and arthritis
• Failure to respond to classic immunosuppressive treatments including methotrexate, azathioprine, or cyclophosphamide
• Elevated C-reactive protein during flare episodes
• Macrocytosis
• Macrocytic anemia
• Thrombocytopenia
• Monocytopenia
• Lymphopenia
• Myelodysplastic syndrome (MDS)
• Clonal hematopoiesis
• Monoclonal gammopathy of unknown significance and multiple myeloma
• Acute kidney injury, with plasma cell-rich interstitial nephritis being the most common histopathologic finding [
• Autoantibodies (antineutrophil cytoplasmic antibodies or antinuclear antibodies)
## Establishing the Diagnosis
The diagnosis of VEXAS syndrome
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
Molecular genetic testing approaches can include a combination of
Note: (1) Because all reported
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in VEXAS 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
To date, all reported pathogenic variants 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. 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 VEXAS 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
To date, all reported pathogenic variants 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. 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
VEXAS syndrome is an autoinflammatory syndrome caused by a somatic
VEXAS syndrome is characterized by inflammatory and hematologic findings [
Before the description of VEXAS syndrome in 2020, most affected individuals had met clinical criteria for other inflammatory disorders including relapsing polychondritis (60%), Sweet syndrome (32%), polyarteritis nodosa, and giant cell arteritis or hematologic conditions including MDS (24%), multiple myeloma, or MGUS (20%) [
The following description of the phenotypic features of VEXAS syndrome in males is based on three large cohorts: 116 individuals from France [
VEXAS Syndrome: Frequency of Select Features
Based on
Lesions can be round maculopapules of various sizes, and are mostly pink/red, often numerous, and on the trunk, limbs, and face. Additional skin lesions include tender, red or violaceous papules that are sometimes edematous; recurrence of pathergy (i.e., skin lesions in response to minor trauma, such as cuts, bruises, or needle sticks); inflammatory edematous papules on the neck; firm erythematous purpuric or pigmented infiltrated plaques and nodules; and livedo racemosa.
Neutrophilic dermatosis is the most typical histologic finding; thus, affected individuals are often initially diagnosed with Sweet syndrome (see
Note: Sequence analysis of paired bone marrow samples and biopsies of skin lesions have identified the same
Arterial thrombosis, which is less frequent (13%), occurs mostly in individuals with arterial risk factors and/or atrial fibrillation [
Myocarditis and pericarditis has been reported in 3%-4% of affected individuals.
Renal involvement seems to be underrecognized. Presentation can include acute kidney injury, with plasma cell-rich interstitial nephritis the most common histopathologic finding [
Rarely observed features include gastrointestinal involvement (abdominal pain and/or chronic diarrhea), myalgias, and hearing loss [
While these infections are mainly due to the high burden of treatment, the increased incidence of atypical infections (e.g., legionellosis) and invasive fungal infections occurring despite anti-infective prophylaxis or in individuals without immunosuppressive treatment at the time of infection may indicate an intrinsic immunodeficiency in VEXAS syndrome [
Rarely, VEXAS syndrome is diagnosed in females; approximately ten females have been reported to date [
The majority of affected females exhibited acquired X-chromosomal monosomy or Turner syndrome. Given the postulated loss-of-function mechanism of disease causation, it remains unclear why some females with the constitutional karyotype 46,XX are affected, because the presence of one wild type (functional)
Estimates of mortality rates from VEXAS syndrome have been as high as 50% five-year mortality from the time of symptom onset; however, studies have been confounded by use of different treatment modalities and varying methods of ascertainment and reporting [
Multiple genotype-phenotype studies have been performed.
Individuals with the valine variant (p.Met41Val) are less likely to develop ear chondritis and are more likely to have an undifferentiated inflammatory syndrome.
Individuals with the threonine variant (p.Met41Thr) have more inflammatory eye disease.
Individuals with the leucine variant (p.Met41Leu) have more frequent skin involvement [
The p.Met41Val variant is associated with a poorer outcome, with a five-year survival rate of 76.7%, compared to a five-year survival rate of 83% with p.Met41Thr and 100% with p.Met41Leu.
A national French study [
Cluster 1 (more often associated with p.Met41Leu) had more mild/moderate disease, less constitutional manifestations, and a lower frequency of lung, lymph node, and venous thromboembolism.
Cluster 2 (without a specific genotype) had a predisposition to chondritis and gastrointestinal, cardiac, and lung involvement, and higher frequency of MGUS and MDS.
Cluster 3 (without a specific genotype) was characterized by older age of affected individuals, weight loss, and cutaneous vasculitis.
In a cohort of 245,368 participants,
Initially considered an ultra-rare disease, VEXAS syndrome is likely underdiagnosed and underrecognized.
In a study involving 163,096 unselected participants,
• Myocarditis and pericarditis has been reported in 3%-4% of affected individuals.
• Renal involvement seems to be underrecognized. Presentation can include acute kidney injury, with plasma cell-rich interstitial nephritis the most common histopathologic finding [
• Rarely observed features include gastrointestinal involvement (abdominal pain and/or chronic diarrhea), myalgias, and hearing loss [
• Individuals with the valine variant (p.Met41Val) are less likely to develop ear chondritis and are more likely to have an undifferentiated inflammatory syndrome.
• Individuals with the threonine variant (p.Met41Thr) have more inflammatory eye disease.
• Individuals with the leucine variant (p.Met41Leu) have more frequent skin involvement [
• The p.Met41Val variant is associated with a poorer outcome, with a five-year survival rate of 76.7%, compared to a five-year survival rate of 83% with p.Met41Thr and 100% with p.Met41Leu.
• Cluster 1 (more often associated with p.Met41Leu) had more mild/moderate disease, less constitutional manifestations, and a lower frequency of lung, lymph node, and venous thromboembolism.
• Cluster 2 (without a specific genotype) had a predisposition to chondritis and gastrointestinal, cardiac, and lung involvement, and higher frequency of MGUS and MDS.
• Cluster 3 (without a specific genotype) was characterized by older age of affected individuals, weight loss, and cutaneous vasculitis.
## Clinical Description
VEXAS syndrome is an autoinflammatory syndrome caused by a somatic
VEXAS syndrome is characterized by inflammatory and hematologic findings [
Before the description of VEXAS syndrome in 2020, most affected individuals had met clinical criteria for other inflammatory disorders including relapsing polychondritis (60%), Sweet syndrome (32%), polyarteritis nodosa, and giant cell arteritis or hematologic conditions including MDS (24%), multiple myeloma, or MGUS (20%) [
The following description of the phenotypic features of VEXAS syndrome in males is based on three large cohorts: 116 individuals from France [
VEXAS Syndrome: Frequency of Select Features
Based on
Lesions can be round maculopapules of various sizes, and are mostly pink/red, often numerous, and on the trunk, limbs, and face. Additional skin lesions include tender, red or violaceous papules that are sometimes edematous; recurrence of pathergy (i.e., skin lesions in response to minor trauma, such as cuts, bruises, or needle sticks); inflammatory edematous papules on the neck; firm erythematous purpuric or pigmented infiltrated plaques and nodules; and livedo racemosa.
Neutrophilic dermatosis is the most typical histologic finding; thus, affected individuals are often initially diagnosed with Sweet syndrome (see
Note: Sequence analysis of paired bone marrow samples and biopsies of skin lesions have identified the same
Arterial thrombosis, which is less frequent (13%), occurs mostly in individuals with arterial risk factors and/or atrial fibrillation [
Myocarditis and pericarditis has been reported in 3%-4% of affected individuals.
Renal involvement seems to be underrecognized. Presentation can include acute kidney injury, with plasma cell-rich interstitial nephritis the most common histopathologic finding [
Rarely observed features include gastrointestinal involvement (abdominal pain and/or chronic diarrhea), myalgias, and hearing loss [
While these infections are mainly due to the high burden of treatment, the increased incidence of atypical infections (e.g., legionellosis) and invasive fungal infections occurring despite anti-infective prophylaxis or in individuals without immunosuppressive treatment at the time of infection may indicate an intrinsic immunodeficiency in VEXAS syndrome [
Rarely, VEXAS syndrome is diagnosed in females; approximately ten females have been reported to date [
The majority of affected females exhibited acquired X-chromosomal monosomy or Turner syndrome. Given the postulated loss-of-function mechanism of disease causation, it remains unclear why some females with the constitutional karyotype 46,XX are affected, because the presence of one wild type (functional)
Estimates of mortality rates from VEXAS syndrome have been as high as 50% five-year mortality from the time of symptom onset; however, studies have been confounded by use of different treatment modalities and varying methods of ascertainment and reporting [
• Myocarditis and pericarditis has been reported in 3%-4% of affected individuals.
• Renal involvement seems to be underrecognized. Presentation can include acute kidney injury, with plasma cell-rich interstitial nephritis the most common histopathologic finding [
• Rarely observed features include gastrointestinal involvement (abdominal pain and/or chronic diarrhea), myalgias, and hearing loss [
## Inflammatory Syndrome
Lesions can be round maculopapules of various sizes, and are mostly pink/red, often numerous, and on the trunk, limbs, and face. Additional skin lesions include tender, red or violaceous papules that are sometimes edematous; recurrence of pathergy (i.e., skin lesions in response to minor trauma, such as cuts, bruises, or needle sticks); inflammatory edematous papules on the neck; firm erythematous purpuric or pigmented infiltrated plaques and nodules; and livedo racemosa.
Neutrophilic dermatosis is the most typical histologic finding; thus, affected individuals are often initially diagnosed with Sweet syndrome (see
Note: Sequence analysis of paired bone marrow samples and biopsies of skin lesions have identified the same
Arterial thrombosis, which is less frequent (13%), occurs mostly in individuals with arterial risk factors and/or atrial fibrillation [
Myocarditis and pericarditis has been reported in 3%-4% of affected individuals.
Renal involvement seems to be underrecognized. Presentation can include acute kidney injury, with plasma cell-rich interstitial nephritis the most common histopathologic finding [
Rarely observed features include gastrointestinal involvement (abdominal pain and/or chronic diarrhea), myalgias, and hearing loss [
• Myocarditis and pericarditis has been reported in 3%-4% of affected individuals.
• Renal involvement seems to be underrecognized. Presentation can include acute kidney injury, with plasma cell-rich interstitial nephritis the most common histopathologic finding [
• Rarely observed features include gastrointestinal involvement (abdominal pain and/or chronic diarrhea), myalgias, and hearing loss [
## Hematologic Involvement
While these infections are mainly due to the high burden of treatment, the increased incidence of atypical infections (e.g., legionellosis) and invasive fungal infections occurring despite anti-infective prophylaxis or in individuals without immunosuppressive treatment at the time of infection may indicate an intrinsic immunodeficiency in VEXAS syndrome [
## Females
Rarely, VEXAS syndrome is diagnosed in females; approximately ten females have been reported to date [
The majority of affected females exhibited acquired X-chromosomal monosomy or Turner syndrome. Given the postulated loss-of-function mechanism of disease causation, it remains unclear why some females with the constitutional karyotype 46,XX are affected, because the presence of one wild type (functional)
## Prognosis
Estimates of mortality rates from VEXAS syndrome have been as high as 50% five-year mortality from the time of symptom onset; however, studies have been confounded by use of different treatment modalities and varying methods of ascertainment and reporting [
## Genotype-Phenotype Correlations
Multiple genotype-phenotype studies have been performed.
Individuals with the valine variant (p.Met41Val) are less likely to develop ear chondritis and are more likely to have an undifferentiated inflammatory syndrome.
Individuals with the threonine variant (p.Met41Thr) have more inflammatory eye disease.
Individuals with the leucine variant (p.Met41Leu) have more frequent skin involvement [
The p.Met41Val variant is associated with a poorer outcome, with a five-year survival rate of 76.7%, compared to a five-year survival rate of 83% with p.Met41Thr and 100% with p.Met41Leu.
A national French study [
Cluster 1 (more often associated with p.Met41Leu) had more mild/moderate disease, less constitutional manifestations, and a lower frequency of lung, lymph node, and venous thromboembolism.
Cluster 2 (without a specific genotype) had a predisposition to chondritis and gastrointestinal, cardiac, and lung involvement, and higher frequency of MGUS and MDS.
Cluster 3 (without a specific genotype) was characterized by older age of affected individuals, weight loss, and cutaneous vasculitis.
In a cohort of 245,368 participants,
• Individuals with the valine variant (p.Met41Val) are less likely to develop ear chondritis and are more likely to have an undifferentiated inflammatory syndrome.
• Individuals with the threonine variant (p.Met41Thr) have more inflammatory eye disease.
• Individuals with the leucine variant (p.Met41Leu) have more frequent skin involvement [
• The p.Met41Val variant is associated with a poorer outcome, with a five-year survival rate of 76.7%, compared to a five-year survival rate of 83% with p.Met41Thr and 100% with p.Met41Leu.
• Cluster 1 (more often associated with p.Met41Leu) had more mild/moderate disease, less constitutional manifestations, and a lower frequency of lung, lymph node, and venous thromboembolism.
• Cluster 2 (without a specific genotype) had a predisposition to chondritis and gastrointestinal, cardiac, and lung involvement, and higher frequency of MGUS and MDS.
• Cluster 3 (without a specific genotype) was characterized by older age of affected individuals, weight loss, and cutaneous vasculitis.
## Prevalence
Initially considered an ultra-rare disease, VEXAS syndrome is likely underdiagnosed and underrecognized.
In a study involving 163,096 unselected participants,
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genetic Disorders of Interest in the Differential Diagnosis of VEXAS Syndrome
Recurrent fever
Skin involvement (migratory rash)
Periorbital edema
Joint pain
Mostly childhood onset
No chondritis or lung involvement
No thrombosis or hematologic disease
Recurrent fever
Neutrophilic dermatosis
Joint pain
Childhood onset (early)
Lipodystrophy is frequent.
No chondritis or lung involvement
No thrombosis or hematologic disease
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Acquired Adult-Onset Inflammatory Disorders of Interest in the Differential Diagnosis of VEXAS Syndrome
Neutrophilic dermatosis
Can be assoc w/hematologic malignancies
Chondritis, ocular involvement, & thrombotic events are usually not observed.
Good response to treatments such as colchicine & dapsone that are not effective in persons w/VEXAS syndrome
Chondritis of airways & costochondritis (usually not observed in VEXAS syndrome)
Lower risk of mortality & relapse
Greater diversity of affected persons (persons w/VEXAS syndrome-related RP are typically male & age ≥45 yrs at disease onset)
Absence of other manifestations suggestive of VEXAS syndrome
Pathogenic
Vasculitis/vasculopathy
Livedo & skin nodules
Aneurysms of medium-sized arteries
Can be assoc w/hematologic malignancies
Fever, relapsing chondritis, lung opacities
Vasculitis/vasculopathy
ANCAs are usually absent in VEXAS syndrome.
No hematologic malignancies
• Recurrent fever
• Skin involvement (migratory rash)
• Periorbital edema
• Joint pain
• Mostly childhood onset
• No chondritis or lung involvement
• No thrombosis or hematologic disease
• Recurrent fever
• Neutrophilic dermatosis
• Joint pain
• Childhood onset (early)
• Lipodystrophy is frequent.
• No chondritis or lung involvement
• No thrombosis or hematologic disease
• Neutrophilic dermatosis
• Can be assoc w/hematologic malignancies
• Chondritis, ocular involvement, & thrombotic events are usually not observed.
• Good response to treatments such as colchicine & dapsone that are not effective in persons w/VEXAS syndrome
• Chondritis of airways & costochondritis (usually not observed in VEXAS syndrome)
• Lower risk of mortality & relapse
• Greater diversity of affected persons (persons w/VEXAS syndrome-related RP are typically male & age ≥45 yrs at disease onset)
• Absence of other manifestations suggestive of VEXAS syndrome
• Pathogenic
• Vasculitis/vasculopathy
• Livedo & skin nodules
• Aneurysms of medium-sized arteries
• Can be assoc w/hematologic malignancies
• Fever, relapsing chondritis, lung opacities
• Vasculitis/vasculopathy
• ANCAs are usually absent in VEXAS syndrome.
• No hematologic malignancies
## Management
No clinical practice guidelines for VEXAS 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 VEXAS syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Blood pressure and other vital signs, as fever is common
Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
Lung auscultation, as lung involvement can be asymptomatic
Joint examination, as polyarthritis is common
Assessment for lymphadenopathy and hepatosplenomegaly
Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
Complete blood count (CBC) to detect cytopenia and macrocytosis
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
Tests of kidney and liver function
Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
Assessment of need for family support and resources including community or online
Because large prospective trials are lacking, the therapeutic management of individuals with VEXAS syndrome is currently poorly standardized and is based on retrospective studies [
In a systematic review of treatments, two thirds of individuals were able to achieve glucocorticoid reduction; however, only 20% achieved complete response [
A prospective trial assessing AZA in 30 individuals with steroid-dependent or refractory inflammatory disorders associated with myeloid neoplasia included 12 individuals with VEXAS syndrome [
Red blood cell transfusions and erythropoiesis-stimulating agents can be used in individuals with symptomatic anemia.
Anti-infection prophylaxis in individuals who are highly susceptible to severe infections includes cotrimoxazole and valaciclovir in addition to vaccinations.
Given the high risk of venous thromboembolism, thromboprophylaxis should be considered in at-risk situations to prevent potential thrombi unless contraindicated. Studies on thromboprophylaxis and efficacy of specific anticoagulants in outpatient settings in individuals with VEXAS syndrome are needed.
For individuals using glucocorticoids as first-line treatment, screening includes measurement of blood pressure, blood glucose concentration, and assessment of bone density, as well as prophylaxis against
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:
Blood pressure and other vital signs
Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
Lung auscultation
Joint examination for manifestations of arthritis
Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
Vascular examination for evidence of arterial or venous thrombotic events
Assessment for lymphadenopathy and hepatosplenomegaly
Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
CBC and differential
ESR and CRP
Tests of kidney and liver function
Quantitative serum immunoglobulins
All abnormal laboratory studies identified during earlier evaluations
Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
Chest CT scan in the presence of pulmonary signs or symptoms
Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
Avoid smoking, which may exacerbate peripheral arterial disease.
A Phase II study of allogeneic HSCT for individuals with VEXAS syndrome is ongoing (
Search
• Blood pressure and other vital signs, as fever is common
• Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
• Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
• Lung auscultation, as lung involvement can be asymptomatic
• Joint examination, as polyarthritis is common
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• Blood pressure and other vital signs, as fever is common
• Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
• Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
• Lung auscultation, as lung involvement can be asymptomatic
• Joint examination, as polyarthritis is common
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
•
• Complete blood count (CBC) to detect cytopenia and macrocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
• Tests of kidney and liver function
• Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
• For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
• Complete blood count (CBC) to detect cytopenia and macrocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
• Tests of kidney and liver function
• Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
• For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
•
• Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
• Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
• Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
• Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
• Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
• Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
• Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
• Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
•
• Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
• Assessment of need for family support and resources including community or online
• Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
• Assessment of need for family support and resources including community or online
• Blood pressure and other vital signs, as fever is common
• Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
• Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
• Lung auscultation, as lung involvement can be asymptomatic
• Joint examination, as polyarthritis is common
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• Complete blood count (CBC) to detect cytopenia and macrocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
• Tests of kidney and liver function
• Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
• For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
• Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
• Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
• Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
• Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
• Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
• Assessment of need for family support and resources including community or online
• In a systematic review of treatments, two thirds of individuals were able to achieve glucocorticoid reduction; however, only 20% achieved complete response [
• Blood pressure and other vital signs
• Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
• Lung auscultation
• Joint examination for manifestations of arthritis
• Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
• Vascular examination for evidence of arterial or venous thrombotic events
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• Blood pressure and other vital signs
• Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
• Lung auscultation
• Joint examination for manifestations of arthritis
• Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
• Vascular examination for evidence of arterial or venous thrombotic events
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• CBC and differential
• ESR and CRP
• Tests of kidney and liver function
• Quantitative serum immunoglobulins
• All abnormal laboratory studies identified during earlier evaluations
• Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
• CBC and differential
• ESR and CRP
• Tests of kidney and liver function
• Quantitative serum immunoglobulins
• All abnormal laboratory studies identified during earlier evaluations
• Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
• Chest CT scan in the presence of pulmonary signs or symptoms
• Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
• Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
• Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
• Chest CT scan in the presence of pulmonary signs or symptoms
• Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
• Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
• Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
• Blood pressure and other vital signs
• Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
• Lung auscultation
• Joint examination for manifestations of arthritis
• Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
• Vascular examination for evidence of arterial or venous thrombotic events
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• CBC and differential
• ESR and CRP
• Tests of kidney and liver function
• Quantitative serum immunoglobulins
• All abnormal laboratory studies identified during earlier evaluations
• Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
• Chest CT scan in the presence of pulmonary signs or symptoms
• Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
• Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
• Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VEXAS syndrome, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Blood pressure and other vital signs, as fever is common
Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
Lung auscultation, as lung involvement can be asymptomatic
Joint examination, as polyarthritis is common
Assessment for lymphadenopathy and hepatosplenomegaly
Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
Complete blood count (CBC) to detect cytopenia and macrocytosis
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
Tests of kidney and liver function
Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
Assessment of need for family support and resources including community or online
• Blood pressure and other vital signs, as fever is common
• Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
• Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
• Lung auscultation, as lung involvement can be asymptomatic
• Joint examination, as polyarthritis is common
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• Blood pressure and other vital signs, as fever is common
• Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
• Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
• Lung auscultation, as lung involvement can be asymptomatic
• Joint examination, as polyarthritis is common
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
•
• Complete blood count (CBC) to detect cytopenia and macrocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
• Tests of kidney and liver function
• Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
• For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
• Complete blood count (CBC) to detect cytopenia and macrocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
• Tests of kidney and liver function
• Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
• For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
•
• Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
• Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
• Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
• Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
• Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
• Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
• Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
• Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
•
• Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
• Assessment of need for family support and resources including community or online
• Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
• Assessment of need for family support and resources including community or online
• Blood pressure and other vital signs, as fever is common
• Skin examination for evidence of specific VEXAS syndrome-related skin lesions and chondritis
• Ophthalmologic examination for episcleritis, scleritis, uveitis, or whole-orbital and periorbital inflammation
• Lung auscultation, as lung involvement can be asymptomatic
• Joint examination, as polyarthritis is common
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• Complete blood count (CBC) to detect cytopenia and macrocytosis
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, as elevated levels may correlate with disease activity
• Tests of kidney and liver function
• Quantitative serum immunoglobulins and immunofixation for evidence of monoclonal gammopathy of undetermined significance (MGUS)
• For individuals with cytopenia, bone marrow examination with karyotype and multigene panel for myeloid genes for evidence of myelodysplastic syndrome (MDS). A concurrent diagnosis of MDS may change management of VEXAS syndrome.
• Chest CT scan to assess thoracic involvement that can include lung opacities, pleural effusion, and/or mediastinal adenomegaly
• Brain MRI in individuals with neurologic manifestations (no specific pattern reported to date)
• Cardiac ultrasound in individuals with cardiac manifestations or abnormal EKG
• Upper- and/or lower-extremity ultrasound to assess for potential venous thrombosis in individuals with concerning clinical manifestations
• Bronchoalveolar lavage in individuals with atypical lung involvement to evaluate for possible infection
• Assessment of need for family support and resources including community or online
## Treatment of Manifestations
Because large prospective trials are lacking, the therapeutic management of individuals with VEXAS syndrome is currently poorly standardized and is based on retrospective studies [
In a systematic review of treatments, two thirds of individuals were able to achieve glucocorticoid reduction; however, only 20% achieved complete response [
A prospective trial assessing AZA in 30 individuals with steroid-dependent or refractory inflammatory disorders associated with myeloid neoplasia included 12 individuals with VEXAS syndrome [
Red blood cell transfusions and erythropoiesis-stimulating agents can be used in individuals with symptomatic anemia.
Anti-infection prophylaxis in individuals who are highly susceptible to severe infections includes cotrimoxazole and valaciclovir in addition to vaccinations.
Given the high risk of venous thromboembolism, thromboprophylaxis should be considered in at-risk situations to prevent potential thrombi unless contraindicated. Studies on thromboprophylaxis and efficacy of specific anticoagulants in outpatient settings in individuals with VEXAS syndrome are needed.
For individuals using glucocorticoids as first-line treatment, screening includes measurement of blood pressure, blood glucose concentration, and assessment of bone density, as well as prophylaxis against
• In a systematic review of treatments, two thirds of individuals were able to achieve glucocorticoid reduction; however, only 20% achieved complete response [
## Targeting Inflammation
In a systematic review of treatments, two thirds of individuals were able to achieve glucocorticoid reduction; however, only 20% achieved complete response [
• In a systematic review of treatments, two thirds of individuals were able to achieve glucocorticoid reduction; however, only 20% achieved complete response [
## Targeting the
A prospective trial assessing AZA in 30 individuals with steroid-dependent or refractory inflammatory disorders associated with myeloid neoplasia included 12 individuals with VEXAS syndrome [
## Supportive Care
Red blood cell transfusions and erythropoiesis-stimulating agents can be used in individuals with symptomatic anemia.
Anti-infection prophylaxis in individuals who are highly susceptible to severe infections includes cotrimoxazole and valaciclovir in addition to vaccinations.
Given the high risk of venous thromboembolism, thromboprophylaxis should be considered in at-risk situations to prevent potential thrombi unless contraindicated. Studies on thromboprophylaxis and efficacy of specific anticoagulants in outpatient settings in individuals with VEXAS syndrome are needed.
For individuals using glucocorticoids as first-line treatment, screening includes measurement of blood pressure, blood glucose concentration, and assessment of bone density, as well as prophylaxis against
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended:
Blood pressure and other vital signs
Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
Lung auscultation
Joint examination for manifestations of arthritis
Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
Vascular examination for evidence of arterial or venous thrombotic events
Assessment for lymphadenopathy and hepatosplenomegaly
Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
CBC and differential
ESR and CRP
Tests of kidney and liver function
Quantitative serum immunoglobulins
All abnormal laboratory studies identified during earlier evaluations
Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
Chest CT scan in the presence of pulmonary signs or symptoms
Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
• Blood pressure and other vital signs
• Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
• Lung auscultation
• Joint examination for manifestations of arthritis
• Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
• Vascular examination for evidence of arterial or venous thrombotic events
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• Blood pressure and other vital signs
• Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
• Lung auscultation
• Joint examination for manifestations of arthritis
• Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
• Vascular examination for evidence of arterial or venous thrombotic events
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• CBC and differential
• ESR and CRP
• Tests of kidney and liver function
• Quantitative serum immunoglobulins
• All abnormal laboratory studies identified during earlier evaluations
• Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
• CBC and differential
• ESR and CRP
• Tests of kidney and liver function
• Quantitative serum immunoglobulins
• All abnormal laboratory studies identified during earlier evaluations
• Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
• Chest CT scan in the presence of pulmonary signs or symptoms
• Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
• Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
• Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
• Chest CT scan in the presence of pulmonary signs or symptoms
• Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
• Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
• Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
• Blood pressure and other vital signs
• Skin examination to assess for neutrophilic dermatosis including Sweet syndrome, cutaneous vasculitis, erythematosus papules, and injection site reactions
• Lung auscultation
• Joint examination for manifestations of arthritis
• Ophthalmologic examination – if symptomatic – for evidence of episcleritis, scleritis, uveitis, and/or periorbital edema
• Vascular examination for evidence of arterial or venous thrombotic events
• Assessment for lymphadenopathy and hepatosplenomegaly
• Neurologic examination for evidence of central nervous system and/or peripheral nervous system involvement
• CBC and differential
• ESR and CRP
• Tests of kidney and liver function
• Quantitative serum immunoglobulins
• All abnormal laboratory studies identified during earlier evaluations
• Bone marrow examination with karyotype and multigene panel for myeloid genes in case of unexplained changes in CBC
• Chest CT scan in the presence of pulmonary signs or symptoms
• Upper- and/or lower-extremity ultrasound to assess for potential thrombus in individuals with concerning clinical manifestations
• Cardiac ultrasound if abnormal in the past or new manifestations suggest cardiac involvement
• Brain MRI if abnormal in the past or new manifestations suggest central nervous system involvement
## Agents/Circumstances to Avoid
Avoid smoking, which may exacerbate peripheral arterial disease.
## Therapies Under Investigation
A Phase II study of allogeneic HSCT for individuals with VEXAS syndrome is ongoing (
Search
## Genetic Counseling
VEXAS syndrome is an X-linked disorder caused by somatic pathogenic variants in
As VEXAS syndrome is not inherited, molecular genetic prenatal and preimplantation genetic testing are not indicated.
## Mode of Inheritance
VEXAS syndrome is an X-linked disorder caused by somatic pathogenic variants in
## Risk to Family Members
## Prenatal Testing and Preimplantation Genetic Testing
As VEXAS syndrome is not inherited, molecular genetic prenatal and preimplantation genetic testing are not indicated.
## Resources
•
•
## Molecular Genetics
VEXAS Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for VEXAS Syndrome (
Intracellular protein degradation is a crucial cellular function that facilitates the removal of abnormal or excess proteins, controlling processes such as proliferation, differentiation, apoptosis, and response to extracellular stimuli [
Pathogenic variants in
Gene expression analysis revealed upregulation of proinflammatory signaling pathways (possibly mediating cell death and inflammation), demonstrating that both inflammation and myeloid dominance originate in hematopoietic stem cells in VEXAS syndrome [
To date, all reported
Low levels of mosaicism for VEXAS syndrome-specific
Reported
UBA1 is expressed as two isoforms differing in translation start site: nuclear UBA1a (initiated at Met1,
Variants listed in the table have been provided by the authors.
• To date, all reported
• Low levels of mosaicism for VEXAS syndrome-specific
• Reported
• UBA1 is expressed as two isoforms differing in translation start site: nuclear UBA1a (initiated at Met1,
## Molecular Pathogenesis
Intracellular protein degradation is a crucial cellular function that facilitates the removal of abnormal or excess proteins, controlling processes such as proliferation, differentiation, apoptosis, and response to extracellular stimuli [
Pathogenic variants in
Gene expression analysis revealed upregulation of proinflammatory signaling pathways (possibly mediating cell death and inflammation), demonstrating that both inflammation and myeloid dominance originate in hematopoietic stem cells in VEXAS syndrome [
To date, all reported
Low levels of mosaicism for VEXAS syndrome-specific
Reported
UBA1 is expressed as two isoforms differing in translation start site: nuclear UBA1a (initiated at Met1,
Variants listed in the table have been provided by the authors.
• To date, all reported
• Low levels of mosaicism for VEXAS syndrome-specific
• Reported
• UBA1 is expressed as two isoforms differing in translation start site: nuclear UBA1a (initiated at Met1,
## Chapter Notes
Dr David Beck is the principal investigator of the Beck Lab and runs the Inflammatory Disease Genetics Clinic in the Department of Medicine at New York University School of Medicine. He received his BA from Brown University in history and biology. He earned his MD/PhD from New York University in the laboratory of Dr Danny Reinberg. He continued with clinical training in the clinician-scientist pathway in Internal Medicine at Columbia University and then went on to perform Clinical Genetics training at the National Institutes of Health and Johns Hopkins combined program. David performed his postdoctoral research with Dr Dan Kastner at the National Institutes of Health.
Beck Lab web page:
Jerome Hadjadj is a postdoctoral fellow working on molecular mechanisms of inflammation in trisomy 8 and cellular models of VEXAS syndrome. He is an MD in France specializing in Internal Medicine at the Saint-Antoine hospital in Paris, focused on autoimmune and autoinflammatory diseases. He did his PhD in Frederic Rieux-Laucat's lab "Immunogenetics of pediatric autoimmune diseases" at Imagine Institute (Paris), focused on the genetic bases and molecular mechanisms of pediatric Evans syndrome, in particular on the JAK/STAT pathway, and made it possible to highlight SOCS1 deficiency. He is working on clinical description and therapeutic management of VEXAS syndrome and somatic mutations in complex inflammatory diseases.
Drs David Beck (
Dr Beck is also interested in hearing from clinicians treating families with periodic fever syndromes or systemic autoinflammatory 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 Beck to inquire about review of
We acknowledge the VEXAS Foundation for their research support and the international VEXAS working group for the fruitful collaboration on VEXAS syndrome.
15 May 2025 (bp) Review posted live
26 September 2024 (db) Original submission
• 15 May 2025 (bp) Review posted live
• 26 September 2024 (db) Original submission
## Author Notes
Dr David Beck is the principal investigator of the Beck Lab and runs the Inflammatory Disease Genetics Clinic in the Department of Medicine at New York University School of Medicine. He received his BA from Brown University in history and biology. He earned his MD/PhD from New York University in the laboratory of Dr Danny Reinberg. He continued with clinical training in the clinician-scientist pathway in Internal Medicine at Columbia University and then went on to perform Clinical Genetics training at the National Institutes of Health and Johns Hopkins combined program. David performed his postdoctoral research with Dr Dan Kastner at the National Institutes of Health.
Beck Lab web page:
Jerome Hadjadj is a postdoctoral fellow working on molecular mechanisms of inflammation in trisomy 8 and cellular models of VEXAS syndrome. He is an MD in France specializing in Internal Medicine at the Saint-Antoine hospital in Paris, focused on autoimmune and autoinflammatory diseases. He did his PhD in Frederic Rieux-Laucat's lab "Immunogenetics of pediatric autoimmune diseases" at Imagine Institute (Paris), focused on the genetic bases and molecular mechanisms of pediatric Evans syndrome, in particular on the JAK/STAT pathway, and made it possible to highlight SOCS1 deficiency. He is working on clinical description and therapeutic management of VEXAS syndrome and somatic mutations in complex inflammatory diseases.
Drs David Beck (
Dr Beck is also interested in hearing from clinicians treating families with periodic fever syndromes or systemic autoinflammatory 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 Beck to inquire about review of
## Acknowledgments
We acknowledge the VEXAS Foundation for their research support and the international VEXAS working group for the fruitful collaboration on VEXAS syndrome.
## Revision History
15 May 2025 (bp) Review posted live
26 September 2024 (db) Original submission
• 15 May 2025 (bp) Review posted live
• 26 September 2024 (db) Original submission
## References
## Literature Cited
|
[] |
15/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
vhl
|
vhl
|
[
"VHL Disease",
"VHL Syndrome",
"Von Hippel-Lindau Disease",
"VHL Syndrome",
"Von Hippel-Lindau Disease",
"VHL Disease",
"Von Hippel-Lindau disease tumor suppressor",
"VHL",
"Von Hippel-Lindau Syndrome"
] |
Von Hippel-Lindau Syndrome
|
Rachel S van Leeuwaarde, Saya Ahmad, Bernadette van Nesselrooij, Wouter Zandee, Rachel H Giles
|
Summary Von Hippel-Lindau syndrome (VHL) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cystadenomas. Retinal hemangioblastomas may be the initial manifestation of VHL and can cause vision loss. Cerebellar hemangioblastomas may be associated with headache, vomiting, gait disturbances, or ataxia. Spinal hemangioblastomas and related syrinx usually present with pain. Sensory and motor loss may develop with cord compression. Renal cell carcinoma occurs in about 70% of individuals with VHL and is the leading cause of mortality. Pheochromocytomas can be asymptomatic but may cause sustained or episodic hypertension. Pancreatic lesions often remain asymptomatic and rarely cause endocrine or exocrine insufficiency. Endolymphatic sac tumors can cause hearing loss of varying severity, which can be a presenting symptom. Cystadenomas of the epididymis are relatively common. They rarely cause problems, unless bilateral, in which case they may result in infertility. The diagnosis of VHL is established in a proband who fulfills existing diagnostic clinical criteria. Identification of a heterozygous germline VHL is inherited in an autosomal dominant manner. Approximately 80% of individuals with VHL have an affected parent and about 20% have VHL as the result of a pathogenic variant that occurred as a
|
## Diagnosis
Clinical diagnostic criteria for von Hippel-Lindau syndrome (VHL) have been proposed and vary slightly between Dutch or Danish guidelines [
VHL
Retinal angioma, especially in a young individual
Multiple spinal or cerebellar hemangioblastoma, or a single hemangioblastoma diagnosed at age ≤50 years
Adrenal or extra-adrenal pheochromocytoma
Renal cell carcinoma diagnosed at age ≤40 years
Multiple renal and pancreatic cysts
Multiple neuroendocrine tumors of the pancreas
Endolymphatic sac tumors
Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament
The clinical diagnosis of VHL
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 [
Von Hippel-Lindau Syndrome Clinical Diagnostic Criteria
Retinal HB
CNS HB
RCC
Pheo
PNET
ELST
Paraganglioma
Multiple kidney cysts
Multiple pancreatic cysts
Adapted from
CNS = central nervous system; ELST = endolymphatic sac tumor; HB = hemangioblastoma; Pheo = pheochromocytoma; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma; VHL = von Hippel-Lindau syndrome
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 von Hippel-Lindau 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
Sequence analysis of intron 1 should be performed in probands without an identified
Approximately 5% of individuals with a clinical diagnosis of von Hippel-Lindau syndrome do not have a pathogenic variant identified.
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.
• Retinal angioma, especially in a young individual
• Multiple spinal or cerebellar hemangioblastoma, or a single hemangioblastoma diagnosed at age ≤50 years
• Adrenal or extra-adrenal pheochromocytoma
• Renal cell carcinoma diagnosed at age ≤40 years
• Multiple renal and pancreatic cysts
• Multiple neuroendocrine tumors of the pancreas
• Endolymphatic sac tumors
• Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament
• Retinal HB
• CNS HB
• RCC
• Pheo
• PNET
• ELST
• Paraganglioma
• Multiple kidney cysts
• Multiple pancreatic cysts
## Suggestive Findings
VHL
Retinal angioma, especially in a young individual
Multiple spinal or cerebellar hemangioblastoma, or a single hemangioblastoma diagnosed at age ≤50 years
Adrenal or extra-adrenal pheochromocytoma
Renal cell carcinoma diagnosed at age ≤40 years
Multiple renal and pancreatic cysts
Multiple neuroendocrine tumors of the pancreas
Endolymphatic sac tumors
Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament
• Retinal angioma, especially in a young individual
• Multiple spinal or cerebellar hemangioblastoma, or a single hemangioblastoma diagnosed at age ≤50 years
• Adrenal or extra-adrenal pheochromocytoma
• Renal cell carcinoma diagnosed at age ≤40 years
• Multiple renal and pancreatic cysts
• Multiple neuroendocrine tumors of the pancreas
• Endolymphatic sac tumors
• Less commonly, multiple papillary cystadenomas of the epididymis or broad ligament
## Establishing the Diagnosis
The clinical diagnosis of VHL
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 [
Von Hippel-Lindau Syndrome Clinical Diagnostic Criteria
Retinal HB
CNS HB
RCC
Pheo
PNET
ELST
Paraganglioma
Multiple kidney cysts
Multiple pancreatic cysts
Adapted from
CNS = central nervous system; ELST = endolymphatic sac tumor; HB = hemangioblastoma; Pheo = pheochromocytoma; PNET = pancreatic neuroendocrine tumor; RCC = renal cell carcinoma; VHL = von Hippel-Lindau syndrome
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 von Hippel-Lindau 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
Sequence analysis of intron 1 should be performed in probands without an identified
Approximately 5% of individuals with a clinical diagnosis of von Hippel-Lindau syndrome do not have a pathogenic variant identified.
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.
• Retinal HB
• CNS HB
• RCC
• Pheo
• PNET
• ELST
• Paraganglioma
• Multiple kidney cysts
• Multiple pancreatic cysts
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in von Hippel-Lindau 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
Sequence analysis of intron 1 should be performed in probands without an identified
Approximately 5% of individuals with a clinical diagnosis of von Hippel-Lindau syndrome do not have a pathogenic variant identified.
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
Von Hippel-Lindau syndrome (VHL) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Some clustering of tumors occurs, resulting in the designation of specific VHL phenotypes. The manifestations and severity are highly variable both within and between families, even among those with the same pathogenic variant.
Growth patterns of CNS hemangioblastomas can be saltatory (72%), linear (6%), or exponential (22%). Increased growth was associated with male sex, symptomatic tumors, hemangioblastoma-associated cysts [
Retinal hemangioblastomas may be asymptomatic and may be detected on routine ophthalmoscopy. Others present with a visual field defect or a loss of visual activity resulting from retinal detachment, exudation, or hemorrhage. Tests of retinal function may be abnormal even in the presence of quiescent retinal hemangioblastomas [
Improved surveillance guidelines have increased the life expectancy of individuals with VHL by more than 16 years since 1990 [
Four general VHL phenotypes (type 1, type 2A, type 2B, type 2C) have been suggested based on the likelihood of pheochromocytoma or renal cell carcinoma. Many lines of research support the conclusion that the molecular etiology of pheochromocytomas appears to be distinct from other VHL lesions. Therefore, the most relevant genotype-phenotype correlations rely mostly on scoring the presence/absence of pheochromocytomas associated with a given allele. The following discussion summarizes the genotype-phenotype studies published to date, with the cautionary note that further investigation is needed. Note: Patterns are not clear-cut, and genotype-phenotype correlations have no current diagnostic or therapeutic value; they are used for academic purposes only.
Several groups report a reduced risk for renal cell carcinoma in individuals with a deletion of
A higher age-related incidence of retinal hemangioblastomas, CNS hemangioblastomas, clear cell renal cell carcinoma, and pancreatic neuroendocrine tumors was described in individuals with a truncating variant compared to individuals with a missense variant or in-frame deletion of a single amino acid [
Obsolete terms for VHL include: angiophakomatosis retinae et cerebelli, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel disease, Hippel-Lindau syndrome, Lindau disease, and retinocerebellar angiomatosis [
The incidence of VHL is thought to be about one in 36,000 births, with an estimated
• Retinal hemangioblastomas may be asymptomatic and may be detected on routine ophthalmoscopy. Others present with a visual field defect or a loss of visual activity resulting from retinal detachment, exudation, or hemorrhage. Tests of retinal function may be abnormal even in the presence of quiescent retinal hemangioblastomas [
## Clinical Description
Von Hippel-Lindau syndrome (VHL) is characterized by hemangioblastomas of the brain, spinal cord, and retina; renal cysts and renal cell carcinoma; pheochromocytoma and paraganglioma; pancreatic cysts and neuroendocrine tumors; endolymphatic sac tumors; and epididymal and broad ligament cysts. Some clustering of tumors occurs, resulting in the designation of specific VHL phenotypes. The manifestations and severity are highly variable both within and between families, even among those with the same pathogenic variant.
Growth patterns of CNS hemangioblastomas can be saltatory (72%), linear (6%), or exponential (22%). Increased growth was associated with male sex, symptomatic tumors, hemangioblastoma-associated cysts [
Retinal hemangioblastomas may be asymptomatic and may be detected on routine ophthalmoscopy. Others present with a visual field defect or a loss of visual activity resulting from retinal detachment, exudation, or hemorrhage. Tests of retinal function may be abnormal even in the presence of quiescent retinal hemangioblastomas [
Improved surveillance guidelines have increased the life expectancy of individuals with VHL by more than 16 years since 1990 [
• Retinal hemangioblastomas may be asymptomatic and may be detected on routine ophthalmoscopy. Others present with a visual field defect or a loss of visual activity resulting from retinal detachment, exudation, or hemorrhage. Tests of retinal function may be abnormal even in the presence of quiescent retinal hemangioblastomas [
## Genotype-Phenotype Correlations
Four general VHL phenotypes (type 1, type 2A, type 2B, type 2C) have been suggested based on the likelihood of pheochromocytoma or renal cell carcinoma. Many lines of research support the conclusion that the molecular etiology of pheochromocytomas appears to be distinct from other VHL lesions. Therefore, the most relevant genotype-phenotype correlations rely mostly on scoring the presence/absence of pheochromocytomas associated with a given allele. The following discussion summarizes the genotype-phenotype studies published to date, with the cautionary note that further investigation is needed. Note: Patterns are not clear-cut, and genotype-phenotype correlations have no current diagnostic or therapeutic value; they are used for academic purposes only.
Several groups report a reduced risk for renal cell carcinoma in individuals with a deletion of
A higher age-related incidence of retinal hemangioblastomas, CNS hemangioblastomas, clear cell renal cell carcinoma, and pancreatic neuroendocrine tumors was described in individuals with a truncating variant compared to individuals with a missense variant or in-frame deletion of a single amino acid [
## Penetrance
## Nomenclature
Obsolete terms for VHL include: angiophakomatosis retinae et cerebelli, familial cerebello-retinal angiomatosis, cerebelloretinal hemangioblastomatosis, Hippel disease, Hippel-Lindau syndrome, Lindau disease, and retinocerebellar angiomatosis [
## Prevalence
The incidence of VHL is thought to be about one in 36,000 births, with an estimated
## Genetically Related (Allelic) Disorders
Note: Congenital erythrocytosis is endemic in subpopulations worldwide; pathogenic variants in
## Differential Diagnosis
The differential diagnosis for an individual suspected of having VHL depends on the further clinical presentation (see
Genetic Disorders Associated with an Increased Risk of Pheochromocytomas
MEN2A: ↑ risk for MTC, Pheo, & parathyroid adenoma or hyperplasia. Pheo usually present after MTC or concomitantly; however, they are 1st manifestation in 13%-27%.
MEN2B: mucosal neuromas of lips & tongue, ganglioneuromatosis of GI tract, marfanoid habitus, & ↑ risk for MTC & Pheo. Pheo occur in 50% of persons w/MEN2B.
AD = autosomal dominant; GI = gastrointestinal; MOI = mode of inheritance; MTC = medullary thyroid cancer; Pheo = pheochromocytomas; PGL = paragangliomas
Pathogenic variants in
Genetic Disorders Associated with Renal Cell Carcinoma
AD = autosomal dominant; MOI = mode of inheritance; Pheo = pheochromocytomas; PGL = paragangliomas
• MEN2A: ↑ risk for MTC, Pheo, & parathyroid adenoma or hyperplasia. Pheo usually present after MTC or concomitantly; however, they are 1st manifestation in 13%-27%.
• MEN2B: mucosal neuromas of lips & tongue, ganglioneuromatosis of GI tract, marfanoid habitus, & ↑ risk for MTC & Pheo. Pheo occur in 50% of persons w/MEN2B.
## Management
The first von Hippel-Lindau syndrome (VHL) care pathway was recently published by a multidisciplinary team from the Netherlands [
To establish the extent of disease and needs in an individual diagnosed with VHL, the evaluations summarized in
Von Hippel-Lindau Syndrome: Recommended Evaluations Following Initial Diagnosis
Neurologic history & physical exam
Brain & total spine MRI
Blood pressure measurement
Measurement of 24-hr urine fractionated metanephrines & catecholamine metabolites or plasma free fractionated metanephrines
CNS = central nervous system; ELST = endolymphatic sac tumors; MOI = mode of inheritance; VHL = von Hippel-Lindau syndrome
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
No guidelines exist for the management of VHL lesions.
Most CNS hemangioblastomas can be surgically removed completely and safely [
Some advocate early surgical removal of both symptomatic and asymptomatic CNS hemangioblastomas, while others follow asymptomatic lesions with yearly imaging studies. A study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [
Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. A minimally invasive approach for the resection of selected spinal hemangioblastomas is considered safe and allows complete tumor resection [
Pathologic findings during intraoperative neurophysiologic monitoring (IONM) appear to predict worse long-term outcomes after microsurgical removal of spinal cord hemangioblastomas [
Surgical intervention for cysts/syrinx in the spinal cord is recommended.
Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [
Factors associated with tumor control are solid, smaller tumors, VHL-associated lesions, and higher margin dose. Thirteen of 186 individuals (7%) experienced complications, 11 individuals needed steroid therapy, and one person died of refractory peritumoral edema. Two individuals required additional surgery [
Another study showed recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [
A case study showed complete loss of stromal cells after a standard dose of stereotactic radiosurgery for hemangioblastoma, indicating the effectiveness of the treatment [
Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblastomas. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [
Most ophthalmologists favor prospective treatment of retinal hemangioblastomas (but not optic nerve hemangioblastomas) to avoid blindness, although spontaneous regression has occurred.
Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease.
Vitreoretinal surgery is indicated when retinal hemangioblastomas are accompanied by complications such as epiretinal membrane development, vitreous hemorrhage, tractional and/or exudative retinal detachment, preretinal fibrosis, or proliferative vitreoretinopathy [
Brachytherapy could be a treatment option for larger peripheral hemangioblastomas with manageable risk and a high eye preservation rate [
External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [
There is no evidence to support the use of sunitinib for retinal hemangioblastomas.
In individuals treated with nephrectomy, the adrenal gland should be left in situ. If contralateral pheochromocytoma occurs requiring adrenalectomy, the remaining adrenal gland will prevent or delay adrenal insufficiency.
Kidney transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL and to exclude those with VHL.
Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [
Preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension and is recommended in treatment guidelines. However, perioperative alpha-adrenergic blockade has recently been under debate. In a multicenter study, mortality rate in pretreated individuals was slightly higher than in non-pretreated individuals [
Adrenal-sparing surgery should be considered and is regarded as a successful treatment strategy. Studies show low recurrence, no metastatic disease, and rare steroid dependency after cortical-sparing techniques [
Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [
Pancreatic neuroendocrine tumors (PNETs) need to be differentiated from cysts and serous cystadenomas. PNETs are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgical resection should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria: (1) size ≥2.5 cm or (2) tumor doubling rate <500 days [
In the United States, the VHL Alliance has worked extensively with health care professionals to assemble guidelines that are generally accepted worldwide (see
Von Hippel-Lindau Syndrome: Recommended Surveillance
CNS = central nervous system; ELST = endolymphatic sac tumors; IAC = internal auditory canals
The best way to detect ELST is unknown.
While current medical surveillance guidelines do not address structured psychological support for individuals with VHL, their partners, and their family members, research suggests a distinct need for psychosocial support [
Avoid the following:
Tobacco products, as they are considered a risk factor for kidney cancer
Chemicals and industrial toxins known to affect VHL-involved organs
Contact sports if adrenal or pancreatic lesions are present
Early recognition of manifestations of VHL may allow for timely intervention and improved outcome; thus, clinical surveillance of asymptomatic at-risk individuals (including children) for early manifestations of VHL is appropriate. The American Society of Clinical Oncology identifies VHL as a Group 1 disorder – a hereditary disease for which genetic testing is considered part of the standard management for at-risk family members [
If the
If the
The use of molecular genetic testing for determining the genetic status of presumably at-risk relatives when a family member with a clinical diagnosis of VHL is not available for testing is not straightforward. Such test results need to be interpreted with caution. A positive test result signals the presence of a
The at-risk family member has not inherited a
The familial
The clinical diagnosis of VHL in the proband is questionable.
In this situation, the presumably at-risk family member has a small but finite residual risk of having inherited a pathogenic allele (i.e., VHL or other hereditary disorder). In counseling such individuals, careful consideration should be given to the strength of the clinical diagnosis of VHL in the affected family member, the relationship of the at-risk individual to the affected family member, the perceived risk of an undetected
See
There is no consensus regarding medical surveillance for pregnant women with VHL. Research by the French VHL Study Group showed a significantly higher complication rate of hemangioblastomas in individuals with VHL who had had at least one pregnancy [
See
Certain
Sunitinib, a tyrosine kinase inhibitor (TKI) that inhibits the action of VEGF receptors, has had some utility in the rare unresectable malignant pheochromocytomas, but simple surgical excision is clearly preferable for these usually benign tumors [
Pazopanib showed favorable effects on the clinical condition of individuals with recurrent and rapidly progressive VHL-associated hemangioblastomas [
Somatostatin analogs could be of use in the treatment of hemangioblastomas. Nine hemangioblastomas demonstrated expression for at least three somatostatin receptor subtypes (1, 2a, 3, 4, or 5). One individual with a symptomatic irresectable suprasellar hemangioblastoma was treated with octreotide long-acting release, which resulted in clinical stability and radiographic response after nine months of treatment [
Propranolol could be an efficient treatment to control hemangioblastoma growth in individuals with VHL because of its antiangiogenic effects demonstrated in infantile hemangioma and the hypothetical impact on HIF levels.
Checkpoint inhibitors such as antibodies targeting programmed cell death ligand 1 (PD-L1) have shown promise in managing tumor load; however, these treatments have unknown toxicity in individuals with VHL, who will likely have dozens to thousands of small subclinical lesions present throughout their body.
Premature termination codon 124 (PTC124), also known as ataluren, may benefit a subset of affected individuals in whom nonsense variants give rise to premature stop codons in the messenger RNA [
An in vivo study of HIF2α inhibitor in
Search
• Neurologic history & physical exam
• Brain & total spine MRI
• Blood pressure measurement
• Measurement of 24-hr urine fractionated metanephrines & catecholamine metabolites or plasma free fractionated metanephrines
• Most CNS hemangioblastomas can be surgically removed completely and safely [
• Some advocate early surgical removal of both symptomatic and asymptomatic CNS hemangioblastomas, while others follow asymptomatic lesions with yearly imaging studies. A study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [
• Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. A minimally invasive approach for the resection of selected spinal hemangioblastomas is considered safe and allows complete tumor resection [
• Pathologic findings during intraoperative neurophysiologic monitoring (IONM) appear to predict worse long-term outcomes after microsurgical removal of spinal cord hemangioblastomas [
• Surgical intervention for cysts/syrinx in the spinal cord is recommended.
• Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [
• Factors associated with tumor control are solid, smaller tumors, VHL-associated lesions, and higher margin dose. Thirteen of 186 individuals (7%) experienced complications, 11 individuals needed steroid therapy, and one person died of refractory peritumoral edema. Two individuals required additional surgery [
• Another study showed recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [
• A case study showed complete loss of stromal cells after a standard dose of stereotactic radiosurgery for hemangioblastoma, indicating the effectiveness of the treatment [
• Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblastomas. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [
• Most ophthalmologists favor prospective treatment of retinal hemangioblastomas (but not optic nerve hemangioblastomas) to avoid blindness, although spontaneous regression has occurred.
• Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease.
• Vitreoretinal surgery is indicated when retinal hemangioblastomas are accompanied by complications such as epiretinal membrane development, vitreous hemorrhage, tractional and/or exudative retinal detachment, preretinal fibrosis, or proliferative vitreoretinopathy [
• Brachytherapy could be a treatment option for larger peripheral hemangioblastomas with manageable risk and a high eye preservation rate [
• External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [
• There is no evidence to support the use of sunitinib for retinal hemangioblastomas.
• In individuals treated with nephrectomy, the adrenal gland should be left in situ. If contralateral pheochromocytoma occurs requiring adrenalectomy, the remaining adrenal gland will prevent or delay adrenal insufficiency.
• Kidney transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL and to exclude those with VHL.
• Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [
• Preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension and is recommended in treatment guidelines. However, perioperative alpha-adrenergic blockade has recently been under debate. In a multicenter study, mortality rate in pretreated individuals was slightly higher than in non-pretreated individuals [
• Adrenal-sparing surgery should be considered and is regarded as a successful treatment strategy. Studies show low recurrence, no metastatic disease, and rare steroid dependency after cortical-sparing techniques [
• Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [
• Pancreatic neuroendocrine tumors (PNETs) need to be differentiated from cysts and serous cystadenomas. PNETs are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgical resection should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria: (1) size ≥2.5 cm or (2) tumor doubling rate <500 days [
• Tobacco products, as they are considered a risk factor for kidney cancer
• Chemicals and industrial toxins known to affect VHL-involved organs
• Contact sports if adrenal or pancreatic lesions are present
• If the
• If the
• The at-risk family member has not inherited a
• The familial
• The clinical diagnosis of VHL in the proband is questionable.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VHL, the evaluations summarized in
Von Hippel-Lindau Syndrome: Recommended Evaluations Following Initial Diagnosis
Neurologic history & physical exam
Brain & total spine MRI
Blood pressure measurement
Measurement of 24-hr urine fractionated metanephrines & catecholamine metabolites or plasma free fractionated metanephrines
CNS = central nervous system; ELST = endolymphatic sac tumors; MOI = mode of inheritance; VHL = von Hippel-Lindau syndrome
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Neurologic history & physical exam
• Brain & total spine MRI
• Blood pressure measurement
• Measurement of 24-hr urine fractionated metanephrines & catecholamine metabolites or plasma free fractionated metanephrines
## Treatment of Manifestations
No guidelines exist for the management of VHL lesions.
Most CNS hemangioblastomas can be surgically removed completely and safely [
Some advocate early surgical removal of both symptomatic and asymptomatic CNS hemangioblastomas, while others follow asymptomatic lesions with yearly imaging studies. A study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [
Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. A minimally invasive approach for the resection of selected spinal hemangioblastomas is considered safe and allows complete tumor resection [
Pathologic findings during intraoperative neurophysiologic monitoring (IONM) appear to predict worse long-term outcomes after microsurgical removal of spinal cord hemangioblastomas [
Surgical intervention for cysts/syrinx in the spinal cord is recommended.
Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [
Factors associated with tumor control are solid, smaller tumors, VHL-associated lesions, and higher margin dose. Thirteen of 186 individuals (7%) experienced complications, 11 individuals needed steroid therapy, and one person died of refractory peritumoral edema. Two individuals required additional surgery [
Another study showed recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [
A case study showed complete loss of stromal cells after a standard dose of stereotactic radiosurgery for hemangioblastoma, indicating the effectiveness of the treatment [
Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblastomas. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [
Most ophthalmologists favor prospective treatment of retinal hemangioblastomas (but not optic nerve hemangioblastomas) to avoid blindness, although spontaneous regression has occurred.
Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease.
Vitreoretinal surgery is indicated when retinal hemangioblastomas are accompanied by complications such as epiretinal membrane development, vitreous hemorrhage, tractional and/or exudative retinal detachment, preretinal fibrosis, or proliferative vitreoretinopathy [
Brachytherapy could be a treatment option for larger peripheral hemangioblastomas with manageable risk and a high eye preservation rate [
External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [
There is no evidence to support the use of sunitinib for retinal hemangioblastomas.
In individuals treated with nephrectomy, the adrenal gland should be left in situ. If contralateral pheochromocytoma occurs requiring adrenalectomy, the remaining adrenal gland will prevent or delay adrenal insufficiency.
Kidney transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL and to exclude those with VHL.
Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [
Preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension and is recommended in treatment guidelines. However, perioperative alpha-adrenergic blockade has recently been under debate. In a multicenter study, mortality rate in pretreated individuals was slightly higher than in non-pretreated individuals [
Adrenal-sparing surgery should be considered and is regarded as a successful treatment strategy. Studies show low recurrence, no metastatic disease, and rare steroid dependency after cortical-sparing techniques [
Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [
Pancreatic neuroendocrine tumors (PNETs) need to be differentiated from cysts and serous cystadenomas. PNETs are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgical resection should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria: (1) size ≥2.5 cm or (2) tumor doubling rate <500 days [
• Most CNS hemangioblastomas can be surgically removed completely and safely [
• Some advocate early surgical removal of both symptomatic and asymptomatic CNS hemangioblastomas, while others follow asymptomatic lesions with yearly imaging studies. A study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [
• Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. A minimally invasive approach for the resection of selected spinal hemangioblastomas is considered safe and allows complete tumor resection [
• Pathologic findings during intraoperative neurophysiologic monitoring (IONM) appear to predict worse long-term outcomes after microsurgical removal of spinal cord hemangioblastomas [
• Surgical intervention for cysts/syrinx in the spinal cord is recommended.
• Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [
• Factors associated with tumor control are solid, smaller tumors, VHL-associated lesions, and higher margin dose. Thirteen of 186 individuals (7%) experienced complications, 11 individuals needed steroid therapy, and one person died of refractory peritumoral edema. Two individuals required additional surgery [
• Another study showed recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [
• A case study showed complete loss of stromal cells after a standard dose of stereotactic radiosurgery for hemangioblastoma, indicating the effectiveness of the treatment [
• Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblastomas. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [
• Most ophthalmologists favor prospective treatment of retinal hemangioblastomas (but not optic nerve hemangioblastomas) to avoid blindness, although spontaneous regression has occurred.
• Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease.
• Vitreoretinal surgery is indicated when retinal hemangioblastomas are accompanied by complications such as epiretinal membrane development, vitreous hemorrhage, tractional and/or exudative retinal detachment, preretinal fibrosis, or proliferative vitreoretinopathy [
• Brachytherapy could be a treatment option for larger peripheral hemangioblastomas with manageable risk and a high eye preservation rate [
• External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [
• There is no evidence to support the use of sunitinib for retinal hemangioblastomas.
• In individuals treated with nephrectomy, the adrenal gland should be left in situ. If contralateral pheochromocytoma occurs requiring adrenalectomy, the remaining adrenal gland will prevent or delay adrenal insufficiency.
• Kidney transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL and to exclude those with VHL.
• Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [
• Preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension and is recommended in treatment guidelines. However, perioperative alpha-adrenergic blockade has recently been under debate. In a multicenter study, mortality rate in pretreated individuals was slightly higher than in non-pretreated individuals [
• Adrenal-sparing surgery should be considered and is regarded as a successful treatment strategy. Studies show low recurrence, no metastatic disease, and rare steroid dependency after cortical-sparing techniques [
• Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [
• Pancreatic neuroendocrine tumors (PNETs) need to be differentiated from cysts and serous cystadenomas. PNETs are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgical resection should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria: (1) size ≥2.5 cm or (2) tumor doubling rate <500 days [
## Targeted Therapies
## Supportive Care
No guidelines exist for the management of VHL lesions.
Most CNS hemangioblastomas can be surgically removed completely and safely [
Some advocate early surgical removal of both symptomatic and asymptomatic CNS hemangioblastomas, while others follow asymptomatic lesions with yearly imaging studies. A study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [
Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. A minimally invasive approach for the resection of selected spinal hemangioblastomas is considered safe and allows complete tumor resection [
Pathologic findings during intraoperative neurophysiologic monitoring (IONM) appear to predict worse long-term outcomes after microsurgical removal of spinal cord hemangioblastomas [
Surgical intervention for cysts/syrinx in the spinal cord is recommended.
Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [
Factors associated with tumor control are solid, smaller tumors, VHL-associated lesions, and higher margin dose. Thirteen of 186 individuals (7%) experienced complications, 11 individuals needed steroid therapy, and one person died of refractory peritumoral edema. Two individuals required additional surgery [
Another study showed recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [
A case study showed complete loss of stromal cells after a standard dose of stereotactic radiosurgery for hemangioblastoma, indicating the effectiveness of the treatment [
Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblastomas. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [
Most ophthalmologists favor prospective treatment of retinal hemangioblastomas (but not optic nerve hemangioblastomas) to avoid blindness, although spontaneous regression has occurred.
Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease.
Vitreoretinal surgery is indicated when retinal hemangioblastomas are accompanied by complications such as epiretinal membrane development, vitreous hemorrhage, tractional and/or exudative retinal detachment, preretinal fibrosis, or proliferative vitreoretinopathy [
Brachytherapy could be a treatment option for larger peripheral hemangioblastomas with manageable risk and a high eye preservation rate [
External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [
There is no evidence to support the use of sunitinib for retinal hemangioblastomas.
In individuals treated with nephrectomy, the adrenal gland should be left in situ. If contralateral pheochromocytoma occurs requiring adrenalectomy, the remaining adrenal gland will prevent or delay adrenal insufficiency.
Kidney transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL and to exclude those with VHL.
Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [
Preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension and is recommended in treatment guidelines. However, perioperative alpha-adrenergic blockade has recently been under debate. In a multicenter study, mortality rate in pretreated individuals was slightly higher than in non-pretreated individuals [
Adrenal-sparing surgery should be considered and is regarded as a successful treatment strategy. Studies show low recurrence, no metastatic disease, and rare steroid dependency after cortical-sparing techniques [
Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [
Pancreatic neuroendocrine tumors (PNETs) need to be differentiated from cysts and serous cystadenomas. PNETs are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgical resection should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria: (1) size ≥2.5 cm or (2) tumor doubling rate <500 days [
• Most CNS hemangioblastomas can be surgically removed completely and safely [
• Some advocate early surgical removal of both symptomatic and asymptomatic CNS hemangioblastomas, while others follow asymptomatic lesions with yearly imaging studies. A study of 15 symptomatic individuals with cauda equina hemangioblastomas revealed a worse outcome in only one individual six months after surgery. The other individuals were stable or improved [
• Preoperative arterial embolization may be indicated, especially for extensive spinal tumors. A minimally invasive approach for the resection of selected spinal hemangioblastomas is considered safe and allows complete tumor resection [
• Pathologic findings during intraoperative neurophysiologic monitoring (IONM) appear to predict worse long-term outcomes after microsurgical removal of spinal cord hemangioblastomas [
• Surgical intervention for cysts/syrinx in the spinal cord is recommended.
• Stereotactic therapy is increasingly popular, but there is still a need for prospective studies [
• Factors associated with tumor control are solid, smaller tumors, VHL-associated lesions, and higher margin dose. Thirteen of 186 individuals (7%) experienced complications, 11 individuals needed steroid therapy, and one person died of refractory peritumoral edema. Two individuals required additional surgery [
• Another study showed recurrence-free survival in six of eight individuals at a mean follow up of 48 months. Two individuals required additional surgery for persisting cerebellar symptoms. One individual showed an increase in cyst volume along with a decrease of the size of the mural nodule [
• A case study showed complete loss of stromal cells after a standard dose of stereotactic radiosurgery for hemangioblastoma, indicating the effectiveness of the treatment [
• Ultra-widefield fluorescein angiography can be useful in the evaluation and management of retinal hemangioblastomas. This technique appears to detect more hemangioblastomas than ophthalmoscopy and conventional angiography [
• Most ophthalmologists favor prospective treatment of retinal hemangioblastomas (but not optic nerve hemangioblastomas) to avoid blindness, although spontaneous regression has occurred.
• Therapeutic modalities used to treat retinal hemangioblastomas include diathermy, xenon, laser, and cryocoagulation, with variable degrees of success depending on the location, size, and number of lesions. Recurrent tumors have been noted, even after many years, but some may be new tumors in the same general area rather than recurrent disease.
• Vitreoretinal surgery is indicated when retinal hemangioblastomas are accompanied by complications such as epiretinal membrane development, vitreous hemorrhage, tractional and/or exudative retinal detachment, preretinal fibrosis, or proliferative vitreoretinopathy [
• Brachytherapy could be a treatment option for larger peripheral hemangioblastomas with manageable risk and a high eye preservation rate [
• External beam radiotherapy has been shown to be useful when standard therapy has not prevented progression [
• There is no evidence to support the use of sunitinib for retinal hemangioblastomas.
• In individuals treated with nephrectomy, the adrenal gland should be left in situ. If contralateral pheochromocytoma occurs requiring adrenalectomy, the remaining adrenal gland will prevent or delay adrenal insufficiency.
• Kidney transplantation has been successful in individuals in whom bilateral nephrectomy has been necessary. It is imperative to evaluate any living related potential donor for VHL and to exclude those with VHL.
• Pheochromocytomas should be surgically removed. Laparoscopic approaches have been shown to be effective and safe [
• Preoperative treatment with alpha-adrenergic blockade and optional additional beta-adrenergic blockade for seven to ten days is appropriate even in individuals with no known hypertension and is recommended in treatment guidelines. However, perioperative alpha-adrenergic blockade has recently been under debate. In a multicenter study, mortality rate in pretreated individuals was slightly higher than in non-pretreated individuals [
• Adrenal-sparing surgery should be considered and is regarded as a successful treatment strategy. Studies show low recurrence, no metastatic disease, and rare steroid dependency after cortical-sparing techniques [
• Pancreatic cysts are common, rarely influence endocrine function, and have no malignant behavior. Therefore, surgical removal is not generally required [
• Pancreatic neuroendocrine tumors (PNETs) need to be differentiated from cysts and serous cystadenomas. PNETs are generally slow growing and are not hormonally active, although they can cause metastatic disease. Surgical resection should be strongly considered when there is a high risk of metastases, as suggested by one of the following prognostic criteria: (1) size ≥2.5 cm or (2) tumor doubling rate <500 days [
## Surveillance
In the United States, the VHL Alliance has worked extensively with health care professionals to assemble guidelines that are generally accepted worldwide (see
Von Hippel-Lindau Syndrome: Recommended Surveillance
CNS = central nervous system; ELST = endolymphatic sac tumors; IAC = internal auditory canals
The best way to detect ELST is unknown.
While current medical surveillance guidelines do not address structured psychological support for individuals with VHL, their partners, and their family members, research suggests a distinct need for psychosocial support [
## Agents/Circumstances to Avoid
Avoid the following:
Tobacco products, as they are considered a risk factor for kidney cancer
Chemicals and industrial toxins known to affect VHL-involved organs
Contact sports if adrenal or pancreatic lesions are present
• Tobacco products, as they are considered a risk factor for kidney cancer
• Chemicals and industrial toxins known to affect VHL-involved organs
• Contact sports if adrenal or pancreatic lesions are present
## Evaluation of Relatives at Risk
Early recognition of manifestations of VHL may allow for timely intervention and improved outcome; thus, clinical surveillance of asymptomatic at-risk individuals (including children) for early manifestations of VHL is appropriate. The American Society of Clinical Oncology identifies VHL as a Group 1 disorder – a hereditary disease for which genetic testing is considered part of the standard management for at-risk family members [
If the
If the
The use of molecular genetic testing for determining the genetic status of presumably at-risk relatives when a family member with a clinical diagnosis of VHL is not available for testing is not straightforward. Such test results need to be interpreted with caution. A positive test result signals the presence of a
The at-risk family member has not inherited a
The familial
The clinical diagnosis of VHL in the proband is questionable.
In this situation, the presumably at-risk family member has a small but finite residual risk of having inherited a pathogenic allele (i.e., VHL or other hereditary disorder). In counseling such individuals, careful consideration should be given to the strength of the clinical diagnosis of VHL in the affected family member, the relationship of the at-risk individual to the affected family member, the perceived risk of an undetected
See
• If the
• If the
• The at-risk family member has not inherited a
• The familial
• The clinical diagnosis of VHL in the proband is questionable.
## Pregnancy Management
There is no consensus regarding medical surveillance for pregnant women with VHL. Research by the French VHL Study Group showed a significantly higher complication rate of hemangioblastomas in individuals with VHL who had had at least one pregnancy [
See
## Therapies Under Investigation
Certain
Sunitinib, a tyrosine kinase inhibitor (TKI) that inhibits the action of VEGF receptors, has had some utility in the rare unresectable malignant pheochromocytomas, but simple surgical excision is clearly preferable for these usually benign tumors [
Pazopanib showed favorable effects on the clinical condition of individuals with recurrent and rapidly progressive VHL-associated hemangioblastomas [
Somatostatin analogs could be of use in the treatment of hemangioblastomas. Nine hemangioblastomas demonstrated expression for at least three somatostatin receptor subtypes (1, 2a, 3, 4, or 5). One individual with a symptomatic irresectable suprasellar hemangioblastoma was treated with octreotide long-acting release, which resulted in clinical stability and radiographic response after nine months of treatment [
Propranolol could be an efficient treatment to control hemangioblastoma growth in individuals with VHL because of its antiangiogenic effects demonstrated in infantile hemangioma and the hypothetical impact on HIF levels.
Checkpoint inhibitors such as antibodies targeting programmed cell death ligand 1 (PD-L1) have shown promise in managing tumor load; however, these treatments have unknown toxicity in individuals with VHL, who will likely have dozens to thousands of small subclinical lesions present throughout their body.
Premature termination codon 124 (PTC124), also known as ataluren, may benefit a subset of affected individuals in whom nonsense variants give rise to premature stop codons in the messenger RNA [
An in vivo study of HIF2α inhibitor in
Search
## Genetic Counseling
Von Hippel-Lindau syndrome (VHL) is inherited in an autosomal dominant manner.
Approximately 80% of individuals diagnosed with VHL have an affected parent.
Some individuals diagnosed with VHL have the disorder as the result of a
If the proband appears to be the only affected family member:
And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
Note: Screening for VHL lesions is warranted for parents without clinical manifestations but who are identified as having 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 germline (or somatic and germline) mosaicism* [
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with VHL 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 syndrome 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
If the proband has a known
If the genetic status of the parents is unknown but the parents are clinically unaffected and are at least age 35 years, the risk to the sibs of a proband appears to be low; however, the sibs are still at increased risk for VHL because of the possibility of failure to recognize the disorder or late onset of the syndrome in an affected parent and the possibility of parental germline mosaicism.
See Management,
Because early detection of at-risk individuals affects medical management, testing of asymptomatic individuals during childhood is beneficial [
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 authors recommend the VHL Kids Handbook by the VHL Alliance (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.
Preconception considerations include possible male infertility due to cysts of the epididymis.
Once the
Differences in perspective may exist among medical professionals and in 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 VHL have an affected parent.
• Some individuals diagnosed with VHL have the disorder as the result of a
• If the proband appears to be the only affected family member:
• And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
• Note: Screening for VHL lesions is warranted for parents without clinical manifestations but who are identified as having a
• And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
• 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* [
• * 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* [
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with VHL 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 syndrome 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.
• And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• If the genetic status of the parents is unknown but the parents are clinically unaffected and are at least age 35 years, the risk to the sibs of a proband appears to be low; however, the sibs are still at increased risk for VHL because of the possibility of failure to recognize the disorder or late onset of the syndrome in an affected parent and the possibility of parental germline 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.
• Preconception considerations include possible male infertility due to cysts of the epididymis.
## Mode of Inheritance
Von Hippel-Lindau syndrome (VHL) is inherited in an autosomal dominant manner.
## Risk to Family Members
Approximately 80% of individuals diagnosed with VHL have an affected parent.
Some individuals diagnosed with VHL have the disorder as the result of a
If the proband appears to be the only affected family member:
And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
Note: Screening for VHL lesions is warranted for parents without clinical manifestations but who are identified as having 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 germline (or somatic and germline) mosaicism* [
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with VHL 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 syndrome 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
If the proband has a known
If the genetic status of the parents is unknown but the parents are clinically unaffected and are at least age 35 years, the risk to the sibs of a proband appears to be low; however, the sibs are still at increased risk for VHL because of the possibility of failure to recognize the disorder or late onset of the syndrome in an affected parent and the possibility of parental germline mosaicism.
• Approximately 80% of individuals diagnosed with VHL have an affected parent.
• Some individuals diagnosed with VHL have the disorder as the result of a
• If the proband appears to be the only affected family member:
• And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
• Note: Screening for VHL lesions is warranted for parents without clinical manifestations but who are identified as having a
• And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
• 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* [
• * 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* [
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with VHL 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 syndrome 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.
• And a molecular diagnosis has been established in the proband, genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• And a molecular diagnosis has not been established in the proband, ophthalmologic screening and abdominal ultrasound evaluation, at a minimum, should be offered to both parents.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism* [
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known
• If the genetic status of the parents is unknown but the parents are clinically unaffected and are at least age 35 years, the risk to the sibs of a proband appears to be low; however, the sibs are still at increased risk for VHL because of the possibility of failure to recognize the disorder or late onset of the syndrome in an affected parent and the possibility of parental germline mosaicism.
## Related Genetic Counseling Issues
See Management,
Because early detection of at-risk individuals affects medical management, testing of asymptomatic individuals during childhood is beneficial [
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 authors recommend the VHL Kids Handbook by the VHL Alliance (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.
Preconception considerations include possible male infertility due to cysts of the epididymis.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• Preconception considerations include possible male infertility due to cysts of the epididymis.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Differences in perspective may exist among medical professionals and in 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
Von Hippel-Lindau Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Von Hippel-Lindau Syndrome (
The role of von Hippel-Lindau disease tumor suppressor (pVHL) in the regulation of hypoxia-inducible genes through the targeted ubiquitinylation and degradation of hypoxia-inducible factor 1 alpha (HIF1α) has been described in great detail and won the 2019 Nobel Prize, leading to a model of how disruption of
Von Hippel-Lindau syndrome (VHL) results from a germline loss-of-function variant coupled with a somatic loss-of-function variant involving the second allele. Pathogenic variants can prevent or reduce
Pathogenic missense variants that lead to pheochromocytoma with a low (or no) risk for renal cell carcinoma (VHL types 2A and 2C) may encode pVHL that retains the ability to ubiquinate (and thereby downregulate) HIF1α in the presence of molecular oxygen to a greater degree than pathogenic variants that result in VHL with pheochromocytoma and renal cell carcinoma (VHL type 2B). Furthermore, mutated pVHL may predispose to pheochromocytoma by altering the balance among a group of proteins in a molecular pathway that controls apoptosis of sympatho-adrenal precursor cells during development.
## Molecular Pathogenesis
The role of von Hippel-Lindau disease tumor suppressor (pVHL) in the regulation of hypoxia-inducible genes through the targeted ubiquitinylation and degradation of hypoxia-inducible factor 1 alpha (HIF1α) has been described in great detail and won the 2019 Nobel Prize, leading to a model of how disruption of
Von Hippel-Lindau syndrome (VHL) results from a germline loss-of-function variant coupled with a somatic loss-of-function variant involving the second allele. Pathogenic variants can prevent or reduce
Pathogenic missense variants that lead to pheochromocytoma with a low (or no) risk for renal cell carcinoma (VHL types 2A and 2C) may encode pVHL that retains the ability to ubiquinate (and thereby downregulate) HIF1α in the presence of molecular oxygen to a greater degree than pathogenic variants that result in VHL with pheochromocytoma and renal cell carcinoma (VHL type 2B). Furthermore, mutated pVHL may predispose to pheochromocytoma by altering the balance among a group of proteins in a molecular pathway that controls apoptosis of sympatho-adrenal precursor cells during development.
## Chapter Notes
Saya Ahmad, BSc (2018-present)Debra L Collins, MS; University of Kansas Medical Center (2000-2012)Carlijn Frantzen, MD; University Medical Center Groningen (2012-2018)Timothy Klasson, BSc; University Medical Center Utrecht (2015-2018)Rachel Giles, MD, PhD (2012-present)Thera P Links, MD, PhD; University Medical Center Groningen (2012-2023)R Neil Schimke, MD; University of Kansas Medical Center (2000-2012)Catherine A Stolle, PhD; The Children's Hospital of Philadelphia (2000-2012)Rachel S van Leeuwaarde, MD (2018-present) Bernadette van Nesselrooij, MD, PhD (2023-present) Wouter Zandee, MD, PhD (2023-present)
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
29 February 2024 (aa) Revision: clinical diagnostic criteria in
21 September 2023 (sw) Comprehensive update posted live
6 September 2018 (sw) Comprehensive update posted live
6 August 2015 (me) Comprehensive update posted live
21 June 2012 (me) Comprehensive update posted live
22 December 2009 (me) Comprehensive update posted live
20 March 2007 (me) Comprehensive update posted live
1 December 2004 (me) Comprehensive update posted live
14 November 2002 (tk,cg) Comprehensive update posted live
17 May 2000 (me) Review posted live
17 September 1999 (rns) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 29 February 2024 (aa) Revision: clinical diagnostic criteria in
• 21 September 2023 (sw) Comprehensive update posted live
• 6 September 2018 (sw) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 22 December 2009 (me) Comprehensive update posted live
• 20 March 2007 (me) Comprehensive update posted live
• 1 December 2004 (me) Comprehensive update posted live
• 14 November 2002 (tk,cg) Comprehensive update posted live
• 17 May 2000 (me) Review posted live
• 17 September 1999 (rns) Original submission
## Author History
Saya Ahmad, BSc (2018-present)Debra L Collins, MS; University of Kansas Medical Center (2000-2012)Carlijn Frantzen, MD; University Medical Center Groningen (2012-2018)Timothy Klasson, BSc; University Medical Center Utrecht (2015-2018)Rachel Giles, MD, PhD (2012-present)Thera P Links, MD, PhD; University Medical Center Groningen (2012-2023)R Neil Schimke, MD; University of Kansas Medical Center (2000-2012)Catherine A Stolle, PhD; The Children's Hospital of Philadelphia (2000-2012)Rachel S van Leeuwaarde, MD (2018-present) Bernadette van Nesselrooij, MD, PhD (2023-present) Wouter Zandee, MD, PhD (2023-present)
## Revision History
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
29 February 2024 (aa) Revision: clinical diagnostic criteria in
21 September 2023 (sw) Comprehensive update posted live
6 September 2018 (sw) Comprehensive update posted live
6 August 2015 (me) Comprehensive update posted live
21 June 2012 (me) Comprehensive update posted live
22 December 2009 (me) Comprehensive update posted live
20 March 2007 (me) Comprehensive update posted live
1 December 2004 (me) Comprehensive update posted live
14 November 2002 (tk,cg) Comprehensive update posted live
17 May 2000 (me) Review posted live
17 September 1999 (rns) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 29 February 2024 (aa) Revision: clinical diagnostic criteria in
• 21 September 2023 (sw) Comprehensive update posted live
• 6 September 2018 (sw) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 21 June 2012 (me) Comprehensive update posted live
• 22 December 2009 (me) Comprehensive update posted live
• 20 March 2007 (me) Comprehensive update posted live
• 1 December 2004 (me) Comprehensive update posted live
• 14 November 2002 (tk,cg) Comprehensive update posted live
• 17 May 2000 (me) Review posted live
• 17 September 1999 (rns) Original submission
## Key Sections in this
## References
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
Binderup MLM, Smerdel M, Borgwadt L, Beck Nielsen SS, Madsen MG, Møller HU, Kiilgaard JF, Friis-Hansen L, Harbud V, Cortnum S, Owen H, Gimsing S, Friis Juhl HA, Munthe S, Geilswijk M, Rasmussen ÅK, Møldrup U, Graumann O, Donskov F, Grønbæk H, Stausbøl-Grøn B, Schaffalitzky de Muckadell O, Knigge U, Dam G, Wadt KA, Bøgeskov L, Bagi P, Lund L, Stochholm K, Ousager LB, Sunde L. Von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022;65:104538. [
Hes FJ, van der Luijt RB, Lips CJ. Clinical management of von Hippel-Lindau (VHL) disease. Neth J Med. 2001;59:225-34. [
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. Von Hippel-Lindau disease. Lancet. 2003;361:2059-67. [
VHL Alliance. VHL Patient and Caregiver Handbook. Available
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
• Binderup MLM, Smerdel M, Borgwadt L, Beck Nielsen SS, Madsen MG, Møller HU, Kiilgaard JF, Friis-Hansen L, Harbud V, Cortnum S, Owen H, Gimsing S, Friis Juhl HA, Munthe S, Geilswijk M, Rasmussen ÅK, Møldrup U, Graumann O, Donskov F, Grønbæk H, Stausbøl-Grøn B, Schaffalitzky de Muckadell O, Knigge U, Dam G, Wadt KA, Bøgeskov L, Bagi P, Lund L, Stochholm K, Ousager LB, Sunde L. Von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022;65:104538. [
• Hes FJ, van der Luijt RB, Lips CJ. Clinical management of von Hippel-Lindau (VHL) disease. Neth J Med. 2001;59:225-34. [
• Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. Von Hippel-Lindau disease. Lancet. 2003;361:2059-67. [
• VHL Alliance. VHL Patient and Caregiver Handbook. Available
## Published Guidelines / Consensus Statements
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
Binderup MLM, Smerdel M, Borgwadt L, Beck Nielsen SS, Madsen MG, Møller HU, Kiilgaard JF, Friis-Hansen L, Harbud V, Cortnum S, Owen H, Gimsing S, Friis Juhl HA, Munthe S, Geilswijk M, Rasmussen ÅK, Møldrup U, Graumann O, Donskov F, Grønbæk H, Stausbøl-Grøn B, Schaffalitzky de Muckadell O, Knigge U, Dam G, Wadt KA, Bøgeskov L, Bagi P, Lund L, Stochholm K, Ousager LB, Sunde L. Von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022;65:104538. [
Hes FJ, van der Luijt RB, Lips CJ. Clinical management of von Hippel-Lindau (VHL) disease. Neth J Med. 2001;59:225-34. [
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. Von Hippel-Lindau disease. Lancet. 2003;361:2059-67. [
VHL Alliance. VHL Patient and Caregiver Handbook. Available
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003.
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2010.
• Binderup MLM, Smerdel M, Borgwadt L, Beck Nielsen SS, Madsen MG, Møller HU, Kiilgaard JF, Friis-Hansen L, Harbud V, Cortnum S, Owen H, Gimsing S, Friis Juhl HA, Munthe S, Geilswijk M, Rasmussen ÅK, Møldrup U, Graumann O, Donskov F, Grønbæk H, Stausbøl-Grøn B, Schaffalitzky de Muckadell O, Knigge U, Dam G, Wadt KA, Bøgeskov L, Bagi P, Lund L, Stochholm K, Ousager LB, Sunde L. Von Hippel-Lindau disease: Updated guideline for diagnosis and surveillance. Eur J Med Genet. 2022;65:104538. [
• Hes FJ, van der Luijt RB, Lips CJ. Clinical management of von Hippel-Lindau (VHL) disease. Neth J Med. 2001;59:225-34. [
• Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH. Von Hippel-Lindau disease. Lancet. 2003;361:2059-67. [
• VHL Alliance. VHL Patient and Caregiver Handbook. Available
## Literature Cited
|
[] |
17/5/2000
|
21/9/2023
|
1/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
vlcad
|
vlcad
|
[
"Very Long-Chain Acyl-CoA Dehydrogenase Deficiency",
"VLCAD Deficiency",
"VLCAD Deficiency",
"Very Long-Chain Acyl-CoA Dehydrogenase Deficiency",
"ACADVL-Related Severe Early-Onset Cardiac and Multiorgan Failure",
"ACADVL-Related Hepatic or Hypoketotic Hypoglycemia",
"ACADVL-Related Later-Onset Episodic Myopathy with Intermittent Rhabdomyolysis",
"Very long-chain specific acyl-CoA dehydrogenase, mitochondrial",
"ACADVL",
"Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency"
] |
Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency
|
Nancy D Leslie, Sofia Saenz-Ayala
|
Summary Deficiency of very long-chain acyl-coenzyme A dehydrogenase (VLCAD), which catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons, is associated with three phenotypes. The severe early-onset cardiac and multiorgan failure form typically presents in the first months of life with hypertrophic or dilated cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The hepatic or hypoketotic hypoglycemic form typically presents during early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy. The later-onset episodic myopathic form presents with intermittent rhabdomyolysis provoked by exercise, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms. The diagnosis of VLCAD deficiency is established in a proband with a specific pattern of abnormal acylcarnitine levels on biochemical testing and/or by identification of biallelic pathogenic variants in VLCAD deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
Severe early-onset cardiac and multiorgan failure
Hepatic or hypoketotic hypoglycemia
Later-onset episodic myopathy with intermittent rhabdomyolysis
For other genetic causes of these phenotypes, see
• Severe early-onset cardiac and multiorgan failure
• Hepatic or hypoketotic hypoglycemia
• Later-onset episodic myopathy with intermittent rhabdomyolysis
## Diagnosis
Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation of long-chain fatty acids with a chain length of 14 to 20 carbons.
NBS for VLCAD deficiency is primarily based on quantification of various acylcarnitine levels (C14:1, C14:2, C14, and C12:1) and ratios of acylcarnitine levels (C14:1/C2, C14:1/C16) on dried blood spots.
Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [
Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no
Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [
A significant number of individuals with an abnormal NBS result have one
If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see
Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.
The following
Evaluation of the newborn to ascertain clinical status
Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy
Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:
Admission to the hospital
Fluid resuscitation
Infusion of IV glucose
Nutritional evaluation
Institution of enteral nutrition with supplementation of medium-chain fat
Cardiac evaluation
See also
A symptomatic individual may have either: findings associated with later-onset VLCAD deficiency; or untreated infantile-onset VLCAD deficiency resulting from any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result.
Supportive – but nonspecific– clinical findings by age and preliminary laboratory findings can include the following.
Newborn/infant:
Severe hypertrophic or dilated cardiomyopathy
Pericardial effusion
Arrhythmias
Hypotonia
Hepatomegaly
Multiorgan failure
Older child / adult:
Myopathy associated with exercise intolerance
Muscle cramps and/or pain
Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
Newborn/infant:
Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
Elevated liver transaminases
Altered hepatic synthetic liver function
Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes
The diagnosis of VLCAD 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 [
For an introduction to multigene panels click
When the diagnosis of VLCAD deficiency has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in VLCAD 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.
Specialized biochemical testing may be used to clarify the diagnosis, particularly when molecular testing reveals only one pathogenic variant.
• Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [
• Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no
• Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [
• A significant number of individuals with an abnormal NBS result have one
• If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see
• Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.
• Evaluation of the newborn to ascertain clinical status
• Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy
• Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• See also
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• Newborn/infant:
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Older child / adult:
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Newborn/infant:
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• For an introduction to multigene panels click
• When the diagnosis of VLCAD deficiency has not been considered,
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
NBS for VLCAD deficiency is primarily based on quantification of various acylcarnitine levels (C14:1, C14:2, C14, and C12:1) and ratios of acylcarnitine levels (C14:1/C2, C14:1/C16) on dried blood spots.
Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [
Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no
Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [
A significant number of individuals with an abnormal NBS result have one
If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see
Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.
The following
Evaluation of the newborn to ascertain clinical status
Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy
Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:
Admission to the hospital
Fluid resuscitation
Infusion of IV glucose
Nutritional evaluation
Institution of enteral nutrition with supplementation of medium-chain fat
Cardiac evaluation
See also
A symptomatic individual may have either: findings associated with later-onset VLCAD deficiency; or untreated infantile-onset VLCAD deficiency resulting from any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result.
Supportive – but nonspecific– clinical findings by age and preliminary laboratory findings can include the following.
Newborn/infant:
Severe hypertrophic or dilated cardiomyopathy
Pericardial effusion
Arrhythmias
Hypotonia
Hepatomegaly
Multiorgan failure
Older child / adult:
Myopathy associated with exercise intolerance
Muscle cramps and/or pain
Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
Newborn/infant:
Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
Elevated liver transaminases
Altered hepatic synthetic liver function
Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes
• Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [
• Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no
• Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [
• A significant number of individuals with an abnormal NBS result have one
• If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see
• Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.
• Evaluation of the newborn to ascertain clinical status
• Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy
• Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• See also
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• Newborn/infant:
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Older child / adult:
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Newborn/infant:
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
## Scenario 1: Abnormal Newborn Screening (NBS) Result
NBS for VLCAD deficiency is primarily based on quantification of various acylcarnitine levels (C14:1, C14:2, C14, and C12:1) and ratios of acylcarnitine levels (C14:1/C2, C14:1/C16) on dried blood spots.
Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [
Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no
Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [
A significant number of individuals with an abnormal NBS result have one
If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see
Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.
The following
Evaluation of the newborn to ascertain clinical status
Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy
Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:
Admission to the hospital
Fluid resuscitation
Infusion of IV glucose
Nutritional evaluation
Institution of enteral nutrition with supplementation of medium-chain fat
Cardiac evaluation
See also
• Although cutoff/abnormal values vary by age, method of collection, and laboratory, a C14:1 level greater than 1 µmol/L [
• Levels of C14:1 greater than 0.8 µmol/L suggest VLCAD deficiency but may also occur in carriers and some healthy individuals having no
• Postanalytic tools, such as those developed by the Region 4 Stork (R4S/CLIR) collaborative, may contribute to refinement of NBS cutoffs and inform clinicians regarding the likelihood of a true positive diagnosis of VLCAD deficiency in individual newborns [
• A significant number of individuals with an abnormal NBS result have one
• If the follow-up biochemical testing supports the likelihood of VLCAD deficiency, additional testing is required to establish the diagnosis (see
• Note: (1) Diagnostic abnormalities may no longer be present if an individual has been fed or has been treated with an IV glucose infusion, or if the episode prompting concern has resolved. (2) NBS data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. (3) Severe body weight loss at the sampling day of NBS could cause false positive elevation of C14:1 and C14:1/C2.
• Evaluation of the newborn to ascertain clinical status
• Education of the caregivers to avoid prolonged fasting and to monitor for decreased oral intake, vomiting, or lethargy
• Immediate intervention (to be considered if the newborn is not doing well clinically) possibly including:
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• See also
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
• Admission to the hospital
• Fluid resuscitation
• Infusion of IV glucose
• Nutritional evaluation
• Institution of enteral nutrition with supplementation of medium-chain fat
• Cardiac evaluation
## Scenario 2: Symptomatic Individual
A symptomatic individual may have either: findings associated with later-onset VLCAD deficiency; or untreated infantile-onset VLCAD deficiency resulting from any of the following: NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment following a positive NBS result.
Supportive – but nonspecific– clinical findings by age and preliminary laboratory findings can include the following.
Newborn/infant:
Severe hypertrophic or dilated cardiomyopathy
Pericardial effusion
Arrhythmias
Hypotonia
Hepatomegaly
Multiorgan failure
Older child / adult:
Myopathy associated with exercise intolerance
Muscle cramps and/or pain
Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
Newborn/infant:
Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
Elevated liver transaminases
Altered hepatic synthetic liver function
Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes
• Newborn/infant:
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Older child / adult:
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Severe hypertrophic or dilated cardiomyopathy
• Pericardial effusion
• Arrhythmias
• Hypotonia
• Hepatomegaly
• Multiorgan failure
• Myopathy associated with exercise intolerance
• Muscle cramps and/or pain
• Episodic intermittent rhabdomyolysis provoked by strenuous exercise, fasting, cold exposure, or fever
• Newborn/infant:
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
• Older child / adult: intermittent elevations in creatine phosphokinase with return to normal between episodes
• Hypoglycemia out of proportion to the duration of fasting and/or unaccompanied by large ketones in the urine
• Elevated liver transaminases
• Altered hepatic synthetic liver function
## Establishing the Diagnosis
The diagnosis of VLCAD 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 [
For an introduction to multigene panels click
When the diagnosis of VLCAD deficiency has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in VLCAD 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.
Specialized biochemical testing may be used to clarify the diagnosis, particularly when molecular testing reveals only one pathogenic variant.
• For an introduction to multigene panels click
• When the diagnosis of VLCAD deficiency has not been considered,
• For an introduction to comprehensive genomic testing click
## Molecular Genetic Testing
For an introduction to multigene panels click
When the diagnosis of VLCAD deficiency has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in VLCAD 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.
• For an introduction to multigene panels click
• When the diagnosis of VLCAD deficiency has not been considered,
• For an introduction to comprehensive genomic testing click
## Specialized Biochemical Testing
Specialized biochemical testing may be used to clarify the diagnosis, particularly when molecular testing reveals only one pathogenic variant.
## Clinical Characteristics
Depending on the severity of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency, individuals can present with hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy with recurrent rhabdomyolysis, triggered by a catabolic state. Therefore, the condition has been divided into three clinical subgroups, including a severe early-onset cardiac and multiorgan failure form, a hepatic or hypoketotic hypoglycemic form, and a later-onset myopathic form [
Developmental and intelligence quotient (IQ) scores were similar to those seen in the general population (developmental quotient / IQ ≥85) [
However, motor and speech delays were reported [
Both
Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
As a general rule, strong genotype-phenotype correlations exist in VLCAD deficiency [
Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in
A specific homozygous missense pathogenic variant (c.709T>C;
Milder childhood and adult forms are often associated with residual enzyme activity. The common
Complete ascertainment by NBS is not assured, but the incidence of VLCAD deficiency is now estimated at 1:30,000 to 1:100,000 births.
NBS has demonstrated that VLCAD deficiency is more prevalent than previously suspected; however, the majority of children ascertained by NBS are asymptomatic during the first few years of observation, suggesting that these individuals may have gone undiagnosed prior to the advent of population-based screening.
• Developmental and intelligence quotient (IQ) scores were similar to those seen in the general population (developmental quotient / IQ ≥85) [
• However, motor and speech delays were reported [
• Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
• Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
• Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
• Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
• Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
• Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
• Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in
• A specific homozygous missense pathogenic variant (c.709T>C;
• Milder childhood and adult forms are often associated with residual enzyme activity. The common
## Clinical Description
Depending on the severity of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency, individuals can present with hypoketotic hypoglycemia, hepatomegaly, cardiomyopathy, and myopathy with recurrent rhabdomyolysis, triggered by a catabolic state. Therefore, the condition has been divided into three clinical subgroups, including a severe early-onset cardiac and multiorgan failure form, a hepatic or hypoketotic hypoglycemic form, and a later-onset myopathic form [
Developmental and intelligence quotient (IQ) scores were similar to those seen in the general population (developmental quotient / IQ ≥85) [
However, motor and speech delays were reported [
Both
Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
• Developmental and intelligence quotient (IQ) scores were similar to those seen in the general population (developmental quotient / IQ ≥85) [
• However, motor and speech delays were reported [
• Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
• Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
• Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
• Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
• Cardiomyopathy and arrhythmias are often lethal. Ventricular tachycardia, ventricular fibrillation, and atrioventricular block have been reported [
• Although the morbidity resulting from cardiomyopathy may be severe, cardiac dysfunction may be reversible with early intensive supportive care and diet modification.
## Genotype-Phenotype Correlations
As a general rule, strong genotype-phenotype correlations exist in VLCAD deficiency [
Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in
A specific homozygous missense pathogenic variant (c.709T>C;
Milder childhood and adult forms are often associated with residual enzyme activity. The common
• Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in
• A specific homozygous missense pathogenic variant (c.709T>C;
• Milder childhood and adult forms are often associated with residual enzyme activity. The common
## Prevalence
Complete ascertainment by NBS is not assured, but the incidence of VLCAD deficiency is now estimated at 1:30,000 to 1:100,000 births.
NBS has demonstrated that VLCAD deficiency is more prevalent than previously suspected; however, the majority of children ascertained by NBS are asymptomatic during the first few years of observation, suggesting that these individuals may have gone undiagnosed prior to the advent of population-based screening.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders in the Differential Diagnosis of Severe Early-Onset VLCAD
Selected Metabolic Myopathies in the Differential Diagnosis of Later-Onset Episodic Myopathic VLCAD Deficiency
## Management
Clinical guidelines for the nutritional management of very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency at various ages have been published [
When VLCAD deficiency is suspected during the diagnostic evaluation – for example, as a result of a suggestive acylcarnitine profile (see
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (e.g., 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 VLCAD deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in a Neonate or Infant
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for crises).
MOI = mode of inheritance
After a new diagnosis of VLCAD deficiency in a neonate or infant, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in an Older Child or Adult
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Frequently updated, succinct emergency care plans should detail the typical clinical issues (either those already experienced by the affected individual or those anticipated based on the diagnosis) and the importance of early management (e.g., use of IV glucose as an energy source, monitoring for cardiac rhythm disturbance, and monitoring of rhabdomyolysis) and avoidance of triggers (fasting, long-chain fats, and irritation of the myocardium) [
Cardiac dysfunction may be reversible with early, intensive supportive care (occasionally including extracorporeal membrane oxygenation) and diet modification.
The use of triheptanoin is based on its action as an anaplerotic molecule that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders.
Benefits include decrease in total days of hospitalization per year and reduction in episodes of rhabdomyolysis [
Triheptanoin was less effective in reducing rhabdomyolysis post treatment compared to its effect on other symptoms of VLCAD deficiency, suggesting a role for other pathophysiologic mechanisms and demonstrating the need for additional therapies (see
Adverse events in all of the clinical trials were similar for C7 and C8 treatment and predominantly consisted of gastrointestinal symptoms (abdominal pain, diarrhea) [
Routine Daily Treatment in Individuals with VLCAD Deficiency
For MCT oil: to provide an addl 15%-18% of calories (See
For triheptanoin: to provide 30% of daily caloric intake
LA (3%-4% of total energy)
ARA (0.5%-1.2% of total energy)
ALA (0.5% of total energy)
DHA (infants/toddlers: 60 mg/day; older persons: 100 mg/day)
MCT oil at 0.5 g/kg lean body weight 20 min prior to exercise
Exercise guided by affected person's tolerance level
Initial oral dosage of 10-25 mg L-carnitine/kg/day divided into 3-4 doses is typical.
Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
Speech therapy
Physical therapy
Rehab therapy
ALA = alpha-linolenic acid; ARA = arachidonic acid; DHA = docosahexaenoic acid; DRI = dietary reference intake; ECMO = extracorporeal membrane oxygenation; EER = estimated energy requirement; LA = linoleic acid; MCT = medium-chain triglycerides
Breast-feeding (or using expressed breast milk) without MCT oil supplements may be considered in asymptomatic neonates predicted to have mild VLCAD deficiency who are growing well, as long as fasting precautions are followed.
In asymptomatic infants with moderate VLCAD deficiency, breast-feeding (or using expressed breast milk) can be used with consideration of supplementation with a low long-chain fat / high MCT medical food [
Triheptanoin, a synthetic seven odd medium-chain fatty acid triglyceride, was approved by the FDA in June 2020 [
The FDA recommends discontinuing MCT products prior to initiation of triheptanoin therapy. In the retrospective study by
Baseline
Adapted from
EER = estimated energy requirement; PAL = physical activity level
When an affected individual is clinically well.
The estimated energy requirement calculated based on age or pregnancy trimester was published by the
Emergency Outpatient Treatment in Individuals with VLCAD Deficiency
Frequent high-carbohydrate feedings
Fasting duration time should be ↓ compared to when person is well.
Trial of outpatient treatment at home for up to 12 hrs
Reassessment frequently for clinical changes
Fever <38.5 °C (101 °F); enteral feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability)
Focusing on foods that will provide glucose polymers, or simple or complex carbohydrates [
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to a hospital.
Acute Inpatient Treatment in Individuals with VLCAD Deficiency
Avoid use of L-carnitine during acute illness.
Avoid use of IV lipids.
A source of essential fatty acids should be provided after 7 days.
Adapted from
Inpatient emergency treatment should (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
Total fluid volumes may need to be adjusted if the affected individual has cardiomyopathy; however, caloric provision should not be compromised. If necessary, decreasing IV fluid rates and increasing dextrose concentration (with supplemental insulin, if necessary, to avoid acute hyperglycemia) is required.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with VLCAD 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.
See Management,
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation results in management that can be administered expediently in the setting of intercurrent illness or other catabolic stressors.
Prevention of Secondary Manifestations in Individuals with VLCAD Deficiency
Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute decompensation / rhabdomyolysis
Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home
Medical alert bracelets/pendants, or car seat stickers
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for VLCAD deficiency & containing contact info for primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
Some anesthetics may be contraindicated (see
Essential information including written treatment protocols should be provided
Parents or local hospitals should immediately inform the designated metabolic center if (1) temperature rises above 38.5 °C, (2) vomiting/diarrhea or other symptoms of intercurrent illness develop, or (3) new neurologic symptoms occur.
For affected individuals deemed to be high risk for perioperative complications, perioperative/perianesthetic management precautions may include an evaluation at a specialty anesthetic clinic.
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the surveillance evaluations summarized in
Recommended Surveillance for Individuals with VLCAD Deficiency
Measurement of growth (w/special attention to obesity)
Assessment of feeding skills in infants/toddlers
Every 3 mos for 1st yr of life
Every 6-12 mos for those age >1 yr
Every 3 mos for 1st yr of life
Every 3-6 mos for those age 1-7 yrs
Every 6-12 mos for those age >7 yrs
Adapted from
BNP = B-type natriuretic protein; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; RBC = red blood cell
Obesity can become a significant problem, and is not easy to remedy in individuals with exercise intolerance and requirement for active management of fasting.
To include electrolytes, kidney function, liver function, and glucose
Particularly in individuals with previous cardiac dysfunction or those with significant exercise intolerance
Decreased bone mineral density is not a primary feature of VLCAD deficiency but can occur in those who have nutritional deficiencies, such as low total 25-hydroxyvitamine D concentrations.
Avoid the following:
Fasting, including periods of preparation and recovery from planned surgery or sedation [
Myocardial irritation (e.g., cardiac catheterization)
Dehydration (risk for acute tubular necrosis)
High-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch [
Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate [
Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from institution of treatment and preventive measures (see Management,
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, plasma or dried blood spot acylcarnitine analysis may not be sufficiently sensitive, and direct VLCAD assay of lymphocytes or fatty acid oxidation probe studies of cultured fibroblasts may be required.
For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening either test for the familial
See
During pregnancy, placental and fetal beta-oxidation may temporize or even improve maternal fatty acid beta-oxidation [
Energy needs and fat intake recommendations for women who are pregnant or lactating are listed in
Recommended Surveillance for Pregnant and Lactating Women with VLCAD Deficiency
Weekly to monthly in pregnant women
At every clinic visit in lactating women
Adapted from
CBC = complete blood count; RBC = red blood cell
Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended. Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity.
To include electrolytes, kidney function, liver function, and glucose
See
An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated [
An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment [
Search
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for crises).
• The use of triheptanoin is based on its action as an anaplerotic molecule that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders.
• Benefits include decrease in total days of hospitalization per year and reduction in episodes of rhabdomyolysis [
• Triheptanoin was less effective in reducing rhabdomyolysis post treatment compared to its effect on other symptoms of VLCAD deficiency, suggesting a role for other pathophysiologic mechanisms and demonstrating the need for additional therapies (see
• Adverse events in all of the clinical trials were similar for C7 and C8 treatment and predominantly consisted of gastrointestinal symptoms (abdominal pain, diarrhea) [
• For MCT oil: to provide an addl 15%-18% of calories (See
• For triheptanoin: to provide 30% of daily caloric intake
• LA (3%-4% of total energy)
• ARA (0.5%-1.2% of total energy)
• ALA (0.5% of total energy)
• DHA (infants/toddlers: 60 mg/day; older persons: 100 mg/day)
• MCT oil at 0.5 g/kg lean body weight 20 min prior to exercise
• Exercise guided by affected person's tolerance level
• Initial oral dosage of 10-25 mg L-carnitine/kg/day divided into 3-4 doses is typical.
• Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
• Speech therapy
• Physical therapy
• Rehab therapy
• Frequent high-carbohydrate feedings
• Fasting duration time should be ↓ compared to when person is well.
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment frequently for clinical changes
• Avoid use of L-carnitine during acute illness.
• Avoid use of IV lipids.
• A source of essential fatty acids should be provided after 7 days.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with VLCAD 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.
• Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute decompensation / rhabdomyolysis
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home
• Medical alert bracelets/pendants, or car seat stickers
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for VLCAD deficiency & containing contact info for primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Some anesthetics may be contraindicated (see
• Measurement of growth (w/special attention to obesity)
• Assessment of feeding skills in infants/toddlers
• Every 3 mos for 1st yr of life
• Every 6-12 mos for those age >1 yr
• Every 3 mos for 1st yr of life
• Every 3-6 mos for those age 1-7 yrs
• Every 6-12 mos for those age >7 yrs
• Fasting, including periods of preparation and recovery from planned surgery or sedation [
• Myocardial irritation (e.g., cardiac catheterization)
• Dehydration (risk for acute tubular necrosis)
• High-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch [
• Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate [
• 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, plasma or dried blood spot acylcarnitine analysis may not be sufficiently sensitive, and direct VLCAD assay of lymphocytes or fatty acid oxidation probe studies of cultured fibroblasts may be required.
• Weekly to monthly in pregnant women
• At every clinic visit in lactating women
• An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated [
• An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VLCAD deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in a Neonate or Infant
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for crises).
MOI = mode of inheritance
After a new diagnosis of VLCAD deficiency in a neonate or infant, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Recommended Evaluations Following Initial Diagnosis of VLCAD Deficiency in an Older Child or Adult
MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases is strongly recommended.
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for crises).
## Treatment of Manifestations
Frequently updated, succinct emergency care plans should detail the typical clinical issues (either those already experienced by the affected individual or those anticipated based on the diagnosis) and the importance of early management (e.g., use of IV glucose as an energy source, monitoring for cardiac rhythm disturbance, and monitoring of rhabdomyolysis) and avoidance of triggers (fasting, long-chain fats, and irritation of the myocardium) [
Cardiac dysfunction may be reversible with early, intensive supportive care (occasionally including extracorporeal membrane oxygenation) and diet modification.
The use of triheptanoin is based on its action as an anaplerotic molecule that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders.
Benefits include decrease in total days of hospitalization per year and reduction in episodes of rhabdomyolysis [
Triheptanoin was less effective in reducing rhabdomyolysis post treatment compared to its effect on other symptoms of VLCAD deficiency, suggesting a role for other pathophysiologic mechanisms and demonstrating the need for additional therapies (see
Adverse events in all of the clinical trials were similar for C7 and C8 treatment and predominantly consisted of gastrointestinal symptoms (abdominal pain, diarrhea) [
Routine Daily Treatment in Individuals with VLCAD Deficiency
For MCT oil: to provide an addl 15%-18% of calories (See
For triheptanoin: to provide 30% of daily caloric intake
LA (3%-4% of total energy)
ARA (0.5%-1.2% of total energy)
ALA (0.5% of total energy)
DHA (infants/toddlers: 60 mg/day; older persons: 100 mg/day)
MCT oil at 0.5 g/kg lean body weight 20 min prior to exercise
Exercise guided by affected person's tolerance level
Initial oral dosage of 10-25 mg L-carnitine/kg/day divided into 3-4 doses is typical.
Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
Speech therapy
Physical therapy
Rehab therapy
ALA = alpha-linolenic acid; ARA = arachidonic acid; DHA = docosahexaenoic acid; DRI = dietary reference intake; ECMO = extracorporeal membrane oxygenation; EER = estimated energy requirement; LA = linoleic acid; MCT = medium-chain triglycerides
Breast-feeding (or using expressed breast milk) without MCT oil supplements may be considered in asymptomatic neonates predicted to have mild VLCAD deficiency who are growing well, as long as fasting precautions are followed.
In asymptomatic infants with moderate VLCAD deficiency, breast-feeding (or using expressed breast milk) can be used with consideration of supplementation with a low long-chain fat / high MCT medical food [
Triheptanoin, a synthetic seven odd medium-chain fatty acid triglyceride, was approved by the FDA in June 2020 [
The FDA recommends discontinuing MCT products prior to initiation of triheptanoin therapy. In the retrospective study by
Baseline
Adapted from
EER = estimated energy requirement; PAL = physical activity level
When an affected individual is clinically well.
The estimated energy requirement calculated based on age or pregnancy trimester was published by the
Emergency Outpatient Treatment in Individuals with VLCAD Deficiency
Frequent high-carbohydrate feedings
Fasting duration time should be ↓ compared to when person is well.
Trial of outpatient treatment at home for up to 12 hrs
Reassessment frequently for clinical changes
Fever <38.5 °C (101 °F); enteral feeding is tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability)
Focusing on foods that will provide glucose polymers, or simple or complex carbohydrates [
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to a hospital.
Acute Inpatient Treatment in Individuals with VLCAD Deficiency
Avoid use of L-carnitine during acute illness.
Avoid use of IV lipids.
A source of essential fatty acids should be provided after 7 days.
Adapted from
Inpatient emergency treatment should (1) take place at the closest medical facility, (2) be started without delay, and (3) be supervised by physicians and specialist dieticians at the responsible metabolic center, who should be contacted without delay.
Total fluid volumes may need to be adjusted if the affected individual has cardiomyopathy; however, caloric provision should not be compromised. If necessary, decreasing IV fluid rates and increasing dextrose concentration (with supplemental insulin, if necessary, to avoid acute hyperglycemia) is required.
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with VLCAD 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 use of triheptanoin is based on its action as an anaplerotic molecule that can correct the secondary depletion of TCA cycle intermediates occurring in these disorders.
• Benefits include decrease in total days of hospitalization per year and reduction in episodes of rhabdomyolysis [
• Triheptanoin was less effective in reducing rhabdomyolysis post treatment compared to its effect on other symptoms of VLCAD deficiency, suggesting a role for other pathophysiologic mechanisms and demonstrating the need for additional therapies (see
• Adverse events in all of the clinical trials were similar for C7 and C8 treatment and predominantly consisted of gastrointestinal symptoms (abdominal pain, diarrhea) [
• For MCT oil: to provide an addl 15%-18% of calories (See
• For triheptanoin: to provide 30% of daily caloric intake
• LA (3%-4% of total energy)
• ARA (0.5%-1.2% of total energy)
• ALA (0.5% of total energy)
• DHA (infants/toddlers: 60 mg/day; older persons: 100 mg/day)
• MCT oil at 0.5 g/kg lean body weight 20 min prior to exercise
• Exercise guided by affected person's tolerance level
• Initial oral dosage of 10-25 mg L-carnitine/kg/day divided into 3-4 doses is typical.
• Dose is adjusted on an individual basis to maintain plasma free L-carnitine concentration w/in normal age-appropriate reference range.
• Speech therapy
• Physical therapy
• Rehab therapy
• Frequent high-carbohydrate feedings
• Fasting duration time should be ↓ compared to when person is well.
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment frequently for clinical changes
• Avoid use of L-carnitine during acute illness.
• Avoid use of IV lipids.
• A source of essential fatty acids should be provided after 7 days.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with VLCAD 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.
## Prevention of Primary Manifestations
See Management,
## Prevention of Secondary Complications
One of the most important components of management (as it relates to prevention of secondary complications) is education of parents and caregivers such that diligent observation results in management that can be administered expediently in the setting of intercurrent illness or other catabolic stressors.
Prevention of Secondary Manifestations in Individuals with VLCAD Deficiency
Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute decompensation / rhabdomyolysis
Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home
Medical alert bracelets/pendants, or car seat stickers
Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for VLCAD deficiency & containing contact info for primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
Some anesthetics may be contraindicated (see
Essential information including written treatment protocols should be provided
Parents or local hospitals should immediately inform the designated metabolic center if (1) temperature rises above 38.5 °C, (2) vomiting/diarrhea or other symptoms of intercurrent illness develop, or (3) new neurologic symptoms occur.
For affected individuals deemed to be high risk for perioperative complications, perioperative/perianesthetic management precautions may include an evaluation at a specialty anesthetic clinic.
• Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute decompensation / rhabdomyolysis
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home
• Medical alert bracelets/pendants, or car seat stickers
• Written protocols for maintenance & emergency treatment should be provided to parents & primary care providers/pediatricians, & to teachers & school staff.
• Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for VLCAD deficiency & containing contact info for primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Some anesthetics may be contraindicated (see
## Surveillance
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the surveillance evaluations summarized in
Recommended Surveillance for Individuals with VLCAD Deficiency
Measurement of growth (w/special attention to obesity)
Assessment of feeding skills in infants/toddlers
Every 3 mos for 1st yr of life
Every 6-12 mos for those age >1 yr
Every 3 mos for 1st yr of life
Every 3-6 mos for those age 1-7 yrs
Every 6-12 mos for those age >7 yrs
Adapted from
BNP = B-type natriuretic protein; CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; RBC = red blood cell
Obesity can become a significant problem, and is not easy to remedy in individuals with exercise intolerance and requirement for active management of fasting.
To include electrolytes, kidney function, liver function, and glucose
Particularly in individuals with previous cardiac dysfunction or those with significant exercise intolerance
Decreased bone mineral density is not a primary feature of VLCAD deficiency but can occur in those who have nutritional deficiencies, such as low total 25-hydroxyvitamine D concentrations.
• Measurement of growth (w/special attention to obesity)
• Assessment of feeding skills in infants/toddlers
• Every 3 mos for 1st yr of life
• Every 6-12 mos for those age >1 yr
• Every 3 mos for 1st yr of life
• Every 3-6 mos for those age 1-7 yrs
• Every 6-12 mos for those age >7 yrs
## Agents/Circumstances to Avoid
Avoid the following:
Fasting, including periods of preparation and recovery from planned surgery or sedation [
Myocardial irritation (e.g., cardiac catheterization)
Dehydration (risk for acute tubular necrosis)
High-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch [
Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate [
• Fasting, including periods of preparation and recovery from planned surgery or sedation [
• Myocardial irritation (e.g., cardiac catheterization)
• Dehydration (risk for acute tubular necrosis)
• High-fat diet (long-chain fats) including ketogenic or carbohydrate-restricted diets for the purpose of weight loss. Careful weight reduction has been accomplished by restricting long-chain fats and calories, supplementing with calories provided through medium-chain triglycerides, and limiting overnight catabolism with uncooked cornstarch [
• Volatile anesthetics and anesthetics that contain high doses of long-chain fatty acids such as propofol and etomidate [
## Evaluation of Relatives at Risk
Testing of all at-risk sibs of any age is warranted to identify as early as possible those who would benefit from institution of treatment and preventive measures (see Management,
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, plasma or dried blood spot acylcarnitine analysis may not be sufficiently sensitive, and direct VLCAD assay of lymphocytes or fatty acid oxidation probe studies of cultured fibroblasts may be required.
For at-risk newborn sibs when prenatal testing was not performed: in parallel with newborn screening either test for the familial
See
• 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, plasma or dried blood spot acylcarnitine analysis may not be sufficiently sensitive, and direct VLCAD assay of lymphocytes or fatty acid oxidation probe studies of cultured fibroblasts may be required.
## Pregnancy Management
During pregnancy, placental and fetal beta-oxidation may temporize or even improve maternal fatty acid beta-oxidation [
Energy needs and fat intake recommendations for women who are pregnant or lactating are listed in
Recommended Surveillance for Pregnant and Lactating Women with VLCAD Deficiency
Weekly to monthly in pregnant women
At every clinic visit in lactating women
Adapted from
CBC = complete blood count; RBC = red blood cell
Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended. Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity.
To include electrolytes, kidney function, liver function, and glucose
See
• Weekly to monthly in pregnant women
• At every clinic visit in lactating women
## Therapies Under Investigation
An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated [
An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment [
Search
• An open-label clinical trial showed continuously improving physical functioning as assessed through quality of life questionnaire scores in all affected individuals who participated [
• An in vitro study found that mitochondrial metabolic capacity and glutathione were affected by benzafibrate treatment [
## Genetic Counseling
Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency 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
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.
The genetic status of full sibs should be determined since many individuals with VLCAD deficiency are not symptomatic during early childhood. 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.
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
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency 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
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.
• 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.
## Carrier Detection
## Related Genetic Counseling Issues
The genetic status of full sibs should be determined since many individuals with VLCAD deficiency are not symptomatic during early childhood. 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
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
Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Very Long-Chain Acyl-Coenzyme A Dehydrogenase Deficiency (
The fatty acid oxidation (FAO) spiral is a series of four reactions occurring in the mitochondrial matrix. Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation (β-oxidation) of long-chain fatty acids with a chain length of 14 to 20 carbons. There are a total of four highly homologous, straight-chain acyl-coenzyme A (CoA) dehydrogenases with differing, but overlapping, substrate specificities:
Short (SCAD; uses C4-C6 fatty acyl-CoAs)
Medium (MCAD; C6-C10 fatty acyl-CoAs)
Long (LCAD; C10-C14 fatty acyl-CoAs)
Very long (VLCAD; C14-C20 fatty acyl-CoAs)
SCAD, MCAD, and LCAD are homotetramers localized to the mitochondrial matrix; VLCAD is a homodimer associated with the inner mitochondrial membrane. These four homologs share about 40% amino acid identity or similarity within the catalytic domain; all use flavin adenine dinucleotide as the electron-accepting cofactor. Electrons are fed into the electron transport chain via ETF and ETF dehydrogenase.
With every turn of the β-oxidation spiral, the chain length is shortened by two carbon atoms. Reactions distal to the long-chain acyl-CoA dehydrogenase (LCAD) include those catalyzed by the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) / trifunctional protein, including a hydratase step, dehydrogenase step, and thiolase step.
As one of the first enzymes in the FAO spiral, the enzyme VLCAD controls a critical point in the supply of electrons to the respiratory chain, and also provides a pathway permissive to the production of ketones. It would be expected that significant reduction at this step of fatty acid oxidation would impair the ability to transition successfully from fetal to neonatal life, maintain cardiac output, adapt to long fasting, and generate energy for exercise.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Short (SCAD; uses C4-C6 fatty acyl-CoAs)
• Medium (MCAD; C6-C10 fatty acyl-CoAs)
• Long (LCAD; C10-C14 fatty acyl-CoAs)
• Very long (VLCAD; C14-C20 fatty acyl-CoAs)
## Molecular Pathogenesis
The fatty acid oxidation (FAO) spiral is a series of four reactions occurring in the mitochondrial matrix. Very long-chain acyl-coenzyme A dehydrogenase (VLCAD) catalyzes the initial step of mitochondrial beta-oxidation (β-oxidation) of long-chain fatty acids with a chain length of 14 to 20 carbons. There are a total of four highly homologous, straight-chain acyl-coenzyme A (CoA) dehydrogenases with differing, but overlapping, substrate specificities:
Short (SCAD; uses C4-C6 fatty acyl-CoAs)
Medium (MCAD; C6-C10 fatty acyl-CoAs)
Long (LCAD; C10-C14 fatty acyl-CoAs)
Very long (VLCAD; C14-C20 fatty acyl-CoAs)
SCAD, MCAD, and LCAD are homotetramers localized to the mitochondrial matrix; VLCAD is a homodimer associated with the inner mitochondrial membrane. These four homologs share about 40% amino acid identity or similarity within the catalytic domain; all use flavin adenine dinucleotide as the electron-accepting cofactor. Electrons are fed into the electron transport chain via ETF and ETF dehydrogenase.
With every turn of the β-oxidation spiral, the chain length is shortened by two carbon atoms. Reactions distal to the long-chain acyl-CoA dehydrogenase (LCAD) include those catalyzed by the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) / trifunctional protein, including a hydratase step, dehydrogenase step, and thiolase step.
As one of the first enzymes in the FAO spiral, the enzyme VLCAD controls a critical point in the supply of electrons to the respiratory chain, and also provides a pathway permissive to the production of ketones. It would be expected that significant reduction at this step of fatty acid oxidation would impair the ability to transition successfully from fetal to neonatal life, maintain cardiac output, adapt to long fasting, and generate energy for exercise.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• Short (SCAD; uses C4-C6 fatty acyl-CoAs)
• Medium (MCAD; C6-C10 fatty acyl-CoAs)
• Long (LCAD; C10-C14 fatty acyl-CoAs)
• Very long (VLCAD; C14-C20 fatty acyl-CoAs)
## Chapter Notes
Jessica A Connor, MS; Counsyl, Inc (2014-2017)Nancy D Leslie, MD (2009-present)Sofia Saenz-Ayala, MD (2022-present)Kerry Shooner, MS, CGC; Cincinnati Children's Hospital Medical Center (2009-2014)Arnold W Strauss, MD; Cincinnati Children's Hospital Medical Center (2009-2022)Brad T Tinkle, MD, PhD; Cincinnati Children's Hospital Medical Center (2009-2014)C Alexander Valencia, PhD; Cincinnati Children's Hospital Medical Center (2014-2022)Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2009-2022)
7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
13 July 2023 (nl) Revision: C14:1 level unit of measurement corrected to µmol/L in
16 June 2022 (ma) Comprehensive update posted live
4 January 2018 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
22 September 2011 (me) Comprehensive update posted live
28 May 2009 (me) Review posted live
29 December 2008 (ks) Original submission
• 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 13 July 2023 (nl) Revision: C14:1 level unit of measurement corrected to µmol/L in
• 16 June 2022 (ma) Comprehensive update posted live
• 4 January 2018 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 28 May 2009 (me) Review posted live
• 29 December 2008 (ks) Original submission
## Author History
Jessica A Connor, MS; Counsyl, Inc (2014-2017)Nancy D Leslie, MD (2009-present)Sofia Saenz-Ayala, MD (2022-present)Kerry Shooner, MS, CGC; Cincinnati Children's Hospital Medical Center (2009-2014)Arnold W Strauss, MD; Cincinnati Children's Hospital Medical Center (2009-2022)Brad T Tinkle, MD, PhD; Cincinnati Children's Hospital Medical Center (2009-2014)C Alexander Valencia, PhD; Cincinnati Children's Hospital Medical Center (2014-2022)Kejian Zhang, MD, MBA; Cincinnati Children's Hospital Medical Center (2009-2022)
## Revision History
7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
13 July 2023 (nl) Revision: C14:1 level unit of measurement corrected to µmol/L in
16 June 2022 (ma) Comprehensive update posted live
4 January 2018 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
22 September 2011 (me) Comprehensive update posted live
28 May 2009 (me) Review posted live
29 December 2008 (ks) Original submission
• 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 13 July 2023 (nl) Revision: C14:1 level unit of measurement corrected to µmol/L in
• 16 June 2022 (ma) Comprehensive update posted live
• 4 January 2018 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Comprehensive update posted live
• 28 May 2009 (me) Review posted live
• 29 December 2008 (ks) Original submission
## References
## Literature Cited
|
[] |
28/5/2009
|
16/6/2022
|
7/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
vldlr-ch
|
vldlr-ch
|
[
"Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)",
"Cerebellar Ataxia, Mental Retardation, and Dysequilibrium Syndrome 1 (CAMRQ1)",
"Very low-density lipoprotein receptor",
"VLDLR",
"VLDLR Cerebellar Hypoplasia"
] |
Kym M Boycott, Stella K MacDonald, Jillian S Parboosingh
|
Summary The diagnosis of
|
## Diagnosis
Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation
Moderate-to-profound intellectual disability
Dysarthria
MRI findings (see
Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
Small brain stem, particularly the pons
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. Because the phenotype of VLDLR cerebellar hypoplasia is often recognizable, individuals with the distinctive MRI findings described in
When the phenotypic and radiographic findings suggest the diagnosis of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
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.
• Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation
• Moderate-to-profound intellectual disability
• Dysarthria
• MRI findings (see
• Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
• Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
• Small brain stem, particularly the pons
• Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
• Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
• Small brain stem, particularly the pons
• Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
• Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
• Small brain stem, particularly the pons
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See
• For an introduction to multigene panels click
## Suggestive Findings
Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation
Moderate-to-profound intellectual disability
Dysarthria
MRI findings (see
Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
Small brain stem, particularly the pons
• Non-progressive congenital ataxia that is predominantly truncal and results in delayed ambulation
• Moderate-to-profound intellectual disability
• Dysarthria
• MRI findings (see
• Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
• Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
• Small brain stem, particularly the pons
• Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
• Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
• Small brain stem, particularly the pons
• Hypoplasia of the inferior portion of the cerebellar vermis and hemispheres
• Simplified gyration of the cerebral hemispheres with minimally thickened but uniform cortex and lack of clear anteroposterior gradient
• Small brain stem, particularly the pons
## 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. Because the phenotype of VLDLR cerebellar hypoplasia is often recognizable, individuals with the distinctive MRI findings described in
When the phenotypic and radiographic findings suggest the diagnosis of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See
For an introduction to multigene panels click
When the diagnosis of
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
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.
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See
• For an introduction to multigene panels click
## Option 1
When the phenotypic and radiographic findings suggest the diagnosis of
Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See
For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first in individuals of Hutterite ancestry. See
• For an introduction to multigene panels click
## Option 2
When the diagnosis of
If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
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.
## Clinical Characteristics
To date, more than 50 individuals have been identified with a pathogenic variant in
Features of
Nystagmus is reported in some individuals and is described as gaze evoked.
Epileptic seizures were reported in 40% of the affected individuals from the Hutterite population [
Deep tendon reflexes in the lower extremities tend to be brisk.
Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.
Short stature (height just below the 2nd centile) is a feature in a few affected individuals.
No genotype-phenotype correlations have been identified.
The actual frequency of
More than 25 individuals with
The estimated carrier frequency in the Hutterite population is one in 15 [
• Nystagmus is reported in some individuals and is described as gaze evoked.
• Epileptic seizures were reported in 40% of the affected individuals from the Hutterite population [
• Deep tendon reflexes in the lower extremities tend to be brisk.
• Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.
• Short stature (height just below the 2nd centile) is a feature in a few affected individuals.
## Clinical Description
To date, more than 50 individuals have been identified with a pathogenic variant in
Features of
Nystagmus is reported in some individuals and is described as gaze evoked.
Epileptic seizures were reported in 40% of the affected individuals from the Hutterite population [
Deep tendon reflexes in the lower extremities tend to be brisk.
Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.
Short stature (height just below the 2nd centile) is a feature in a few affected individuals.
• Nystagmus is reported in some individuals and is described as gaze evoked.
• Epileptic seizures were reported in 40% of the affected individuals from the Hutterite population [
• Deep tendon reflexes in the lower extremities tend to be brisk.
• Microcephaly (2-4 SD below the mean) has been reported in a few affected individuals.
• Short stature (height just below the 2nd centile) is a feature in a few affected individuals.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
## Prevalence
The actual frequency of
More than 25 individuals with
The estimated carrier frequency in the Hutterite population is one in 15 [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of
Note: Diverse phenotypes associated with childhood- and adult-onset ataxia are to be excluded (see
Genes and Disorders of Interest in the Differential Diagnosis of
DD & severe cognitive impairment (in some individuals)
Episodic hyperpnea or apnea &/or atypical eye movements
Truncal ataxia
DD/ID
Hypotonia & ataxia
Strabismus
Cerebellar ataxia w/wide-based gait
Dysarthria
Intention tremor
DD/ID
Choreoathetosis
Oculomotor apraxia
Progressive cerebellar ataxia beginning at ages 1-4 yrs
Congenital cerebellar ataxia
ID
Congenital cerebellar ataxia
ID
Progressive motor degeneration (similar to
Dyskinesia in PCH2
Congenital cerebellar ataxia
Hypotonia
ID
Epilepsy
Strabismus
Distal muscle wasting
Distal sensorimotor neuropathy (predominant in legs)
Dysarthria
Early-onset ataxia
Extensor plantar reflexes
Horizontal gaze-evoked nystagmus
Spasticity
Cerebellar ataxia
Mild-to-severe cognitive impairment
Hypotonia & muscle weakness
Normal development until age 1 yr, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, athetosis, ophthalmoplegia, & sensorineural deafness in childhood
Epilepsy can → serious & often fatal encephalopathy.
Congenital cerebellar ataxia
ID
CAMRQ = cerebellar ataxia, mental retardation, and dysequilibrium syndrome; CDG = congenital disorder of glycosylation; CH = cerebellar hypoplasia; DD = developmental delay; ID = intellectual disability; LCH = lissencephaly with cerebellar hypoplasia; PCH = pontocerebellar hypoplasia
To date, pathogenic variants in 34 genes are known to cause Joubert syndrome.
Variable features include: retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities.
Affected individuals are from a Grand Cayman Island isolate.
Also characterized by immunodeficiency, frequent infections, telangiectasias of the conjunctivae, and increased risk for malignancy (particularly leukemia and lymphoma)
About 50% of individuals with pontocerebellar hypoplasia type 1 (PCH1) have pathogenic variants in
The presentation of lissencephalies with cerebellar hypoplasia (LCH) ranges from the classic pattern of pachygyria/agyria to less severe phenotypes. The cerebellar manifestations range from relatively preserved hemispheres to marked hypoplasia with foliation defects. The malformations seen in VLDLR-CH fall within the LCH spectrum. Forms of LCH other than
Also characterized by early-onset cataracts
Infantile-onset spinocerebellar ataxia is well recognized in Finland.
By adolescence affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident.
• DD & severe cognitive impairment (in some individuals)
• Episodic hyperpnea or apnea &/or atypical eye movements
• Truncal ataxia
• DD/ID
• Hypotonia & ataxia
• Strabismus
• Cerebellar ataxia w/wide-based gait
• Dysarthria
• Intention tremor
• DD/ID
• Choreoathetosis
• Oculomotor apraxia
• Progressive cerebellar ataxia beginning at ages 1-4 yrs
• Congenital cerebellar ataxia
• ID
• Congenital cerebellar ataxia
• ID
• Progressive motor degeneration (similar to
• Dyskinesia in PCH2
• Congenital cerebellar ataxia
• Hypotonia
• ID
• Epilepsy
• Strabismus
• Distal muscle wasting
• Distal sensorimotor neuropathy (predominant in legs)
• Dysarthria
• Early-onset ataxia
• Extensor plantar reflexes
• Horizontal gaze-evoked nystagmus
• Spasticity
• Cerebellar ataxia
• Mild-to-severe cognitive impairment
• Hypotonia & muscle weakness
• Normal development until age 1 yr, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, athetosis, ophthalmoplegia, & sensorineural deafness in childhood
• Epilepsy can → serious & often fatal encephalopathy.
• Congenital cerebellar ataxia
• ID
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Brain MRI
Consider EEG if seizures are a concern.
Mobility, activities of daily living, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
School support
Community support
OT = occupational therapy; PT = physical therapy
Treatment of seizures and strabismus is done in the standard manner.
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.
Physical therapy is recommended to maximize mobility and to promote ambulation.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Recommended Surveillance for Individuals with
See
Search
• Brain MRI
• Consider EEG if seizures are a concern.
• Mobility, activities of daily living, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
• School support
• Community support
• 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.
• Physical therapy is recommended to maximize mobility and to promote ambulation.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## 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
Brain MRI
Consider EEG if seizures are a concern.
Mobility, activities of daily living, & need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
School support
Community support
OT = occupational therapy; PT = physical therapy
• Brain MRI
• Consider EEG if seizures are a concern.
• Mobility, activities of daily living, & need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
• School support
• Community support
## Treatment of Manifestations
Treatment of seizures and strabismus is done in the standard manner.
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.
Physical therapy is recommended to maximize mobility and to promote ambulation.
Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• 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.
• Physical therapy is recommended to maximize mobility and to promote ambulation.
• 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.
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.
## Motor Dysfunction
Physical therapy is recommended to maximize mobility and to promote ambulation.
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 promote ambulation.
• Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## 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
PO Box 5801
Bethesda MD 20824
•
• PO Box 5801
• Bethesda MD 20824
•
•
•
•
•
•
•
## Molecular Genetics
VLDLR Cerebellar Hypoplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for VLDLR Cerebellar Hypoplasia (
VLDLR belongs to a subset of cell surface receptors called the LDL receptor protein family. Family members share a number of domains arranged in a similar pattern: ligand-binding repeat domain, EGF repeat, YWTD domain, O-linked sugar domain, transmembrane domain, and a cytoplasmic domain containing a NPXY motif. VLDLR was initially identified to function in the receptor-mediated endocytosis of apoE-containing lipoproteins.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
VLDLR belongs to a subset of cell surface receptors called the LDL receptor protein family. Family members share a number of domains arranged in a similar pattern: ligand-binding repeat domain, EGF repeat, YWTD domain, O-linked sugar domain, transmembrane domain, and a cytoplasmic domain containing a NPXY motif. VLDLR was initially identified to function in the receptor-mediated endocytosis of apoE-containing lipoproteins.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
27 February 2020 (ha) Comprehensive update posted live
8 August 2013 (me) Comprehensive update posted live
26 August 2008 (cg) Review posted live
7 July 2008 (kmb) Original submission
• 27 February 2020 (ha) Comprehensive update posted live
• 8 August 2013 (me) Comprehensive update posted live
• 26 August 2008 (cg) Review posted live
• 7 July 2008 (kmb) Original submission
## Revision History
27 February 2020 (ha) Comprehensive update posted live
8 August 2013 (me) Comprehensive update posted live
26 August 2008 (cg) Review posted live
7 July 2008 (kmb) Original submission
• 27 February 2020 (ha) Comprehensive update posted live
• 8 August 2013 (me) Comprehensive update posted live
• 26 August 2008 (cg) Review posted live
• 7 July 2008 (kmb) Original submission
## References
## Literature Cited
MRI of the brain demonstrating typical neuroimaging findings of VLDLR-CH
A. Sagittal T
B. Coronal T
C. Axial T
|
[] |
26/8/2008
|
27/2/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
vmcm
|
vmcm
|
[
"TEK-Related Unifocal (Isolated) Venous Malformation",
"TEK-Related Multiple Cutaneous and Mucosal Venous Malformations (VMCM)",
"TEK-Related Multifocal Sporadic Venous Malformations (MSVM)",
"Blue Rubber Bleb Nevus (BRBN) Syndrome",
"Angiopoietin-1 receptor",
"TEK",
"TEK-Related Venous Malformations"
] |
Emmanuel Seront, Laurence M Boon, Miikka Vikkula
|
Summary The diagnosis of For With regards to other
|
VM = venous malformations
Adapted from Figure 4 in
See
## Diagnosis
Cutaneous and/or mucosal bluish-purple VM can be either single or multiple, and can vary in size from a few millimeters in diameter to larger lesions affecting an entire extremity (see
Lesions are soft and usually compressible.
Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.
In
In
Chronic consumptive coagulopathy (CCC) or localized intravascular coagulopathy (LIC) is frequent in
CCC/LIC is characterized by elevated D-dimer levels in the absence of other conditions associated with elevated D-dimers; levels of D-dimers are highly variable and can be more than three to five times the normal level (normal: <500 ng/mL).
Fibrinogen levels can be below the normal range (normal: 150-450 ng/mL) in cases of severe CCC/LIC. CCC/LIC is considered severe when high D-dimer levels (≥1,800 ng/mL) are associated with low fibrinogen levels (<150 mg/dL).
Although not always present, CCC/LIC is pathognomonic of VM in general, and thus can help establish the diagnosis.
A family history that is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) is suggestive of
Other
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 both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
As many
Given the possibility of mosaicism, the following are considerations for molecular testing and sample selection:
Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from the vascular lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic testing.
The level of mosaicism for an activating
Testing peripheral blood or DNA isolated from blood alone is only recommended when a clear family history is present suggesting the diagnosis of
Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: On analysis of DNA derived from affected tissues, the method used for testing must be sensitive enough to detect low-level mosaicism of a pathogenic variant (see
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 disorders characterized by VM, or if the individual has atypical 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 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 is not indicated as most identified pathogenic
• Lesions are soft and usually compressible.
• Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.
• Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from the vascular lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic testing.
• The level of mosaicism for an activating
• Testing peripheral blood or DNA isolated from blood alone is only recommended when a clear family history is present suggesting the diagnosis of
• For an introduction to multigene panels click
## Suggestive Findings
Cutaneous and/or mucosal bluish-purple VM can be either single or multiple, and can vary in size from a few millimeters in diameter to larger lesions affecting an entire extremity (see
Lesions are soft and usually compressible.
Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.
In
In
Chronic consumptive coagulopathy (CCC) or localized intravascular coagulopathy (LIC) is frequent in
CCC/LIC is characterized by elevated D-dimer levels in the absence of other conditions associated with elevated D-dimers; levels of D-dimers are highly variable and can be more than three to five times the normal level (normal: <500 ng/mL).
Fibrinogen levels can be below the normal range (normal: 150-450 ng/mL) in cases of severe CCC/LIC. CCC/LIC is considered severe when high D-dimer levels (≥1,800 ng/mL) are associated with low fibrinogen levels (<150 mg/dL).
Although not always present, CCC/LIC is pathognomonic of VM in general, and thus can help establish the diagnosis.
A family history that is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) is suggestive of
Other
• Lesions are soft and usually compressible.
• Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.
## Clinical Features
Cutaneous and/or mucosal bluish-purple VM can be either single or multiple, and can vary in size from a few millimeters in diameter to larger lesions affecting an entire extremity (see
Lesions are soft and usually compressible.
Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.
In
In
• Lesions are soft and usually compressible.
• Ultrasound examination reveals saccular compressible venous-like cavities and Doppler confirms slow blood flow.
## Laboratory Findings
Chronic consumptive coagulopathy (CCC) or localized intravascular coagulopathy (LIC) is frequent in
CCC/LIC is characterized by elevated D-dimer levels in the absence of other conditions associated with elevated D-dimers; levels of D-dimers are highly variable and can be more than three to five times the normal level (normal: <500 ng/mL).
Fibrinogen levels can be below the normal range (normal: 150-450 ng/mL) in cases of severe CCC/LIC. CCC/LIC is considered severe when high D-dimer levels (≥1,800 ng/mL) are associated with low fibrinogen levels (<150 mg/dL).
Although not always present, CCC/LIC is pathognomonic of VM in general, and thus can help establish the diagnosis.
## Family History
A family history that is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations) is suggestive of
Other
## 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 both can be used for clinical decision making [
Molecular genetic testing approaches can include a combination of
As many
Given the possibility of mosaicism, the following are considerations for molecular testing and sample selection:
Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from the vascular lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic testing.
The level of mosaicism for an activating
Testing peripheral blood or DNA isolated from blood alone is only recommended when a clear family history is present suggesting the diagnosis of
Gene-targeted testing requires that the clinician determines which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in
Note: On analysis of DNA derived from affected tissues, the method used for testing must be sensitive enough to detect low-level mosaicism of a pathogenic variant (see
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 disorders characterized by VM, or if the individual has atypical 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 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 is not indicated as most identified pathogenic
• Sequence analysis of DNA derived from clinically affected tissue samples ‒ preferably from the vascular lesion, requiring a surgical or skin biopsy ‒ should be prioritized for genetic testing.
• The level of mosaicism for an activating
• Testing peripheral blood or DNA isolated from blood alone is only recommended when a clear family history is present suggesting the diagnosis 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 disorders characterized by VM, or if the individual has atypical 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 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 is not indicated as most identified pathogenic
## Clinical Characteristics
Slow-flow blood vascular lesion
Light-to-dark skin discoloration overlying soft, often compressible mass that develops primarily in cutaneous, subcutaneous, or mucosal tissues
Nipple-like bluish nodules w/rubbery consistency
Tend to aggregate & become hyperkeratotic w/time
40% on extremities
40% on cervicofacial area
20% on trunk
All over body
Skin & oral mucosa
Rarely on palms & soles
All over body
Skin & oral mucosa
Rarely on palms & soles
All over body
Skin & mucosa
Predilection for palms & soles
Typically, large dominant lesion present at birth
Multiple VM located in small intestines (pathognomonic)
Can cause bleeding & chronic anemia
Complications incl intussusception, volvulus, & intestinal infarction
BRBN = blue rubber bleb nevus; GI = gastrointestinal; MSVM = multifocal sporadic venous malformations; VM = venous malformation; VMCM = multiple cutaneous and mucosal venous malformations
For other causes of venous malformations, see
Based on the focality (unifocal or multifocal) and the location of the lesions, there are several types of
Depending on the organ or area involved, functional limitations range from muscle weakness and limb length discrepancy to difficulties feeding, speaking, and breathing, as well as physical deformities. Other symptoms include bleeding and, in combined venolymphatic malformations, recurrent infections and oozing. In some cases, VM can be life-threatening due to expansion or obstruction of vital structures such as the airways [
Gastrointestinal lesions (grape-like mucosal venous nodules), documented by endoscopy, colonoscopy, or magnetic resonance imaging, are pathognomonic of BRBN syndrome. These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction [
All
The palpation of phleboliths that develop due to stagnation of blood flow is also pathognomonic of VM. Normal D-dimer levels do not rule out a VM, as small VM may have limited intravascular clotting.
D-dimer levels are also helpful in differentiating between different types of VM, as more than 95% of individuals with multifocal glomuvenous malformations have normal D-dimer levels (see
The risk of disseminated intravascular coagulopathy (DIC) caused by elevated D-dimer concentration is low unless the affected individual undergoes an intervention, such as a surgical procedure or sclerotherapy (see
Enlarged venous-like channels with walls of smooth muscle of variable thickness are observed in
The phenotypic spectrum of individuals with somatic pathogenic variants in
Some
See the
Approximately 90% of individuals who have a germline pathogenic gain-of-function variant in
The penetrance of other
The title of this
Terms used previously to describe VM include "cavernous angioma" and "cavernous hemangioma." The term "mucocutaneous venous malformation" was coined by
VM are often considered the most common subtype of vascular malformations seen in specialty clinics, with an incidence between 1:2,000 and 1:5,000 live births. More than 90% of VM are sporadic and isolated [
Although unknown, the prevalence of
• Slow-flow blood vascular lesion
• Light-to-dark skin discoloration overlying soft, often compressible mass that develops primarily in cutaneous, subcutaneous, or mucosal tissues
• Nipple-like bluish nodules w/rubbery consistency
• Tend to aggregate & become hyperkeratotic w/time
• 40% on extremities
• 40% on cervicofacial area
• 20% on trunk
• All over body
• Skin & oral mucosa
• Rarely on palms & soles
• All over body
• Skin & oral mucosa
• Rarely on palms & soles
• All over body
• Skin & mucosa
• Predilection for palms & soles
• Typically, large dominant lesion present at birth
• Multiple VM located in small intestines (pathognomonic)
• Can cause bleeding & chronic anemia
• Complications incl intussusception, volvulus, & intestinal infarction
## Clinical Description
Slow-flow blood vascular lesion
Light-to-dark skin discoloration overlying soft, often compressible mass that develops primarily in cutaneous, subcutaneous, or mucosal tissues
Nipple-like bluish nodules w/rubbery consistency
Tend to aggregate & become hyperkeratotic w/time
40% on extremities
40% on cervicofacial area
20% on trunk
All over body
Skin & oral mucosa
Rarely on palms & soles
All over body
Skin & oral mucosa
Rarely on palms & soles
All over body
Skin & mucosa
Predilection for palms & soles
Typically, large dominant lesion present at birth
Multiple VM located in small intestines (pathognomonic)
Can cause bleeding & chronic anemia
Complications incl intussusception, volvulus, & intestinal infarction
BRBN = blue rubber bleb nevus; GI = gastrointestinal; MSVM = multifocal sporadic venous malformations; VM = venous malformation; VMCM = multiple cutaneous and mucosal venous malformations
For other causes of venous malformations, see
Based on the focality (unifocal or multifocal) and the location of the lesions, there are several types of
Depending on the organ or area involved, functional limitations range from muscle weakness and limb length discrepancy to difficulties feeding, speaking, and breathing, as well as physical deformities. Other symptoms include bleeding and, in combined venolymphatic malformations, recurrent infections and oozing. In some cases, VM can be life-threatening due to expansion or obstruction of vital structures such as the airways [
Gastrointestinal lesions (grape-like mucosal venous nodules), documented by endoscopy, colonoscopy, or magnetic resonance imaging, are pathognomonic of BRBN syndrome. These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction [
All
The palpation of phleboliths that develop due to stagnation of blood flow is also pathognomonic of VM. Normal D-dimer levels do not rule out a VM, as small VM may have limited intravascular clotting.
D-dimer levels are also helpful in differentiating between different types of VM, as more than 95% of individuals with multifocal glomuvenous malformations have normal D-dimer levels (see
The risk of disseminated intravascular coagulopathy (DIC) caused by elevated D-dimer concentration is low unless the affected individual undergoes an intervention, such as a surgical procedure or sclerotherapy (see
Enlarged venous-like channels with walls of smooth muscle of variable thickness are observed in
• Slow-flow blood vascular lesion
• Light-to-dark skin discoloration overlying soft, often compressible mass that develops primarily in cutaneous, subcutaneous, or mucosal tissues
• Nipple-like bluish nodules w/rubbery consistency
• Tend to aggregate & become hyperkeratotic w/time
• 40% on extremities
• 40% on cervicofacial area
• 20% on trunk
• All over body
• Skin & oral mucosa
• Rarely on palms & soles
• All over body
• Skin & oral mucosa
• Rarely on palms & soles
• All over body
• Skin & mucosa
• Predilection for palms & soles
• Typically, large dominant lesion present at birth
• Multiple VM located in small intestines (pathognomonic)
• Can cause bleeding & chronic anemia
• Complications incl intussusception, volvulus, & intestinal infarction
## Venous Malformations
Based on the focality (unifocal or multifocal) and the location of the lesions, there are several types of
Depending on the organ or area involved, functional limitations range from muscle weakness and limb length discrepancy to difficulties feeding, speaking, and breathing, as well as physical deformities. Other symptoms include bleeding and, in combined venolymphatic malformations, recurrent infections and oozing. In some cases, VM can be life-threatening due to expansion or obstruction of vital structures such as the airways [
Gastrointestinal lesions (grape-like mucosal venous nodules), documented by endoscopy, colonoscopy, or magnetic resonance imaging, are pathognomonic of BRBN syndrome. These are commonly located in the small intestine and can cause hemorrhage, intussusception, volvulus, and intestinal infarction [
## Coagulopathy
All
The palpation of phleboliths that develop due to stagnation of blood flow is also pathognomonic of VM. Normal D-dimer levels do not rule out a VM, as small VM may have limited intravascular clotting.
D-dimer levels are also helpful in differentiating between different types of VM, as more than 95% of individuals with multifocal glomuvenous malformations have normal D-dimer levels (see
The risk of disseminated intravascular coagulopathy (DIC) caused by elevated D-dimer concentration is low unless the affected individual undergoes an intervention, such as a surgical procedure or sclerotherapy (see
## Histologic Findings
Enlarged venous-like channels with walls of smooth muscle of variable thickness are observed in
## Genotype-Phenotype Correlations
The phenotypic spectrum of individuals with somatic pathogenic variants in
Some
See the
## Penetrance
Approximately 90% of individuals who have a germline pathogenic gain-of-function variant in
The penetrance of other
## Nomenclature
The title of this
Terms used previously to describe VM include "cavernous angioma" and "cavernous hemangioma." The term "mucocutaneous venous malformation" was coined by
## Prevalence
VM are often considered the most common subtype of vascular malformations seen in specialty clinics, with an incidence between 1:2,000 and 1:5,000 live births. More than 90% of VM are sporadic and isolated [
Although unknown, the prevalence of
## Genetically Related Disorders
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
Inherited
Multifocal
Small cutaneous venous-like lesions
Most lesions located on extremities
Not usually seen on mucous membranes
Cobblestone appearance
Deeper purple in color than VMCM
Painful on palpation
Less invasive than sporadic VM
GoF of
9% of persons w/CCM have cutaneous vascular malformations, incl nodular cutaneous VM
Single or multiple nodules, typically all over body
Most lesions are not present at birth, & new lesions may emerge into adulthood.
Size ranges from 1 mm to <5 cm.
CCM affects up to 0.5% of population.
Vascular lesions typically arise in central nervous system.
CCM usually manifests between age 20-30 years, but clinical manifestations can occur at any age.
VVM present at birth or early during infancy.
Most commonly affecting lower limbs
Well-circumscribed purple & hyperkeratotic linear plaques
Size ranges from 2 to 20 cm.
GoF = gain of function; VM = venous malformations; VMCM = multiple cutaneous and mucosal venous malformations
Inheritance is autosomal dominant, although the pathophysiologic mechanism is recessive at the cellular level (i.e., disease caused by presence of a germline pathogenic variant on one allele and an acquired somatic pathogenic variant on the other allele), most frequently due to an acquired uniparental isodisomy [
• Inherited
• Multifocal
• Small cutaneous venous-like lesions
• Most lesions located on extremities
• Not usually seen on mucous membranes
• Cobblestone appearance
• Deeper purple in color than VMCM
• Painful on palpation
• Less invasive than sporadic VM
• GoF of
• 9% of persons w/CCM have cutaneous vascular malformations, incl nodular cutaneous VM
• Single or multiple nodules, typically all over body
• Most lesions are not present at birth, & new lesions may emerge into adulthood.
• Size ranges from 1 mm to <5 cm.
• CCM affects up to 0.5% of population.
• Vascular lesions typically arise in central nervous system.
• CCM usually manifests between age 20-30 years, but clinical manifestations can occur at any age.
• VVM present at birth or early during infancy.
• Most commonly affecting lower limbs
• Well-circumscribed purple & hyperkeratotic linear plaques
• Size ranges from 2 to 20 cm.
## Management
No clinical practice guidelines for
To establish the extent of disease and management needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Eval by vascular anomalies specialist
MRI of affected area
Eval by vascular anomalies specialist
Consider whole-body MRI.
D-dimer level
Fibrinogen level
Community or
Social work involvement for parental support;
Home nursing referral.
CCC = chronic consumptive coagulopathy; LIC = localized intravascular coagulopathy; MRI = magnetic resonance imaging; MOI = mode of inheritance; VM = venous malformations
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is required for any symptomatic VM. Management depends largely on the size and location of the lesions. Small lesions can be surgically resected or treated with sclerotherapy with very favorable outcomes (often complete cure). However, in many instances complete resection or embolization is not possible.
If affected individuals are asymptomatic, with no lesion that may cause severe or life-threatening complications (e.g., medullary compression, pathologic bone fracture, airway compression), it is preferable to delay any therapeutic intervention and clinically monitor the individual over time.
Treatment of
Treatment of Manifestations in Individuals with
Mgmt depends largely on size & location of lesion(s).
Although sclerotherapy is the treatment of choice, sclerosing agents are not specific & can lead to ulceration if the VM is mucosal or involves the epidermis.
More effective for well delineated &/or small lesions
For large VM, surgical resection gives better long-term result if performed after sclerotherapy.
Iron replacement or transfusions in case of anemia from chronic bleeding
Other treatment options incl endoscopic sclerotherapy, band ligation, laser photocoagulation, & surgical resection.
If D-dimers are ↑ & fibrinogen levels are low, LMWH should be initiated 1-2 weeks before surgery, depending on severity of coagulation abnormality, & continued for 2 weeks after surgery to reduce pre- and post-operative bleeding.
If fibrinogen levels are normal, LMWH can be initiated the day before surgery.
If lesions are painful & D-dimers are ↑ (higher than 2x normal range), LMWH can be used to alleviate pain.
Should be administered prior to any invasive procedure (i.e., surgery &/or sclerotherapy) to ↓ risk of DIC.
D-dimer levels can be used to evaluate efficacy of sclerotherapy & LMWH treatments, as levels will ↓ w/reduction of lesion size.
Ensure appropriate social work involvement to connect families w/local resources, despite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement and/or home nursing
Consider involvement in adaptive sports or Special Olympics.
DIC = disseminated intravascular coagulopathy; GI = gastrointestinal; LMWH = low-molecular-weight heparin; VM = venous malformation(s)
Sirolimus has not been approved by the FDA or EMA for the treatment of VM, and thus despite its efficacy it remains an off-label treatment to date.
Sclerotherapy is the first-line treatment for VM. It is performed to decrease the volume of the VM before surgery or as monotherapy in individuals in whom surgery is not technically feasible.
If the lesion is small and complete resection is possible without anatomic or functional consequences, surgical excision should be performed as the treatment of choice. However, these approaches have limitations, including inaccessibility and failure to completely cure the VM.
Sirolimus has been shown to reduce pain and functional limitations due to VM [
Targeted Off-label Treatment of
Adults: 2 mg 1x/day
Children age <18 yrs: 0.8 mg/m
Persons w/VM who are refractory to sclerotherapy &/or surgery, or for persons who are ineligible for surgery &/or sclerotherapy.
Sirolimus has been shown to ↓ pain, improve quality of life & functional limitations, & ↓ bleeding.
VM = venous malformations
The decision to treat VM using sirolimus should be initiated by a vascular anomalies expert.
Sirolimus has not been approved by the FDA or EMA for the treatment of VM, and thus despite its efficacy remains an off-label treatment. A large prospective Phase III trial (VASE) studying the efficacy of sirolimus in VM is ongoing. Side effects with sirolimus therapy have been reported in many individuals. For details, see
To monitor existing manifestations of
Recommended Surveillance for Individuals with
Annually or as needed (esp around puberty or other hormonal changes, as VM can become painful)
Lesions can ↑ in size over time & become painful or symptomatic.
CBC incl Hgb & hematocrit level
Iron levels (incl serum iron, serum ferritin, & transferrin levels)
Endoscopy
Annually or more frequently in case of symptoms (fatigue, bloody stools)
Consider endoscopy based on blood results.
Every 5 yrs;
If lesions become painful;
Before any surgical &/or sclerotherapeutic procedure.
CBC = complete blood count; GI = gastrointestinal; Hgb = hemoglobin; VM = venous malformations
For individuals on MTOR inhibitor therapy such as sirolimus, a targeted off-label therapy, several surveillance guidelines are recommended (see
Recommended Surveillance: Targeted Off-label Therapy for
Based on the VASE study (see
The optimal treatment duration is at treating clinician's discretion. After 2 yrs of treatment, frequency of consultation is at treating clinician's discretion.
Hemogram (Hgb, leukocytes, platelets)
Thyroid function tests (TSH, T4) to exclude reversible causes of fatigue
Cholesterol level
Fasting blood glucose level
Renal function tests
Liver function tests
Hgb = hemoglobin; T4 = thyroxine; TSH = thyroid-stimulating hormone
The decision to treat VM using sirolimus should be initiated by a vascular anomalies expert.
Sirolimus has not been approved by the FDA or EMA for treatment of VM, and thus despite its efficacy remains an off-label therapy. A large prospective Phase III trial (VASE) studying the efficacy of sirolimus in VM is ongoing (see
Contraceptive pills with high estrogen concentration should be avoided, as VM are estrogen responsive. VM can increase in size and become symptomatic, especially at the initiation of estrogen-based contraception. In some but not all instances stabilization of a VM lesion and diminution of pain may be observed after three months of contraceptive pill use.
Lesions arising after infancy usually stay small and therefore are rarely symptomatic. If no lesions are seen at birth, a second evaluation should be done around puberty.
Once a germline
See
During pregnancy, affected women may develop new small lesions; in addition, existing lesions may increase in size and become painful.
If D-dimer levels are high, low-molecular-weight heparin may be used to alleviate pain.
D-dimer levels should be evaluated every one to three months during pregnancy depending on the symptoms and before delivery to adjust medication and avoid abnormal bleeding during delivery.
In individuals on sirolimus, avoiding pregnancy and lactation is recommended, as this drug is classified as an FDA category C drug in pregnancy and lactation.
See
In recent years, multiple trials have reported on the efficacy of MTOR inhibitors in the treatment of slow-flow vascular malformations. A pilot study on rapamycin therapy for venous malformations (VM) reported beneficial results, especially regarding pain reduction and improvement in quality of life [
A prospective multicentric Phase III trial (VASE) is currently evaluating the efficacy and safety of sirolimus in slow-flow vascular anomalies that are refractory to standard care (
Adverse events were frequent, occurring in 96% of individuals receiving sirolimus therapy, but were most commonly mild, with the majority being grade 1 and 2 in severity and thus easily manageable. The most common toxicities were asthenia (70% grade 1-2, 4% grade 3-4), mucositis (66% grade 1-2, 8% grade 3-4), diarrhea (40% grade 1-2, 2% grade 3-4), headache (25% grade 1-2, 5% grade 3-4), cutaneous rash (31% grade 1-2, 1% grade 3-4), and pyrosis (21% grade 1-2, 0% grade 3-4). These results are consistent with other previous reports, highlighting the efficacy and safety of sirolimus in VM [Seront et al, unpublished data]. Sirolimus has also shown to improve gastrointestinal bleeding in BRBN syndrome, with fast recovery of hemoglobin levels, and is currently considered the best therapeutic option when there is multiorgan involvement in BRBN syndrome [
Search
• Eval by vascular anomalies specialist
• MRI of affected area
• Eval by vascular anomalies specialist
• Consider whole-body MRI.
• D-dimer level
• Fibrinogen level
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Mgmt depends largely on size & location of lesion(s).
• Although sclerotherapy is the treatment of choice, sclerosing agents are not specific & can lead to ulceration if the VM is mucosal or involves the epidermis.
• More effective for well delineated &/or small lesions
• For large VM, surgical resection gives better long-term result if performed after sclerotherapy.
• Iron replacement or transfusions in case of anemia from chronic bleeding
• Other treatment options incl endoscopic sclerotherapy, band ligation, laser photocoagulation, & surgical resection.
• If D-dimers are ↑ & fibrinogen levels are low, LMWH should be initiated 1-2 weeks before surgery, depending on severity of coagulation abnormality, & continued for 2 weeks after surgery to reduce pre- and post-operative bleeding.
• If fibrinogen levels are normal, LMWH can be initiated the day before surgery.
• If lesions are painful & D-dimers are ↑ (higher than 2x normal range), LMWH can be used to alleviate pain.
• Should be administered prior to any invasive procedure (i.e., surgery &/or sclerotherapy) to ↓ risk of DIC.
• D-dimer levels can be used to evaluate efficacy of sclerotherapy & LMWH treatments, as levels will ↓ w/reduction of lesion size.
• Ensure appropriate social work involvement to connect families w/local resources, despite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement and/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• Adults: 2 mg 1x/day
• Children age <18 yrs: 0.8 mg/m
• Persons w/VM who are refractory to sclerotherapy &/or surgery, or for persons who are ineligible for surgery &/or sclerotherapy.
• Sirolimus has been shown to ↓ pain, improve quality of life & functional limitations, & ↓ bleeding.
• Annually or as needed (esp around puberty or other hormonal changes, as VM can become painful)
• Lesions can ↑ in size over time & become painful or symptomatic.
• CBC incl Hgb & hematocrit level
• Iron levels (incl serum iron, serum ferritin, & transferrin levels)
• Endoscopy
• Annually or more frequently in case of symptoms (fatigue, bloody stools)
• Consider endoscopy based on blood results.
• Every 5 yrs;
• If lesions become painful;
• Before any surgical &/or sclerotherapeutic procedure.
• Based on the VASE study (see
• The optimal treatment duration is at treating clinician's discretion. After 2 yrs of treatment, frequency of consultation is at treating clinician's discretion.
• Hemogram (Hgb, leukocytes, platelets)
• Thyroid function tests (TSH, T4) to exclude reversible causes of fatigue
• Cholesterol level
• Fasting blood glucose level
• Renal function tests
• Liver function tests
## Evaluations Following Initial Diagnosis
To establish the extent of disease and management needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Eval by vascular anomalies specialist
MRI of affected area
Eval by vascular anomalies specialist
Consider whole-body MRI.
D-dimer level
Fibrinogen level
Community or
Social work involvement for parental support;
Home nursing referral.
CCC = chronic consumptive coagulopathy; LIC = localized intravascular coagulopathy; MRI = magnetic resonance imaging; MOI = mode of inheritance; VM = venous malformations
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Eval by vascular anomalies specialist
• MRI of affected area
• Eval by vascular anomalies specialist
• Consider whole-body MRI.
• D-dimer level
• Fibrinogen level
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment is required for any symptomatic VM. Management depends largely on the size and location of the lesions. Small lesions can be surgically resected or treated with sclerotherapy with very favorable outcomes (often complete cure). However, in many instances complete resection or embolization is not possible.
If affected individuals are asymptomatic, with no lesion that may cause severe or life-threatening complications (e.g., medullary compression, pathologic bone fracture, airway compression), it is preferable to delay any therapeutic intervention and clinically monitor the individual over time.
Treatment of
Treatment of Manifestations in Individuals with
Mgmt depends largely on size & location of lesion(s).
Although sclerotherapy is the treatment of choice, sclerosing agents are not specific & can lead to ulceration if the VM is mucosal or involves the epidermis.
More effective for well delineated &/or small lesions
For large VM, surgical resection gives better long-term result if performed after sclerotherapy.
Iron replacement or transfusions in case of anemia from chronic bleeding
Other treatment options incl endoscopic sclerotherapy, band ligation, laser photocoagulation, & surgical resection.
If D-dimers are ↑ & fibrinogen levels are low, LMWH should be initiated 1-2 weeks before surgery, depending on severity of coagulation abnormality, & continued for 2 weeks after surgery to reduce pre- and post-operative bleeding.
If fibrinogen levels are normal, LMWH can be initiated the day before surgery.
If lesions are painful & D-dimers are ↑ (higher than 2x normal range), LMWH can be used to alleviate pain.
Should be administered prior to any invasive procedure (i.e., surgery &/or sclerotherapy) to ↓ risk of DIC.
D-dimer levels can be used to evaluate efficacy of sclerotherapy & LMWH treatments, as levels will ↓ w/reduction of lesion size.
Ensure appropriate social work involvement to connect families w/local resources, despite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Ongoing assessment of need for palliative care involvement and/or home nursing
Consider involvement in adaptive sports or Special Olympics.
DIC = disseminated intravascular coagulopathy; GI = gastrointestinal; LMWH = low-molecular-weight heparin; VM = venous malformation(s)
Sirolimus has not been approved by the FDA or EMA for the treatment of VM, and thus despite its efficacy it remains an off-label treatment to date.
Sclerotherapy is the first-line treatment for VM. It is performed to decrease the volume of the VM before surgery or as monotherapy in individuals in whom surgery is not technically feasible.
If the lesion is small and complete resection is possible without anatomic or functional consequences, surgical excision should be performed as the treatment of choice. However, these approaches have limitations, including inaccessibility and failure to completely cure the VM.
Sirolimus has been shown to reduce pain and functional limitations due to VM [
Targeted Off-label Treatment of
Adults: 2 mg 1x/day
Children age <18 yrs: 0.8 mg/m
Persons w/VM who are refractory to sclerotherapy &/or surgery, or for persons who are ineligible for surgery &/or sclerotherapy.
Sirolimus has been shown to ↓ pain, improve quality of life & functional limitations, & ↓ bleeding.
VM = venous malformations
The decision to treat VM using sirolimus should be initiated by a vascular anomalies expert.
Sirolimus has not been approved by the FDA or EMA for the treatment of VM, and thus despite its efficacy remains an off-label treatment. A large prospective Phase III trial (VASE) studying the efficacy of sirolimus in VM is ongoing. Side effects with sirolimus therapy have been reported in many individuals. For details, see
• Mgmt depends largely on size & location of lesion(s).
• Although sclerotherapy is the treatment of choice, sclerosing agents are not specific & can lead to ulceration if the VM is mucosal or involves the epidermis.
• More effective for well delineated &/or small lesions
• For large VM, surgical resection gives better long-term result if performed after sclerotherapy.
• Iron replacement or transfusions in case of anemia from chronic bleeding
• Other treatment options incl endoscopic sclerotherapy, band ligation, laser photocoagulation, & surgical resection.
• If D-dimers are ↑ & fibrinogen levels are low, LMWH should be initiated 1-2 weeks before surgery, depending on severity of coagulation abnormality, & continued for 2 weeks after surgery to reduce pre- and post-operative bleeding.
• If fibrinogen levels are normal, LMWH can be initiated the day before surgery.
• If lesions are painful & D-dimers are ↑ (higher than 2x normal range), LMWH can be used to alleviate pain.
• Should be administered prior to any invasive procedure (i.e., surgery &/or sclerotherapy) to ↓ risk of DIC.
• D-dimer levels can be used to evaluate efficacy of sclerotherapy & LMWH treatments, as levels will ↓ w/reduction of lesion size.
• Ensure appropriate social work involvement to connect families w/local resources, despite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Ongoing assessment of need for palliative care involvement and/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• Adults: 2 mg 1x/day
• Children age <18 yrs: 0.8 mg/m
• Persons w/VM who are refractory to sclerotherapy &/or surgery, or for persons who are ineligible for surgery &/or sclerotherapy.
• Sirolimus has been shown to ↓ pain, improve quality of life & functional limitations, & ↓ bleeding.
## Sclerotherapy and Surgery
Sclerotherapy is the first-line treatment for VM. It is performed to decrease the volume of the VM before surgery or as monotherapy in individuals in whom surgery is not technically feasible.
If the lesion is small and complete resection is possible without anatomic or functional consequences, surgical excision should be performed as the treatment of choice. However, these approaches have limitations, including inaccessibility and failure to completely cure the VM.
## Targeted Off-label Therapies
Sirolimus has been shown to reduce pain and functional limitations due to VM [
Targeted Off-label Treatment of
Adults: 2 mg 1x/day
Children age <18 yrs: 0.8 mg/m
Persons w/VM who are refractory to sclerotherapy &/or surgery, or for persons who are ineligible for surgery &/or sclerotherapy.
Sirolimus has been shown to ↓ pain, improve quality of life & functional limitations, & ↓ bleeding.
VM = venous malformations
The decision to treat VM using sirolimus should be initiated by a vascular anomalies expert.
Sirolimus has not been approved by the FDA or EMA for the treatment of VM, and thus despite its efficacy remains an off-label treatment. A large prospective Phase III trial (VASE) studying the efficacy of sirolimus in VM is ongoing. Side effects with sirolimus therapy have been reported in many individuals. For details, see
• Adults: 2 mg 1x/day
• Children age <18 yrs: 0.8 mg/m
• Persons w/VM who are refractory to sclerotherapy &/or surgery, or for persons who are ineligible for surgery &/or sclerotherapy.
• Sirolimus has been shown to ↓ pain, improve quality of life & functional limitations, & ↓ bleeding.
## Surveillance
To monitor existing manifestations of
Recommended Surveillance for Individuals with
Annually or as needed (esp around puberty or other hormonal changes, as VM can become painful)
Lesions can ↑ in size over time & become painful or symptomatic.
CBC incl Hgb & hematocrit level
Iron levels (incl serum iron, serum ferritin, & transferrin levels)
Endoscopy
Annually or more frequently in case of symptoms (fatigue, bloody stools)
Consider endoscopy based on blood results.
Every 5 yrs;
If lesions become painful;
Before any surgical &/or sclerotherapeutic procedure.
CBC = complete blood count; GI = gastrointestinal; Hgb = hemoglobin; VM = venous malformations
For individuals on MTOR inhibitor therapy such as sirolimus, a targeted off-label therapy, several surveillance guidelines are recommended (see
Recommended Surveillance: Targeted Off-label Therapy for
Based on the VASE study (see
The optimal treatment duration is at treating clinician's discretion. After 2 yrs of treatment, frequency of consultation is at treating clinician's discretion.
Hemogram (Hgb, leukocytes, platelets)
Thyroid function tests (TSH, T4) to exclude reversible causes of fatigue
Cholesterol level
Fasting blood glucose level
Renal function tests
Liver function tests
Hgb = hemoglobin; T4 = thyroxine; TSH = thyroid-stimulating hormone
The decision to treat VM using sirolimus should be initiated by a vascular anomalies expert.
Sirolimus has not been approved by the FDA or EMA for treatment of VM, and thus despite its efficacy remains an off-label therapy. A large prospective Phase III trial (VASE) studying the efficacy of sirolimus in VM is ongoing (see
• Annually or as needed (esp around puberty or other hormonal changes, as VM can become painful)
• Lesions can ↑ in size over time & become painful or symptomatic.
• CBC incl Hgb & hematocrit level
• Iron levels (incl serum iron, serum ferritin, & transferrin levels)
• Endoscopy
• Annually or more frequently in case of symptoms (fatigue, bloody stools)
• Consider endoscopy based on blood results.
• Every 5 yrs;
• If lesions become painful;
• Before any surgical &/or sclerotherapeutic procedure.
• Based on the VASE study (see
• The optimal treatment duration is at treating clinician's discretion. After 2 yrs of treatment, frequency of consultation is at treating clinician's discretion.
• Hemogram (Hgb, leukocytes, platelets)
• Thyroid function tests (TSH, T4) to exclude reversible causes of fatigue
• Cholesterol level
• Fasting blood glucose level
• Renal function tests
• Liver function tests
## Agents/Circumstances to Avoid
Contraceptive pills with high estrogen concentration should be avoided, as VM are estrogen responsive. VM can increase in size and become symptomatic, especially at the initiation of estrogen-based contraception. In some but not all instances stabilization of a VM lesion and diminution of pain may be observed after three months of contraceptive pill use.
## Evaluation of Relatives at Risk
Lesions arising after infancy usually stay small and therefore are rarely symptomatic. If no lesions are seen at birth, a second evaluation should be done around puberty.
Once a germline
See
## Pregnancy Management
During pregnancy, affected women may develop new small lesions; in addition, existing lesions may increase in size and become painful.
If D-dimer levels are high, low-molecular-weight heparin may be used to alleviate pain.
D-dimer levels should be evaluated every one to three months during pregnancy depending on the symptoms and before delivery to adjust medication and avoid abnormal bleeding during delivery.
In individuals on sirolimus, avoiding pregnancy and lactation is recommended, as this drug is classified as an FDA category C drug in pregnancy and lactation.
See
## Therapies Under Investigation
In recent years, multiple trials have reported on the efficacy of MTOR inhibitors in the treatment of slow-flow vascular malformations. A pilot study on rapamycin therapy for venous malformations (VM) reported beneficial results, especially regarding pain reduction and improvement in quality of life [
A prospective multicentric Phase III trial (VASE) is currently evaluating the efficacy and safety of sirolimus in slow-flow vascular anomalies that are refractory to standard care (
Adverse events were frequent, occurring in 96% of individuals receiving sirolimus therapy, but were most commonly mild, with the majority being grade 1 and 2 in severity and thus easily manageable. The most common toxicities were asthenia (70% grade 1-2, 4% grade 3-4), mucositis (66% grade 1-2, 8% grade 3-4), diarrhea (40% grade 1-2, 2% grade 3-4), headache (25% grade 1-2, 5% grade 3-4), cutaneous rash (31% grade 1-2, 1% grade 3-4), and pyrosis (21% grade 1-2, 0% grade 3-4). These results are consistent with other previous reports, highlighting the efficacy and safety of sirolimus in VM [Seront et al, unpublished data]. Sirolimus has also shown to improve gastrointestinal bleeding in BRBN syndrome, with fast recovery of hemoglobin levels, and is currently considered the best therapeutic option when there is multiorgan involvement in BRBN syndrome [
Search
## Genetic Counseling
The autosomal dominant disorder multiple cutaneous and mucosal venous malformations (VMCM), caused by germline heterozygous
The sporadic (or mosaic) disorders unifocal/isolated VM, multifocal sporadic VM (MSVM), and blue rubber bleb nevus (BRBN) syndrome, caused by postzygotic (mosaic)
Molecular genetic testing of leukocyte DNA from the proband is necessary to distinguish between these categories of
Most individuals diagnosed with VMCM have an affected parent.
To date, VMCM caused by a
If the proband appears to be the only affected family member (i.e., neither parent of the proband has clinical evidence of VMCM on dermatologic evaluation), 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 VMCM may appear to be negative because of a milder phenotypic presentation, 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 unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If a parent of the proband is affected and/or known to have the
Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
The size, number, and localization of lesions vary between family members with the same
If the
If the parents have not been tested for the
See Management,
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.
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 autosomal dominant disorder multiple cutaneous and mucosal venous malformations (VMCM), caused by germline heterozygous
• The sporadic (or mosaic) disorders unifocal/isolated VM, multifocal sporadic VM (MSVM), and blue rubber bleb nevus (BRBN) syndrome, caused by postzygotic (mosaic)
• Most individuals diagnosed with VMCM have an affected parent.
• To date, VMCM caused by a
• If the proband appears to be the only affected family member (i.e., neither parent of the proband has clinical evidence of VMCM on dermatologic evaluation), 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 VMCM may appear to be negative because of a milder phenotypic presentation, 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 unless molecular genetic testing has demonstrated that neither parent is heterozygous for 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 known to have the
• Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
• The size, number, and localization of lesions vary between family members with the same
• Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
• The size, number, and localization of lesions vary between family members with the same
• If the
• If the parents have not been tested for the
• Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
• The size, number, and localization of lesions vary between family members with the same
• 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.
## Mode of Inheritance
The autosomal dominant disorder multiple cutaneous and mucosal venous malformations (VMCM), caused by germline heterozygous
The sporadic (or mosaic) disorders unifocal/isolated VM, multifocal sporadic VM (MSVM), and blue rubber bleb nevus (BRBN) syndrome, caused by postzygotic (mosaic)
Molecular genetic testing of leukocyte DNA from the proband is necessary to distinguish between these categories of
• The autosomal dominant disorder multiple cutaneous and mucosal venous malformations (VMCM), caused by germline heterozygous
• The sporadic (or mosaic) disorders unifocal/isolated VM, multifocal sporadic VM (MSVM), and blue rubber bleb nevus (BRBN) syndrome, caused by postzygotic (mosaic)
## VMCM – Risk to Family Members
Most individuals diagnosed with VMCM have an affected parent.
To date, VMCM caused by a
If the proband appears to be the only affected family member (i.e., neither parent of the proband has clinical evidence of VMCM on dermatologic evaluation), 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 VMCM may appear to be negative because of a milder phenotypic presentation, 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 unless molecular genetic testing has demonstrated that neither parent is heterozygous for the
If a parent of the proband is affected and/or known to have the
Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
The size, number, and localization of lesions vary between family members with the same
If the
If the parents have not been tested for the
• Most individuals diagnosed with VMCM have an affected parent.
• To date, VMCM caused by a
• If the proband appears to be the only affected family member (i.e., neither parent of the proband has clinical evidence of VMCM on dermatologic evaluation), 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 VMCM may appear to be negative because of a milder phenotypic presentation, 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 unless molecular genetic testing has demonstrated that neither parent is heterozygous for 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 known to have the
• Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
• The size, number, and localization of lesions vary between family members with the same
• Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
• The size, number, and localization of lesions vary between family members with the same
• If the
• If the parents have not been tested for the
• Approximately 90% of individuals who inherit a germline pathogenic gain-of-function variant in
• The size, number, and localization of lesions vary between family members with the same
## Unifocal VM, MSVM, and BRBN Syndrome – Risk to Family Members
## Related Genetic Counseling Issues
See Management,
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.
• 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
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
ISSVA list of Multidisciplinary Centers
ISSVA list of Patient Advocacy Organizations
Belgium
•
•
•
•
•
•
•
• ISSVA list of Multidisciplinary Centers
•
•
• ISSVA list of Patient Advocacy Organizations
•
•
• Belgium
•
## Molecular Genetics
TEK-Related Venous Malformations: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for TEK-Related Venous Malformations (
Most
Although all VM-associated
Gain-of-function mutations in
BRBN = blue rubber bleb nevus; MSVM = multifocal sporadic venous malformations; VM = venous malformation; VMCM = multiple cutaneous and mucosal venous malformations
Notable
BRBN = blue rubber bleb nevus; MSVM = multifocal sporadic venous malformations; VM = venous malformation; VMCM = multiple cutaneous and mucosal venous malformations
Variants listed in the table have been provided by the authors.
The allele
## Molecular Pathogenesis
Most
Although all VM-associated
Gain-of-function mutations in
BRBN = blue rubber bleb nevus; MSVM = multifocal sporadic venous malformations; VM = venous malformation; VMCM = multiple cutaneous and mucosal venous malformations
Notable
BRBN = blue rubber bleb nevus; MSVM = multifocal sporadic venous malformations; VM = venous malformation; VMCM = multiple cutaneous and mucosal venous malformations
Variants listed in the table have been provided by the authors.
The allele
## Chapter Notes
Prof Vikkula,
Google Scholar
Google Scholar
All authors are actively involved in clinical research regarding individuals with
Contact Prof Miikka Vikkula to inquire about
All authors are also interested in hearing from clinicians treating families affected by VMCM in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.
All three authors of this publication are members of the Vascular Anomaly Working Group (VASCA) of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), Project ID: 769036.
We are grateful to all the affected individuals and their family members for their invaluable participation during the years of our research studies. Our studies have been financially supported by the Fonds de la Recherche Scientifique – FNRS Grants, most recently by T.0026.14 and T.0247.19 (to MV), T.0146.16 and P.C013.20 (to LMB), the Fund Generet managed by the King Baudouin Foundation (Grant 2018-J1810250-211305) (to MV), and by the Walloon Region through the FRFS-WELBIO strategic research program (WELBIO-CR-2019C-06) (to MV). Our work has also been funded by the MSCA-ITN network VA Cure No 814316 (to MV), the Lymphatic Malformation Institute (LMI), USA (to MV), and the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR Grant 21CVD03). Our groups have also been funded by the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694 (LB/MV), and by a continued Pierre M fellowship. We also thank the National Lottery, Belgium, and the Foundation against Cancer (2010-101), Belgium, for their support to the Genomics Platform of Université catholique de Louvain and de Duve Institute, as well as the Fonds de la Recherche Scientifique – FNRS Eguipment Grant U.N035.17 for the "Big Data Analysis Cluster for NGS at UCLouvain."
2 March 2023 (gm) Comprehensive update posted live
17 May 2018 (ma) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
23 August 2012 (me) Comprehensive update posted live
18 September 2008 (me) Review posted live
17 January 2008 (mv) Original submission
• 2 March 2023 (gm) Comprehensive update posted live
• 17 May 2018 (ma) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 23 August 2012 (me) Comprehensive update posted live
• 18 September 2008 (me) Review posted live
• 17 January 2008 (mv) Original submission
## Author Notes
Prof Vikkula,
Google Scholar
Google Scholar
All authors are actively involved in clinical research regarding individuals with
Contact Prof Miikka Vikkula to inquire about
All authors are also interested in hearing from clinicians treating families affected by VMCM 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
All three authors of this publication are members of the Vascular Anomaly Working Group (VASCA) of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), Project ID: 769036.
We are grateful to all the affected individuals and their family members for their invaluable participation during the years of our research studies. Our studies have been financially supported by the Fonds de la Recherche Scientifique – FNRS Grants, most recently by T.0026.14 and T.0247.19 (to MV), T.0146.16 and P.C013.20 (to LMB), the Fund Generet managed by the King Baudouin Foundation (Grant 2018-J1810250-211305) (to MV), and by the Walloon Region through the FRFS-WELBIO strategic research program (WELBIO-CR-2019C-06) (to MV). Our work has also been funded by the MSCA-ITN network VA Cure No 814316 (to MV), the Lymphatic Malformation Institute (LMI), USA (to MV), and the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR Grant 21CVD03). Our groups have also been funded by the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694 (LB/MV), and by a continued Pierre M fellowship. We also thank the National Lottery, Belgium, and the Foundation against Cancer (2010-101), Belgium, for their support to the Genomics Platform of Université catholique de Louvain and de Duve Institute, as well as the Fonds de la Recherche Scientifique – FNRS Eguipment Grant U.N035.17 for the "Big Data Analysis Cluster for NGS at UCLouvain."
## Revision History
2 March 2023 (gm) Comprehensive update posted live
17 May 2018 (ma) Comprehensive update posted live
29 January 2015 (me) Comprehensive update posted live
23 August 2012 (me) Comprehensive update posted live
18 September 2008 (me) Review posted live
17 January 2008 (mv) Original submission
• 2 March 2023 (gm) Comprehensive update posted live
• 17 May 2018 (ma) Comprehensive update posted live
• 29 January 2015 (me) Comprehensive update posted live
• 23 August 2012 (me) Comprehensive update posted live
• 18 September 2008 (me) Review posted live
• 17 January 2008 (mv) Original submission
## References
## Literature Cited
Multiple cutaneous and mucosal venous malformations (VMCM) (marked by arrows) in one affected individual
A. On the tongue
B. On the neck
C. In the supraclavicular area (scar of a resected VMCM, arrowheads)
D. On the distal forearm/wrist
Various venous malformations (VM)
Common sporadic VM of the arm (A); multifocal sporadic VM (MSVM) of the hand and forearm (B); in blue rubber bleb nevus (BRBN) syndrome, large "dominant" congenital VM of the buttock seen on MRI (C); multiple small and pathognomonic hyperkeratotic VM on sole (D); gastrointestinal VM (E); VM of the lower right extremity (F).
|
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"M Wassef, F Blei, D Adams, A Alomari, E Baselga, A Berenstein, P Burrows, IJ Frieden, MC Garzon, JC Lopez-Gutierrez, DJ Lord, S Mitchel, J Powell, J Prendiville, M Vikkula. Vascular anomalies classification: recommendations from the International Society for the Study of Vascular Anomalies.. Pediatrics. 2015;136:e203-14",
"A Wonaga, JL Fernández, A Barsanti, LA Viola. An infrequent cause of iron-deficiency anemia: blue rubber bleb nevus syndrome.. Rev Gastroenterol Mex. 2014;79:151-2",
"V Wouters, N Limaye, M Uebelhoer, A Irrthum, LM Boon, JB Mulliken, O Enjolras, E Baselga, J Berg, A Dompmartin, SA Ivarsson, L Kangesu, Y Lacassie, AS Teebi, A Pennington, P Rieu, M Vikkula. Hereditary cutaneomucosal venous malformations are caused by TIE2 mutations with widely variable hyper-phosphorylating effects.. Eur J Hum Genet 2010;18:414-20",
"J Zhou, Z Zhao, T Sun, W Liu, Z Yu, J Liu, Y Yu, S Ning, H. Zhang. Efficacy and safety of sirolimus for blue rubber bleb nevus syndrome: a prospective study.. Am J Gastroenterol. 2021;116:1044-52"
] |
18/9/2008
|
2/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
vodi
|
vodi
|
[
"VODI",
"Sp110 nuclear body protein",
"SP110",
"Hepatic Veno-Occlusive Disease with Immunodeficiency"
] |
Hepatic Veno-Occlusive Disease with Immunodeficiency
|
Melanie Wong
|
Summary Hepatic veno-occlusive disease with immunodeficiency (VODI) is characterized by (1) combined immunodeficiency and (2) terminal hepatic lobular vascular occlusion and hepatic fibrosis manifesting as hepatomegaly and/or hepatic failure. Onset is usually before age six months. The immunodeficiency comprises severe hypogammaglobulinemia, clinical evidence of T-cell immunodeficiency with normal numbers of circulating T and B cells, absent lymph node germinal centers, and absent tissue plasma cells. Bacterial and opportunistic infections including The diagnosis of VODI is established in a proband who meets clinical diagnostic criteria or by identification of biallelic pathogenic variants in VODI is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
Clinical diagnostic criteria for hepatic veno-occlusive disease with immunodeficiency (VODI) have been established [
VODI
Clinical evidence of immunodeficiency with bacterial and opportunistic infections including
Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
Note: Hepatic veno-occlusive disease (hVOD; also known as sinusoidal obstruction syndrome) is usually present and pathognomonic but may not be found, or may have resolved.
Onset usually before age six months
Low serum concentrations of immunoglobulin A (IgA), IgM, and IgG
Note: Immunoglobulin levels are age specific and laboratory specific and thus should be compared against appropriate local reference ranges.
Normal lymphocyte numbers and CD4 and CD8 percentages
Normal lymphocyte proliferative responses to mitogens
Hepatic ultrasonography. Features consistent with hVOD may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and recanalization of the
Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the paraumbilical vein, and increased resistance in the hepatic artery.
The
The clinical diagnosis of VODI can be established in a proband with ALL of the following clinical diagnostic criteria [
Hypogammaglobulinemia with clinical evidence of T-cell immunodeficiency with bacterial and opportunistic infections including
Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
Onset prior to age 12 months
Family history consistent with autosomal recessive inheritance
The molecular diagnosis can be established in a proband with
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 the
For an introduction to multigene panels click
When the diagnosis of VODI has not been considered because an individual has atypical features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with Immunodeficiency
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 most common pathogenic variant is
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 evidence of immunodeficiency with bacterial and opportunistic infections including
• Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
• Note: Hepatic veno-occlusive disease (hVOD; also known as sinusoidal obstruction syndrome) is usually present and pathognomonic but may not be found, or may have resolved.
• Onset usually before age six months
• Low serum concentrations of immunoglobulin A (IgA), IgM, and IgG
• Note: Immunoglobulin levels are age specific and laboratory specific and thus should be compared against appropriate local reference ranges.
• Normal lymphocyte numbers and CD4 and CD8 percentages
• Normal lymphocyte proliferative responses to mitogens
• Hepatic ultrasonography. Features consistent with hVOD may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and recanalization of the
• Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the paraumbilical vein, and increased resistance in the hepatic artery.
• Hypogammaglobulinemia with clinical evidence of T-cell immunodeficiency with bacterial and opportunistic infections including
• Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
• Onset prior to age 12 months
• Family history consistent with autosomal recessive inheritance
## Suggestive Findings
VODI
Clinical evidence of immunodeficiency with bacterial and opportunistic infections including
Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
Note: Hepatic veno-occlusive disease (hVOD; also known as sinusoidal obstruction syndrome) is usually present and pathognomonic but may not be found, or may have resolved.
Onset usually before age six months
Low serum concentrations of immunoglobulin A (IgA), IgM, and IgG
Note: Immunoglobulin levels are age specific and laboratory specific and thus should be compared against appropriate local reference ranges.
Normal lymphocyte numbers and CD4 and CD8 percentages
Normal lymphocyte proliferative responses to mitogens
Hepatic ultrasonography. Features consistent with hVOD may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and recanalization of the
Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the paraumbilical vein, and increased resistance in the hepatic artery.
• Clinical evidence of immunodeficiency with bacterial and opportunistic infections including
• Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
• Note: Hepatic veno-occlusive disease (hVOD; also known as sinusoidal obstruction syndrome) is usually present and pathognomonic but may not be found, or may have resolved.
• Onset usually before age six months
• Low serum concentrations of immunoglobulin A (IgA), IgM, and IgG
• Note: Immunoglobulin levels are age specific and laboratory specific and thus should be compared against appropriate local reference ranges.
• Normal lymphocyte numbers and CD4 and CD8 percentages
• Normal lymphocyte proliferative responses to mitogens
• Hepatic ultrasonography. Features consistent with hVOD may include hepatosplenomegaly, gallbladder wall thickening, increased portal vein diameter, reduced hepatic vein diameter, ascites, and recanalization of the
• Doppler ultrasound examination. Features consistent with hVOD may include reduced portal venous flow, flow in the paraumbilical vein, and increased resistance in the hepatic artery.
## Establishing the Diagnosis
The
The clinical diagnosis of VODI can be established in a proband with ALL of the following clinical diagnostic criteria [
Hypogammaglobulinemia with clinical evidence of T-cell immunodeficiency with bacterial and opportunistic infections including
Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
Onset prior to age 12 months
Family history consistent with autosomal recessive inheritance
The molecular diagnosis can be established in a proband with
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 the
For an introduction to multigene panels click
When the diagnosis of VODI has not been considered because an individual has atypical features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with Immunodeficiency
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 most common pathogenic variant is
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.
• Hypogammaglobulinemia with clinical evidence of T-cell immunodeficiency with bacterial and opportunistic infections including
• Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
• Onset prior to age 12 months
• Family history consistent with autosomal recessive inheritance
## Clinical Diagnosis
The clinical diagnosis of VODI can be established in a proband with ALL of the following clinical diagnostic criteria [
Hypogammaglobulinemia with clinical evidence of T-cell immunodeficiency with bacterial and opportunistic infections including
Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
Onset prior to age 12 months
Family history consistent with autosomal recessive inheritance
• Hypogammaglobulinemia with clinical evidence of T-cell immunodeficiency with bacterial and opportunistic infections including
• Hepatomegaly or evidence of hepatic failure, not explained by other factors, in the affected individual or a first-degree relative
• Onset prior to age 12 months
• Family history consistent with autosomal recessive inheritance
## Molecular Diagnosis
The molecular diagnosis can be established in a proband with
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 the
For an introduction to multigene panels click
When the diagnosis of VODI has not been considered because an individual has atypical features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with Immunodeficiency
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 most common pathogenic variant is
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.
##
Note: Targeted analysis for the
For an introduction to multigene panels click
##
When the diagnosis of VODI has not been considered because an individual has atypical features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Hepatic Veno-Occlusive Disease with Immunodeficiency
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 most common pathogenic variant is
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
Hepatic veno-occlusive disease with immunodeficiency (VODI) is a primary immunodeficiency associated with terminal hepatic lobular vascular occlusion and hepatic lobule zone 3 fibrosis. Infants typically present prior to age six months with tachypnea, poor weight gain, interstitial pneumonitis, jaundice, ascites, hypogammaglobulinemia, and thrombocytopenia. Some individuals develop neurologic sequelae (cerebral infarction, leukodystrophy). The following description of the phenotypic features associated with this condition is based on published case series [
Hepatic Veno-Occlusive Disease with Immunodeficiency: Frequency of Select Features
CMV = cytomegalovirus; SIADH = syndrome of inappropriate antidiuretic hormone secretion; TREC = T cell receptor excision circle
In individuals with less severe disease, treatment of the precipitating infection, commencement of long-term immunoglobulin replacement therapy (intravenous immunoglobulin [IVIG] or subcutaneous immunoglobulin [SCIG]), continuation of prophylactic cotrimoxazole, and other supportive measures may result in stabilization of liver function, and the liver gradually heals by nodular regeneration. Associated hepatosplenomegaly, anemia, and thrombocytopenia also resolve. Affected individuals may continue to have compromised liver function. Although maintenance immunoglobulin replacement therapy and cotrimoxazole prophylaxis significantly reduces the risk, recurrence of hVOD can occur, especially precipitated by infection or other metabolic stress.
The hepatic injury in VODI is identical clinically and histologically to hVOD (also known as sinusoidal obstruction syndrome) following high-dose myeloablative conditioning therapy in hematopoietic stem cell transplantation (HSCT) [
It is unclear whether other neurologic features in single reports are complications of VODI or coincidental findings. These include syndrome of inappropriate antidiuretic hormone secretion (SIADH) during the presenting illness, microcephaly, nonspecific calcified central nervous system (CNS) lesions on imaging, developmental delay, and attention-deficit/hyperactivity disorder (ADHD).
Milder phenotypes associated with missense pathogenic variants have been reported [
The poor long-term prognosis and the fact that
There are limited clinical reports of outcomes following HSCT for VODI. The first published report of HSCT for VODI described five individuals from one extended family (out of a total of 14 affected family members) who had matched related donor transplants [
One child presented at age four months with probable herpetic hepatitis that initially responded clinically to acyclovir, but then developed florid hVOD following a transfusion. She responded well to defibrotide, IVIG, and prophylactic cotrimoxazole. She was neurologically normal, but asymptomatic bilateral subdural hematomas were found on routine pre-transplant MRI despite a normal head ultrasound a week prior when coagulation studies and platelets had already normalized. At age six months she underwent an unrelated cord blood transplant with alemtuzumab, fludarabine, treosulfan, and antithymocyte globulin conditioning. Defibrotide was prophylactically continued until two months post transplant. She remained well and neurologically normal at age ten years. Her MRI scan at age two years showed no anatomic abnormality [M Wong, personal obervation].
Another infant presented at age four months with PJP and CMV infections, hVOD, and hypogammaglobinemia. At age five months, after control of pneumonitis and hVOD, he received a haploidentical paternal (CMV positive) HSCT after depletion of α/β TCR and CD19+ cells. He received conditioning with fludarabine, treosulfan, and antithymocyte globulin. Defibrotide was given as hVOD prophylaxis. Two months post transplant he was well and had engrafted without graft-vs-host disease or recurrence of hVOD but with moderate CMV hepatitis. Defibrotide was able to be discontinued at Day 60. Seventy days following HSCT he developed seizures secondary to CMV reactivation with CNS involvement, leading to his death [T Cole, J Smart, & T Soosay Raj, personal communication].
This child's sib was diagnosed soon after birth and underwent HSCT with alemtuzumab, fludarabine, treosulfan, and antithymocyte globulin conditioning and defibrotide prophylaxis at age nine weeks. He was alive and well at last review, age six years.
A further infant, whose brother died in infancy from hemophagocytic lymphohistiocytosis (HLH) and had biallelic
No significant difference in the clinical manifestations of VODI is observed between individuals with different pathogenic variants. The majority of
Hepatic veno-occlusive disease alone was known previously as Jamaican bush tea disease due to a dietary and geographic association. This term is now superseded by hepatic veno-occlusive disease (hVOD) or sinusoidal obstruction syndrome (SOS), terms less limiting given the occurrence of hVOD worldwide and it being secondary to other precipitants. The combination of hVOD and a combined immunodeficiency is termed hepatic veno-occlusive disease with immunodeficiency (VODI).
The majority of children reported with VODI are of Lebanese origin due to founder pathogenic variant
## Clinical Description
Hepatic veno-occlusive disease with immunodeficiency (VODI) is a primary immunodeficiency associated with terminal hepatic lobular vascular occlusion and hepatic lobule zone 3 fibrosis. Infants typically present prior to age six months with tachypnea, poor weight gain, interstitial pneumonitis, jaundice, ascites, hypogammaglobulinemia, and thrombocytopenia. Some individuals develop neurologic sequelae (cerebral infarction, leukodystrophy). The following description of the phenotypic features associated with this condition is based on published case series [
Hepatic Veno-Occlusive Disease with Immunodeficiency: Frequency of Select Features
CMV = cytomegalovirus; SIADH = syndrome of inappropriate antidiuretic hormone secretion; TREC = T cell receptor excision circle
In individuals with less severe disease, treatment of the precipitating infection, commencement of long-term immunoglobulin replacement therapy (intravenous immunoglobulin [IVIG] or subcutaneous immunoglobulin [SCIG]), continuation of prophylactic cotrimoxazole, and other supportive measures may result in stabilization of liver function, and the liver gradually heals by nodular regeneration. Associated hepatosplenomegaly, anemia, and thrombocytopenia also resolve. Affected individuals may continue to have compromised liver function. Although maintenance immunoglobulin replacement therapy and cotrimoxazole prophylaxis significantly reduces the risk, recurrence of hVOD can occur, especially precipitated by infection or other metabolic stress.
The hepatic injury in VODI is identical clinically and histologically to hVOD (also known as sinusoidal obstruction syndrome) following high-dose myeloablative conditioning therapy in hematopoietic stem cell transplantation (HSCT) [
It is unclear whether other neurologic features in single reports are complications of VODI or coincidental findings. These include syndrome of inappropriate antidiuretic hormone secretion (SIADH) during the presenting illness, microcephaly, nonspecific calcified central nervous system (CNS) lesions on imaging, developmental delay, and attention-deficit/hyperactivity disorder (ADHD).
Milder phenotypes associated with missense pathogenic variants have been reported [
The poor long-term prognosis and the fact that
There are limited clinical reports of outcomes following HSCT for VODI. The first published report of HSCT for VODI described five individuals from one extended family (out of a total of 14 affected family members) who had matched related donor transplants [
One child presented at age four months with probable herpetic hepatitis that initially responded clinically to acyclovir, but then developed florid hVOD following a transfusion. She responded well to defibrotide, IVIG, and prophylactic cotrimoxazole. She was neurologically normal, but asymptomatic bilateral subdural hematomas were found on routine pre-transplant MRI despite a normal head ultrasound a week prior when coagulation studies and platelets had already normalized. At age six months she underwent an unrelated cord blood transplant with alemtuzumab, fludarabine, treosulfan, and antithymocyte globulin conditioning. Defibrotide was prophylactically continued until two months post transplant. She remained well and neurologically normal at age ten years. Her MRI scan at age two years showed no anatomic abnormality [M Wong, personal obervation].
Another infant presented at age four months with PJP and CMV infections, hVOD, and hypogammaglobinemia. At age five months, after control of pneumonitis and hVOD, he received a haploidentical paternal (CMV positive) HSCT after depletion of α/β TCR and CD19+ cells. He received conditioning with fludarabine, treosulfan, and antithymocyte globulin. Defibrotide was given as hVOD prophylaxis. Two months post transplant he was well and had engrafted without graft-vs-host disease or recurrence of hVOD but with moderate CMV hepatitis. Defibrotide was able to be discontinued at Day 60. Seventy days following HSCT he developed seizures secondary to CMV reactivation with CNS involvement, leading to his death [T Cole, J Smart, & T Soosay Raj, personal communication].
This child's sib was diagnosed soon after birth and underwent HSCT with alemtuzumab, fludarabine, treosulfan, and antithymocyte globulin conditioning and defibrotide prophylaxis at age nine weeks. He was alive and well at last review, age six years.
A further infant, whose brother died in infancy from hemophagocytic lymphohistiocytosis (HLH) and had biallelic
## Genotype-Phenotype Correlations
No significant difference in the clinical manifestations of VODI is observed between individuals with different pathogenic variants. The majority of
## Nomenclature
Hepatic veno-occlusive disease alone was known previously as Jamaican bush tea disease due to a dietary and geographic association. This term is now superseded by hepatic veno-occlusive disease (hVOD) or sinusoidal obstruction syndrome (SOS), terms less limiting given the occurrence of hVOD worldwide and it being secondary to other precipitants. The combination of hVOD and a combined immunodeficiency is termed hepatic veno-occlusive disease with immunodeficiency (VODI).
## Prevalence
The majority of children reported with VODI are of Lebanese origin due to founder pathogenic variant
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
To date, there has been no report of
## Management
No clinical practice guidelines for hepatic veno-occlusive disease with immunodeficiency (VODI) 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 VODI, the evaluations summarized in
Hepatic Veno-Occlusive Disease with Immunodeficiency: Recommended Evaluations Following Initial Diagnosis
Eval by immunologist
Serum Ig levels
T & B cell numbers & percentages
T cell proliferative response to mitogens
Serum aminotransferases, bilirubin, & albumin
Complete blood count to assess anemia & thrombocytopenia
Early involvement of dietary support to optimize nutritional intake
In sick infants w/feeding intolerance, consider early supplementation w/parenteral nutrition.
Community or
Social work involvement for parental support
Home nursing referral
CNS = central nervous system; hVOD = hepatic veno-occlusive disease; IFN = interferon; Ig = immunoglobulin; IL = interleukin; MOI = mode of inheritance; VODI = hepatic veno-occlusive disease with immunodeficiency
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Hepatic Veno-Occlusive Disease with Immunodeficiency: Targeted Therapies
HSCT = hematopoietic stem cell transplantation; hVOD = hepatic veno-occlusive disease; Ig = immunoglobulin; IVIG = intravenous immunoglobulin; SCIG = subcutaneous immunoglobulin; VOD = veno-occlusive disease
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
Hepatic Veno-Occlusive Disease with Immunodeficiency: Treatment of Manifestations
The complications of liver disease (incl anemia, thrombocytopenia, hypoalbuminemia, ascites, coagulopathy, encephalopathy) require treatment as appropriate for severity per other causes of liver failure.
Liver transplantation may need to be considered.
Liver transplantation is not curative & is assoc w/high mortality rate.
AML was reported in a child age 7 yrs after liver transplantation for VODI at age 5 mos.
AML = acute myeloid leukemia; VODI = hepatic veno-occlusive disease with immunodeficiency
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hepatic Veno-Occlusive Disease with Immunodeficiency: Recommended Surveillance
Bronchoalveolar lavage to diagnose
Viral & bacterial cultures/PCR
Serum aminotransferases, bilirubin, & albumin
Complete blood count incl platelet count to assess for anemia & thrombocytopenia
CNS = central nervous system; Ig = immunoglobulin; PCR = polymerase chain reaction
Agents known to predispose to hepatic veno-occlusive disease (e.g., cyclophosphamide and
It is appropriate to evaluate sibs of a proband who are younger than age 12 months in order to identify as early as possible those who would benefit from initiation of intravenous or subcutaneous immunoglobulin treatment,
Molecular genetic testing if the pathogenic variants in the family are known;
Serum immunoglobulins, complete blood count, and liver function tests at birth and repeated at age six months if the pathogenic variants in the family are not known.
All individuals reported to date with biallelic pathogenic variants in
See
Search
• Eval by immunologist
• Serum Ig levels
• T & B cell numbers & percentages
• T cell proliferative response to mitogens
• Serum aminotransferases, bilirubin, & albumin
• Complete blood count to assess anemia & thrombocytopenia
• Early involvement of dietary support to optimize nutritional intake
• In sick infants w/feeding intolerance, consider early supplementation w/parenteral nutrition.
• Community or
• Social work involvement for parental support
• Home nursing referral
• The complications of liver disease (incl anemia, thrombocytopenia, hypoalbuminemia, ascites, coagulopathy, encephalopathy) require treatment as appropriate for severity per other causes of liver failure.
• Liver transplantation may need to be considered.
• Liver transplantation is not curative & is assoc w/high mortality rate.
• AML was reported in a child age 7 yrs after liver transplantation for VODI at age 5 mos.
• Bronchoalveolar lavage to diagnose
• Viral & bacterial cultures/PCR
• Serum aminotransferases, bilirubin, & albumin
• Complete blood count incl platelet count to assess for anemia & thrombocytopenia
• Molecular genetic testing if the pathogenic variants in the family are known;
• Serum immunoglobulins, complete blood count, and liver function tests at birth and repeated at age six months if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VODI, the evaluations summarized in
Hepatic Veno-Occlusive Disease with Immunodeficiency: Recommended Evaluations Following Initial Diagnosis
Eval by immunologist
Serum Ig levels
T & B cell numbers & percentages
T cell proliferative response to mitogens
Serum aminotransferases, bilirubin, & albumin
Complete blood count to assess anemia & thrombocytopenia
Early involvement of dietary support to optimize nutritional intake
In sick infants w/feeding intolerance, consider early supplementation w/parenteral nutrition.
Community or
Social work involvement for parental support
Home nursing referral
CNS = central nervous system; hVOD = hepatic veno-occlusive disease; IFN = interferon; Ig = immunoglobulin; IL = interleukin; MOI = mode of inheritance; VODI = hepatic veno-occlusive disease with immunodeficiency
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Eval by immunologist
• Serum Ig levels
• T & B cell numbers & percentages
• T cell proliferative response to mitogens
• Serum aminotransferases, bilirubin, & albumin
• Complete blood count to assess anemia & thrombocytopenia
• Early involvement of dietary support to optimize nutritional intake
• In sick infants w/feeding intolerance, consider early supplementation w/parenteral nutrition.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Hepatic Veno-Occlusive Disease with Immunodeficiency: Targeted Therapies
HSCT = hematopoietic stem cell transplantation; hVOD = hepatic veno-occlusive disease; Ig = immunoglobulin; IVIG = intravenous immunoglobulin; SCIG = subcutaneous immunoglobulin; VOD = veno-occlusive disease
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
Hepatic Veno-Occlusive Disease with Immunodeficiency: Treatment of Manifestations
The complications of liver disease (incl anemia, thrombocytopenia, hypoalbuminemia, ascites, coagulopathy, encephalopathy) require treatment as appropriate for severity per other causes of liver failure.
Liver transplantation may need to be considered.
Liver transplantation is not curative & is assoc w/high mortality rate.
AML was reported in a child age 7 yrs after liver transplantation for VODI at age 5 mos.
AML = acute myeloid leukemia; VODI = hepatic veno-occlusive disease with immunodeficiency
• The complications of liver disease (incl anemia, thrombocytopenia, hypoalbuminemia, ascites, coagulopathy, encephalopathy) require treatment as appropriate for severity per other causes of liver failure.
• Liver transplantation may need to be considered.
• Liver transplantation is not curative & is assoc w/high mortality rate.
• AML was reported in a child age 7 yrs after liver transplantation for VODI at age 5 mos.
## Targeted Therapies
Hepatic Veno-Occlusive Disease with Immunodeficiency: Targeted Therapies
HSCT = hematopoietic stem cell transplantation; hVOD = hepatic veno-occlusive disease; Ig = immunoglobulin; IVIG = intravenous immunoglobulin; SCIG = subcutaneous immunoglobulin; VOD = veno-occlusive disease
## 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
Hepatic Veno-Occlusive Disease with Immunodeficiency: Treatment of Manifestations
The complications of liver disease (incl anemia, thrombocytopenia, hypoalbuminemia, ascites, coagulopathy, encephalopathy) require treatment as appropriate for severity per other causes of liver failure.
Liver transplantation may need to be considered.
Liver transplantation is not curative & is assoc w/high mortality rate.
AML was reported in a child age 7 yrs after liver transplantation for VODI at age 5 mos.
AML = acute myeloid leukemia; VODI = hepatic veno-occlusive disease with immunodeficiency
• The complications of liver disease (incl anemia, thrombocytopenia, hypoalbuminemia, ascites, coagulopathy, encephalopathy) require treatment as appropriate for severity per other causes of liver failure.
• Liver transplantation may need to be considered.
• Liver transplantation is not curative & is assoc w/high mortality rate.
• AML was reported in a child age 7 yrs after liver transplantation for VODI at age 5 mos.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Hepatic Veno-Occlusive Disease with Immunodeficiency: Recommended Surveillance
Bronchoalveolar lavage to diagnose
Viral & bacterial cultures/PCR
Serum aminotransferases, bilirubin, & albumin
Complete blood count incl platelet count to assess for anemia & thrombocytopenia
CNS = central nervous system; Ig = immunoglobulin; PCR = polymerase chain reaction
• Bronchoalveolar lavage to diagnose
• Viral & bacterial cultures/PCR
• Serum aminotransferases, bilirubin, & albumin
• Complete blood count incl platelet count to assess for anemia & thrombocytopenia
## Agents/Circumstances to Avoid
Agents known to predispose to hepatic veno-occlusive disease (e.g., cyclophosphamide and
## Evaluation of Relatives at Risk
It is appropriate to evaluate sibs of a proband who are younger than age 12 months in order to identify as early as possible those who would benefit from initiation of intravenous or subcutaneous immunoglobulin treatment,
Molecular genetic testing if the pathogenic variants in the family are known;
Serum immunoglobulins, complete blood count, and liver function tests at birth and repeated at age six months if the pathogenic variants in the family are not known.
All individuals reported to date with biallelic pathogenic variants in
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Serum immunoglobulins, complete blood count, and liver function tests at birth and repeated at age six months if the pathogenic variants in the family are not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Hepatic veno-occlusive disease with immunodeficiency (VODI) is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for an
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 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
All individuals reported to date with biallelic pathogenic variants in
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 should be considered for the reproductive partners of individuals affected with VODI and individuals known to be carriers of an
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
• 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 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
• All individuals reported to date with biallelic pathogenic variants in
• 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 individuals affected with VODI and individuals known to be carriers of an
## Mode of Inheritance
Hepatic veno-occlusive disease with immunodeficiency (VODI) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for an
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 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
All individuals reported to date with biallelic pathogenic variants in
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
• 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 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
• All individuals reported to date with biallelic pathogenic variants in
• 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 should be considered for the reproductive partners of individuals affected with VODI and individuals known to be carriers of 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 individuals affected with VODI and individuals known to be carriers of an
## 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
Hepatic Veno-Occlusive Disease with Immunodeficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Hepatic Veno-Occlusive Disease with Immunodeficiency (
Sp110 nuclear body protein is a member of the Sp100/Sp140 promyelocytic leukemia nuclear body (PML NB) protein family. The protein has an Sp100 domain (amino acids 6-159), which is involved in dimerization with other Sp100 family proteins, a nuclear localization signal (amino acids 288-306), and a nuclear hormone interaction domain (LXXLL type), which may act as an ATRA response element. Other domains that are common features of modular proteins involved in chromatin-mediated gene transcription include a SAND domain (amino acids 452-532), a plant homeobox domain (amino acids 537-577), and a bromodomain (amino acids 606-674) [
Sp110 nuclear body protein associates with the PML NB, a nuclear macromolecular complex, which is deployed to areas of active host or viral DNA replication, transcription, and repair and has been reported to be involved in apoptosis, cell cycle control, and the immune response [
Epstein-Barr virus-transformed B cells from an individual with hepatic veno-occlusive disease with immunodeficiency (VODI) and a homozygous inactivating
There is no mouse model of Sp110 nuclear body protein deficiency, and the mechanisms leading to clinical disease are yet to be fully elucidated. It is currently unknown whether hepatic veno-occlusive disease (hVOD) is a direct manifestation of
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Sp110 nuclear body protein is a member of the Sp100/Sp140 promyelocytic leukemia nuclear body (PML NB) protein family. The protein has an Sp100 domain (amino acids 6-159), which is involved in dimerization with other Sp100 family proteins, a nuclear localization signal (amino acids 288-306), and a nuclear hormone interaction domain (LXXLL type), which may act as an ATRA response element. Other domains that are common features of modular proteins involved in chromatin-mediated gene transcription include a SAND domain (amino acids 452-532), a plant homeobox domain (amino acids 537-577), and a bromodomain (amino acids 606-674) [
Sp110 nuclear body protein associates with the PML NB, a nuclear macromolecular complex, which is deployed to areas of active host or viral DNA replication, transcription, and repair and has been reported to be involved in apoptosis, cell cycle control, and the immune response [
Epstein-Barr virus-transformed B cells from an individual with hepatic veno-occlusive disease with immunodeficiency (VODI) and a homozygous inactivating
There is no mouse model of Sp110 nuclear body protein deficiency, and the mechanisms leading to clinical disease are yet to be fully elucidated. It is currently unknown whether hepatic veno-occlusive disease (hVOD) is a direct manifestation of
Variants listed in the table have been provided by the author.
## Chapter Notes
Michael Buckley, MBChB, PhD, FRCPA, FHGSA; Prince of Wales Hospital (2007-2025)Tony Roscioli, MBBS, FRACP, PhD; Sydney Children's Hospital (2007-2025)Melanie Wong, MBBS, FRACP, FRCPA, PhD (2007-present)John B Ziegler, MBBS, FRACP, MD; Sydney Children's Hospital (2007-2025)
23 January 2025 (sw) Comprehensive update posted live
12 January 2017 (sw) Comprehensive update posted live
3 July 2013 (me) Comprehensive update posted live
15 September 2009 (me) Comprehensive update posted live
21 February 2007 (me) Review posted live
29 November 2006 (mb) Original submission
• 23 January 2025 (sw) Comprehensive update posted live
• 12 January 2017 (sw) Comprehensive update posted live
• 3 July 2013 (me) Comprehensive update posted live
• 15 September 2009 (me) Comprehensive update posted live
• 21 February 2007 (me) Review posted live
• 29 November 2006 (mb) Original submission
## Author History
Michael Buckley, MBChB, PhD, FRCPA, FHGSA; Prince of Wales Hospital (2007-2025)Tony Roscioli, MBBS, FRACP, PhD; Sydney Children's Hospital (2007-2025)Melanie Wong, MBBS, FRACP, FRCPA, PhD (2007-present)John B Ziegler, MBBS, FRACP, MD; Sydney Children's Hospital (2007-2025)
## Revision History
23 January 2025 (sw) Comprehensive update posted live
12 January 2017 (sw) Comprehensive update posted live
3 July 2013 (me) Comprehensive update posted live
15 September 2009 (me) Comprehensive update posted live
21 February 2007 (me) Review posted live
29 November 2006 (mb) Original submission
• 23 January 2025 (sw) Comprehensive update posted live
• 12 January 2017 (sw) Comprehensive update posted live
• 3 July 2013 (me) Comprehensive update posted live
• 15 September 2009 (me) Comprehensive update posted live
• 21 February 2007 (me) Review posted live
• 29 November 2006 (mb) Original submission
## Key Sections in This
## References
## Literature Cited
Hepatic biopsy showing vascular obliteration, perivenular fibrosis, zone 3 fibrosis, and hepatocyte dropout from a girl who presented at age five months with hepatomegaly and ascites (Picro-Mallory stain, 100x)
|
[] |
21/2/2007
|
23/1/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
von-willebrand
|
von-willebrand
|
[
"Von Willebrand Factor Deficiency",
"Type 1 Von Willebrand Disease",
"Type 2A Von Willebrand Disease",
"Type 2B Von Willebrand Disease",
"Type 2M Von Willebrand Disease",
"Type 2N Von Willebrand Disease",
"Type 3 Von Willebrand Disease",
"Type 1C Von Willebrand Disease",
"von Willebrand factor",
"VWF",
"Von Willebrand Disease"
] |
Von Willebrand Disease
|
Jill Johnsen
|
Summary Von Willebrand disease (VWD) is characterized by mucocutaneous bleeding and excessive bleeding with trauma and procedures. Individuals with more severe forms of VWD are also at-risk for musculoskeletal bleeding. Mucocutaneous bleeding can include easy bruising, prolonged bleeding from minor wounds, epistaxis, oral cavity bleeding, heavy menstrual bleeding, gastrointestinal bleeding, and bleeding with hemostatic challenges such as dental work, childbirth, and surgery. Bleeding severity can vary widely in VWD, even between affected individuals within the same family. For some with VWD the bleeding phenotype may only become apparent upon hemostatic challenge, while others may have frequent spontaneous bleeding. The diagnosis of VWD is established in a proband with excessive bleeding by identification of a quantitative or qualitative deficiency in von Willebrand factor (VWF) and/or identification of a VWD-causative variant(s) in Type 1, type 2A, and type 2M VWD are typically caused by a heterozygous Once the familial VWD-causing variant(s) have been identified, prenatal and preimplantation genetic testing for VWD are possible.
|
Von Willebrand Disease: Phenotypic Spectrum
VWD = von Willebrand disease; VWF = von Willebrand factor
## Diagnosis
International guidelines on the diagnosis of von Willebrand disease (VWD) have been published [
VWD
Excessive bruising, particularly without recognized trauma
Prolonged bleeding from cutaneous wounds
Prolonged, recurrent, and/or severe nosebleeds
Bleeding from the gums after brushing or flossing teeth, particularly lifelong or in the absence of periodontal disease, and/or prolonged bleeding following dental cleaning or dental extractions
Excessive female reproductive tract bleeding including uterine bleeding (e.g., heavy menstrual bleeding, postpartum hemorrhage) and ovarian hemorrhage
Prolonged bleeding following invasive procedures, surgery, or trauma
Excessive gastrointestinal bleeding, or gastrointestinal bleeding with angiodysplasia
More severe forms may develop hemarthrosis and/or hemarthropathy
The diagnosis of VWD
Decreased quantity of von Willebrand factor (VWF)
Qualitative defect in VWF identified on a VWF activity assay or VWF multimer gel
VWD-causative variant(s) in
Note: Additional testing can inform VWD type (see
Classification of VWD Based on Specific Laboratory Tests
FVIII = factor VIII; HMW = high-molecular-weight VWF multimers; NA = not applicable; RIPA = ristocetin-induced platelet agglutination; VWD = von Willebrand disease; VWF = von Willebrand factor; VWF:Act = platelet-dependent VWF activity; VWF:Ag = VWF antigen; VWF:CB = VWF collagen binding; VWF:FVIIIB = binding of FVIII by VWF
VWF:Act assays include VWF:RCo, VWF:GPIbR, and VWF:GPIbM. VWF activity assays that do not use ristocetin are preferred when available [
"Low" refers to VWF:Act <50 IU/dL, VWF:Ag <50 IU/dL, VWF:CB <50 IU/dL, or FVIII activity below the laboratory reference range (usually <50 IU/dL).
All sizes of multimers are present, but there may be subtle abnormalities in multimer pattern.
Clinical presentation of type 2B VWD is identical to platelet-type VWD (PT-VWD). Type 2B VWD is distinguished from PT-VWD using molecular genetic testing or specialized RIPA mixing studies.
Thrombocytopenia and decrease in high-molecular-weight VWF multimers usually occur together. In those with a normal platelet count and normal VWF multimer distribution, the predisposition to thrombocytopenia and abnormal VWF multimer distribution is often unmasked by physical stressors.
Reduction in the ability of VWF to bind to collagen. Collagen types I/III are bound by the VWF A3 domain, while collagen types IV and VI are bound by the VWF A1 domain. Most clinical laboratories do not have assays to test VWF binding to all relevant collagen types.
Clinical presentation of type 2N VWD is similar to
Identification of a heterozygous (or, rarely, biallelic) VWD-causing variant in
Identification of biallelic VWD-causing variants in
Note: (1) Molecular genetic testing should be done in a laboratory experienced in testing for VWD. (2) Laboratories may not report the common benign
For an introduction to multigene panels click
Molecular Genetic Testing Used in von Willebrand Disease
VWD = von Willebrand disease
See
See
Sequence analysis detects missense, nonsense, splice site variants, and small insertions or deletions. Sequence analysis should include regulatory regions and the
Gene-targeted deletion/duplication methods can detect deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, custom analyses of next generation sequencing data, multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Sequencing and analysis of
• Excessive bruising, particularly without recognized trauma
• Prolonged bleeding from cutaneous wounds
• Prolonged, recurrent, and/or severe nosebleeds
• Bleeding from the gums after brushing or flossing teeth, particularly lifelong or in the absence of periodontal disease, and/or prolonged bleeding following dental cleaning or dental extractions
• Excessive female reproductive tract bleeding including uterine bleeding (e.g., heavy menstrual bleeding, postpartum hemorrhage) and ovarian hemorrhage
• Prolonged bleeding following invasive procedures, surgery, or trauma
• Excessive gastrointestinal bleeding, or gastrointestinal bleeding with angiodysplasia
• More severe forms may develop hemarthrosis and/or hemarthropathy
• Decreased quantity of von Willebrand factor (VWF)
• Qualitative defect in VWF identified on a VWF activity assay or VWF multimer gel
• VWD-causative variant(s) in
•
• Identification of a heterozygous (or, rarely, biallelic) VWD-causing variant in
• Identification of biallelic VWD-causing variants in
• For an introduction to multigene panels click
## Suggestive Findings
VWD
Excessive bruising, particularly without recognized trauma
Prolonged bleeding from cutaneous wounds
Prolonged, recurrent, and/or severe nosebleeds
Bleeding from the gums after brushing or flossing teeth, particularly lifelong or in the absence of periodontal disease, and/or prolonged bleeding following dental cleaning or dental extractions
Excessive female reproductive tract bleeding including uterine bleeding (e.g., heavy menstrual bleeding, postpartum hemorrhage) and ovarian hemorrhage
Prolonged bleeding following invasive procedures, surgery, or trauma
Excessive gastrointestinal bleeding, or gastrointestinal bleeding with angiodysplasia
More severe forms may develop hemarthrosis and/or hemarthropathy
• Excessive bruising, particularly without recognized trauma
• Prolonged bleeding from cutaneous wounds
• Prolonged, recurrent, and/or severe nosebleeds
• Bleeding from the gums after brushing or flossing teeth, particularly lifelong or in the absence of periodontal disease, and/or prolonged bleeding following dental cleaning or dental extractions
• Excessive female reproductive tract bleeding including uterine bleeding (e.g., heavy menstrual bleeding, postpartum hemorrhage) and ovarian hemorrhage
• Prolonged bleeding following invasive procedures, surgery, or trauma
• Excessive gastrointestinal bleeding, or gastrointestinal bleeding with angiodysplasia
• More severe forms may develop hemarthrosis and/or hemarthropathy
## Establishing the Diagnosis
The diagnosis of VWD
Decreased quantity of von Willebrand factor (VWF)
Qualitative defect in VWF identified on a VWF activity assay or VWF multimer gel
VWD-causative variant(s) in
Note: Additional testing can inform VWD type (see
Classification of VWD Based on Specific Laboratory Tests
FVIII = factor VIII; HMW = high-molecular-weight VWF multimers; NA = not applicable; RIPA = ristocetin-induced platelet agglutination; VWD = von Willebrand disease; VWF = von Willebrand factor; VWF:Act = platelet-dependent VWF activity; VWF:Ag = VWF antigen; VWF:CB = VWF collagen binding; VWF:FVIIIB = binding of FVIII by VWF
VWF:Act assays include VWF:RCo, VWF:GPIbR, and VWF:GPIbM. VWF activity assays that do not use ristocetin are preferred when available [
"Low" refers to VWF:Act <50 IU/dL, VWF:Ag <50 IU/dL, VWF:CB <50 IU/dL, or FVIII activity below the laboratory reference range (usually <50 IU/dL).
All sizes of multimers are present, but there may be subtle abnormalities in multimer pattern.
Clinical presentation of type 2B VWD is identical to platelet-type VWD (PT-VWD). Type 2B VWD is distinguished from PT-VWD using molecular genetic testing or specialized RIPA mixing studies.
Thrombocytopenia and decrease in high-molecular-weight VWF multimers usually occur together. In those with a normal platelet count and normal VWF multimer distribution, the predisposition to thrombocytopenia and abnormal VWF multimer distribution is often unmasked by physical stressors.
Reduction in the ability of VWF to bind to collagen. Collagen types I/III are bound by the VWF A3 domain, while collagen types IV and VI are bound by the VWF A1 domain. Most clinical laboratories do not have assays to test VWF binding to all relevant collagen types.
Clinical presentation of type 2N VWD is similar to
Identification of a heterozygous (or, rarely, biallelic) VWD-causing variant in
Identification of biallelic VWD-causing variants in
Note: (1) Molecular genetic testing should be done in a laboratory experienced in testing for VWD. (2) Laboratories may not report the common benign
For an introduction to multigene panels click
Molecular Genetic Testing Used in von Willebrand Disease
VWD = von Willebrand disease
See
See
Sequence analysis detects missense, nonsense, splice site variants, and small insertions or deletions. Sequence analysis should include regulatory regions and the
Gene-targeted deletion/duplication methods can detect deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, custom analyses of next generation sequencing data, multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Sequencing and analysis of
• Decreased quantity of von Willebrand factor (VWF)
• Qualitative defect in VWF identified on a VWF activity assay or VWF multimer gel
• VWD-causative variant(s) in
•
• Identification of a heterozygous (or, rarely, biallelic) VWD-causing variant in
• Identification of biallelic VWD-causing variants in
• For an introduction to multigene panels click
## Clinical Characteristics
Von Willebrand disease (VWD) is a congenital bleeding disorder. Symptoms may only become apparent on hemostatic challenge, and increased or prolonged bleeding may only be identified after recurrent exposure to hemostatic challenges. Thus, it may take some time before a bleeding history becomes apparent. Individuals with VWD primarily manifest excessive mucocutaneous bleeding (e.g., bruising, epistaxis, ear, nose, and throat bleeding, oral bleeding, heavy menstrual bleeding) and do not tend to experience musculoskeletal bleeding in the absence of trauma unless the factor VIII clotting (FVIII:C) level is low, as can be seen in individuals with type 2N or type 3 VWD.
The three phenotypes reflect a partial quantitative deficiency of VWF (type 1 VWD), complete quantitative deficiency of VWF (type 3 VWD), or qualitative defects in VWF (type 2 VWD). See
Individuals with large deletions of
Clarifications and changes in VWD nomenclature are listed in
Clarifications and Changes in von Willebrand Disease Nomenclature
VWD = von Willebrand disease; VWF = von Willebrand factor
See
VWD affects 0.1% of the population. Prior estimates that VWD affects up to 1% of the population likely included people with low VWF without excessive bleeding. One in 10,000 individuals seek tertiary care referral for VWD.
Type 3 VWD affects 0.5:1,000,000 to 6:1,000,000.
Founder variants in
## Clinical Description
Von Willebrand disease (VWD) is a congenital bleeding disorder. Symptoms may only become apparent on hemostatic challenge, and increased or prolonged bleeding may only be identified after recurrent exposure to hemostatic challenges. Thus, it may take some time before a bleeding history becomes apparent. Individuals with VWD primarily manifest excessive mucocutaneous bleeding (e.g., bruising, epistaxis, ear, nose, and throat bleeding, oral bleeding, heavy menstrual bleeding) and do not tend to experience musculoskeletal bleeding in the absence of trauma unless the factor VIII clotting (FVIII:C) level is low, as can be seen in individuals with type 2N or type 3 VWD.
## Genotype-Phenotype Correlations
The three phenotypes reflect a partial quantitative deficiency of VWF (type 1 VWD), complete quantitative deficiency of VWF (type 3 VWD), or qualitative defects in VWF (type 2 VWD). See
Individuals with large deletions of
## Penetrance
## Nomenclature
Clarifications and changes in VWD nomenclature are listed in
Clarifications and Changes in von Willebrand Disease Nomenclature
VWD = von Willebrand disease; VWF = von Willebrand factor
See
## Prevalence
VWD affects 0.1% of the population. Prior estimates that VWD affects up to 1% of the population likely included people with low VWF without excessive bleeding. One in 10,000 individuals seek tertiary care referral for VWD.
Type 3 VWD affects 0.5:1,000,000 to 6:1,000,000.
Founder variants in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Mild-to-moderate hemophilia A and platelet-type von Willebrand disease (PT-VWD) can be difficult to distinguish phenotypically from von Willebrand disease (VWD) (see
Genetic Disorders in the Differential Diagnosis of von Willebrand Disease
AD = autosomal dominant; FVIII = factor VIII; FVIII:C = factor VIII clotting; MOI = mode of inheritance; RIPA = ristocetin-induced platelet agglutination; VWD = von Willebrand disease; VWF = von Willebrand factor; VWF:FVIIIB = VWF factor VIII binding; XL = X-linked
VWF:FVIIIB assay determines ability of VWF to bind FVIII; it is available although on a limited basis.
One study identified pathogenic variants in
Lymphoproliferative or plasma cell proliferative disorders, paraproteinemias (monoclonal gammopathy of unknown significance), chronic lymphocytic leukemia, multiple myeloma, and Waldenstrom macroglobulinemia. Antibodies against VWF have been detected in some individuals with these disorders.
Autoimmune disorders including systemic lupus erythematosus, scleroderma, and antiphospholipid antibody syndrome
Shear-induced VWF conformational changes leading to relative loss of high-molecular-weight VWF multimers (e.g., aortic valve stenosis, ventricular septal defect, left ventricular assist devices)
Markedly increased blood platelet count (e.g., essential thrombocythemia or other myeloproliferative disorders)
Removal of VWF from circulation by aberrant binding to tumor cells (e.g., Wilms tumor or certain lymphoproliferative disorders) or amyloidosis
Decreased VWF synthesis (e.g., hypothyroidism)
Certain drugs (e.g., valproic acid, ciprofloxacin, griseofulvin, hydroxyethyl starch, N-acetylcysteine)
• Lymphoproliferative or plasma cell proliferative disorders, paraproteinemias (monoclonal gammopathy of unknown significance), chronic lymphocytic leukemia, multiple myeloma, and Waldenstrom macroglobulinemia. Antibodies against VWF have been detected in some individuals with these disorders.
• Autoimmune disorders including systemic lupus erythematosus, scleroderma, and antiphospholipid antibody syndrome
• Shear-induced VWF conformational changes leading to relative loss of high-molecular-weight VWF multimers (e.g., aortic valve stenosis, ventricular septal defect, left ventricular assist devices)
• Markedly increased blood platelet count (e.g., essential thrombocythemia or other myeloproliferative disorders)
• Removal of VWF from circulation by aberrant binding to tumor cells (e.g., Wilms tumor or certain lymphoproliferative disorders) or amyloidosis
• Decreased VWF synthesis (e.g., hypothyroidism)
• Certain drugs (e.g., valproic acid, ciprofloxacin, griseofulvin, hydroxyethyl starch, N-acetylcysteine)
## Management
Clinical practice guidelines for von Willebrand disease (VWD) have been published [
To establish the extent of disease and needs in an individual diagnosed with VWD, the evaluations summarized in
Von Willebrand Disease: Recommended Evaluations Following Initial Diagnosis
Ensure complete & modern VWD eval has been performed whenever possible prior to invasive procedures or other hemostatic risks.
Assess history of bleeding.
Assess VWF levels.
Assess FVIII levels.
CBC = complete blood count; FVIII = factor VIII; IUD = intrauterine device; MOI = mode of inheritance; VWD = von Willebrand disease; VWF = von Willebrand factor
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Von Willebrand factor (VWF) factor replacement (plasma derived or recombinant) is the mainstay of VWD treatment. Desmopressin can be used in individuals who are responsive to desmopressin for non-major, time-limited hemostatic challenges. Guidance on the treatment of VWD has been published [
VWF replacement options include pathogen-inactivated plasma-derived products containing both VWF and factor VIII (FVIII), plasma-derived products depleted of FVIII, and recombinant VWF that does not provide FVIII [
Bleeding episodes can be prevented or controlled with intravenous infusion of VWF-containing replacement treatments.
Plasma-derived concentrates are prepared from pooled blood donations from many donors. Procedures such as pasteurization and detergents inactivate potential pathogens.
Recombinant VWF is manufactured in vitro [
Many individuals with type 1 VWD respond to intranasal, intravenous, or subcutaneous treatment with desmopressin [
Following the diagnosis of type 1 VWD, a desmopressin challenge is recommended to assess VWF response [
Individuals with type 1C VWD will have accelerated VWF clearance after diagnostic desmopressin challenge [
Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group.
Repeat dosing of desmopressin over a short period of time results in tachyphylaxis: a decrease of released VWF after repeated administration.
Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years.
In persons who do not tolerate desmopressin, who have a poor VWF response, who face a moderate or major hemostatic challenge, who cannot sufficiently fluid restrict, or who have a duration of hemostatic need longer than a few days, VWF replacement treatment is required.
Note: Because desmopressin can cause hyponatremia through the retention of free water (which can lead to seizures, coma, or death), fluid intake should be restricted for 24 hours following its administration to minimize this risk.
Targeted Therapy by von Willebrand Disease Type
Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
Desmopressin response is generally poor.
Treatment w/VWF replacement is usually required for moderate or severe hemostatic challenges & is often required for minor challenges.
Many individuals require prophylaxis w/VWF replacement to prevent musculoskeletal bleeding & subsequent joint damage.
Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
Desmopressin is not effective.
Some persons w/type 3 VWD can develop alloantibodies (inhibitors) against VWF.
FVIII = factor VIII; VWD = von Willebrand disease; VWF = von Willebrand factor
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by a comprehensive bleeding disorders program (see
Von Willebrand Disease: Treatment of Manifestations
Fibrinolytic inhibitors (i.e., tranexamic acid, aminocaproic acid) for treatment or prevention of bleeding episodes & as adjunctive therapy for invasive procedures
Tranexamic acid can be used alone for minor bleeding
Nasal care (humidity, water-based gels, saline sprays, treatment of allergies or infections), nasal clamps, nasal packing, nasal cautery, VWF replacement
VWF prophylaxis for refractive or severe recurrent bleeding
Treatment w/tranexamic acid (or aminocaproic acid) ± VWF replacement should be considered for frequent bleeding.
Treatment should be given prior to cautery.
Hormonal treatments (e.g., combined oral contraceptive pill, progestin-only pills, progestin-only injections, hormonal IUDs)
Tranexamic acid (or aminocaproic acid)
Desmopressin
VWF replacement
Combination treatment w/antifibrinolytic &/or hormonal treatment &/or VWD treatment
Risks & benefits of hormonal therapy should be discussed w/affected person prior to starting treatment.
Use of tranexamic acid w/hormonal therapy (in those not desiring pregnancy) or tranexamic acid w/o hormonal therapy (in those desiring conception or w/contraindication) are suggested over desmopressin. Responsiveness to desmopressin should be confirmed prior to therapeutic use.
Endoscopic intervention for active lesions (cautery, injection), VWF replacement, tranexamic acid
VWF prophylaxis for more severe GI bleeding
GI = gastrointestinal; IUD = intrauterine device; VWF = von Willebrand factor
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Von Willebrand Disease: Recommended Surveillance
Assessment at hematology treatment center w/experience w/bleeding disorders
Determination of frequency of bleeding, factors causing incr bleeding, & treatment efficacy & tolerability
CBC & iron levels
VWF levels
Assess for VWD inhibitors in those at risk (type 3 VWD)
Annually, particularly in those receiving treatment
Every 2-3 years in those w/o bleeding & not on treatment
Assessment of joint scores & mobility by PT
Musculoskeletal ultrasound when applicable
CBC = complete blood count; FVIII = factor VIII; GI = gastrointestinal; PT = physical therapist; VWD = von Willebrand disease; VWF = von Willebrand factor
Activities with a high risk of trauma should be approached with caution and full protective gear should be used in sports and recreational activities; high contact sports with risk of head injury should be avoided.
Medications that affect platelet function (e.g., aspirin, clopidogrel) should only be used for clear medical indications and with counseling and monitoring for bleeding, as these medications can worsen bleeding symptoms.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can increase bleeding risk and should be used cautiously and only for brief periods.
Nutritional supplements that may impair hemostasis (e.g., fish oil, turmeric) should be avoided.
All invasive procedures require prior consultation with a hematologist regardless of how minor they are perceived to be by the proceduralist, including common outpatient medical procedures (e.g., circumcision, dental, dermatologic) and non-medical procedures (e.g., piercings).
In newborns with early life complications and anticipated hemostatic challenges (e.g., invasive procedures and/or NICU hospitalization), it is important to assess VWF and FVIII levels as early as possible. More definitive VWD testing (see
VWD hemostasis factor assays sensitive and specific for VWD (see
Molecular genetic testing if the VWD-causing variant(s) in the family are known.
See
VWF levels increase throughout pregnancy, with the peak occurring four hours after delivery [
The 2021 VWD guidelines do not address target VWF levels for delivery [
Although deliveries should occur based on obstetric indications, use of instrumentation to assist delivery (e.g., forceps, vacuum) should be minimized whenever possible [
Delayed, secondary postpartum bleeding rates are high in individuals with VWD. VWD 2021 guidelines suggest the use of tranexamic acid for postpartum hemorrhage prophylaxis. The guidelines do not address duration of postpartum treatment [
Search
• Ensure complete & modern VWD eval has been performed whenever possible prior to invasive procedures or other hemostatic risks.
• Assess history of bleeding.
• Assess VWF levels.
• Assess FVIII levels.
• VWF replacement options include pathogen-inactivated plasma-derived products containing both VWF and factor VIII (FVIII), plasma-derived products depleted of FVIII, and recombinant VWF that does not provide FVIII [
• Bleeding episodes can be prevented or controlled with intravenous infusion of VWF-containing replacement treatments.
• Plasma-derived concentrates are prepared from pooled blood donations from many donors. Procedures such as pasteurization and detergents inactivate potential pathogens.
• Recombinant VWF is manufactured in vitro [
• Many individuals with type 1 VWD respond to intranasal, intravenous, or subcutaneous treatment with desmopressin [
• Following the diagnosis of type 1 VWD, a desmopressin challenge is recommended to assess VWF response [
• Individuals with type 1C VWD will have accelerated VWF clearance after diagnostic desmopressin challenge [
• Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group.
• Repeat dosing of desmopressin over a short period of time results in tachyphylaxis: a decrease of released VWF after repeated administration.
• Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years.
• In persons who do not tolerate desmopressin, who have a poor VWF response, who face a moderate or major hemostatic challenge, who cannot sufficiently fluid restrict, or who have a duration of hemostatic need longer than a few days, VWF replacement treatment is required.
• Note: Because desmopressin can cause hyponatremia through the retention of free water (which can lead to seizures, coma, or death), fluid intake should be restricted for 24 hours following its administration to minimize this risk.
• Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
• Desmopressin response is generally poor.
• Treatment w/VWF replacement is usually required for moderate or severe hemostatic challenges & is often required for minor challenges.
• Many individuals require prophylaxis w/VWF replacement to prevent musculoskeletal bleeding & subsequent joint damage.
• Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
• Desmopressin is not effective.
• Some persons w/type 3 VWD can develop alloantibodies (inhibitors) against VWF.
• Fibrinolytic inhibitors (i.e., tranexamic acid, aminocaproic acid) for treatment or prevention of bleeding episodes & as adjunctive therapy for invasive procedures
• Tranexamic acid can be used alone for minor bleeding
• Nasal care (humidity, water-based gels, saline sprays, treatment of allergies or infections), nasal clamps, nasal packing, nasal cautery, VWF replacement
• VWF prophylaxis for refractive or severe recurrent bleeding
• Treatment w/tranexamic acid (or aminocaproic acid) ± VWF replacement should be considered for frequent bleeding.
• Treatment should be given prior to cautery.
• Hormonal treatments (e.g., combined oral contraceptive pill, progestin-only pills, progestin-only injections, hormonal IUDs)
• Tranexamic acid (or aminocaproic acid)
• Desmopressin
• VWF replacement
• Combination treatment w/antifibrinolytic &/or hormonal treatment &/or VWD treatment
• Risks & benefits of hormonal therapy should be discussed w/affected person prior to starting treatment.
• Use of tranexamic acid w/hormonal therapy (in those not desiring pregnancy) or tranexamic acid w/o hormonal therapy (in those desiring conception or w/contraindication) are suggested over desmopressin. Responsiveness to desmopressin should be confirmed prior to therapeutic use.
• Endoscopic intervention for active lesions (cautery, injection), VWF replacement, tranexamic acid
• VWF prophylaxis for more severe GI bleeding
• Assessment at hematology treatment center w/experience w/bleeding disorders
• Determination of frequency of bleeding, factors causing incr bleeding, & treatment efficacy & tolerability
• CBC & iron levels
• VWF levels
• Assess for VWD inhibitors in those at risk (type 3 VWD)
• Annually, particularly in those receiving treatment
• Every 2-3 years in those w/o bleeding & not on treatment
• Assessment of joint scores & mobility by PT
• Musculoskeletal ultrasound when applicable
• In newborns with early life complications and anticipated hemostatic challenges (e.g., invasive procedures and/or NICU hospitalization), it is important to assess VWF and FVIII levels as early as possible. More definitive VWD testing (see
• VWD hemostasis factor assays sensitive and specific for VWD (see
• Molecular genetic testing if the VWD-causing variant(s) in the family are known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with VWD, the evaluations summarized in
Von Willebrand Disease: Recommended Evaluations Following Initial Diagnosis
Ensure complete & modern VWD eval has been performed whenever possible prior to invasive procedures or other hemostatic risks.
Assess history of bleeding.
Assess VWF levels.
Assess FVIII levels.
CBC = complete blood count; FVIII = factor VIII; IUD = intrauterine device; MOI = mode of inheritance; VWD = von Willebrand disease; VWF = von Willebrand factor
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Ensure complete & modern VWD eval has been performed whenever possible prior to invasive procedures or other hemostatic risks.
• Assess history of bleeding.
• Assess VWF levels.
• Assess FVIII levels.
## Treatment of Manifestations
Von Willebrand factor (VWF) factor replacement (plasma derived or recombinant) is the mainstay of VWD treatment. Desmopressin can be used in individuals who are responsive to desmopressin for non-major, time-limited hemostatic challenges. Guidance on the treatment of VWD has been published [
VWF replacement options include pathogen-inactivated plasma-derived products containing both VWF and factor VIII (FVIII), plasma-derived products depleted of FVIII, and recombinant VWF that does not provide FVIII [
Bleeding episodes can be prevented or controlled with intravenous infusion of VWF-containing replacement treatments.
Plasma-derived concentrates are prepared from pooled blood donations from many donors. Procedures such as pasteurization and detergents inactivate potential pathogens.
Recombinant VWF is manufactured in vitro [
Many individuals with type 1 VWD respond to intranasal, intravenous, or subcutaneous treatment with desmopressin [
Following the diagnosis of type 1 VWD, a desmopressin challenge is recommended to assess VWF response [
Individuals with type 1C VWD will have accelerated VWF clearance after diagnostic desmopressin challenge [
Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group.
Repeat dosing of desmopressin over a short period of time results in tachyphylaxis: a decrease of released VWF after repeated administration.
Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years.
In persons who do not tolerate desmopressin, who have a poor VWF response, who face a moderate or major hemostatic challenge, who cannot sufficiently fluid restrict, or who have a duration of hemostatic need longer than a few days, VWF replacement treatment is required.
Note: Because desmopressin can cause hyponatremia through the retention of free water (which can lead to seizures, coma, or death), fluid intake should be restricted for 24 hours following its administration to minimize this risk.
Targeted Therapy by von Willebrand Disease Type
Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
Desmopressin response is generally poor.
Treatment w/VWF replacement is usually required for moderate or severe hemostatic challenges & is often required for minor challenges.
Many individuals require prophylaxis w/VWF replacement to prevent musculoskeletal bleeding & subsequent joint damage.
Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
Desmopressin is not effective.
Some persons w/type 3 VWD can develop alloantibodies (inhibitors) against VWF.
FVIII = factor VIII; VWD = von Willebrand disease; VWF = von Willebrand factor
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by a comprehensive bleeding disorders program (see
Von Willebrand Disease: Treatment of Manifestations
Fibrinolytic inhibitors (i.e., tranexamic acid, aminocaproic acid) for treatment or prevention of bleeding episodes & as adjunctive therapy for invasive procedures
Tranexamic acid can be used alone for minor bleeding
Nasal care (humidity, water-based gels, saline sprays, treatment of allergies or infections), nasal clamps, nasal packing, nasal cautery, VWF replacement
VWF prophylaxis for refractive or severe recurrent bleeding
Treatment w/tranexamic acid (or aminocaproic acid) ± VWF replacement should be considered for frequent bleeding.
Treatment should be given prior to cautery.
Hormonal treatments (e.g., combined oral contraceptive pill, progestin-only pills, progestin-only injections, hormonal IUDs)
Tranexamic acid (or aminocaproic acid)
Desmopressin
VWF replacement
Combination treatment w/antifibrinolytic &/or hormonal treatment &/or VWD treatment
Risks & benefits of hormonal therapy should be discussed w/affected person prior to starting treatment.
Use of tranexamic acid w/hormonal therapy (in those not desiring pregnancy) or tranexamic acid w/o hormonal therapy (in those desiring conception or w/contraindication) are suggested over desmopressin. Responsiveness to desmopressin should be confirmed prior to therapeutic use.
Endoscopic intervention for active lesions (cautery, injection), VWF replacement, tranexamic acid
VWF prophylaxis for more severe GI bleeding
GI = gastrointestinal; IUD = intrauterine device; VWF = von Willebrand factor
• VWF replacement options include pathogen-inactivated plasma-derived products containing both VWF and factor VIII (FVIII), plasma-derived products depleted of FVIII, and recombinant VWF that does not provide FVIII [
• Bleeding episodes can be prevented or controlled with intravenous infusion of VWF-containing replacement treatments.
• Plasma-derived concentrates are prepared from pooled blood donations from many donors. Procedures such as pasteurization and detergents inactivate potential pathogens.
• Recombinant VWF is manufactured in vitro [
• Many individuals with type 1 VWD respond to intranasal, intravenous, or subcutaneous treatment with desmopressin [
• Following the diagnosis of type 1 VWD, a desmopressin challenge is recommended to assess VWF response [
• Individuals with type 1C VWD will have accelerated VWF clearance after diagnostic desmopressin challenge [
• Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group.
• Repeat dosing of desmopressin over a short period of time results in tachyphylaxis: a decrease of released VWF after repeated administration.
• Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years.
• In persons who do not tolerate desmopressin, who have a poor VWF response, who face a moderate or major hemostatic challenge, who cannot sufficiently fluid restrict, or who have a duration of hemostatic need longer than a few days, VWF replacement treatment is required.
• Note: Because desmopressin can cause hyponatremia through the retention of free water (which can lead to seizures, coma, or death), fluid intake should be restricted for 24 hours following its administration to minimize this risk.
• Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
• Desmopressin response is generally poor.
• Treatment w/VWF replacement is usually required for moderate or severe hemostatic challenges & is often required for minor challenges.
• Many individuals require prophylaxis w/VWF replacement to prevent musculoskeletal bleeding & subsequent joint damage.
• Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
• Desmopressin is not effective.
• Some persons w/type 3 VWD can develop alloantibodies (inhibitors) against VWF.
• Fibrinolytic inhibitors (i.e., tranexamic acid, aminocaproic acid) for treatment or prevention of bleeding episodes & as adjunctive therapy for invasive procedures
• Tranexamic acid can be used alone for minor bleeding
• Nasal care (humidity, water-based gels, saline sprays, treatment of allergies or infections), nasal clamps, nasal packing, nasal cautery, VWF replacement
• VWF prophylaxis for refractive or severe recurrent bleeding
• Treatment w/tranexamic acid (or aminocaproic acid) ± VWF replacement should be considered for frequent bleeding.
• Treatment should be given prior to cautery.
• Hormonal treatments (e.g., combined oral contraceptive pill, progestin-only pills, progestin-only injections, hormonal IUDs)
• Tranexamic acid (or aminocaproic acid)
• Desmopressin
• VWF replacement
• Combination treatment w/antifibrinolytic &/or hormonal treatment &/or VWD treatment
• Risks & benefits of hormonal therapy should be discussed w/affected person prior to starting treatment.
• Use of tranexamic acid w/hormonal therapy (in those not desiring pregnancy) or tranexamic acid w/o hormonal therapy (in those desiring conception or w/contraindication) are suggested over desmopressin. Responsiveness to desmopressin should be confirmed prior to therapeutic use.
• Endoscopic intervention for active lesions (cautery, injection), VWF replacement, tranexamic acid
• VWF prophylaxis for more severe GI bleeding
## Targeted Therapy
Von Willebrand factor (VWF) factor replacement (plasma derived or recombinant) is the mainstay of VWD treatment. Desmopressin can be used in individuals who are responsive to desmopressin for non-major, time-limited hemostatic challenges. Guidance on the treatment of VWD has been published [
VWF replacement options include pathogen-inactivated plasma-derived products containing both VWF and factor VIII (FVIII), plasma-derived products depleted of FVIII, and recombinant VWF that does not provide FVIII [
Bleeding episodes can be prevented or controlled with intravenous infusion of VWF-containing replacement treatments.
Plasma-derived concentrates are prepared from pooled blood donations from many donors. Procedures such as pasteurization and detergents inactivate potential pathogens.
Recombinant VWF is manufactured in vitro [
Many individuals with type 1 VWD respond to intranasal, intravenous, or subcutaneous treatment with desmopressin [
Following the diagnosis of type 1 VWD, a desmopressin challenge is recommended to assess VWF response [
Individuals with type 1C VWD will have accelerated VWF clearance after diagnostic desmopressin challenge [
Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group.
Repeat dosing of desmopressin over a short period of time results in tachyphylaxis: a decrease of released VWF after repeated administration.
Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years.
In persons who do not tolerate desmopressin, who have a poor VWF response, who face a moderate or major hemostatic challenge, who cannot sufficiently fluid restrict, or who have a duration of hemostatic need longer than a few days, VWF replacement treatment is required.
Note: Because desmopressin can cause hyponatremia through the retention of free water (which can lead to seizures, coma, or death), fluid intake should be restricted for 24 hours following its administration to minimize this risk.
Targeted Therapy by von Willebrand Disease Type
Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
Desmopressin response is generally poor.
Treatment w/VWF replacement is usually required for moderate or severe hemostatic challenges & is often required for minor challenges.
Many individuals require prophylaxis w/VWF replacement to prevent musculoskeletal bleeding & subsequent joint damage.
Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
Desmopressin is not effective.
Some persons w/type 3 VWD can develop alloantibodies (inhibitors) against VWF.
FVIII = factor VIII; VWD = von Willebrand disease; VWF = von Willebrand factor
• VWF replacement options include pathogen-inactivated plasma-derived products containing both VWF and factor VIII (FVIII), plasma-derived products depleted of FVIII, and recombinant VWF that does not provide FVIII [
• Bleeding episodes can be prevented or controlled with intravenous infusion of VWF-containing replacement treatments.
• Plasma-derived concentrates are prepared from pooled blood donations from many donors. Procedures such as pasteurization and detergents inactivate potential pathogens.
• Recombinant VWF is manufactured in vitro [
• Many individuals with type 1 VWD respond to intranasal, intravenous, or subcutaneous treatment with desmopressin [
• Following the diagnosis of type 1 VWD, a desmopressin challenge is recommended to assess VWF response [
• Individuals with type 1C VWD will have accelerated VWF clearance after diagnostic desmopressin challenge [
• Desmopressin should be used with caution, particularly in those younger than age two years, because of the potential difficulty in restricting fluids in this age group.
• Repeat dosing of desmopressin over a short period of time results in tachyphylaxis: a decrease of released VWF after repeated administration.
• Desmopressin is contraindicated in individuals with arteriovascular disease and in those older than age 70 years.
• In persons who do not tolerate desmopressin, who have a poor VWF response, who face a moderate or major hemostatic challenge, who cannot sufficiently fluid restrict, or who have a duration of hemostatic need longer than a few days, VWF replacement treatment is required.
• Note: Because desmopressin can cause hyponatremia through the retention of free water (which can lead to seizures, coma, or death), fluid intake should be restricted for 24 hours following its administration to minimize this risk.
• Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
• Desmopressin response is generally poor.
• Treatment w/VWF replacement is usually required for moderate or severe hemostatic challenges & is often required for minor challenges.
• Many individuals require prophylaxis w/VWF replacement to prevent musculoskeletal bleeding & subsequent joint damage.
• Because the FVIII levels are low, a VWF replacement product containing VWF as well as FVIII is preferred in initial treatment over a product containing VWF alone.
• Desmopressin is not effective.
• Some persons w/type 3 VWD can develop alloantibodies (inhibitors) against VWF.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by a comprehensive bleeding disorders program (see
Von Willebrand Disease: Treatment of Manifestations
Fibrinolytic inhibitors (i.e., tranexamic acid, aminocaproic acid) for treatment or prevention of bleeding episodes & as adjunctive therapy for invasive procedures
Tranexamic acid can be used alone for minor bleeding
Nasal care (humidity, water-based gels, saline sprays, treatment of allergies or infections), nasal clamps, nasal packing, nasal cautery, VWF replacement
VWF prophylaxis for refractive or severe recurrent bleeding
Treatment w/tranexamic acid (or aminocaproic acid) ± VWF replacement should be considered for frequent bleeding.
Treatment should be given prior to cautery.
Hormonal treatments (e.g., combined oral contraceptive pill, progestin-only pills, progestin-only injections, hormonal IUDs)
Tranexamic acid (or aminocaproic acid)
Desmopressin
VWF replacement
Combination treatment w/antifibrinolytic &/or hormonal treatment &/or VWD treatment
Risks & benefits of hormonal therapy should be discussed w/affected person prior to starting treatment.
Use of tranexamic acid w/hormonal therapy (in those not desiring pregnancy) or tranexamic acid w/o hormonal therapy (in those desiring conception or w/contraindication) are suggested over desmopressin. Responsiveness to desmopressin should be confirmed prior to therapeutic use.
Endoscopic intervention for active lesions (cautery, injection), VWF replacement, tranexamic acid
VWF prophylaxis for more severe GI bleeding
GI = gastrointestinal; IUD = intrauterine device; VWF = von Willebrand factor
• Fibrinolytic inhibitors (i.e., tranexamic acid, aminocaproic acid) for treatment or prevention of bleeding episodes & as adjunctive therapy for invasive procedures
• Tranexamic acid can be used alone for minor bleeding
• Nasal care (humidity, water-based gels, saline sprays, treatment of allergies or infections), nasal clamps, nasal packing, nasal cautery, VWF replacement
• VWF prophylaxis for refractive or severe recurrent bleeding
• Treatment w/tranexamic acid (or aminocaproic acid) ± VWF replacement should be considered for frequent bleeding.
• Treatment should be given prior to cautery.
• Hormonal treatments (e.g., combined oral contraceptive pill, progestin-only pills, progestin-only injections, hormonal IUDs)
• Tranexamic acid (or aminocaproic acid)
• Desmopressin
• VWF replacement
• Combination treatment w/antifibrinolytic &/or hormonal treatment &/or VWD treatment
• Risks & benefits of hormonal therapy should be discussed w/affected person prior to starting treatment.
• Use of tranexamic acid w/hormonal therapy (in those not desiring pregnancy) or tranexamic acid w/o hormonal therapy (in those desiring conception or w/contraindication) are suggested over desmopressin. Responsiveness to desmopressin should be confirmed prior to therapeutic use.
• Endoscopic intervention for active lesions (cautery, injection), VWF replacement, tranexamic acid
• VWF prophylaxis for more severe GI bleeding
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Von Willebrand Disease: Recommended Surveillance
Assessment at hematology treatment center w/experience w/bleeding disorders
Determination of frequency of bleeding, factors causing incr bleeding, & treatment efficacy & tolerability
CBC & iron levels
VWF levels
Assess for VWD inhibitors in those at risk (type 3 VWD)
Annually, particularly in those receiving treatment
Every 2-3 years in those w/o bleeding & not on treatment
Assessment of joint scores & mobility by PT
Musculoskeletal ultrasound when applicable
CBC = complete blood count; FVIII = factor VIII; GI = gastrointestinal; PT = physical therapist; VWD = von Willebrand disease; VWF = von Willebrand factor
• Assessment at hematology treatment center w/experience w/bleeding disorders
• Determination of frequency of bleeding, factors causing incr bleeding, & treatment efficacy & tolerability
• CBC & iron levels
• VWF levels
• Assess for VWD inhibitors in those at risk (type 3 VWD)
• Annually, particularly in those receiving treatment
• Every 2-3 years in those w/o bleeding & not on treatment
• Assessment of joint scores & mobility by PT
• Musculoskeletal ultrasound when applicable
## Agents/Circumstances to Avoid
Activities with a high risk of trauma should be approached with caution and full protective gear should be used in sports and recreational activities; high contact sports with risk of head injury should be avoided.
Medications that affect platelet function (e.g., aspirin, clopidogrel) should only be used for clear medical indications and with counseling and monitoring for bleeding, as these medications can worsen bleeding symptoms.
Nonsteroidal anti-inflammatory drugs (NSAIDs) can increase bleeding risk and should be used cautiously and only for brief periods.
Nutritional supplements that may impair hemostasis (e.g., fish oil, turmeric) should be avoided.
All invasive procedures require prior consultation with a hematologist regardless of how minor they are perceived to be by the proceduralist, including common outpatient medical procedures (e.g., circumcision, dental, dermatologic) and non-medical procedures (e.g., piercings).
## Evaluation of Relatives at Risk
In newborns with early life complications and anticipated hemostatic challenges (e.g., invasive procedures and/or NICU hospitalization), it is important to assess VWF and FVIII levels as early as possible. More definitive VWD testing (see
VWD hemostasis factor assays sensitive and specific for VWD (see
Molecular genetic testing if the VWD-causing variant(s) in the family are known.
See
• In newborns with early life complications and anticipated hemostatic challenges (e.g., invasive procedures and/or NICU hospitalization), it is important to assess VWF and FVIII levels as early as possible. More definitive VWD testing (see
• VWD hemostasis factor assays sensitive and specific for VWD (see
• Molecular genetic testing if the VWD-causing variant(s) in the family are known.
## Pregnancy Management
VWF levels increase throughout pregnancy, with the peak occurring four hours after delivery [
The 2021 VWD guidelines do not address target VWF levels for delivery [
Although deliveries should occur based on obstetric indications, use of instrumentation to assist delivery (e.g., forceps, vacuum) should be minimized whenever possible [
Delayed, secondary postpartum bleeding rates are high in individuals with VWD. VWD 2021 guidelines suggest the use of tranexamic acid for postpartum hemorrhage prophylaxis. The guidelines do not address duration of postpartum treatment [
## Therapies Under Investigation
Search
## Genetic Counseling
Type 1, type 2A, and type 2M von Willebrand disease (VWD) are typically caused by a heterozygous
Type 2B VWD is typically caused by a heterozygous
Type 2N and type 3 VWD are caused by biallelic
Many individuals diagnosed with autosomal dominant VWD have an affected parent.
A proband with autosomal dominant VWD 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), hemostasis laboratory assays and (if a molecular diagnosis has been established in the proband)
If the VWD-causing 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 VWD-causing 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 VWD-causing variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with autosomal dominant VWD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, variable expressivity, early death of an informative relative (such as a parent) before the recognition of symptoms, or delay of significant hemostatic challenges in affected relatives. Therefore, an apparently negative family history cannot be confirmed without appropriate evaluations (e.g., VWD laboratory assays) and/or molecular genetic testing (to establish that neither parent has VWD-causing variant[s]).
If a parent of the proband is affected and/or is known to have the VWD-causing variant identified in the proband, the risk to the sibs is 50%. VWD often exhibits variable penetrance and expressivity, meaning that not all sibs who inherit a
If the proband has a known VWD-causing 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 gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent (see
Each child of an individual with autosomal dominant VWD has a 50% chance of inheriting the VWD-causing variant.
If the proband's reproductive partner also has VWD-causing variant(s), offspring are at risk of inheriting biallelic VWD
The parents of an individual with autosomal recessive VWD are typically heterozygous for one VWD-causing variant. Alternatively, it is possible that one or both parents have biallelic VWD-causing variants.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and allow reliable recurrence risk assessment. If a VWD-causing 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 VWD-causing variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
Heterozygous parents of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower factor VIII (FVIII) levels and may be diagnosed with VWD.
Heterozygous parents of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may show some mild bleeding symptoms and may be diagnosed with type 1 VWD [
If both parents are known to be heterozygous for a VWD-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial VWD-causing variants.
Heterozygous sibs of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower FVIII levels and may be diagnosed with VWD.
Heterozygous sibs of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may have some bleeding symptoms and low VWF levels and be diagnosed with type 1 VWD [
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 have VWD-causing variant(s).
Genetic testing should be considered for the reproductive partners of individuals with VWD-causing variant(s), particularly if consanguinity is likely and/or if both partners have the same ancestral background.
Once the VWD-causing variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for VWD 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.
• Many individuals diagnosed with autosomal dominant VWD have an affected parent.
• A proband with autosomal dominant VWD 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), hemostasis laboratory assays and (if a molecular diagnosis has been established in the proband)
• If the VWD-causing 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 VWD-causing 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 VWD-causing variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a VWD-causing 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 VWD-causing variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with autosomal dominant VWD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, variable expressivity, early death of an informative relative (such as a parent) before the recognition of symptoms, or delay of significant hemostatic challenges in affected relatives. Therefore, an apparently negative family history cannot be confirmed without appropriate evaluations (e.g., VWD laboratory assays) and/or molecular genetic testing (to establish that neither parent has VWD-causing variant[s]).
• The proband has a
• The proband inherited a VWD-causing 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 VWD-causing 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 VWD-causing variant identified in the proband, the risk to the sibs is 50%. VWD often exhibits variable penetrance and expressivity, meaning that not all sibs who inherit a
• If the proband has a known VWD-causing 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 gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent (see
• Each child of an individual with autosomal dominant VWD has a 50% chance of inheriting the VWD-causing variant.
• If the proband's reproductive partner also has VWD-causing variant(s), offspring are at risk of inheriting biallelic VWD
• The parents of an individual with autosomal recessive VWD are typically heterozygous for one VWD-causing variant. Alternatively, it is possible that one or both parents have biallelic VWD-causing variants.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and allow reliable recurrence risk assessment. If a VWD-causing 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 VWD-causing variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
• One of the VWD-causing variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
• Heterozygous parents of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower factor VIII (FVIII) levels and may be diagnosed with VWD.
• Heterozygous parents of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may show some mild bleeding symptoms and may be diagnosed with type 1 VWD [
• One of the VWD-causing variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
• If both parents are known to be heterozygous for a VWD-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial VWD-causing variants.
• Heterozygous sibs of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower FVIII levels and may be diagnosed with VWD.
• Heterozygous sibs of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may have some bleeding symptoms and low VWF levels and be diagnosed with type 1 VWD [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have VWD-causing variant(s).
• Genetic testing should be considered for the reproductive partners of individuals with VWD-causing variant(s), particularly if consanguinity is likely and/or if both partners have the same ancestral background.
## Mode of Inheritance
Type 1, type 2A, and type 2M von Willebrand disease (VWD) are typically caused by a heterozygous
Type 2B VWD is typically caused by a heterozygous
Type 2N and type 3 VWD are caused by biallelic
## Autosomal Dominant Inheritance – Risk to Family Members
Many individuals diagnosed with autosomal dominant VWD have an affected parent.
A proband with autosomal dominant VWD 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), hemostasis laboratory assays and (if a molecular diagnosis has been established in the proband)
If the VWD-causing 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 VWD-causing 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 VWD-causing variant that is present in the germ (gonadal) cells only.
The family history of some individuals diagnosed with autosomal dominant VWD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, variable expressivity, early death of an informative relative (such as a parent) before the recognition of symptoms, or delay of significant hemostatic challenges in affected relatives. Therefore, an apparently negative family history cannot be confirmed without appropriate evaluations (e.g., VWD laboratory assays) and/or molecular genetic testing (to establish that neither parent has VWD-causing variant[s]).
If a parent of the proband is affected and/or is known to have the VWD-causing variant identified in the proband, the risk to the sibs is 50%. VWD often exhibits variable penetrance and expressivity, meaning that not all sibs who inherit a
If the proband has a known VWD-causing 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 gonadal mosaicism [
If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent (see
Each child of an individual with autosomal dominant VWD has a 50% chance of inheriting the VWD-causing variant.
If the proband's reproductive partner also has VWD-causing variant(s), offspring are at risk of inheriting biallelic VWD
• Many individuals diagnosed with autosomal dominant VWD have an affected parent.
• A proband with autosomal dominant VWD 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), hemostasis laboratory assays and (if a molecular diagnosis has been established in the proband)
• If the VWD-causing 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 VWD-causing 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 VWD-causing variant that is present in the germ (gonadal) cells only.
• The proband has a
• The proband inherited a VWD-causing 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 VWD-causing variant that is present in the germ (gonadal) cells only.
• The family history of some individuals diagnosed with autosomal dominant VWD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, variable expressivity, early death of an informative relative (such as a parent) before the recognition of symptoms, or delay of significant hemostatic challenges in affected relatives. Therefore, an apparently negative family history cannot be confirmed without appropriate evaluations (e.g., VWD laboratory assays) and/or molecular genetic testing (to establish that neither parent has VWD-causing variant[s]).
• The proband has a
• The proband inherited a VWD-causing 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 VWD-causing 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 VWD-causing variant identified in the proband, the risk to the sibs is 50%. VWD often exhibits variable penetrance and expressivity, meaning that not all sibs who inherit a
• If the proband has a known VWD-causing 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 gonadal mosaicism [
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband is increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent (see
• Each child of an individual with autosomal dominant VWD has a 50% chance of inheriting the VWD-causing variant.
• If the proband's reproductive partner also has VWD-causing variant(s), offspring are at risk of inheriting biallelic VWD
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an individual with autosomal recessive VWD are typically heterozygous for one VWD-causing variant. Alternatively, it is possible that one or both parents have biallelic VWD-causing variants.
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and allow reliable recurrence risk assessment. If a VWD-causing 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 VWD-causing variants identified in the proband occurred as a
Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
Heterozygous parents of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower factor VIII (FVIII) levels and may be diagnosed with VWD.
Heterozygous parents of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may show some mild bleeding symptoms and may be diagnosed with type 1 VWD [
If both parents are known to be heterozygous for a VWD-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial VWD-causing variants.
Heterozygous sibs of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower FVIII levels and may be diagnosed with VWD.
Heterozygous sibs of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may have some bleeding symptoms and low VWF levels and be diagnosed with type 1 VWD [
• The parents of an individual with autosomal recessive VWD are typically heterozygous for one VWD-causing variant. Alternatively, it is possible that one or both parents have biallelic VWD-causing variants.
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and allow reliable recurrence risk assessment. If a VWD-causing 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 VWD-causing variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
• One of the VWD-causing variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
• Heterozygous parents of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower factor VIII (FVIII) levels and may be diagnosed with VWD.
• Heterozygous parents of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may show some mild bleeding symptoms and may be diagnosed with type 1 VWD [
• One of the VWD-causing variants identified in the proband occurred as a
• Uniparental isodisomy for the parental chromosome with the VWD-causing variant resulted in homozygosity for the VWD-causing variant in the proband. Maternal uniparental isodisomy has been reported in type 3 VWD [
• If both parents are known to be heterozygous for a VWD-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial VWD-causing variants.
• Heterozygous sibs of an individual with type 2N VWD are often asymptomatic. However, a small proportion of these heterozygous individuals may show some mild bleeding symptoms and lower FVIII levels and may be diagnosed with VWD.
• Heterozygous sibs of an individual with type 3 VWD can have normal VWF levels and be asymptomatic. However, between 15% and 50% may have some bleeding symptoms and low VWF levels and be diagnosed with type 1 VWD [
## 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 have VWD-causing variant(s).
Genetic testing should be considered for the reproductive partners of individuals with VWD-causing variant(s), particularly if consanguinity is likely and/or if both partners have the same ancestral 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 have VWD-causing variant(s).
• Genetic testing should be considered for the reproductive partners of individuals with VWD-causing variant(s), particularly if consanguinity is likely and/or if both partners have the same ancestral background.
## Prenatal Testing and Preimplantation Genetic Testing
Once the VWD-causing variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for VWD 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
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## Molecular Genetics
Von Willebrand Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Von Willebrand Disease (
The von Willebrand facto (VWF) protein is comprised of a 22-amino acid signal peptide, a 741-amino acid propeptide, and a 2,050-amino acid mature protein (see
Binding to the subendothelium at sites of vascular damage and recruiting platelets to sites of clotting; and
Protecting factor VIII (FVIII) from proteolytic degradation in circulation and transporting it to sites of clot generation.
VWF has two sites of synthesis: endothelial cells and megakaryocytes, the precursors of platelets. During synthesis, tail-to-tail disulfide-linked dimers are formed through the C-terminal cystine knot (CK) domains, followed by head-to-head disulfide-linked VWF oligomers of up to 40 dimers in length.
During intracellular processing, the VWF propeptide (VWFpp) is cleaved by furin in the Golgi, plays a critical role in VWF multimerization, remains non-covalently associated with VWF through intracellular trafficking and storage, and is secreted into the plasma along with VWF [
In circulation, high-molecular-wight VWF is cleaved to smaller VWF multimer forms by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif) between amino acids 1605 and 1606 following secretion. The pattern of multimer proteolysis products by agarose-SDS gel analysis can help inform the underlying mechanism [
VWD = von Willebrand disease; VWF = von Willebrand factor; VWF:GPIbR = ristocetin-induced binding of VWF to glycoprotein Ib (GPIb); VWF:RCo = ristocetin cofactor activity testing ability of VWF to agglutinate platelets
Variants listed in the table have been provided by the author.
• Binding to the subendothelium at sites of vascular damage and recruiting platelets to sites of clotting; and
• Protecting factor VIII (FVIII) from proteolytic degradation in circulation and transporting it to sites of clot generation.
## Molecular Pathogenesis
The von Willebrand facto (VWF) protein is comprised of a 22-amino acid signal peptide, a 741-amino acid propeptide, and a 2,050-amino acid mature protein (see
Binding to the subendothelium at sites of vascular damage and recruiting platelets to sites of clotting; and
Protecting factor VIII (FVIII) from proteolytic degradation in circulation and transporting it to sites of clot generation.
VWF has two sites of synthesis: endothelial cells and megakaryocytes, the precursors of platelets. During synthesis, tail-to-tail disulfide-linked dimers are formed through the C-terminal cystine knot (CK) domains, followed by head-to-head disulfide-linked VWF oligomers of up to 40 dimers in length.
During intracellular processing, the VWF propeptide (VWFpp) is cleaved by furin in the Golgi, plays a critical role in VWF multimerization, remains non-covalently associated with VWF through intracellular trafficking and storage, and is secreted into the plasma along with VWF [
In circulation, high-molecular-wight VWF is cleaved to smaller VWF multimer forms by ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif) between amino acids 1605 and 1606 following secretion. The pattern of multimer proteolysis products by agarose-SDS gel analysis can help inform the underlying mechanism [
VWD = von Willebrand disease; VWF = von Willebrand factor; VWF:GPIbR = ristocetin-induced binding of VWF to glycoprotein Ib (GPIb); VWF:RCo = ristocetin cofactor activity testing ability of VWF to agglutinate platelets
Variants listed in the table have been provided by the author.
• Binding to the subendothelium at sites of vascular damage and recruiting platelets to sites of clotting; and
• Protecting factor VIII (FVIII) from proteolytic degradation in circulation and transporting it to sites of clot generation.
## Chapter Notes
Dr Jill Johnsen is a Professor of Medicine at the University of Washington and a physician scientist with expertise in classic hematology. Dr Johnsen sees people with bleeding disorders at the Washington Center for Bleeding Disorders and studies the genetics and biology of variation in clotting factors and blood groups (blood types). A major focus of her work is on the genetics of von Willebrand factor. Dr Johnsen's academic program is dedicated to improving the diagnosis and care of patients through research. More information and links can be found at
Dr Johnsen would like to acknowledge funding that has supported research in VWD including the National Heart Lung and Blood Institute (NIH), Octapharma, Takeda, and the Washington Center for Bleeding Disorders; funding from Hemophilia Alliance that supports genotyping for eligible people with VWD at member HTCs in the US; colleagues that have collaborated with in VWD care and research including Kerry Lannert, Shelley Fletcher, Gayle Teramura, Barbara Konkle, Rebecca Kruse-Jarres, Livia Hegerova, Dan Sabath, Tracy Tun, David Lillicrap, Dan Hampshire, Pam Christopherson, Veronica Flood, Andrew Yee, and David Ginsburg; and the many people living with and impacted by von Willebrand disease who have been critical to advancing this field and improving care.
Anne Goodeve, PhD; University of Sheffield (2009-2024)Paula James, MD, FRCPC; Queen's University (2009-2024)Jill Johnsen, MD (2024-present)
14 November 2024 (sw) Comprehensive update posted live
5 October 2017 (ha) Comprehensive update posted live
24 July 2014 (me) Comprehensive update posted live
13 October 2011 (me) Comprehensive update posted live
4 June 2009 (et) Review posted live
4 December 2008 (ag) Original submission
• 14 November 2024 (sw) Comprehensive update posted live
• 5 October 2017 (ha) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 13 October 2011 (me) Comprehensive update posted live
• 4 June 2009 (et) Review posted live
• 4 December 2008 (ag) Original submission
## Author Notes
Dr Jill Johnsen is a Professor of Medicine at the University of Washington and a physician scientist with expertise in classic hematology. Dr Johnsen sees people with bleeding disorders at the Washington Center for Bleeding Disorders and studies the genetics and biology of variation in clotting factors and blood groups (blood types). A major focus of her work is on the genetics of von Willebrand factor. Dr Johnsen's academic program is dedicated to improving the diagnosis and care of patients through research. More information and links can be found at
## Acknowledgments
Dr Johnsen would like to acknowledge funding that has supported research in VWD including the National Heart Lung and Blood Institute (NIH), Octapharma, Takeda, and the Washington Center for Bleeding Disorders; funding from Hemophilia Alliance that supports genotyping for eligible people with VWD at member HTCs in the US; colleagues that have collaborated with in VWD care and research including Kerry Lannert, Shelley Fletcher, Gayle Teramura, Barbara Konkle, Rebecca Kruse-Jarres, Livia Hegerova, Dan Sabath, Tracy Tun, David Lillicrap, Dan Hampshire, Pam Christopherson, Veronica Flood, Andrew Yee, and David Ginsburg; and the many people living with and impacted by von Willebrand disease who have been critical to advancing this field and improving care.
## Author History
Anne Goodeve, PhD; University of Sheffield (2009-2024)Paula James, MD, FRCPC; Queen's University (2009-2024)Jill Johnsen, MD (2024-present)
## Revision History
14 November 2024 (sw) Comprehensive update posted live
5 October 2017 (ha) Comprehensive update posted live
24 July 2014 (me) Comprehensive update posted live
13 October 2011 (me) Comprehensive update posted live
4 June 2009 (et) Review posted live
4 December 2008 (ag) Original submission
• 14 November 2024 (sw) Comprehensive update posted live
• 5 October 2017 (ha) Comprehensive update posted live
• 24 July 2014 (me) Comprehensive update posted live
• 13 October 2011 (me) Comprehensive update posted live
• 4 June 2009 (et) Review posted live
• 4 December 2008 (ag) Original submission
## Key Sections in This
## References
Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Available
Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O'Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5:301-25. [
James PD, Connell NT, Ameer B, Di Paola J, Eikenboom J, Giraud N, Haberichter S, Jacobs-Pratt V, Konkle B, McLintock C, McRae S, R Montgomery R, O'Donnell JS, Scappe N, Sidonio R, Flood VH, Husainat N, Kalot MA, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5:280-300. [
Johnsen J, Ginsburg D. von Willebrand Disease. In: Kaushansky K, Levi M, eds.
Laffan M, Benson G, Farrelly C, Gomez K, Jones A, Maclean R, O'Donnell J, Lavin M. An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland. Haemophilia. 2023;29:819-26. [
Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167:453-65. [
Platton S, Baker P, Bowyer A, Keenan C, Lawrence C, Lester W, Riddell A, Sutherland M. Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology. Br J Haematol. 2024;204:1714-31. [
• Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Available
• Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O'Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5:301-25. [
• James PD, Connell NT, Ameer B, Di Paola J, Eikenboom J, Giraud N, Haberichter S, Jacobs-Pratt V, Konkle B, McLintock C, McRae S, R Montgomery R, O'Donnell JS, Scappe N, Sidonio R, Flood VH, Husainat N, Kalot MA, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5:280-300. [
• Johnsen J, Ginsburg D. von Willebrand Disease. In: Kaushansky K, Levi M, eds.
• Laffan M, Benson G, Farrelly C, Gomez K, Jones A, Maclean R, O'Donnell J, Lavin M. An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland. Haemophilia. 2023;29:819-26. [
• Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167:453-65. [
• Platton S, Baker P, Bowyer A, Keenan C, Lawrence C, Lester W, Riddell A, Sutherland M. Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology. Br J Haematol. 2024;204:1714-31. [
## Published Guidelines / Consensus Statements
Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Available
Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O'Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5:301-25. [
James PD, Connell NT, Ameer B, Di Paola J, Eikenboom J, Giraud N, Haberichter S, Jacobs-Pratt V, Konkle B, McLintock C, McRae S, R Montgomery R, O'Donnell JS, Scappe N, Sidonio R, Flood VH, Husainat N, Kalot MA, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5:280-300. [
Johnsen J, Ginsburg D. von Willebrand Disease. In: Kaushansky K, Levi M, eds.
Laffan M, Benson G, Farrelly C, Gomez K, Jones A, Maclean R, O'Donnell J, Lavin M. An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland. Haemophilia. 2023;29:819-26. [
Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167:453-65. [
Platton S, Baker P, Bowyer A, Keenan C, Lawrence C, Lester W, Riddell A, Sutherland M. Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology. Br J Haematol. 2024;204:1714-31. [
• Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease. Principles of care for the diagnosis and treatment of von Willebrand disease. Available
• Connell NT, Flood VH, Brignardello-Petersen R, Abdul-Kadir R, Arapshian A, Couper S, Grow JM, Kouides P, Laffan M, Lavin M, Leebeek FWG, O'Brien SH, Ozelo MC, Tosetto A, Weyand AC, James PD, Kalot MA, Husainat N, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5:301-25. [
• James PD, Connell NT, Ameer B, Di Paola J, Eikenboom J, Giraud N, Haberichter S, Jacobs-Pratt V, Konkle B, McLintock C, McRae S, R Montgomery R, O'Donnell JS, Scappe N, Sidonio R, Flood VH, Husainat N, Kalot MA, Mustafa RA. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5:280-300. [
• Johnsen J, Ginsburg D. von Willebrand Disease. In: Kaushansky K, Levi M, eds.
• Laffan M, Benson G, Farrelly C, Gomez K, Jones A, Maclean R, O'Donnell J, Lavin M. An expert consensus to define how higher standards of equitable care for von Willebrand disease can be achieved in the UK and Republic of Ireland. Haemophilia. 2023;29:819-26. [
• Laffan MA, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014;167:453-65. [
• Platton S, Baker P, Bowyer A, Keenan C, Lawrence C, Lester W, Riddell A, Sutherland M. Guideline for laboratory diagnosis and monitoring of von Willebrand disease: A joint guideline from the United Kingdom Haemophilia Centre Doctors' Organisation and the British Society for Haematology. Br J Haematol. 2024;204:1714-31. [
## Literature Cited
An approach to the diagnosis of von Willebrand disease (VWD) [
BS = bleeding score; CBC = complete blood count; DDAVP = desmopressin; FVIII = factor FVIII; FVIII:C = factor VIII coagulant activity; PT = prothrombin time; PTT = partial thromboplastin time; r/o = rule out; TT = thrombin time; VWF:CB/Ag = ratio of VWF collagen binding to VWF antigen; VWF:FVIIIB = VWF FVIII binding.
Adapted with permission from James et al 2021.
Algorithms for additional testing in suspected type 2B von Willebrand disease (VWD) (left) and suspected type 2N VWD (right).
GPIb = glycoprotein Ib; RIPA = ristocetin-induced platelet agglutination; VWF:FVIII = von Willebrand factor/Factor VIII ratio.
Adapted with permission from
VWF protein structure and location of VWD-causing VWF variants by VWD type. Bold horizontal lines indicate the approximate position of exons where VWD-causing variants are most prevalent; thinner lines indicate exons with variants of lower frequency. VWD-causing variants that result in type 2 VWD affect VWF function and cluster in domains primarily disrupted by missense variants.
[reprinted with permission from
|
[] |
4/6/2009
|
14/11/2024
|
26/10/2010
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
vps13d-md
|
vps13d-md
|
[
"Spinocerebellar Ataxia, Recessive, Type 4 (SCAR4)",
"Spinocerebellar Ataxia with Saccadic Intrusion (SCASI)",
"VPS13D Hyperkinetic Movement Disorder",
"VPS13D Hyperkinetic Movement Disorder",
"Spinocerebellar Ataxia with Saccadic Intrusion (SCASI)",
"Spinocerebellar Ataxia, Recessive, Type 4 (SCAR4)",
"Intermembrane lipid transfer protein VPS13D",
"VPS13D",
"VPS13D Movement Disorder"
] |
Inge A Meijer
|
Summary The diagnosis of
|
## Diagnosis
Infantile-onset hypotonia and severe developmental delay or motor delay that progresses to severe generalized dystonia or spastic ataxia
Childhood-onset chorea or dystonia
Early-adulthood-onset progressive spastic ataxia, dystonia, and myoclonus
Macro-saccadic intrusions; these large abnormal back-and-forth eye movements with stationary inter-saccadic intervals are often triggered by saccades.
Pyramidal signs (e.g., hyperreflexia, Babinski signs)
Peripheral axonal neuropathy
Seizures
Elevated CSF lactate (in 1 individual) [
Enlarged mitochondria with altered morphology on muscle biopsy; identified in the only individual evaluated by muscle biopsy [
Symmetric T
Hyperintense T
Hypointense basal ganglia (globus pallidus)
Thin corpus callosum [
Mild cerebellar atrophy, often involving the vermis [
Note: Brain MRI findings can be striking, but imaging results vary among individuals with
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. Because the phenotype 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 developmental delay and/or movement disorder,
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.
Partial duplication of
• Infantile-onset hypotonia and severe developmental delay or motor delay that progresses to severe generalized dystonia or spastic ataxia
• Childhood-onset chorea or dystonia
• Early-adulthood-onset progressive spastic ataxia, dystonia, and myoclonus
• Macro-saccadic intrusions; these large abnormal back-and-forth eye movements with stationary inter-saccadic intervals are often triggered by saccades.
• Pyramidal signs (e.g., hyperreflexia, Babinski signs)
• Peripheral axonal neuropathy
• Seizures
• Elevated CSF lactate (in 1 individual) [
• Enlarged mitochondria with altered morphology on muscle biopsy; identified in the only individual evaluated by muscle biopsy [
• Symmetric T
• Hyperintense T
• Hypointense basal ganglia (globus pallidus)
• Thin corpus callosum [
• Mild cerebellar atrophy, often involving the vermis [
• For an introduction to multigene panels click
## Suggestive Findings
Infantile-onset hypotonia and severe developmental delay or motor delay that progresses to severe generalized dystonia or spastic ataxia
Childhood-onset chorea or dystonia
Early-adulthood-onset progressive spastic ataxia, dystonia, and myoclonus
Macro-saccadic intrusions; these large abnormal back-and-forth eye movements with stationary inter-saccadic intervals are often triggered by saccades.
Pyramidal signs (e.g., hyperreflexia, Babinski signs)
Peripheral axonal neuropathy
Seizures
Elevated CSF lactate (in 1 individual) [
Enlarged mitochondria with altered morphology on muscle biopsy; identified in the only individual evaluated by muscle biopsy [
Symmetric T
Hyperintense T
Hypointense basal ganglia (globus pallidus)
Thin corpus callosum [
Mild cerebellar atrophy, often involving the vermis [
Note: Brain MRI findings can be striking, but imaging results vary among individuals with
• Infantile-onset hypotonia and severe developmental delay or motor delay that progresses to severe generalized dystonia or spastic ataxia
• Childhood-onset chorea or dystonia
• Early-adulthood-onset progressive spastic ataxia, dystonia, and myoclonus
• Macro-saccadic intrusions; these large abnormal back-and-forth eye movements with stationary inter-saccadic intervals are often triggered by saccades.
• Pyramidal signs (e.g., hyperreflexia, Babinski signs)
• Peripheral axonal neuropathy
• Seizures
• Elevated CSF lactate (in 1 individual) [
• Enlarged mitochondria with altered morphology on muscle biopsy; identified in the only individual evaluated by muscle biopsy [
• Symmetric T
• Hyperintense T
• Hypointense basal ganglia (globus pallidus)
• Thin corpus callosum [
• Mild cerebellar atrophy, often involving the vermis [
## 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. Because the phenotype 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 developmental delay and/or movement disorder,
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.
Partial duplication 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 developmental delay and/or movement disorder,
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.
Partial duplication of
## Clinical Characteristics
To date, 19 individuals from 12 families have been identified with
No clear genotype-phenotype correlations are known.
## Clinical Description
To date, 19 individuals from 12 families have been identified with
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlations are known.
## Nomenclature
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of
Adult onset
No dystonia
Normal brain MRI
Spastic ataxic gait
White matter abnormalities
Pediatric-onset spastic ataxia
Dystonia
Myoclonic epilepsy
Oculomotor apraxia
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; HSP = hereditary spastic paraplegia; MOI = mode of inheritance; mt = mitochondrial
SCAR = spinocerebellar ataxia, autosomal recessive; XL = X-linked
See
See
These are the more common subtypes of hereditary spastic paraplegia with onset in childhood.
• Adult onset
• No dystonia
• Normal brain MRI
• Spastic ataxic gait
• White matter abnormalities
• Pediatric-onset spastic ataxia
• Dystonia
• Myoclonic epilepsy
• Oculomotor apraxia
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
EEG = electroencephalogram; EMG = electromyogram; NCS = nerve conduction study; PT = physical therapy
A multidisciplinary team including occupational and physical therapists as well as a physiatrist is important in the care of individuals with this complex movement disorder.
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.
No specific surveillance guidelines exist. The authors recommend following standard ataxia and spasticity guidelines. Care should include regular visits to a neurologist and physiatrist. A speech therapist and a urologist should be consulted when indicated.
Recommended Surveillance for Individuals with
No specific agents or circumstances are to be avoided aside from excessive alcohol use, which could worsen 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 would benefit from developmental services and/or seizure management when appropriate.
See
Studies are currently under way to understand the role of
Search
## 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
EEG = electroencephalogram; EMG = electromyogram; NCS = nerve conduction study; PT = physical therapy
## Treatment of Manifestations
A multidisciplinary team including occupational and physical therapists as well as a physiatrist is important in the care of individuals with this complex movement disorder.
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.
## Developmental Delay / Intellectual Disability Educational 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.
## Surveillance
No specific surveillance guidelines exist. The authors recommend following standard ataxia and spasticity guidelines. Care should include regular visits to a neurologist and physiatrist. A speech therapist and a urologist should be consulted when indicated.
Recommended Surveillance for Individuals with
## Agents/Circumstances to Avoid
No specific agents or circumstances are to be avoided aside from excessive alcohol use, which could worsen 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 would benefit from developmental services and/or seizure management when appropriate.
See
## Therapies Under Investigation
Studies are currently under way to understand the role of
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
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 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 affected, 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
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 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
VPS13D Movement Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for VPS13D Movement Disorder (
In all but one of the 12 reported families, affected individuals have compound heterozygous pathogenic variants with a loss-of-function variant and a presumptive milder missense or splice site variant [
Variants listed in the table have been provided by the author.
N1 or chorein domain (aa 2-115)
VPS13 2nd N-terminal domain (aa 137-356)
Repeat coiled region domain (aa 613-901)
UBA (ubiquitin-associated) domain (aa 2627-2679)
SHR domain (aa 3276-3558)
VPS13 C-terminal domain (aa 3983-4129)
The UBA domain is the only domain unique to VPS13D compared to the other VPS13 family members and is thought to be important for ubiquitin binding. Studies suggest that VPS13D is involved in mitochondrial fission and fusion [
Abnormal mitochondrial morphology has been demonstrated in cell lines of affected individuals. Interestingly,
• N1 or chorein domain (aa 2-115)
• VPS13 2nd N-terminal domain (aa 137-356)
• Repeat coiled region domain (aa 613-901)
• UBA (ubiquitin-associated) domain (aa 2627-2679)
• SHR domain (aa 3276-3558)
• VPS13 C-terminal domain (aa 3983-4129)
## Chapter Notes
The author recently joined the pediatric neurology team and the research center at CHU Sainte Justine, Montreal. As a clinician researcher specializing in pediatric movement disorders, she focuses on expanding our understanding of the genetic basis of pediatric movement disorders including Tourette syndrome and dystonia. Ongoing research includes investigating the role of mitochondria in the
We would like to thank the families for their participation in these studies as well as the various groups who collaborated on this project.
21 February 2019 (sw) Review posted live
25 July 2018 (im) Original submission
• 21 February 2019 (sw) Review posted live
• 25 July 2018 (im) Original submission
## Author Notes
The author recently joined the pediatric neurology team and the research center at CHU Sainte Justine, Montreal. As a clinician researcher specializing in pediatric movement disorders, she focuses on expanding our understanding of the genetic basis of pediatric movement disorders including Tourette syndrome and dystonia. Ongoing research includes investigating the role of mitochondria in the
## Acknowledgments
We would like to thank the families for their participation in these studies as well as the various groups who collaborated on this project.
## Revision History
21 February 2019 (sw) Review posted live
25 July 2018 (im) Original submission
• 21 February 2019 (sw) Review posted live
• 25 July 2018 (im) Original submission
## References
## Literature Cited
|
[
"AL Anding, C Wang, TK Chang, DA Sliter, CM Powers, K Hofmann, RJ Youle, EH Baehrecke. Vps13D encodes a ubiquitin-binding protein that is required for the regulation of mitochondrial size and clearance.. Curr Biol. 2018;28:287-95.e6",
"LA Corben, D Lynch, M Pandolfo, JB Schulz, MB Delatycki. Consensus clinical management guidelines for Friedreich ataxia.. Orphanet J Rare Dis. 2014;9:184",
"J Gauthier, IA Meijer, D Lessel, NE Mencacci, D Krainc, M Hempel, K Tsiakas, H Prokisch, E Rossignol, MH Helm, LH Rodan, J Karamchandani, M Carecchio, SJ Lubbe, A Telegrafi, LB Henderson, K Lorenzo, SE Wallace, IA Glass, FF Hamdan, JL Michaud, GA Rouleau, PM Campeau. Recessive mutations in >VPS13D cause childhood onset movement disorders.. Ann Neurol. 2018;83:1089-95",
"HA Jinnah, SA Factor. Diagnosis and treatment of dystonia.. Neurol Clin. 2015;33:77-100",
"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 Seong, R Insolera, M Dulovic, EJ Kamsteeg, J Trinh, N Brüggemann, E Sandford, S Li, AB Ozel, JZ Li, T Jewett, AJA Kievit, A Münchau, V Shakkottai, C Klein, CA Collins, K Lohmann, BP van de Warrenburg, M Burmeister. Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.. Ann Neurol. 2018;83:1075-88",
"BE Swartz, M Burmeister, JT Somers, KG Rottach, IN Bespalova, RJ Leigh. A form of inherited cerebellar ataxia with saccadic intrusions, increased saccadic speed, sensory neuropathy, and myoclonus.. Ann N Y Acad Sci. 2002;956:441-4",
"BP van de Warrenburg, J van Gaalen, S Boesch, JM Burgunder, A Dürr, P Giunti, T Klockgether, C Mariotti, M Pandolfo, O Riess. EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.. Eur J Neurol. 2014;21:552-62"
] |
21/2/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
vps35-pd
|
vps35-pd
|
[
"PARK17",
"PARK-VPS35",
"PARK17",
"PARK-VPS35",
"Vacuolar protein sorting-associated protein 35",
"VPS35",
"VPS35-Related Parkinson Disease"
] |
Jaroslaw Dulski, Owen A Ross, Zbigniew K Wszolek
|
Summary The diagnosis of PARK- PARK
|
## Diagnosis
Bradykinesia (slowness of movement AND decrement in amplitude or speed) in combination with at least one of the following:
Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
Rigidity (increased muscle tone resulting in resistance to passive movement)
Additional clinical findings of PARK
Adult onset
Typically unilateral onset
Slow disease progression
Good response to levodopa therapy
The diagnosis of PARK-
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 the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of inherited Parkinson disease are largely indistinguishable, most individuals with PARK
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: Single-gene testing (sequence analysis of
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected 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.
• Bradykinesia (slowness of movement AND decrement in amplitude or speed) in combination with at least one of the following:
• Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
• Rigidity (increased muscle tone resulting in resistance to passive movement)
• Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
• Rigidity (increased muscle tone resulting in resistance to passive movement)
• Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
• Rigidity (increased muscle tone resulting in resistance to passive movement)
• Adult onset
• Typically unilateral onset
• Slow disease progression
• Good response to levodopa therapy
## Suggestive Findings
Bradykinesia (slowness of movement AND decrement in amplitude or speed) in combination with at least one of the following:
Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
Rigidity (increased muscle tone resulting in resistance to passive movement)
Additional clinical findings of PARK
Adult onset
Typically unilateral onset
Slow disease progression
Good response to levodopa therapy
• Bradykinesia (slowness of movement AND decrement in amplitude or speed) in combination with at least one of the following:
• Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
• Rigidity (increased muscle tone resulting in resistance to passive movement)
• Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
• Rigidity (increased muscle tone resulting in resistance to passive movement)
• Resting tremor (rhythmic tremor usually of the hands and forearms when relaxed, which disappears with active limb movement)
• Rigidity (increased muscle tone resulting in resistance to passive movement)
• Adult onset
• Typically unilateral onset
• Slow disease progression
• Good response to levodopa therapy
## Establishing the Diagnosis
The diagnosis of PARK-
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 the clinician to determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of inherited Parkinson disease are largely indistinguishable, most individuals with PARK
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: Single-gene testing (sequence analysis of
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected 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.
## Recommended Testing
For an introduction to multigene panels click
## Testing to Consider
For an introduction to comprehensive genomic testing click
Note: Single-gene testing (sequence analysis of
Molecular Genetic Testing Used in
See
See
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants detected 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
Select Features of
Presentation is asymmetric.
The disease course is usually milder than that of simplex Parkinson disease of unknown cause.
Dyskinesia and motor fluctuations may occur.
Atypical signs are very rare. To date, atypical features were observed in only one individual, who developed classic manifestations of Parkinson disease in his early 70s, followed by bulbar symptoms, gait apraxia, falls, supranuclear gaze palsy, apraxia of eyelid opening, and dysexecutive syndrome. However, this individual also had a
Depression was observed in up to 70% of individuals [
Psychotic symptoms occurred in up to 25% of individuals [
Anxiety is rare [
Impaired sense of smell was reported in most individuals. However, the reported number of affected individuals is small, and further investigation is required [
Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation) affect up to 75% of individuals [
Single photon emission computed tomography (SPECT) of cerebral blood flow was normal in one individual [
[
No genotype-phenotype correlations have been identified [
To date, data is too limited to allow quantification of penetrance.
Based on the International Parkinson and Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by
"Idiopathic Parkinson disease" and "sporadic Parkinson disease" are terms used in the Parkinson disease medical literature to describe Parkinson disease of unknown cause diagnosed in an individual with a negative family history. Because future advances in the understanding of genetic risk factors are likely to identify genetic causes /risk factors for some Parkinson disease currently considered "idiopathic" or "sporadic," these terms are generally not used in this
PARK-
The largest study to date included 67 individuals with PARK-
The prevalence of PARK
• Presentation is asymmetric.
• The disease course is usually milder than that of simplex Parkinson disease of unknown cause.
• Dyskinesia and motor fluctuations may occur.
• Atypical signs are very rare. To date, atypical features were observed in only one individual, who developed classic manifestations of Parkinson disease in his early 70s, followed by bulbar symptoms, gait apraxia, falls, supranuclear gaze palsy, apraxia of eyelid opening, and dysexecutive syndrome. However, this individual also had a
• Depression was observed in up to 70% of individuals [
• Psychotic symptoms occurred in up to 25% of individuals [
• Anxiety is rare [
• Impaired sense of smell was reported in most individuals. However, the reported number of affected individuals is small, and further investigation is required [
• Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation) affect up to 75% of individuals [
## Clinical Description
Select Features of
Presentation is asymmetric.
The disease course is usually milder than that of simplex Parkinson disease of unknown cause.
Dyskinesia and motor fluctuations may occur.
Atypical signs are very rare. To date, atypical features were observed in only one individual, who developed classic manifestations of Parkinson disease in his early 70s, followed by bulbar symptoms, gait apraxia, falls, supranuclear gaze palsy, apraxia of eyelid opening, and dysexecutive syndrome. However, this individual also had a
Depression was observed in up to 70% of individuals [
Psychotic symptoms occurred in up to 25% of individuals [
Anxiety is rare [
Impaired sense of smell was reported in most individuals. However, the reported number of affected individuals is small, and further investigation is required [
Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation) affect up to 75% of individuals [
Single photon emission computed tomography (SPECT) of cerebral blood flow was normal in one individual [
[
• Presentation is asymmetric.
• The disease course is usually milder than that of simplex Parkinson disease of unknown cause.
• Dyskinesia and motor fluctuations may occur.
• Atypical signs are very rare. To date, atypical features were observed in only one individual, who developed classic manifestations of Parkinson disease in his early 70s, followed by bulbar symptoms, gait apraxia, falls, supranuclear gaze palsy, apraxia of eyelid opening, and dysexecutive syndrome. However, this individual also had a
• Depression was observed in up to 70% of individuals [
• Psychotic symptoms occurred in up to 25% of individuals [
• Anxiety is rare [
• Impaired sense of smell was reported in most individuals. However, the reported number of affected individuals is small, and further investigation is required [
• Autonomic manifestations including orthostasis and gastrointestinal symptoms (constipation) affect up to 75% of individuals [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified [
## Penetrance
To date, data is too limited to allow quantification of penetrance.
## Nomenclature
Based on the International Parkinson and Movement Disorder Society Task Force for the Nomenclature of Genetic Movement Disorders, the recommended name for Parkinson disease caused by
"Idiopathic Parkinson disease" and "sporadic Parkinson disease" are terms used in the Parkinson disease medical literature to describe Parkinson disease of unknown cause diagnosed in an individual with a negative family history. Because future advances in the understanding of genetic risk factors are likely to identify genetic causes /risk factors for some Parkinson disease currently considered "idiopathic" or "sporadic," these terms are generally not used in this
## Prevalence
PARK-
The largest study to date included 67 individuals with PARK-
The prevalence of PARK
## Genetically Related (Allelic) Disorders
A germline
In another study
## Differential Diagnosis
The differential diagnosis of PARK-
Apart from a younger age at onset and typically slower progression, the phenotype of PARK-
Genes Associated with Early-Onset Adult Parkinson Disease (Age 20-50 Years) and Late-Onset Adult Parkinson Disease (Age >50 Years)
Onset age may be <50 yrs.
Higher likelihood of cognitive impairment & atypical motor findings
Faster progression
Assoc w/dementia w/Lewy bodies
Variable penetrance dependent on age, variant, & ethnicity
Consider if family history of
Classic manifestations w/less non-motor involvement
Variable penetrance dependent on age, variant, & ethnicity
Phenotype similar to PARK-
ID &/or seizures occasionally
Risk to heterozygotes unknown
Phenotype similar to PARK-
Non-motor manifestations (incl psychiatric features) more common
Heterozygotes may have ↑ PD risk.
Slow progression
Can have lower-limb dystonia, dyskinesias, hyperreflexia
Mild non-motor manifestations
Heterozygotes may have ↑ PD risk.
Onset age may be <50 yrs.
Cognitive & psychiatric features more likely
Early-onset PD w/very rapid progression
Truncating variants cause severe disease.
Based on
AD = autosomal dominant; AJ = Ashkenazi Jewish; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; PD = Parkinson disease
Genes are listed in alphabetic order.
Nomenclature based on
There is some disagreement among researchers as to whether
Suspected Genetic Risk Factors for Parkinson Disease
Juvenile-, early-, or late-onset PD
Tremor-dominant parkinsonism
Slow progression
Good response to levodopa
Mild cognitive impairment
Autonomic dysfunction
Early or late onset
Frequent depression
Dementia uncommon
Good response to levodopa
Persons of Asian descent
Late-onset PD
High prevalence of dementia, which may be a first sign
Good response to levodopa
Early- or late-onset PD
Motor fluctuations
Dyskinesia
Good response to levodopa
Persons of Japanese descent
Early- or late-onset PD
Dystonia
Restless legs syndrome
REM sleep behavior disorder
Psychosis
Persons of South Indian descent
Late-onset PD
Slow progression
Good response to levodopa
Based on
Nomenclature based on
2. In a large family with multiple affected family members, hereditary Parkinson disease was attributed to a variant in
• Onset age may be <50 yrs.
• Higher likelihood of cognitive impairment & atypical motor findings
• Faster progression
• Assoc w/dementia w/Lewy bodies
• Variable penetrance dependent on age, variant, & ethnicity
• Consider if family history of
• Classic manifestations w/less non-motor involvement
• Variable penetrance dependent on age, variant, & ethnicity
• Phenotype similar to PARK-
• ID &/or seizures occasionally
• Risk to heterozygotes unknown
• Phenotype similar to PARK-
• Non-motor manifestations (incl psychiatric features) more common
• Heterozygotes may have ↑ PD risk.
• Slow progression
• Can have lower-limb dystonia, dyskinesias, hyperreflexia
• Mild non-motor manifestations
• Heterozygotes may have ↑ PD risk.
• Onset age may be <50 yrs.
• Cognitive & psychiatric features more likely
• Early-onset PD w/very rapid progression
• Truncating variants cause severe disease.
• Juvenile-, early-, or late-onset PD
• Tremor-dominant parkinsonism
• Slow progression
• Good response to levodopa
• Mild cognitive impairment
• Autonomic dysfunction
• Early or late onset
• Frequent depression
• Dementia uncommon
• Good response to levodopa
• Persons of Asian descent
• Late-onset PD
• High prevalence of dementia, which may be a first sign
• Good response to levodopa
• Early- or late-onset PD
• Motor fluctuations
• Dyskinesia
• Good response to levodopa
• Persons of Japanese descent
• Early- or late-onset PD
• Dystonia
• Restless legs syndrome
• REM sleep behavior disorder
• Psychosis
• Persons of South Indian descent
• Late-onset PD
• Slow progression
• Good response to levodopa
## Management
To establish the extent of disease and needs in an individual diagnosed with PARK-
Recommended Evaluations Following Initial Diagnosis in Individuals with
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)
Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
Assess for constipation.
Community or
Social work support;
Home nursing referral.
ADL = activities of daily living; BP = blood pressure; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; PARK
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
To date, the treatment of individuals with PARK-
Treatment of Manifestations in Individuals with
Immediate-release (IR) tablets
Disintegrating tablets
Controlled-release (CR) tablets
Extended-release (ER) capsules
Inhalation powder
Enteral suspension (pump)
IR & CR tablets
Subcutaneous injections & infusion pump (apomorphine)
Transdermal patch (rotigotine)
A good levodopa response was seen in nearly all persons w/PARK
Since there is low risk of neuropsychiatric symptoms in PARK-
To ↓ or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa & dopaminergic medication, doses should not exceed levels required for satisfactory clinical response.
In younger persons, treatment w/dopamine agonists should be given preference.
PT &/or OT to improve &/or maintain gross motor & fine motor skills.
Speech therapy
Reduction of levodopa dose
Use of dopamine receptor agonists
Deep brain stimulation
Continuous application of levodopa or apomorphine
Atypical neuroleptic agents such as low-dose clozapine, quetiepine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations.
Standard treatments for depression
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
Assess for constipation.
Community or
Social work support;
Home nursing referral.
BP = blood pressure
Caused by ergot-derived dopamine agonists
Neuroleptic drugs may increase the severity of parkinsonism in individuals with PARK
Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified [
See
Reports addressing pregnancy management in women with PARK-
The effect of Parkinson disease of any cause on pregnancy has not been well characterized, since pregnancy is uncommon in women with Parkinson disease. In general, half of affected individuals experience improvement or no change in manifestations during pregnancy, whereas half experience worsening manifestations [
No long-term outcome data exist for children born to mothers with Parkinson disease.
Levodopa has not been linked with a higher risk of spontaneous abortions, teratogenicity, or birth complications [
There is insufficient evidence to determine the safety of dopamine agonists, selegiline, and rasagiline in affected individuals during pregnancy [
Anticholinergics were associated with minor birth defects, but no other complications [
Amantadine should be avoided during pregnancy due to teratogenicity [
Discussion of the risks and benefits of using a given medication during pregnancy should ideally take place prior to conception. See
Search
• 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)
• Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
• Assess for constipation.
• Community or
• Social work support;
• Home nursing referral.
• Immediate-release (IR) tablets
• Disintegrating tablets
• Controlled-release (CR) tablets
• Extended-release (ER) capsules
• Inhalation powder
• Enteral suspension (pump)
• IR & CR tablets
• Subcutaneous injections & infusion pump (apomorphine)
• Transdermal patch (rotigotine)
• A good levodopa response was seen in nearly all persons w/PARK
• Since there is low risk of neuropsychiatric symptoms in PARK-
• To ↓ or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa & dopaminergic medication, doses should not exceed levels required for satisfactory clinical response.
• In younger persons, treatment w/dopamine agonists should be given preference.
• PT &/or OT to improve &/or maintain gross motor & fine motor skills.
• Speech therapy
• Reduction of levodopa dose
• Use of dopamine receptor agonists
• Deep brain stimulation
• Continuous application of levodopa or apomorphine
• Atypical neuroleptic agents such as low-dose clozapine, quetiepine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations.
• Standard treatments for depression
• Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
• Assess for constipation.
• Community or
• Social work support;
• Home nursing referral.
• Levodopa has not been linked with a higher risk of spontaneous abortions, teratogenicity, or birth complications [
• There is insufficient evidence to determine the safety of dopamine agonists, selegiline, and rasagiline in affected individuals during pregnancy [
• Anticholinergics were associated with minor birth defects, but no other complications [
• Amantadine should be avoided during pregnancy due to teratogenicity [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PARK-
Recommended Evaluations Following Initial Diagnosis in Individuals with
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)
Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
Assess for constipation.
Community or
Social work support;
Home nursing referral.
ADL = activities of daily living; BP = blood pressure; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; PARK
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• 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)
• Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
• Assess for constipation.
• Community or
• Social work support;
• Home nursing referral.
## Treatment of Manifestations
To date, the treatment of individuals with PARK-
Treatment of Manifestations in Individuals with
Immediate-release (IR) tablets
Disintegrating tablets
Controlled-release (CR) tablets
Extended-release (ER) capsules
Inhalation powder
Enteral suspension (pump)
IR & CR tablets
Subcutaneous injections & infusion pump (apomorphine)
Transdermal patch (rotigotine)
A good levodopa response was seen in nearly all persons w/PARK
Since there is low risk of neuropsychiatric symptoms in PARK-
To ↓ or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa & dopaminergic medication, doses should not exceed levels required for satisfactory clinical response.
In younger persons, treatment w/dopamine agonists should be given preference.
PT &/or OT to improve &/or maintain gross motor & fine motor skills.
Speech therapy
Reduction of levodopa dose
Use of dopamine receptor agonists
Deep brain stimulation
Continuous application of levodopa or apomorphine
Atypical neuroleptic agents such as low-dose clozapine, quetiepine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations.
Standard treatments for depression
• Immediate-release (IR) tablets
• Disintegrating tablets
• Controlled-release (CR) tablets
• Extended-release (ER) capsules
• Inhalation powder
• Enteral suspension (pump)
• IR & CR tablets
• Subcutaneous injections & infusion pump (apomorphine)
• Transdermal patch (rotigotine)
• A good levodopa response was seen in nearly all persons w/PARK
• Since there is low risk of neuropsychiatric symptoms in PARK-
• To ↓ or delay side effects (e.g., dyskinesias, hallucinations, impulse control disorder) of levodopa & dopaminergic medication, doses should not exceed levels required for satisfactory clinical response.
• In younger persons, treatment w/dopamine agonists should be given preference.
• PT &/or OT to improve &/or maintain gross motor & fine motor skills.
• Speech therapy
• Reduction of levodopa dose
• Use of dopamine receptor agonists
• Deep brain stimulation
• Continuous application of levodopa or apomorphine
• Atypical neuroleptic agents such as low-dose clozapine, quetiepine, or pimavanserin & reduction of dopaminergic therapy can ↓ delusions & hallucinations.
• Standard treatments for depression
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
Assess for constipation.
Community or
Social work support;
Home nursing referral.
BP = blood pressure
Caused by ergot-derived dopamine agonists
• Assess for symptoms of orthostasis & measure supine & standing BP & pulse.
• Assess for constipation.
• Community or
• Social work support;
• Home nursing referral.
## Agents/Circumstances to Avoid
Neuroleptic drugs may increase the severity of parkinsonism in individuals with PARK
Ergot-derived dopaminergic drugs should be discontinued if fibrotic heart-valve changes are identified [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Reports addressing pregnancy management in women with PARK-
The effect of Parkinson disease of any cause on pregnancy has not been well characterized, since pregnancy is uncommon in women with Parkinson disease. In general, half of affected individuals experience improvement or no change in manifestations during pregnancy, whereas half experience worsening manifestations [
No long-term outcome data exist for children born to mothers with Parkinson disease.
Levodopa has not been linked with a higher risk of spontaneous abortions, teratogenicity, or birth complications [
There is insufficient evidence to determine the safety of dopamine agonists, selegiline, and rasagiline in affected individuals during pregnancy [
Anticholinergics were associated with minor birth defects, but no other complications [
Amantadine should be avoided during pregnancy due to teratogenicity [
Discussion of the risks and benefits of using a given medication during pregnancy should ideally take place prior to conception. See
• Levodopa has not been linked with a higher risk of spontaneous abortions, teratogenicity, or birth complications [
• There is insufficient evidence to determine the safety of dopamine agonists, selegiline, and rasagiline in affected individuals during pregnancy [
• Anticholinergics were associated with minor birth defects, but no other complications [
• Amantadine should be avoided during pregnancy due to teratogenicity [
## Therapies Under Investigation
Search
## Genetic Counseling
About 90% of individuals diagnosed with PARK
About 10% of individuals with PARK
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 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 PARK
If a parent of the proband has the
To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
The manifestations of PARK
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 found to be heterozygous) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing may facilitate participation in research to better understand PARK
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
Note: It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of PARK
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• About 90% of individuals diagnosed with PARK
• About 10% of individuals with PARK
• 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 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 PARK
• 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 has the
• To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
• The manifestations of PARK
• To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
• The manifestations of PARK
• If the
• If the parents have not been tested for the
• To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
• The manifestations of PARK
• 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 found to be heterozygous) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing may facilitate participation in research to better understand PARK
• 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
About 90% of individuals diagnosed with PARK
About 10% of individuals with PARK
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 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 PARK
If a parent of the proband has the
To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
The manifestations of PARK
If the
If the parents have not been tested for the
• About 90% of individuals diagnosed with PARK
• About 10% of individuals with PARK
• 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 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 PARK
• 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 has the
• To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
• The manifestations of PARK
• To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
• The manifestations of PARK
• If the
• If the parents have not been tested for the
• To date, data are too limited to allow quantification of penetrance; the likelihood that a sib who inherits a familial
• The manifestations of PARK
## 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 found to be heterozygous) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Predictive testing may facilitate participation in research to better understand PARK
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
Note: It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of PARK
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 found to be heterozygous) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing may facilitate participation in research to better understand PARK
• 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.
## Resources
United Kingdom
•
• United Kingdom
•
•
•
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
VPS35-Related Parkinson Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for VPS35-Related Parkinson Disease (
The retromer comprises two assembling subunits: one consists of a trimeric complex of VPS35, VPS26, and VPS29 proteins and is also termed a cargo-selective complex, and the other consists of a sortin nexin dimer (SNX). VPS35 forms a horseshoe-shaped alpha-helical solenoid predicted to contain 33 helices [
Increase the activation of the LRRK2 kinase, thus exerting similar effects as
Affect VPS35 binding to FAM21 of the WASH complex, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [
Redistribute endosomes to a perinuclear localization [
Enlarge endosomes [
Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
Impair VPS35 interaction with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [
Damage dopaminergic pathways, including loss of dopaminergic neurons and axonal degeneration [
Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
Cause mitochondrial dysfunction [
Induce tau pathology and accumulation of total alpha-synuclein in animal models [
Notable
Variants listed in the table have been provided by the authors.
• Increase the activation of the LRRK2 kinase, thus exerting similar effects as
• Affect VPS35 binding to FAM21 of the WASH complex, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [
• Redistribute endosomes to a perinuclear localization [
• Enlarge endosomes [
• Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
• Impair VPS35 interaction with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [
• Damage dopaminergic pathways, including loss of dopaminergic neurons and axonal degeneration [
• Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
• Cause mitochondrial dysfunction [
• Induce tau pathology and accumulation of total alpha-synuclein in animal models [
## Molecular Pathogenesis
The retromer comprises two assembling subunits: one consists of a trimeric complex of VPS35, VPS26, and VPS29 proteins and is also termed a cargo-selective complex, and the other consists of a sortin nexin dimer (SNX). VPS35 forms a horseshoe-shaped alpha-helical solenoid predicted to contain 33 helices [
Increase the activation of the LRRK2 kinase, thus exerting similar effects as
Affect VPS35 binding to FAM21 of the WASH complex, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [
Redistribute endosomes to a perinuclear localization [
Enlarge endosomes [
Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
Impair VPS35 interaction with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [
Damage dopaminergic pathways, including loss of dopaminergic neurons and axonal degeneration [
Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
Cause mitochondrial dysfunction [
Induce tau pathology and accumulation of total alpha-synuclein in animal models [
Notable
Variants listed in the table have been provided by the authors.
• Increase the activation of the LRRK2 kinase, thus exerting similar effects as
• Affect VPS35 binding to FAM21 of the WASH complex, resulting in impairment of recruitment of the WASH complex to endosomes, retromer-mediated sorting of proteins, and autophagy [
• Redistribute endosomes to a perinuclear localization [
• Enlarge endosomes [
• Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
• Impair VPS35 interaction with dopamine receptor D1 (DRD1), causing dysregulation of DRD1 trafficking and impairment of DRD1-mediated dopamine signaling [
• Damage dopaminergic pathways, including loss of dopaminergic neurons and axonal degeneration [
• Lead to lysosomal dysfunction through abnormal sorting of cathepsin D [
• Cause mitochondrial dysfunction [
• Induce tau pathology and accumulation of total alpha-synuclein in animal models [
## Chapter Notes
Dr Zbigniew Wszolek (
Contact Dr Zbigniew Wszolek (
The authors would like to thank the patients and their families for participating in research and their contributions to the field.
JD is partially supported by the Polish National Agency for Academic Exchange (BPN/WAL/2022/1/00007/U/00001), and the Haworth Family Professorship in Neurodegenerative Diseases Fund.
OAR is supported by NIH (RF1 NS085070; U01 NS100620; R01 AG056366; U19 AG071754), DOD (W81XWH-17-1-0249), The Michael J Fox Foundation, American Brain Foundation, and the Mayo Clinic LBD Center without Walls (U54-NS110435). Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and a Lewy Body Dementia Association (LBDA) Research Center of Excellence.
ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, gifts from 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), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and Csf1r biomarker and repository project) 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.
Angela Deutschländer, MD; Mayo Clinic (2017-2023)Jaroslaw Dulski, MD, PhD (2023-present)Owen A Ross, PhD (2017-present)Zbigniew K Wszolek, MD (2017-present)
23 March 2023 (sw) Comprehensive updated posted live
10 August 2017 (bp) Review posted live
15 December 2016 (ad) Original submission
• 23 March 2023 (sw) Comprehensive updated posted live
• 10 August 2017 (bp) Review posted live
• 15 December 2016 (ad) Original submission
## Author Notes
Dr Zbigniew Wszolek (
Contact Dr Zbigniew Wszolek (
## Acknowledgments
The authors would like to thank the patients and their families for participating in research and their contributions to the field.
JD is partially supported by the Polish National Agency for Academic Exchange (BPN/WAL/2022/1/00007/U/00001), and the Haworth Family Professorship in Neurodegenerative Diseases Fund.
OAR is supported by NIH (RF1 NS085070; U01 NS100620; R01 AG056366; U19 AG071754), DOD (W81XWH-17-1-0249), The Michael J Fox Foundation, American Brain Foundation, and the Mayo Clinic LBD Center without Walls (U54-NS110435). Mayo Clinic is an American Parkinson Disease Association (APDA) Mayo Clinic Information and Referral Center, an APDA Center for Advanced Research, and a Lewy Body Dementia Association (LBDA) Research Center of Excellence.
ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, gifts from 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), Neuraly, Inc (NLY01-PD-1), and Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and Csf1r biomarker and repository project) 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.
## Author History
Angela Deutschländer, MD; Mayo Clinic (2017-2023)Jaroslaw Dulski, MD, PhD (2023-present)Owen A Ross, PhD (2017-present)Zbigniew K Wszolek, MD (2017-present)
## Revision History
23 March 2023 (sw) Comprehensive updated posted live
10 August 2017 (bp) Review posted live
15 December 2016 (ad) Original submission
• 23 March 2023 (sw) Comprehensive updated posted live
• 10 August 2017 (bp) Review posted live
• 15 December 2016 (ad) Original submission
## References
## Literature Cited
|
[] |
10/8/2017
|
23/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
vws
|
vws
|
[
"van der Woude Syndrome (VWS)",
"Popliteal Pterygium Syndrome (PPS)",
"IRF6-Related Neural Tube Defect",
"IRF6-Related Orofacial Cleft",
"Interferon regulatory factor 6",
"IRF6",
"IRF6-Related Disorders"
] |
Brian C Schutte, Howard M Saal, Steven Goudy, Elizabeth J Leslie
|
Summary Most commonly, Individuals with VWS show Congenital, usually bilateral, paramedian lower-lip fistulae (pits) or sometimes small mounds with a sinus tract leading from a mucous gland of the lip Cleft lip (CL) Cleft palate (CP) Note: Cleft lip with or without cleft palate (CL±P) is observed about twice as often as CP only. Submucous cleft palate (SMCP) The PPS phenotype includes the following: CL±P Fistulae of the lower lip Webbing of the skin extending from the ischial tuberosities to the heels In males: bifid scrotum and cryptorchidism In females: hypoplasia of the labia majora Syndactyly of fingers and/or toes Anomalies of the skin around the nails A characteristic pyramidal fold of skin overlying the nail of the hallux (almost pathognomonic) In some nonclassic forms of PPS: filiform synechiae connecting the upper and lower jaws (syngnathia) or the upper and lower eyelids (ankyloblepharon) Other musculoskeletal anomalies may include spina bifida occulta, talipes equinovarus, digital reduction, bifid ribs, and short sternum. In VWS, PPS, Diagnosis of an
|
Van der Woude syndrome (VWS)
Popliteal pterygium syndrome (PPS)
For synonyms and outdated names see
• Van der Woude syndrome (VWS)
• Popliteal pterygium syndrome (PPS)
## Diagnosis
Cleft lip with or without cleft palate (CL±P)
Cleft palate (CP)
Submucous cleft palate (SMCP)
CL or CL+P and CP in the same family
* Lip pits are most often paramedian on the lower lip, and can include mounds with a sinus tract leading from a mucous gland of the lip.
Popliteal pterygia
Syndactyly
Abnormal external genitalia
Ankyloblepharon
Pyramidal skin on the hallux
A spectrum of intraoral adhesions, the most severe of which is complete syngnathia
Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
The diagnosis of an
Molecular genetic testing approaches include single-gene testing or a multigene panel.
For an introduction to multigene panels click
Molecular Genetic Testing Used in
NTD = neural tube defect; OFC = orofacial cleft; PPS = popliteal pterygium syndrome; VWS = Van der Woude 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Sequence analysis of
Whole- and partial-gene deletions have been identified in several families with VWS [
Sequence analysis of exon 4 of the
Incidence of deletions/duplications unknown; likely rare as pathogenic variants were identified on sequence analysis in 36 of 37 individuals with PPS [
• Cleft lip with or without cleft palate (CL±P)
• Cleft palate (CP)
• Submucous cleft palate (SMCP)
• Cleft lip with or without cleft palate (CL±P)
• Cleft palate (CP)
• Submucous cleft palate (SMCP)
• CL or CL+P and CP in the same family
• Cleft lip with or without cleft palate (CL±P)
• Cleft palate (CP)
• Submucous cleft palate (SMCP)
• Popliteal pterygia
• Syndactyly
• Abnormal external genitalia
• Ankyloblepharon
• Pyramidal skin on the hallux
• A spectrum of intraoral adhesions, the most severe of which is complete syngnathia
• Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
• For an introduction to multigene panels click
## Suggestive Findings
Cleft lip with or without cleft palate (CL±P)
Cleft palate (CP)
Submucous cleft palate (SMCP)
CL or CL+P and CP in the same family
* Lip pits are most often paramedian on the lower lip, and can include mounds with a sinus tract leading from a mucous gland of the lip.
Popliteal pterygia
Syndactyly
Abnormal external genitalia
Ankyloblepharon
Pyramidal skin on the hallux
A spectrum of intraoral adhesions, the most severe of which is complete syngnathia
Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
• Cleft lip with or without cleft palate (CL±P)
• Cleft palate (CP)
• Submucous cleft palate (SMCP)
• Cleft lip with or without cleft palate (CL±P)
• Cleft palate (CP)
• Submucous cleft palate (SMCP)
• CL or CL+P and CP in the same family
• Cleft lip with or without cleft palate (CL±P)
• Cleft palate (CP)
• Submucous cleft palate (SMCP)
• Popliteal pterygia
• Syndactyly
• Abnormal external genitalia
• Ankyloblepharon
• Pyramidal skin on the hallux
• A spectrum of intraoral adhesions, the most severe of which is complete syngnathia
• Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
## Establishing the Diagnosis
The diagnosis of an
Molecular genetic testing approaches include single-gene testing or a multigene panel.
For an introduction to multigene panels click
Molecular Genetic Testing Used in
NTD = neural tube defect; OFC = orofacial cleft; PPS = popliteal pterygium syndrome; VWS = Van der Woude 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Sequence analysis of
Whole- and partial-gene deletions have been identified in several families with VWS [
Sequence analysis of exon 4 of the
Incidence of deletions/duplications unknown; likely rare as pathogenic variants were identified on sequence analysis in 36 of 37 individuals with PPS [
• For an introduction to multigene panels click
## Clinical Characteristics
The craniofacial features of nonsyndromic orofacial clefting, Van der Woude syndrome (VWS), and popliteal pterygium syndrome (PPS) form a continuum such that it is often difficult to distinguish mildly affected individuals with VWS from those with nonsyndromic orofacial clefting, and mildly affected individuals with PPS from those with VWS. To date, pathogenic variants in
– = not reported; NTD = neural tube defect; OFC = orofacial cleft; PPS = popliteal pterygium syndrome; VWS = Van der Woude syndrome
Individuals with VWS show one or more of the following anomalies: lip pits, cleft lip (CL), cleft palate (CP), and submucous cleft palate (SMCP) [
Growth and intelligence are normal.
In a small study,
The PPS phenotype includes cleft lip and/or palate, fistulae of the lower lip, pterygia, genital anomalies, and characteristic digit anomalies.
Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon) may occur.
Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
Growth and intelligence are normal.
Two individuals with spina bifida were found to have a heterozygous
Eighteen individuals with orofacial cleft were found to have a heterozygous
It appears likely that certain pathogenic variants (
There are examples of variable expressivity, where at least one member of the same family is diagnosed with PPS, while at least one other member is diagnosed with VWS.
The following terms were used in the original description of Van der Woude syndrome by Anne
Congenital pits of the lower lip
Fistula labii inferioris congenita
Congenital fistulae of the lower lip
Current nomenclature is "lip pits," "lip eminences," or more inclusively "lip abnormalities."
• Growth and intelligence are normal.
• In a small study,
• Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon) may occur.
• Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
• Growth and intelligence are normal.
• Congenital pits of the lower lip
• Fistula labii inferioris congenita
• Congenital fistulae of the lower lip
## Clinical Description
The craniofacial features of nonsyndromic orofacial clefting, Van der Woude syndrome (VWS), and popliteal pterygium syndrome (PPS) form a continuum such that it is often difficult to distinguish mildly affected individuals with VWS from those with nonsyndromic orofacial clefting, and mildly affected individuals with PPS from those with VWS. To date, pathogenic variants in
– = not reported; NTD = neural tube defect; OFC = orofacial cleft; PPS = popliteal pterygium syndrome; VWS = Van der Woude syndrome
Individuals with VWS show one or more of the following anomalies: lip pits, cleft lip (CL), cleft palate (CP), and submucous cleft palate (SMCP) [
Growth and intelligence are normal.
In a small study,
The PPS phenotype includes cleft lip and/or palate, fistulae of the lower lip, pterygia, genital anomalies, and characteristic digit anomalies.
Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon) may occur.
Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
Growth and intelligence are normal.
Two individuals with spina bifida were found to have a heterozygous
Eighteen individuals with orofacial cleft were found to have a heterozygous
• Growth and intelligence are normal.
• In a small study,
• Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon) may occur.
• Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
• Growth and intelligence are normal.
## Van der Woude Syndrome
Individuals with VWS show one or more of the following anomalies: lip pits, cleft lip (CL), cleft palate (CP), and submucous cleft palate (SMCP) [
Growth and intelligence are normal.
In a small study,
• Growth and intelligence are normal.
• In a small study,
## Popliteal Pterygium Syndrome
The PPS phenotype includes cleft lip and/or palate, fistulae of the lower lip, pterygia, genital anomalies, and characteristic digit anomalies.
Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon) may occur.
Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
Growth and intelligence are normal.
• Filiform synechiae connecting the upper and lower jaws (syngnathia) and/or the upper and lower eyelids (ankyloblepharon) may occur.
• Musculoskeletal anomalies are rarely reported (e.g., talipes equinovarus, digital reduction, spina bifida occulta, bifid ribs, short sternum).
• Growth and intelligence are normal.
Two individuals with spina bifida were found to have a heterozygous
Eighteen individuals with orofacial cleft were found to have a heterozygous
## Genotype-Phenotype Correlations
It appears likely that certain pathogenic variants (
There are examples of variable expressivity, where at least one member of the same family is diagnosed with PPS, while at least one other member is diagnosed with VWS.
## Penetrance
## Nomenclature
The following terms were used in the original description of Van der Woude syndrome by Anne
Congenital pits of the lower lip
Fistula labii inferioris congenita
Congenital fistulae of the lower lip
Current nomenclature is "lip pits," "lip eminences," or more inclusively "lip abnormalities."
• Congenital pits of the lower lip
• Fistula labii inferioris congenita
• Congenital fistulae of the lower lip
## Prevalence
## Genetically Related (Allelic) Disorders
Large contiguous gene deletions that include
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AEC = ankyloblepharon-ectodermal defects-cleft lip/palate; AR = autosomal recessive; CL = cleft lip; CL±P = cleft lip with or without cleft palate; CP = cleft palate; EEC3 = ectrodactyly, ectodermal dysplasia, cleft lip/palate 3; ID = intellectual disability; MOI = mode of inheritance; PPS = popliteal pterygium syndrome; VWS = Van der Woude syndrome; XL = X-linked
Ankyloblepharon (or eyelid synechiae) present at birth is seen occasionally in popliteal pterygium syndrome.
Prominent philtral pillars that give the appearance of a repaired cleft lip (formerly called "pseudocleft lip").
The mixed clefting seen in
Ankyloblepharon (or eyelid synechiae) present at birth is seen occasionally in popliteal pterygium syndrome. These may also be seen in
• The mixed clefting seen in
• Ankyloblepharon (or eyelid synechiae) present at birth is seen occasionally in popliteal pterygium syndrome. These may also be seen in
## 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
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; PPS = popliteal pterygium syndrome
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Management is supportive/symptomatic.
Treatment of Manifestations in Individuals with
In addition to surgery, dentistry, & orthodontics, speech therapy & audiologic eval are usually needed.
Otolaryngology eval is needed for mgmt of middle ear effusions.
Speech therapy or other interventions are appropriate for child w/secondary hearing loss.
Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss
Some may have pressure-equalizing tubes placed.
May require surgery esp in presence of cryptorchidism
Genital anomalies may result in infertility.
PT = physical therapy
The following surveillance guidelines are adapted from the
Recommended Surveillance for Individuals with
Follow-up eval w/in 1st 6 mos of life
Continue evals throughout adolescence.
Follow-up eval w/infant's 1st visit to cleft clinic
Timing & frequency of follow-up evals based on person's history of ear disease or hearing loss
Routine evals through adolescence
Follow up by age 6 mos for assessment of prelinguistic speech-language development
During 1st 2 yrs of life, evaluate children at least twice, then at least annually until adenoid involution.
After adenoid involution, evaluate at least every 2 yrs until dental & skeletal maturity.
Follow-up eval w/in 6 mos of 1st tooth erupting; no later than age 12 mos
Continue routine dental eval throughout life.
Offspring and/or sibs of an affected individual should be clinically examined for evidence of cleft palate including submucous cleft, lip abnormalities (pits or mounds), and the pyramidal skin fold on the nail of the hallux, given the variable expressivity and incomplete penetrance of VWS and PPS.
See
Search
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• In addition to surgery, dentistry, & orthodontics, speech therapy & audiologic eval are usually needed.
• Otolaryngology eval is needed for mgmt of middle ear effusions.
• Speech therapy or other interventions are appropriate for child w/secondary hearing loss.
• Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss
• Some may have pressure-equalizing tubes placed.
• May require surgery esp in presence of cryptorchidism
• Genital anomalies may result in infertility.
• Follow-up eval w/in 1st 6 mos of life
• Continue evals throughout adolescence.
• Follow-up eval w/infant's 1st visit to cleft clinic
• Timing & frequency of follow-up evals based on person's history of ear disease or hearing loss
• Routine evals through adolescence
• Follow up by age 6 mos for assessment of prelinguistic speech-language development
• During 1st 2 yrs of life, evaluate children at least twice, then at least annually until adenoid involution.
• After adenoid involution, evaluate at least every 2 yrs until dental & skeletal maturity.
• Follow-up eval w/in 6 mos of 1st tooth erupting; no later than age 12 mos
• Continue routine dental eval throughout life.
## 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
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; PPS = popliteal pterygium syndrome
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Management is supportive/symptomatic.
Treatment of Manifestations in Individuals with
In addition to surgery, dentistry, & orthodontics, speech therapy & audiologic eval are usually needed.
Otolaryngology eval is needed for mgmt of middle ear effusions.
Speech therapy or other interventions are appropriate for child w/secondary hearing loss.
Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss
Some may have pressure-equalizing tubes placed.
May require surgery esp in presence of cryptorchidism
Genital anomalies may result in infertility.
PT = physical therapy
• In addition to surgery, dentistry, & orthodontics, speech therapy & audiologic eval are usually needed.
• Otolaryngology eval is needed for mgmt of middle ear effusions.
• Speech therapy or other interventions are appropriate for child w/secondary hearing loss.
• Timely treatment of otitis media secondary to eustachian tube dysfunction due to cleft palate to prevent secondary hearing loss
• Some may have pressure-equalizing tubes placed.
• May require surgery esp in presence of cryptorchidism
• Genital anomalies may result in infertility.
## Surveillance
The following surveillance guidelines are adapted from the
Recommended Surveillance for Individuals with
Follow-up eval w/in 1st 6 mos of life
Continue evals throughout adolescence.
Follow-up eval w/infant's 1st visit to cleft clinic
Timing & frequency of follow-up evals based on person's history of ear disease or hearing loss
Routine evals through adolescence
Follow up by age 6 mos for assessment of prelinguistic speech-language development
During 1st 2 yrs of life, evaluate children at least twice, then at least annually until adenoid involution.
After adenoid involution, evaluate at least every 2 yrs until dental & skeletal maturity.
Follow-up eval w/in 6 mos of 1st tooth erupting; no later than age 12 mos
Continue routine dental eval throughout life.
• Follow-up eval w/in 1st 6 mos of life
• Continue evals throughout adolescence.
• Follow-up eval w/infant's 1st visit to cleft clinic
• Timing & frequency of follow-up evals based on person's history of ear disease or hearing loss
• Routine evals through adolescence
• Follow up by age 6 mos for assessment of prelinguistic speech-language development
• During 1st 2 yrs of life, evaluate children at least twice, then at least annually until adenoid involution.
• After adenoid involution, evaluate at least every 2 yrs until dental & skeletal maturity.
• Follow-up eval w/in 6 mos of 1st tooth erupting; no later than age 12 mos
• Continue routine dental eval throughout life.
## Evaluation of Relatives at Risk
Offspring and/or sibs of an affected individual should be clinically examined for evidence of cleft palate including submucous cleft, lip abnormalities (pits or mounds), and the pyramidal skin fold on the nail of the hallux, given the variable expressivity and incomplete penetrance of VWS and PPS.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with an
A proband with an
In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had 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 only in the germ cells.
The family history of some individuals diagnosed with an
If a parent of the proband is affected and/or is known to have the
The clinical manifestations of
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 of transmitting the disorder.
Once 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.
• Most individuals diagnosed with an
• A proband with an
• In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
• A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had a
• In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
• A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had 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 only in the germ cells.
• 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 only in the germ cells.
• The family history of some individuals diagnosed with an
• In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
• A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had 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 and will not detect a pathogenic variant that is present only in the germ cells.
• If a parent of the proband is affected and/or is known to have the
• The clinical manifestations of
• 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 of transmitting the disorder.
## Mode of Inheritance
## Risk to Family Members
Most individuals diagnosed with an
A proband with an
In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had 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 only in the germ cells.
The family history of some individuals diagnosed with an
If a parent of the proband is affected and/or is known to have the
The clinical manifestations of
If the parents have not been tested for the
• Most individuals diagnosed with an
• A proband with an
• In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
• A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had a
• In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
• A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had 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 only in the germ cells.
• 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 only in the germ cells.
• The family history of some individuals diagnosed with an
• In a study of 16 families with VWS and one family with PPS, two individuals with VWS who represented simplex cases (i.e., a single affected family member) had a
• A female born with ankyloblepharon and lip pits, diagnosed as a mild form of PPS, had 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 and will not detect a pathogenic variant that is present only in the germ cells.
• If a parent of the proband is affected and/or is known to have the
• The clinical manifestations of
• 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 of transmitting 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 of transmitting the disorder.
## Prenatal Testing and Preimplantation Genetic Testing
Once 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.
## Resources
United Kingdom
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
IRF6-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for IRF6-Related Disorders (
The function of the normal gene product of
The IRFs are best known to regulate the expression of interferon-alpha and interferon-beta after viral infection [
Mice deficient for
Notable
–
PPS = popliteal pterygium syndrome; VWS = Van der Woude syndrome
Variants listed in the table have been provided by the authors.
See
## Molecular Pathogenesis
The function of the normal gene product of
The IRFs are best known to regulate the expression of interferon-alpha and interferon-beta after viral infection [
Mice deficient for
Notable
–
PPS = popliteal pterygium syndrome; VWS = Van der Woude syndrome
Variants listed in the table have been provided by the authors.
See
## Chapter Notes
Bryan Cary Bjork, PhD; Harvard Medical School (2003-2011)Kate M Durda, MS; University of Iowa (2011-2014)Steven Goudy, MD, FACS, FAAP (2014-present)Katherine Nash Krahn, MS; University of Iowa (2003-2011) Elizabeth J Leslie, PhD (2014-present)Jeffrey C Murray, MD; University of Iowa (2003-2014)Howard M Saal, MD, FACMG (2014-present)Brian C Schutte, PhD (2003-present)
4 March 2021 (sw) Comprehensive update posted live
3 July 2014 (me) Comprehensive update posted live
1 March 2011 (me) Comprehensive update posted live
15 May 2006 (me) Comprehensive update posted live
30 October 2003 (me) Review posted live
27 May 2003 (jcm) Original submission
• 4 March 2021 (sw) Comprehensive update posted live
• 3 July 2014 (me) Comprehensive update posted live
• 1 March 2011 (me) Comprehensive update posted live
• 15 May 2006 (me) Comprehensive update posted live
• 30 October 2003 (me) Review posted live
• 27 May 2003 (jcm) Original submission
## Author History
Bryan Cary Bjork, PhD; Harvard Medical School (2003-2011)Kate M Durda, MS; University of Iowa (2011-2014)Steven Goudy, MD, FACS, FAAP (2014-present)Katherine Nash Krahn, MS; University of Iowa (2003-2011) Elizabeth J Leslie, PhD (2014-present)Jeffrey C Murray, MD; University of Iowa (2003-2014)Howard M Saal, MD, FACMG (2014-present)Brian C Schutte, PhD (2003-present)
## Revision History
4 March 2021 (sw) Comprehensive update posted live
3 July 2014 (me) Comprehensive update posted live
1 March 2011 (me) Comprehensive update posted live
15 May 2006 (me) Comprehensive update posted live
30 October 2003 (me) Review posted live
27 May 2003 (jcm) Original submission
• 4 March 2021 (sw) Comprehensive update posted live
• 3 July 2014 (me) Comprehensive update posted live
• 1 March 2011 (me) Comprehensive update posted live
• 15 May 2006 (me) Comprehensive update posted live
• 30 October 2003 (me) Review posted live
• 27 May 2003 (jcm) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
30/10/2003
|
4/3/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
wac-id
|
wac-id
|
[
"WW domain-containing adapter protein with coiled-coil",
"WAC",
"WAC-Related Intellectual Disability"
] |
Konstantinos Varvagiannis, Bert BA de Vries, Lisenka ELM Vissers
|
Summary The diagnosis of
|
## Diagnosis
No formal clinical diagnostic criteria exist for
Developmental delay or variable degrees of intellectual disability
One or more of the following:
Generalized hypotonia in infancy with or without associated oral hypotonia
Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
Abnormal vision including cortical visual impairment, strabismus, and refractive errors
Other less specific features that may prompt further consideration of this diagnosis include:
Seizures
Abnormalities of the extremities including brachydactyly, presence of fetal finger pads, and planovalgus deformity of the feet
Inverted nipples
The diagnosis of
Note: Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
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 phenotypes of inherited intellectual disability overlap, most individuals with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: Single-gene testing (sequence analysis of
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.
Individuals reported to have larger deletions that include more genes in the 10p12.1 region have phenotypic features that overlap those of
To date, one individual has been reported with an intragenic deletion encompassing exons 5 to 14 (originally detected by CMA) [
• Developmental delay or variable degrees of intellectual disability
• One or more of the following:
• Generalized hypotonia in infancy with or without associated oral hypotonia
• Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
• Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
• Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
• Abnormal vision including cortical visual impairment, strabismus, and refractive errors
• Generalized hypotonia in infancy with or without associated oral hypotonia
• Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
• Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
• Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
• Abnormal vision including cortical visual impairment, strabismus, and refractive errors
• Generalized hypotonia in infancy with or without associated oral hypotonia
• Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
• Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
• Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
• Abnormal vision including cortical visual impairment, strabismus, and refractive errors
• Seizures
• Abnormalities of the extremities including brachydactyly, presence of fetal finger pads, and planovalgus deformity of the feet
• Inverted nipples
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Developmental delay or variable degrees of intellectual disability
One or more of the following:
Generalized hypotonia in infancy with or without associated oral hypotonia
Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
Abnormal vision including cortical visual impairment, strabismus, and refractive errors
Other less specific features that may prompt further consideration of this diagnosis include:
Seizures
Abnormalities of the extremities including brachydactyly, presence of fetal finger pads, and planovalgus deformity of the feet
Inverted nipples
• Developmental delay or variable degrees of intellectual disability
• One or more of the following:
• Generalized hypotonia in infancy with or without associated oral hypotonia
• Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
• Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
• Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
• Abnormal vision including cortical visual impairment, strabismus, and refractive errors
• Generalized hypotonia in infancy with or without associated oral hypotonia
• Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
• Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
• Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
• Abnormal vision including cortical visual impairment, strabismus, and refractive errors
• Generalized hypotonia in infancy with or without associated oral hypotonia
• Neonatal feeding difficulties, gastroesophageal reflux, and/or constipation
• Behavioral abnormalities including anxiety, attention-deficit/hyperactivity disorder (ADHD), aggression, sleep disturbances, and autism spectrum disorder (ASD)
• Respiratory problems: recurrent infections, asthma, and/or abnormal breathing pattern
• Abnormal vision including cortical visual impairment, strabismus, and refractive errors
• Seizures
• Abnormalities of the extremities including brachydactyly, presence of fetal finger pads, and planovalgus deformity of the feet
• Inverted nipples
## Establishing the Diagnosis
The diagnosis of
Note: Per ACMG 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. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.
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 phenotypes of inherited intellectual disability overlap, most individuals with
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Note: Single-gene testing (sequence analysis of
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.
Individuals reported to have larger deletions that include more genes in the 10p12.1 region have phenotypic features that overlap those of
To date, one individual has been reported with an intragenic deletion encompassing exons 5 to 14 (originally detected by CMA) [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, 18 individuals have been identified with a pathogenic variant in
While the preliminary information available does not allow firm conclusions, approximately two thirds of the individuals reported to date are nonverbal at age 18 months. Although severe speech delay does not seem to be the rule, a few children remained nonverbal at age four years (and in some cases beyond). Dysarthria secondary to oral hypotonia was reported in some [
Variable degrees of both fine motor and gross motor delay have been observed in almost all individuals for whom this information is available. Walking was achieved after age 21 months in the majority. Fine motor development may be equally affected as some individuals have been reported to have poor hand dexterity or clumsiness and difficulty in global coordination.
Intellectual disability, which appears to be present in the majority of affected individuals, is typically in the mild end of the spectrum and was only observed in the moderate-to-severe range in fewer than 20% (3/18). Of note, on formal IQ testing two individuals had results within the normal range (full-scale IQ scores 98 [
Attention-deficit/hyperactivity disorder and anxiety have been observed in 30%-40% of individuals.
Approximately 20% of reported individuals had a formal diagnosis of autism spectrum disorder (ASD). Autistic traits were reported in one individual.
Aggressive and self-injurious behavior was reported in a few individuals.
Minor ear anomalies have been described in 50% of affected individuals (8/16), including posteriorly rotated ears and prominence of the antihelix (most commonly of the stem, although the superior and inferior crus can also be prominent).
Tonic-clonic seizures
Absence episodes
Seizure-like activity
Febrile convulsions
Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [
A girl age nine years with unspecified kidney problems [
To date only loss-of-function
Variability in intellectual function has been observed in individuals with the same
In two unrelated individuals with the variant
In two sibs with the same variant, intellectual functioning was borderline in one and normal in the other, who (despite a full-scale IQ score of 98) was reported to perform below average in some verbal and nonverbal skills (e.g., confrontation naming or spatial orientation) and to score low in evaluation of motor function [
To date all individuals with
To date, 18 individuals with
In each of the following cohorts of children with ID and/or autism spectrum disorder (ASD), one child was found to have a
One of 1,133 children with severe, undiagnosed, developmental disorders [
One of 258 unrelated children with ASD, all of whom were initially tested by chromosomal microarray analysis and 95 of whom were further investigated by trio exome sequencing (i.e., exome sequencing of the proband and both parents) [
The prevalence of
• Tonic-clonic seizures
• Absence episodes
• Seizure-like activity
• Febrile convulsions
• Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [
• A girl age nine years with unspecified kidney problems [
•
• In two unrelated individuals with the variant
• In two sibs with the same variant, intellectual functioning was borderline in one and normal in the other, who (despite a full-scale IQ score of 98) was reported to perform below average in some verbal and nonverbal skills (e.g., confrontation naming or spatial orientation) and to score low in evaluation of motor function [
• One of 1,133 children with severe, undiagnosed, developmental disorders [
• One of 258 unrelated children with ASD, all of whom were initially tested by chromosomal microarray analysis and 95 of whom were further investigated by trio exome sequencing (i.e., exome sequencing of the proband and both parents) [
## Clinical Description
To date, 18 individuals have been identified with a pathogenic variant in
While the preliminary information available does not allow firm conclusions, approximately two thirds of the individuals reported to date are nonverbal at age 18 months. Although severe speech delay does not seem to be the rule, a few children remained nonverbal at age four years (and in some cases beyond). Dysarthria secondary to oral hypotonia was reported in some [
Variable degrees of both fine motor and gross motor delay have been observed in almost all individuals for whom this information is available. Walking was achieved after age 21 months in the majority. Fine motor development may be equally affected as some individuals have been reported to have poor hand dexterity or clumsiness and difficulty in global coordination.
Intellectual disability, which appears to be present in the majority of affected individuals, is typically in the mild end of the spectrum and was only observed in the moderate-to-severe range in fewer than 20% (3/18). Of note, on formal IQ testing two individuals had results within the normal range (full-scale IQ scores 98 [
Attention-deficit/hyperactivity disorder and anxiety have been observed in 30%-40% of individuals.
Approximately 20% of reported individuals had a formal diagnosis of autism spectrum disorder (ASD). Autistic traits were reported in one individual.
Aggressive and self-injurious behavior was reported in a few individuals.
Minor ear anomalies have been described in 50% of affected individuals (8/16), including posteriorly rotated ears and prominence of the antihelix (most commonly of the stem, although the superior and inferior crus can also be prominent).
Tonic-clonic seizures
Absence episodes
Seizure-like activity
Febrile convulsions
Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [
A girl age nine years with unspecified kidney problems [
• Tonic-clonic seizures
• Absence episodes
• Seizure-like activity
• Febrile convulsions
• Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [
• A girl age nine years with unspecified kidney problems [
•
## Most Commonly Seen Features
While the preliminary information available does not allow firm conclusions, approximately two thirds of the individuals reported to date are nonverbal at age 18 months. Although severe speech delay does not seem to be the rule, a few children remained nonverbal at age four years (and in some cases beyond). Dysarthria secondary to oral hypotonia was reported in some [
Variable degrees of both fine motor and gross motor delay have been observed in almost all individuals for whom this information is available. Walking was achieved after age 21 months in the majority. Fine motor development may be equally affected as some individuals have been reported to have poor hand dexterity or clumsiness and difficulty in global coordination.
Intellectual disability, which appears to be present in the majority of affected individuals, is typically in the mild end of the spectrum and was only observed in the moderate-to-severe range in fewer than 20% (3/18). Of note, on formal IQ testing two individuals had results within the normal range (full-scale IQ scores 98 [
Attention-deficit/hyperactivity disorder and anxiety have been observed in 30%-40% of individuals.
Approximately 20% of reported individuals had a formal diagnosis of autism spectrum disorder (ASD). Autistic traits were reported in one individual.
Aggressive and self-injurious behavior was reported in a few individuals.
Minor ear anomalies have been described in 50% of affected individuals (8/16), including posteriorly rotated ears and prominence of the antihelix (most commonly of the stem, although the superior and inferior crus can also be prominent).
## Features Reported in 10%-30% of Affected Individuals
Tonic-clonic seizures
Absence episodes
Seizure-like activity
Febrile convulsions
Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [
A girl age nine years with unspecified kidney problems [
• Tonic-clonic seizures
• Absence episodes
• Seizure-like activity
• Febrile convulsions
• Mild unilateral renal caliectasis in one individual and right pelvic kidney in another [
• A girl age nine years with unspecified kidney problems [
•
## Genotype-Phenotype Correlations
To date only loss-of-function
Variability in intellectual function has been observed in individuals with the same
In two unrelated individuals with the variant
In two sibs with the same variant, intellectual functioning was borderline in one and normal in the other, who (despite a full-scale IQ score of 98) was reported to perform below average in some verbal and nonverbal skills (e.g., confrontation naming or spatial orientation) and to score low in evaluation of motor function [
• In two unrelated individuals with the variant
• In two sibs with the same variant, intellectual functioning was borderline in one and normal in the other, who (despite a full-scale IQ score of 98) was reported to perform below average in some verbal and nonverbal skills (e.g., confrontation naming or spatial orientation) and to score low in evaluation of motor function [
## Nomenclature
## Penetrance
To date all individuals with
## Prevalence
To date, 18 individuals with
In each of the following cohorts of children with ID and/or autism spectrum disorder (ASD), one child was found to have a
One of 1,133 children with severe, undiagnosed, developmental disorders [
One of 258 unrelated children with ASD, all of whom were initially tested by chromosomal microarray analysis and 95 of whom were further investigated by trio exome sequencing (i.e., exome sequencing of the proband and both parents) [
The prevalence of
• One of 1,133 children with severe, undiagnosed, developmental disorders [
• One of 258 unrelated children with ASD, all of whom were initially tested by chromosomal microarray analysis and 95 of whom were further investigated by trio exome sequencing (i.e., exome sequencing of the proband and both parents) [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Developmental delay, neonatal feeding difficulties, and hypotonia, the most frequent features in
The syndromes in
Disorders to Consider in the Differential Diagnosis of
Hypotonia, feeding difficulties in early infancy
Delayed motor milestones & language development
DD, ID, sleep disturbances, seizures, constipation
Facial features incl deep-set eyes & wide mouth w/prominent lower face
Abnormal breathing pattern (seen in 2 persons w/
DD, ID, sleep disorders
Seizures variably present in both (rare in
Neonatal/childhood hypotonia & DD w/associated ID
Abnormal vision, epilepsy, & renal anomalies variably seen in both disorders (rare in
DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
One individual reported by
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.
Among the ten individuals with
Approximately 95% of individuals with Smith-Magenis syndrome have the disorder as a result of an interstitial 17p11.2 deletion, which may have been previously excluded by chromosomal microarray testing.
Two individuals reported by
One individual reported by
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of
• Hypotonia, feeding difficulties in early infancy
• Delayed motor milestones & language development
• DD, ID, sleep disturbances, seizures, constipation
• Facial features incl deep-set eyes & wide mouth w/prominent lower face
• Abnormal breathing pattern (seen in 2 persons w/
• DD, ID, sleep disorders
• Seizures variably present in both (rare in
• Neonatal/childhood hypotonia & DD w/associated ID
• Abnormal vision, epilepsy, & renal anomalies variably seen in both disorders (rare in
## Management
To establish the extent of disease and needs in an individual diagnosed with
Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis (e.g., recommendation for traits suggestive of autism spectrum disorder [ASD] in an infant).
Recommended Evaluations and Referrals Following Initial Diagnosis of
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Treatment can include the following.
Treatment of Manifestations in Individuals with
Diet diary and calorie counts may be requested.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary by country.
In the US, an IEP can be developed by the local public school district based on each individual's level of function. Severely 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., 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.
The following are appropriate.
Recommended Surveillance for Individuals with
The frequency with which each evaluation or reassessment occurs should be tailored to the needs of the affected individual.
See
Search
• In the US, an IEP can be developed by the local public school district based on each individual's level of function. Severely 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., orthotics, adaptive strollers).
## Evaluations and Referrals Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Note: Some evaluations are age dependent and may not be relevant at the time of initial diagnosis (e.g., recommendation for traits suggestive of autism spectrum disorder [ASD] in an infant).
Recommended Evaluations and Referrals Following Initial Diagnosis of
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
## Treatment of Manifestations
Treatment can include the following.
Treatment of Manifestations in Individuals with
Diet diary and calorie counts may be requested.
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary by country.
In the US, an IEP can be developed by the local public school district based on each individual's level of function. Severely 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., 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.
• In the US, an IEP can be developed by the local public school district based on each individual's level of function. Severely 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., 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 by country.
In the US, an IEP can be developed by the local public school district based on each individual's level of function. Severely 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 can be developed by the local public school district based on each individual's level of function. Severely 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., orthotics, adaptive strollers).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment as needed (e.g., 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
The following are appropriate.
Recommended Surveillance for Individuals with
The frequency with which each evaluation or reassessment occurs should be tailored to the needs of the affected individual.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
To date, vertical transmission of
With the exception of one family with presumed parental germline mosaicism [
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, the most likely explanation is a
The family history of some individuals diagnosed with
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 risk to the sibs of the proband depends on the genetic status of the proband's parents.
If the
If the parents have not been tested for the
Each child of an individual with
The degree of severity in offspring who inherit 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 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, vertical transmission of
• With the exception of one family with presumed parental germline mosaicism [
• 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, the most likely explanation is a
• The family history of some individuals diagnosed with
• 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 risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If the
• If the parents have not been tested for the
• Each child of an individual with
• The degree of severity in offspring who inherit 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 or at risk.
## Mode of Inheritance
## Risk to Family Members
To date, vertical transmission of
With the exception of one family with presumed parental germline mosaicism [
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, the most likely explanation is a
The family history of some individuals diagnosed with
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 risk to the sibs of the proband depends on the genetic status of the proband's parents.
If the
If the parents have not been tested for the
Each child of an individual with
The degree of severity in offspring who inherit a
• To date, vertical transmission of
• With the exception of one family with presumed parental germline mosaicism [
• 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, the most likely explanation is a
• The family history of some individuals diagnosed with
• 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 risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If the
• If the parents have not been tested for the
• Each child of an individual with
• The degree of severity in offspring who inherit 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 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
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
## Molecular Genetics
WAC-Related Intellectual Disability: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for WAC-Related Intellectual Disability (
As also explicitly stated for at least some of these databases, attempts have been made to exclude individuals with severe pediatric diseases – which may not be the case for less severe phenotypes [
The smallest region of overlap among 11 deletions of 10p12.1 is an 80-kb region containing only
One frameshift variant (
One variant (c.1648C>T) was found in two unrelated individuals with mild and moderate ID [
Variants listed in the table have been provided by the authors.
See
## Chapter Notes
30 November 2017 (bp) Review posted live
17 February 2017 (kv) Original submission
• 30 November 2017 (bp) Review posted live
• 17 February 2017 (kv) Original submission
## Revision History
30 November 2017 (bp) Review posted live
17 February 2017 (kv) Original submission
• 30 November 2017 (bp) Review posted live
• 17 February 2017 (kv) Original submission
## References
## Literature Cited
Three individuals with
Female age 19 years (1)
Male age 12 years (2a, 2b, 2c)
Female at age three years (3a) and at age 20 years (3b, 3c). Note the deeply set eyes, long palpebral fissures, wide mouth, and broad chin.
Note the broad/prominent forehead (in 2a, 3a) and depressed nasal bridge (3a).
|
[
"F Abdelhedi, L El Khattabi, N Essid, G Viot, D Letessier, A Lebbar, JM Dupont. A de novo 10p11.23-p12.1 deletion recapitulates the phenotype observed in WAC mutations and strengthens the role of WAC in intellectual disability and behavior disorders.. Am J Med Genet A. 2016;170:1912-7",
"C DeSanto, K D'Aco, GC Araujo, N Shannon, H Vernon, A Rahrig, KG Monaghan, Z Niu, P Vitazka, J Dodd, S Tang, L Manwaring, A Martir-Negron, RE Schnur, J Juusola, A Schroeder, V Pan, KL Helbig, B Friedman, M Shinawi. WAC loss-of-function mutations cause a recognisable syndrome characterised by dysmorphic features, developmental delay and hypotonia and recapitulate 10p11.23 microdeletion syndrome.. J Med Genet. 2015;52:754-61",
"TW Fitzgerald, SS Gerety, WD Jones, M van Kogelenberg, DA King, J McRae, KI Morley, V Parthiban, S Al-Turki, K Ambridge, DM Barrett, T Bayzetinova, S Clayton, EL Coomber, S Gribble, P Jones, N Krishnappa, LE Mason, A Middleton, R Miller, E Prigmore, D Rajan, A Sifrim, AR Tivey, M Ahmed, N Akawi, R Andrews, U Anjum, H Archer, R Armstrong, M Balasubramanian, R Banerjee, D Baralle, P Batstone, D Baty, C Bennett, J Berg, B Bernhard, AP Bevan, E Blair, M Blyth, D Bohanna, L Bourdon, D Bourn, A Brady, E Bragin, C Brewer, L Brueton, K Brunstrom, SJ Bumpstead, DJ Bunyan, J Burn, J Burton, N Canham, B Castle, K Chandler, S Clasper, J Clayton-Smith, T Cole, A Collins, MN Collinson, F Connell, N Cooper, H Cox, L Cresswell, G Cross, Y Crow. Deciphering Developmental Disorders Study: Large-scale discovery of novel genetic causes of developmental disorders.. Nature. 2015;519:223-8",
"FF Hamdan, M Srour, JM Capo-Chichi, H Daoud, C Nassif, L Patry, C Massicotte, A Ambalavanan, D Spiegelman, O Diallo, E Henrion, A Dionne-Laporte, A Fougerat, AV Pshezhetsky, S Venkateswaran, GA Rouleau, JL Michaud. De novo mutations in moderate or severe intellectual disability.. PLoS Genet. 2014;10",
"M Lek, KJ Karczewski, EV Minikel, KE Samocha, E Banks, T Fennell, AH O'Donnell-Luria, JS Ware, AJ Hill, BB Cummings, T Tukiainen, DP Birnbaum, JA Kosmicki, LE Duncan, K Estrada, F Zhao, J Zou, E Pierce-Hoffman, J Berghout, DN Cooper, N Deflaux, M DePristo, R Do, J Flannick, M Fromer, L Gauthier, J Goldstein, N Gupta, D Howrigan, A Kiezun, MI Kurki, AL Moonshine, P Natarajan, L Orozco, GM Peloso, R Poplin, MA Rivas, V Ruano-Rubio, SA Rose, DM Ruderfer, K Shakir, PD Stenson, C Stevens, BP Thomas, G Tiao, MT Tusie-Luna, B Weisburd, HH Won, D Yu, DM Altshuler, D Ardissino, M Boehnke, J Danesh, S Donnelly, R Elosua, JC Florez, SB Gabriel, G Getz, SJ Glatt, CM Hultman, S Kathiresan, M Laakso, S McCarroll, MI McCarthy, D McGovern, R McPherson, BM Neale, A Palotie, SM Purcell, D Saleheen, JM Scharf, P Sklar, PF Sullivan, J Tuomilehto, MT Tsuang, HC Watkins, JG Wilson, MJ Daly, DG MacArthur. Analysis of protein-coding genetic variation in 60,706 humans.. Nature. 2016;536:285-91",
"D Lugtenberg, MR Reijnders, M Fenckova, EK Bijlsma, R Bernier, BW van Bon, E Smeets, AT Vulto-van Silfhout, D Bosch, EE Eichler, HC Mefford, GL Carvill, EM Bongers, JH Schuurs-Hoeijmakers, CA Ruivenkamp, GW Santen, AM van den Maagdenberg, CM Peeters-Scholte, S Kuenen, P Verstreken, R Pfundt, HG Yntema, PF de Vries, JA Veltman, A Hoischen, C Gilissen, BB de Vries, A Schenck, T Kleefstra, LE Vissers. De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila.. Eur J Hum Genet. 2016;24:1145-53",
"HJ Mroczkowski, G Arnold, FX Schneck, A Rajkovic, SA Yatsenko. Interstitial 10p11.23-p12.1 microdeletions associated with developmental delay, craniofacial abnormalities, and cryptorchidism.. Am J Med Genet A. 2014;164A:2623-6",
"N Okamoto, S Hayashi, A Masui, R Kosaki, I Oguri, T Hasegawa, I Imoto, Y Makita, A Hata, K Moriyama, J. Inazawa. Deletion at chromosome 10p11.23-p12.1 defines characteristic phenotypes with marked midface retrusion.. J Hum Genet. 2012;57:191-6",
"R Shahdadpuri, B de Vries, R Pfundt, N de Leeuw, W Reardon. Pseudoarthrosis of the clavicle and copper beaten skull associated with chromosome 10p11.21p12.1 microdeletion.. Am J Med Genet A. 2008;146A:233-7",
"S Sosoi, I Streata, S Tudorache, F Burada, M Siminel, N Cernea, M Ioana, DG Iliescu, F Mixich. Prenatal and postnatal findings in a 10.6 Mb interstitial deletion at 10p11.22-p12.31.. J Hum Genet. 2015;60:183-5",
"K Tammimies, CR Marshall, S Walker, G Kaur, B Thiruvahindrapuram, AC Lionel, RK Yuen, M Uddin, W Roberts, R Weksberg, M Woodbury-Smith, L Zwaigenbaum, E Anagnostou, Z Wang, J Wei, JL Howe, MJ Gazzellone, L Lau, WW Sung, K Whitten, C Vardy, V Crosbie, B Tsang, L D'Abate, WW Tong, S Luscombe, T Doyle, MT Carter, P Szatmari, S Stuckless, D Merico, DJ Stavropoulos, SW Scherer, BA Fernandez. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder.. JAMA 2015;314:895-903",
"C Wentzel, E Rajcan-Separovic, CA Ruivenkamp, S Chantot-Bastaraud, C Metay, J Andrieux, G Annerén, AC Gijsbers, L Druart, C Hyon, MF Portnoi, EL Stattin, C Vincent-Delorme, SG Kant, M Steinraths, S Marlin, I Giurgea, AC Thuresson. Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11.. Eur J Hum Genet. 2011;19:959-64",
"GM Xu, MA Arnaout. WAC, a novel WW domain-containing adapter with a coiled-coil region, is colocalized with splicing factor SC35.. Genomics. 2002;79:87-94",
"F Zhang, X. Yu. WAC, a functional partner of RNF20/40, regulates histone H2B ubiquitination and gene transcription.. Mol Cell. 2011;41:384-97"
] |
30/11/2017
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
wagner
|
wagner
|
[
"Wagner Vitreoretinal Degeneration (Wagner Synrdome)",
"Erosive Vitreoretinopathy (ERVR)",
"Versican core protein",
"VCAN",
"VCAN-Related Vitreoretinopathy"
] |
Barbara Kloeckener-Gruissem, Christoph Amstutz
|
Summary The diagnosis of
|
Wagner vitreoretinal degeneration (Wagner syndrome)
Erosive vitreoretinopathy (ERVR)
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Wagner vitreoretinal degeneration (Wagner syndrome)
• Erosive vitreoretinopathy (ERVR)
## Diagnosis
"Optically empty vitreous" on slit-lamp examination and avascular vitreous strands and veils
Mild or occasionally moderate to severe myopia
Presenile cataract
Night blindness of variable degree associated with progressive chorioretinal atrophy
Retinal traction and detachment at advanced stages of the disease
Reduced visual acuity resulting from the above manifestations
Uveitis
Absence of systemic abnormalities
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 testing approaches can include
For an introduction to multigene panels 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
In 18 of 20 families 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• "Optically empty vitreous" on slit-lamp examination and avascular vitreous strands and veils
• Mild or occasionally moderate to severe myopia
• Presenile cataract
• Night blindness of variable degree associated with progressive chorioretinal atrophy
• Retinal traction and detachment at advanced stages of the disease
• Reduced visual acuity resulting from the above manifestations
• Uveitis
• Absence of systemic abnormalities
• For an introduction to multigene panels click
## Suggestive Findings
"Optically empty vitreous" on slit-lamp examination and avascular vitreous strands and veils
Mild or occasionally moderate to severe myopia
Presenile cataract
Night blindness of variable degree associated with progressive chorioretinal atrophy
Retinal traction and detachment at advanced stages of the disease
Reduced visual acuity resulting from the above manifestations
Uveitis
Absence of systemic abnormalities
• "Optically empty vitreous" on slit-lamp examination and avascular vitreous strands and veils
• Mild or occasionally moderate to severe myopia
• Presenile cataract
• Night blindness of variable degree associated with progressive chorioretinal atrophy
• Retinal traction and detachment at advanced stages of the disease
• Reduced visual acuity resulting from the above manifestations
• Uveitis
• Absence of systemic abnormalities
## 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 testing approaches can include
For an introduction to multigene panels 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
In 18 of 20 families 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
## Clinical Characteristics
The first signs usually become apparent during early adolescence, but onset can be as early as age two years [
No sex-specific difference in the occurrence or frequency of any particular ocular features has been observed.
The vitreous degeneration, which is assumed to be the primary pathology, leads to a number of secondary changes, including presenile cataract, degeneration and atrophy of the retina and the underlying retinal pigment epithelium (RPE) and choroid, and retinal detachment [
In a Japanese family, approximately 50% of affected individuals underwent cataract surgery; the oldest was age 35 years [
The full-field electroretinogram (ERG) becomes attenuated. Typically both the amplitudes of the a-waves (response of the photoreceptor layer) and the b-waves (response of the bipolar cell layer) are reduced. The rod and cone systems (as measured by the scotopic and photopic response, respectively) are affected to varying degrees but in a family-specific manner, as demonstrated by the Swiss family originally reported by Wagner, the Japanese family, and the British family [
Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, in a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.
In the original publication by Wagner the incidence of retinal detachment at age 20 years was one in four, whereas in the Dutch pedigrees published by Jansen bilateral retinal detachment was a frequent finding at a young age. Of note, follow-up publications of the original Wagner pedigree reported an incidence of retinal detachment of greater than one in two. Of the few retinal detachments described in the Swiss family reported originally by Wagner and in the Dutch families reported by Jansen, some were peripheral tractional [
In the Japanese family reported by
The following features have been reported rarely. Some may not be part of
Because of the highly variable frequency of findings and the low number of pathogenic variants identified to date, no definite genotype-phenotype correlations have been established.
Penetrance appears to be complete. Within families reported to date, no unaffected individuals had a
Some authors have referred to
Wagner syndrome is a very rare disorder. After the first Swiss pedigree reported by
Wagner syndrome has been reported in families of various ethnic backgrounds including northern European, Japanese, and Chinese.
• Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
• Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, in a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.
## Clinical Description
The first signs usually become apparent during early adolescence, but onset can be as early as age two years [
No sex-specific difference in the occurrence or frequency of any particular ocular features has been observed.
The vitreous degeneration, which is assumed to be the primary pathology, leads to a number of secondary changes, including presenile cataract, degeneration and atrophy of the retina and the underlying retinal pigment epithelium (RPE) and choroid, and retinal detachment [
In a Japanese family, approximately 50% of affected individuals underwent cataract surgery; the oldest was age 35 years [
The full-field electroretinogram (ERG) becomes attenuated. Typically both the amplitudes of the a-waves (response of the photoreceptor layer) and the b-waves (response of the bipolar cell layer) are reduced. The rod and cone systems (as measured by the scotopic and photopic response, respectively) are affected to varying degrees but in a family-specific manner, as demonstrated by the Swiss family originally reported by Wagner, the Japanese family, and the British family [
Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, in a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.
In the original publication by Wagner the incidence of retinal detachment at age 20 years was one in four, whereas in the Dutch pedigrees published by Jansen bilateral retinal detachment was a frequent finding at a young age. Of note, follow-up publications of the original Wagner pedigree reported an incidence of retinal detachment of greater than one in two. Of the few retinal detachments described in the Swiss family reported originally by Wagner and in the Dutch families reported by Jansen, some were peripheral tractional [
In the Japanese family reported by
The following features have been reported rarely. Some may not be part of
• Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
• Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, in a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.
## Common Ocular Features (≤60% of Affected Individuals)
In a Japanese family, approximately 50% of affected individuals underwent cataract surgery; the oldest was age 35 years [
The full-field electroretinogram (ERG) becomes attenuated. Typically both the amplitudes of the a-waves (response of the photoreceptor layer) and the b-waves (response of the bipolar cell layer) are reduced. The rod and cone systems (as measured by the scotopic and photopic response, respectively) are affected to varying degrees but in a family-specific manner, as demonstrated by the Swiss family originally reported by Wagner, the Japanese family, and the British family [
Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, in a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.
In the original publication by Wagner the incidence of retinal detachment at age 20 years was one in four, whereas in the Dutch pedigrees published by Jansen bilateral retinal detachment was a frequent finding at a young age. Of note, follow-up publications of the original Wagner pedigree reported an incidence of retinal detachment of greater than one in two. Of the few retinal detachments described in the Swiss family reported originally by Wagner and in the Dutch families reported by Jansen, some were peripheral tractional [
In the Japanese family reported by
• Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
• Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, in a considerable number of young individuals, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.
## Occasional Ocular Features
The following features have been reported rarely. Some may not be part of
## Genotype-Phenotype Correlations
Because of the highly variable frequency of findings and the low number of pathogenic variants identified to date, no definite genotype-phenotype correlations have been established.
## Penetrance
Penetrance appears to be complete. Within families reported to date, no unaffected individuals had a
## Nomenclature
Some authors have referred to
## Prevalence
Wagner syndrome is a very rare disorder. After the first Swiss pedigree reported by
Wagner syndrome has been reported in families of various ethnic backgrounds including northern European, Japanese, and Chinese.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Both SVD and
In SVD, however, membranous degeneration of the vitreous with avascular strands and veils is not observed. Retinal defects start in the superficial retinal layers, whereas in
Retinal detachment is much more common in Stickler syndrome (50%) than in
Abnormal dark adaptation associated with alterations in the electroretinogram (ERG) that is common in
Type 1 Stickler syndrome (in which individuals have the membranous type of vitreous abnormality) is caused by pathogenic variants in
Fibrillar condensation of the vitreous, but not optically empty vitreous
Chorioretinal hyperpigmentation with peripheral pigmentary clumping
Macular atrophy
Breakdown of the blood retinal barrier (observed in one family)
Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern
Cataract
The classic Goldmann-Favre phenotype includes progressive vitreous changes (vitreous liquefaction and fibrillar strands and veils); night blindness and severe reduction in the ERG in early childhood; chorioretinal atrophy and pigmentary retinal degeneration later in the disease course resulting in marked visual field loss; retinoschisis in the periphery, macula, or both; presenile cataract; and a hyperopic rather than myopic refractive error.
Although ESCS lacks the marked vitreous changes typical of the Goldmann-Favre phenotype, vitreous cells are a very common feature, and more prominent vitreous changes including vitreous opacities, haze, and veils can occur. Peripheral retinoschisis has been observed in ESCS, and foveal schisis, eventually associated with cystoid changes, may even be a common feature. The fundus appearance varies, and features are overlapping with clumped pigmentary retinal degeneration, in which the retinal pigmentary changes are the most prominent feature of the phenotype [
• Both SVD and
• In SVD, however, membranous degeneration of the vitreous with avascular strands and veils is not observed. Retinal defects start in the superficial retinal layers, whereas in
• Retinal detachment is much more common in Stickler syndrome (50%) than in
• Abnormal dark adaptation associated with alterations in the electroretinogram (ERG) that is common in
• Type 1 Stickler syndrome (in which individuals have the membranous type of vitreous abnormality) is caused by pathogenic variants in
• Fibrillar condensation of the vitreous, but not optically empty vitreous
• Chorioretinal hyperpigmentation with peripheral pigmentary clumping
• Macular atrophy
• Breakdown of the blood retinal barrier (observed in one family)
• Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern
• Cataract
• The classic Goldmann-Favre phenotype includes progressive vitreous changes (vitreous liquefaction and fibrillar strands and veils); night blindness and severe reduction in the ERG in early childhood; chorioretinal atrophy and pigmentary retinal degeneration later in the disease course resulting in marked visual field loss; retinoschisis in the periphery, macula, or both; presenile cataract; and a hyperopic rather than myopic refractive error.
• Although ESCS lacks the marked vitreous changes typical of the Goldmann-Favre phenotype, vitreous cells are a very common feature, and more prominent vitreous changes including vitreous opacities, haze, and veils can occur. Peripheral retinoschisis has been observed in ESCS, and foveal schisis, eventually associated with cystoid changes, may even be a common feature. The fundus appearance varies, and features are overlapping with clumped pigmentary retinal degeneration, in which the retinal pigmentary changes are the most prominent feature of the phenotype [
## Autosomal Dominant Vitreoretinopathies
Both SVD and
In SVD, however, membranous degeneration of the vitreous with avascular strands and veils is not observed. Retinal defects start in the superficial retinal layers, whereas in
Retinal detachment is much more common in Stickler syndrome (50%) than in
Abnormal dark adaptation associated with alterations in the electroretinogram (ERG) that is common in
Type 1 Stickler syndrome (in which individuals have the membranous type of vitreous abnormality) is caused by pathogenic variants in
Fibrillar condensation of the vitreous, but not optically empty vitreous
Chorioretinal hyperpigmentation with peripheral pigmentary clumping
Macular atrophy
Breakdown of the blood retinal barrier (observed in one family)
Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern
Cataract
• Both SVD and
• In SVD, however, membranous degeneration of the vitreous with avascular strands and veils is not observed. Retinal defects start in the superficial retinal layers, whereas in
• Retinal detachment is much more common in Stickler syndrome (50%) than in
• Abnormal dark adaptation associated with alterations in the electroretinogram (ERG) that is common in
• Type 1 Stickler syndrome (in which individuals have the membranous type of vitreous abnormality) is caused by pathogenic variants in
• Fibrillar condensation of the vitreous, but not optically empty vitreous
• Chorioretinal hyperpigmentation with peripheral pigmentary clumping
• Macular atrophy
• Breakdown of the blood retinal barrier (observed in one family)
• Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern
• Cataract
## Autosomal Recessive Vitreoretinopathies
The classic Goldmann-Favre phenotype includes progressive vitreous changes (vitreous liquefaction and fibrillar strands and veils); night blindness and severe reduction in the ERG in early childhood; chorioretinal atrophy and pigmentary retinal degeneration later in the disease course resulting in marked visual field loss; retinoschisis in the periphery, macula, or both; presenile cataract; and a hyperopic rather than myopic refractive error.
Although ESCS lacks the marked vitreous changes typical of the Goldmann-Favre phenotype, vitreous cells are a very common feature, and more prominent vitreous changes including vitreous opacities, haze, and veils can occur. Peripheral retinoschisis has been observed in ESCS, and foveal schisis, eventually associated with cystoid changes, may even be a common feature. The fundus appearance varies, and features are overlapping with clumped pigmentary retinal degeneration, in which the retinal pigmentary changes are the most prominent feature of the phenotype [
• The classic Goldmann-Favre phenotype includes progressive vitreous changes (vitreous liquefaction and fibrillar strands and veils); night blindness and severe reduction in the ERG in early childhood; chorioretinal atrophy and pigmentary retinal degeneration later in the disease course resulting in marked visual field loss; retinoschisis in the periphery, macula, or both; presenile cataract; and a hyperopic rather than myopic refractive error.
• Although ESCS lacks the marked vitreous changes typical of the Goldmann-Favre phenotype, vitreous cells are a very common feature, and more prominent vitreous changes including vitreous opacities, haze, and veils can occur. Peripheral retinoschisis has been observed in ESCS, and foveal schisis, eventually associated with cystoid changes, may even be a common feature. The fundus appearance varies, and features are overlapping with clumped pigmentary retinal degeneration, in which the retinal pigmentary changes are the most prominent feature of the phenotype [
## Management
To establish the extent of disease and needs in an individual diagnosed with
Baseline ophthalmologic examination including best corrected visual acuity, assessment of intraocular pressure, slit-lamp examination of the anterior segment, and biomicroscopy and indirect ophthalmoscopy of the posterior segment
Visual field examination
Photographic fundus documentation
Optical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful to assess the vitreoretinal interface, quantify atrophic changes of the central retina, and evaluate for cystoid macular edema.
Electroretinogram
Orthoptic assessment
Consultation with a clinical geneticist and/or genetic counselor
Annual ophthalmologic examination by a vitreoretinal specialist is indicated.
It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to reduce morbidity by early diagnosis and treatment of ophthalmologic complications. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known.
Ophthalmologic exam if the pathogenic variant in the family is not known
See
Search
• Baseline ophthalmologic examination including best corrected visual acuity, assessment of intraocular pressure, slit-lamp examination of the anterior segment, and biomicroscopy and indirect ophthalmoscopy of the posterior segment
• Visual field examination
• Photographic fundus documentation
• Optical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful to assess the vitreoretinal interface, quantify atrophic changes of the central retina, and evaluate for cystoid macular edema.
• Electroretinogram
• Orthoptic assessment
• Consultation with a clinical geneticist and/or genetic counselor
• Molecular genetic testing if the pathogenic variant in the family is known.
• Ophthalmologic exam 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
Baseline ophthalmologic examination including best corrected visual acuity, assessment of intraocular pressure, slit-lamp examination of the anterior segment, and biomicroscopy and indirect ophthalmoscopy of the posterior segment
Visual field examination
Photographic fundus documentation
Optical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful to assess the vitreoretinal interface, quantify atrophic changes of the central retina, and evaluate for cystoid macular edema.
Electroretinogram
Orthoptic assessment
Consultation with a clinical geneticist and/or genetic counselor
• Baseline ophthalmologic examination including best corrected visual acuity, assessment of intraocular pressure, slit-lamp examination of the anterior segment, and biomicroscopy and indirect ophthalmoscopy of the posterior segment
• Visual field examination
• Photographic fundus documentation
• Optical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful to assess the vitreoretinal interface, quantify atrophic changes of the central retina, and evaluate for cystoid macular edema.
• Electroretinogram
• Orthoptic assessment
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
## Surveillance
Annual ophthalmologic examination by a vitreoretinal specialist is indicated.
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual in order to reduce morbidity by early diagnosis and treatment of ophthalmologic complications. Evaluations can include:
Molecular genetic testing if the pathogenic variant in the family is known.
Ophthalmologic exam if the pathogenic variant in the family is not known
See
• Molecular genetic testing if the pathogenic variant in the family is known.
• Ophthalmologic exam if the pathogenic variant in the family is not known
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with
A proband 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
The family history of some individuals diagnosed with
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 has
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.
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.
• Most individuals diagnosed with
• A proband 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
• The family history of some individuals diagnosed with
• 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 has
• 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
Most individuals diagnosed with
A proband 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
The family history of some individuals diagnosed with
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 has
If the
• Most individuals diagnosed with
• A proband 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
• The family history of some individuals diagnosed with
• 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 has
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
31 Center Drive
MSC 2510
Bethesda MD 20892-2510
31 Center Drive
MSC 2510
Bethesda MD 20892-2510
211 West Wacker Drive
Suite 1700
Chicago IL 60606
•
•
•
• 31 Center Drive
• MSC 2510
• Bethesda MD 20892-2510
•
•
• 31 Center Drive
• MSC 2510
• Bethesda MD 20892-2510
•
•
• 211 West Wacker Drive
• Suite 1700
• Chicago IL 60606
•
## Molecular Genetics
VCAN-Related Vitreoretinopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for VCAN-Related Vitreoretinopathy (
Since
Selected
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Since
Selected
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors would like to thank Drs Wolfgang Berger and John Neidhardt for critical reading of the manuscript.
16 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
7 January 2016 (me) Comprehensive update posted live
16 August 2012 (me) Comprehensive update posted live
3 February 2009 (me) Review posted live
18 April 2008 (bkg) Original submission
• 16 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
• 7 January 2016 (me) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 3 February 2009 (me) Review posted live
• 18 April 2008 (bkg) Original submission
## Acknowledgments
The authors would like to thank Drs Wolfgang Berger and John Neidhardt for critical reading of the manuscript.
## Revision History
16 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
7 January 2016 (me) Comprehensive update posted live
16 August 2012 (me) Comprehensive update posted live
3 February 2009 (me) Review posted live
18 April 2008 (bkg) Original submission
• 16 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
• 7 January 2016 (me) Comprehensive update posted live
• 16 August 2012 (me) Comprehensive update posted live
• 3 February 2009 (me) Review posted live
• 18 April 2008 (bkg) Original submission
## References
## Literature Cited
Vitreoretinopathy-associated pathogenic variants in
|
[] |
3/2/2009
|
7/1/2016
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
wars2-def
|
wars2-def
|
[
"WARS2-Related Epilepsy",
"WARS2-Related Movement Disorder",
"Tryptophan--tRNA ligase, mitochondrial",
"WARS2",
"WARS2 Deficiency"
] |
WARS2 Deficiency
|
Magdalena Mroczek, Aynekin Busra, Henry Houlden, Stephanie Efthymiou, Sara Nagy
|
Summary The current (but limited) understanding of the WARS2 deficiency phenotypic spectrum, based on 29 individuals from 24 families reported to date, can be viewed as a clustering of hallmark features within the broad phenotypes of epilepsy and movement disorder. Of note, the continua within and between the epilepsy spectrum and the movement disorder spectrum remain to be determined pending reporting of more individuals with WARS2 deficiency. The diagnosis of WARS2 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in WARS2 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a Biallelic loss-of-function pathogenic variants are likely to have A One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency; Neither of the familial Once the WARS2 deficiency-related variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
|
WARS2 Deficiency: Phenotypic Spectrum
Including developmental and epileptic encephalopathy (DEE) and other seizure types
Primarily levodopa-responsive parkinsonism/dystonia and progressive myoclonus-ataxia/hyperkinetic movement disorder
The
## Diagnosis
No consensus clinical diagnostic criteria for WARS2 deficiency have been published.
WARS2 deficiency
Initial manifestations:
Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
Note: For the purposes of this
Hypotonia with or without peripheral spasticity
Global developmental delay
Poor suck
Manifestations over time:
Intellectual disability
Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
Cerebral and cerebellar volume loss
White matter abnormalities (including absent myelination, nonspecific periventricular signal changes)
Thin corpus callosum
Hypoplastic cerebellar vermis, cerebellar peduncles, and brain stem
Hypoxemic-ischemic basal ganglia lesions
Initial manifestations:
Action tremor of the hand, unilateral leg tremor, occasional jerks
Tremor
Distal limb myoclonus
Ataxia
Ballistic and dystonic movements
Axial hypotonia with trunk instability
Developmental delay
Manifestations over time:
Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
Mild-to-moderate developmental delay / intellectual disability
Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
Spasticity, peripheral hypertonia
The diagnosis of WARS2 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
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 WARS2 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Includes the hypomorphic variant
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 individual with a 36-kb deletion including exon 2 of
• Initial manifestations:
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Manifestations over time:
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Cerebral and cerebellar volume loss
• White matter abnormalities (including absent myelination, nonspecific periventricular signal changes)
• Thin corpus callosum
• Hypoplastic cerebellar vermis, cerebellar peduncles, and brain stem
• Hypoxemic-ischemic basal ganglia lesions
• Initial manifestations:
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Manifestations over time:
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
## Suggestive Findings
WARS2 deficiency
Initial manifestations:
Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
Note: For the purposes of this
Hypotonia with or without peripheral spasticity
Global developmental delay
Poor suck
Manifestations over time:
Intellectual disability
Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
Cerebral and cerebellar volume loss
White matter abnormalities (including absent myelination, nonspecific periventricular signal changes)
Thin corpus callosum
Hypoplastic cerebellar vermis, cerebellar peduncles, and brain stem
Hypoxemic-ischemic basal ganglia lesions
Initial manifestations:
Action tremor of the hand, unilateral leg tremor, occasional jerks
Tremor
Distal limb myoclonus
Ataxia
Ballistic and dystonic movements
Axial hypotonia with trunk instability
Developmental delay
Manifestations over time:
Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
Mild-to-moderate developmental delay / intellectual disability
Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
Spasticity, peripheral hypertonia
• Initial manifestations:
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Manifestations over time:
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Cerebral and cerebellar volume loss
• White matter abnormalities (including absent myelination, nonspecific periventricular signal changes)
• Thin corpus callosum
• Hypoplastic cerebellar vermis, cerebellar peduncles, and brain stem
• Hypoxemic-ischemic basal ganglia lesions
• Initial manifestations:
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Manifestations over time:
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
## Epilepsy Spectrum – Neonatal or Infantile Onset
Initial manifestations:
Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
Note: For the purposes of this
Hypotonia with or without peripheral spasticity
Global developmental delay
Poor suck
Manifestations over time:
Intellectual disability
Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
Cerebral and cerebellar volume loss
White matter abnormalities (including absent myelination, nonspecific periventricular signal changes)
Thin corpus callosum
Hypoplastic cerebellar vermis, cerebellar peduncles, and brain stem
Hypoxemic-ischemic basal ganglia lesions
• Initial manifestations:
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Manifestations over time:
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Seizures ranging from developmental and epileptic encephalopathy (DEE) to other seizure types.
• Note: For the purposes of this
• Hypotonia with or without peripheral spasticity
• Global developmental delay
• Poor suck
• Intellectual disability
• Speech impairment (no speech, slurred and slow speech) with receptive language relatively spared
• Often movement disorder (e.g., mild ataxia, dystonia, athetosis) and/or neuropsychiatric findings
• Cerebral and cerebellar volume loss
• White matter abnormalities (including absent myelination, nonspecific periventricular signal changes)
• Thin corpus callosum
• Hypoplastic cerebellar vermis, cerebellar peduncles, and brain stem
• Hypoxemic-ischemic basal ganglia lesions
## Movement Disorder Spectrum – Childhood or Early Adulthood Onset
Initial manifestations:
Action tremor of the hand, unilateral leg tremor, occasional jerks
Tremor
Distal limb myoclonus
Ataxia
Ballistic and dystonic movements
Axial hypotonia with trunk instability
Developmental delay
Manifestations over time:
Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
Mild-to-moderate developmental delay / intellectual disability
Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
Spasticity, peripheral hypertonia
• Initial manifestations:
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Manifestations over time:
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
• Action tremor of the hand, unilateral leg tremor, occasional jerks
• Tremor
• Distal limb myoclonus
• Ataxia
• Ballistic and dystonic movements
• Axial hypotonia with trunk instability
• Developmental delay
• Movement disorders, such as parkinsonism (rigidity, bradykinesia, akinesia, dysarthria, dysphagia, hypomimia); other movement disorders such as dystonia, myoclonus, ataxia, tremor (resting, action, and postural), and chorea; and ocular disorders such as oculogyric crisis (spasmodic movements of the eyeballs into a fixed position, usually upward), ptosis, supranuclear gaze palsy, and exotropia
• Mild-to-moderate developmental delay / intellectual disability
• Versive seizures (a forced and involuntary turning of the head and eyes in one direction with an associated neck extension resulting in a sustained unnatural position of both)
• Neuropsychiatric manifestations such as social phobia, anxiety, depression, aggressive behavior, psychosis, and apathy
• Spasticity, peripheral hypertonia
## Establishing the Diagnosis
The diagnosis of WARS2 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
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 WARS2 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Includes the hypomorphic variant
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 individual with a 36-kb deletion including exon 2 of
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in WARS2 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
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Includes the hypomorphic variant
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 individual with a 36-kb deletion including exon 2 of
## Clinical Characteristics
The current (but limited) understanding of the WARS2 deficiency phenotypic spectrum can be viewed as a clustering of hallmark features within the broad phenotypes of epilepsy and movement disorder. The epilepsy spectrum encompasses neonatal- or infantile-onset developmental and epileptic encephalopathy (DEE) and other seizure types. The movement disorder spectrum encompasses levodopa-responsive parkinsonism/dystonia and progressive myoclonus-ataxia/hyperkinetic movement disorder. Of note, the continua within and between the epilepsy spectrum and the movement disorder spectrum remain to be determined pending reporting of more individuals with WARS2 deficiency.
To date, 29 individuals from 24 families with biallelic variants in
DEE manifests mostly in the neonatal period or within the first year of life. Seizures are generally difficult to control and may lead to status epilepticus and death.
Evolution of manifestations over time include global developmental delay, mild-to-severe intellectual disability, speech impairment (slurred and slow speech, dysarthria, or no speech production but preserved receptive speech), muscle weakness, muscle atrophy, motor hyperactivity with athetosis, and neuropsychiatric manifestations including aggressiveness and sleep disorders. Other findings are dysmorphic features.
Developmental delay and intellectual disability were observed in 12/13 individuals with
In early childhood, delay is especially in expressive language, whereas receptive language is relatively spared. Some individuals never speak [
Global motor delay, especially in the first year of life, has been reported [
Intellectual disability ranges from mild to severe, usually in the moderate-to-severe range. Except for information that one child attended a special school [
One child developed acute hepatopathy at age 6.5 years after the administration of valproic acid [
The movement disorder spectrum is primarily comprised of an early-onset levodopa-responsive parkinsonism/dystonia phenotype (12/16 individuals) [
Occasional myoclonic limb jerks have also been reported [
Choreiform movements are rare but have been described [
A hyperkinetic movement disorder with uncontrollable ballistic and dystonic movements and loss of already acquired skills has been described in one individual to date [
Several genotype-phenotype correlations have been observed.
In general, clinically significant intrafamilial clinical variability has not observed among sibs who have the same biallelic
The title of this
Other designations used in the literature to refer to individuals with phenotypes within the WARS2 deficiency spectrum include:
NEMMLAS (
Childhood-onset parkinsonism-dystonia 3 (OMIM
To date, 29 individuals from 24 families have been identified with WARS2 deficiency (see
• One child developed acute hepatopathy at age 6.5 years after the administration of valproic acid [
• Choreiform movements are rare but have been described [
• A hyperkinetic movement disorder with uncontrollable ballistic and dystonic movements and loss of already acquired skills has been described in one individual to date [
• NEMMLAS (
• Childhood-onset parkinsonism-dystonia 3 (OMIM
## Clinical Description
The current (but limited) understanding of the WARS2 deficiency phenotypic spectrum can be viewed as a clustering of hallmark features within the broad phenotypes of epilepsy and movement disorder. The epilepsy spectrum encompasses neonatal- or infantile-onset developmental and epileptic encephalopathy (DEE) and other seizure types. The movement disorder spectrum encompasses levodopa-responsive parkinsonism/dystonia and progressive myoclonus-ataxia/hyperkinetic movement disorder. Of note, the continua within and between the epilepsy spectrum and the movement disorder spectrum remain to be determined pending reporting of more individuals with WARS2 deficiency.
To date, 29 individuals from 24 families with biallelic variants in
DEE manifests mostly in the neonatal period or within the first year of life. Seizures are generally difficult to control and may lead to status epilepticus and death.
Evolution of manifestations over time include global developmental delay, mild-to-severe intellectual disability, speech impairment (slurred and slow speech, dysarthria, or no speech production but preserved receptive speech), muscle weakness, muscle atrophy, motor hyperactivity with athetosis, and neuropsychiatric manifestations including aggressiveness and sleep disorders. Other findings are dysmorphic features.
Developmental delay and intellectual disability were observed in 12/13 individuals with
In early childhood, delay is especially in expressive language, whereas receptive language is relatively spared. Some individuals never speak [
Global motor delay, especially in the first year of life, has been reported [
Intellectual disability ranges from mild to severe, usually in the moderate-to-severe range. Except for information that one child attended a special school [
One child developed acute hepatopathy at age 6.5 years after the administration of valproic acid [
The movement disorder spectrum is primarily comprised of an early-onset levodopa-responsive parkinsonism/dystonia phenotype (12/16 individuals) [
Occasional myoclonic limb jerks have also been reported [
Choreiform movements are rare but have been described [
A hyperkinetic movement disorder with uncontrollable ballistic and dystonic movements and loss of already acquired skills has been described in one individual to date [
• One child developed acute hepatopathy at age 6.5 years after the administration of valproic acid [
• Choreiform movements are rare but have been described [
• A hyperkinetic movement disorder with uncontrollable ballistic and dystonic movements and loss of already acquired skills has been described in one individual to date [
## Epilepsy Spectrum
DEE manifests mostly in the neonatal period or within the first year of life. Seizures are generally difficult to control and may lead to status epilepticus and death.
Evolution of manifestations over time include global developmental delay, mild-to-severe intellectual disability, speech impairment (slurred and slow speech, dysarthria, or no speech production but preserved receptive speech), muscle weakness, muscle atrophy, motor hyperactivity with athetosis, and neuropsychiatric manifestations including aggressiveness and sleep disorders. Other findings are dysmorphic features.
Developmental delay and intellectual disability were observed in 12/13 individuals with
In early childhood, delay is especially in expressive language, whereas receptive language is relatively spared. Some individuals never speak [
Global motor delay, especially in the first year of life, has been reported [
Intellectual disability ranges from mild to severe, usually in the moderate-to-severe range. Except for information that one child attended a special school [
One child developed acute hepatopathy at age 6.5 years after the administration of valproic acid [
• One child developed acute hepatopathy at age 6.5 years after the administration of valproic acid [
## Movement Disorder Spectrum
The movement disorder spectrum is primarily comprised of an early-onset levodopa-responsive parkinsonism/dystonia phenotype (12/16 individuals) [
Occasional myoclonic limb jerks have also been reported [
Choreiform movements are rare but have been described [
A hyperkinetic movement disorder with uncontrollable ballistic and dystonic movements and loss of already acquired skills has been described in one individual to date [
• Choreiform movements are rare but have been described [
• A hyperkinetic movement disorder with uncontrollable ballistic and dystonic movements and loss of already acquired skills has been described in one individual to date [
## Genotype-Phenotype Correlations
Several genotype-phenotype correlations have been observed.
In general, clinically significant intrafamilial clinical variability has not observed among sibs who have the same biallelic
## Nomenclature
The title of this
Other designations used in the literature to refer to individuals with phenotypes within the WARS2 deficiency spectrum include:
NEMMLAS (
Childhood-onset parkinsonism-dystonia 3 (OMIM
• NEMMLAS (
• Childhood-onset parkinsonism-dystonia 3 (OMIM
## Prevalence
To date, 29 individuals from 24 families have been identified with WARS2 deficiency (see
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Intellectual disability without other distinctive findings: OMIM
DEE: OMIM
Additionally, the infantile-onset disorders in
Selected Genes of Interest in the Differential Diagnosis of
Movement disorders less common
Macrocephaly
Infantile-onset hypotonia that develops into hypertonia & spasticity
Severe seizure onset shortly after birth
May be assoc w/prominent movement disorder
No distinguishing brain MRI findings
Central hypotonia, global DD, severe ID
Movement disorder may be severe; most persons show mixed pattern of permanent or paroxysmal hyperkinetic & hypertonic movements that affect the whole body.
Overlap between movement disorders & epilepsy in most affected persons
Hypotonia & seizures assoc w/↑ serum glycine & lactate in 1st days of life
DD
Death in childhood
ID/DD w/speech delay, hypotonia, ataxia, seizures
↑ serum lactate
ID, seizures, rigidity, muscle hypotonia, microcephaly
Early death due to respiratory failure
Muscle hypotonia
Microcephaly
Bilateral polymicrogyria
Not reported in females
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Genes of Interest in the Differential Diagnosis of
Juvenile onset
Atypical parkinsonism
Iron deposition in basal ganglia on brain MRI
ID/DD, seizures, movement disorders (dystonia, spasticity, myoclonus)
Neuropsychiatric features
Onset of parkinsonism is between 2nd & 4th decade
Nonresponsive to levodopa
Loss of ambulation
Tremor, rigidity, akinesia, scissor gait, hyperreflexia
Mostly good responsiveness to levodopa
Early-onset parkinsonism w/tremor, bradykinesia, loss of postural reflexes; asymmetric onset of symptoms
Neuropsychiatric symptoms
Age of onset is typically older than in
Absence of multisystem involvement
Rigidity, bradykinesia, postural instability, resting tremor, frozen gait, dystonia hyperreflexia w/asymmetric onset
Favorable response to levodopa
Very slow disease progression
Postural instability
Neuropsychiatric symptoms are not common.
Often iron deposition is seen on brain imaging.
Onset is mostly in young adulthood/adulthood.
Slow disease progression
No neuropsychiatric features
Myoclonus of proximal limbs, dystonia (torticollis or writer's cramp), often responding to alcohol
Psychiatric features
Responsive to alcohol
Dystonia can be only manifestation.
Infantile-onset parkinsonism w/dystonia, poor fine motor skills, ataxia, limb hypertonia, autonomic dysfunction
Variable DD
Normal brain imaging
↑ levels of neurotransmitter metabolites & ↓ levels of norepinephrine & dopamine in urine analysis
Exacerbation of symptoms under levodopa, but symptom control under dopamine receptor agonists
Rigidity, tremor, dystonia, staring gaze, supranuclear gaze palsy
Seizures
Cognitive impairment
Seizures, mental deterioration, ataxia, myoclonus
Vision loss
Late infantile onset w/rapid deterioration
Multiple seizure types, refractory to treatment
EEG w/photoparoxysmal response at low-frequency photic stimulation
Cerebellar & cortical atrophy of predominantly the posterior region on brain MRI
Akineto-rigid syndrome, resting tremor
Dysautonomia
Cognitive impairment
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PARK = Parkinson disease
For a general review of the clinical characteristics and causes of monogenic Parkinson disease, see
Myoclonus-ataxia predominate phenotypes should further be differentiated from:
Myoclonus epilepsy syndromes (See
Neuraminidase deficiency (OMIM
Neuronal ceroid lipofuscinosis (OMIM Phenotypic Series:
• Intellectual disability without other distinctive findings: OMIM
• DEE: OMIM
• Movement disorders less common
• Macrocephaly
• Infantile-onset hypotonia that develops into hypertonia & spasticity
• Severe seizure onset shortly after birth
• May be assoc w/prominent movement disorder
• No distinguishing brain MRI findings
• Central hypotonia, global DD, severe ID
• Movement disorder may be severe; most persons show mixed pattern of permanent or paroxysmal hyperkinetic & hypertonic movements that affect the whole body.
• Overlap between movement disorders & epilepsy in most affected persons
• Hypotonia & seizures assoc w/↑ serum glycine & lactate in 1st days of life
• DD
• Death in childhood
• ID/DD w/speech delay, hypotonia, ataxia, seizures
• ↑ serum lactate
• ID, seizures, rigidity, muscle hypotonia, microcephaly
• Early death due to respiratory failure
• Muscle hypotonia
• Microcephaly
• Bilateral polymicrogyria
• Not reported in females
• Juvenile onset
• Atypical parkinsonism
• Iron deposition in basal ganglia on brain MRI
• ID/DD, seizures, movement disorders (dystonia, spasticity, myoclonus)
• Neuropsychiatric features
• Onset of parkinsonism is between 2nd & 4th decade
• Nonresponsive to levodopa
• Loss of ambulation
• Tremor, rigidity, akinesia, scissor gait, hyperreflexia
• Mostly good responsiveness to levodopa
• Early-onset parkinsonism w/tremor, bradykinesia, loss of postural reflexes; asymmetric onset of symptoms
• Neuropsychiatric symptoms
• Age of onset is typically older than in
• Absence of multisystem involvement
• Rigidity, bradykinesia, postural instability, resting tremor, frozen gait, dystonia hyperreflexia w/asymmetric onset
• Favorable response to levodopa
• Very slow disease progression
• Postural instability
• Neuropsychiatric symptoms are not common.
• Often iron deposition is seen on brain imaging.
• Onset is mostly in young adulthood/adulthood.
• Slow disease progression
• No neuropsychiatric features
• Myoclonus of proximal limbs, dystonia (torticollis or writer's cramp), often responding to alcohol
• Psychiatric features
• Responsive to alcohol
• Dystonia can be only manifestation.
• Infantile-onset parkinsonism w/dystonia, poor fine motor skills, ataxia, limb hypertonia, autonomic dysfunction
• Variable DD
• Normal brain imaging
• ↑ levels of neurotransmitter metabolites & ↓ levels of norepinephrine & dopamine in urine analysis
• Exacerbation of symptoms under levodopa, but symptom control under dopamine receptor agonists
• Rigidity, tremor, dystonia, staring gaze, supranuclear gaze palsy
• Seizures
• Cognitive impairment
• Seizures, mental deterioration, ataxia, myoclonus
• Vision loss
• Late infantile onset w/rapid deterioration
• Multiple seizure types, refractory to treatment
• EEG w/photoparoxysmal response at low-frequency photic stimulation
• Cerebellar & cortical atrophy of predominantly the posterior region on brain MRI
• Akineto-rigid syndrome, resting tremor
• Dysautonomia
• Cognitive impairment
• Myoclonus epilepsy syndromes (See
• Neuraminidase deficiency (OMIM
•
• Neuronal ceroid lipofuscinosis (OMIM Phenotypic Series:
## Epilepsy Spectrum
Intellectual disability without other distinctive findings: OMIM
DEE: OMIM
Additionally, the infantile-onset disorders in
Selected Genes of Interest in the Differential Diagnosis of
Movement disorders less common
Macrocephaly
Infantile-onset hypotonia that develops into hypertonia & spasticity
Severe seizure onset shortly after birth
May be assoc w/prominent movement disorder
No distinguishing brain MRI findings
Central hypotonia, global DD, severe ID
Movement disorder may be severe; most persons show mixed pattern of permanent or paroxysmal hyperkinetic & hypertonic movements that affect the whole body.
Overlap between movement disorders & epilepsy in most affected persons
Hypotonia & seizures assoc w/↑ serum glycine & lactate in 1st days of life
DD
Death in childhood
ID/DD w/speech delay, hypotonia, ataxia, seizures
↑ serum lactate
ID, seizures, rigidity, muscle hypotonia, microcephaly
Early death due to respiratory failure
Muscle hypotonia
Microcephaly
Bilateral polymicrogyria
Not reported in females
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
• Intellectual disability without other distinctive findings: OMIM
• DEE: OMIM
• Movement disorders less common
• Macrocephaly
• Infantile-onset hypotonia that develops into hypertonia & spasticity
• Severe seizure onset shortly after birth
• May be assoc w/prominent movement disorder
• No distinguishing brain MRI findings
• Central hypotonia, global DD, severe ID
• Movement disorder may be severe; most persons show mixed pattern of permanent or paroxysmal hyperkinetic & hypertonic movements that affect the whole body.
• Overlap between movement disorders & epilepsy in most affected persons
• Hypotonia & seizures assoc w/↑ serum glycine & lactate in 1st days of life
• DD
• Death in childhood
• ID/DD w/speech delay, hypotonia, ataxia, seizures
• ↑ serum lactate
• ID, seizures, rigidity, muscle hypotonia, microcephaly
• Early death due to respiratory failure
• Muscle hypotonia
• Microcephaly
• Bilateral polymicrogyria
• Not reported in females
## Movement Disorder Spectrum
Genes of Interest in the Differential Diagnosis of
Juvenile onset
Atypical parkinsonism
Iron deposition in basal ganglia on brain MRI
ID/DD, seizures, movement disorders (dystonia, spasticity, myoclonus)
Neuropsychiatric features
Onset of parkinsonism is between 2nd & 4th decade
Nonresponsive to levodopa
Loss of ambulation
Tremor, rigidity, akinesia, scissor gait, hyperreflexia
Mostly good responsiveness to levodopa
Early-onset parkinsonism w/tremor, bradykinesia, loss of postural reflexes; asymmetric onset of symptoms
Neuropsychiatric symptoms
Age of onset is typically older than in
Absence of multisystem involvement
Rigidity, bradykinesia, postural instability, resting tremor, frozen gait, dystonia hyperreflexia w/asymmetric onset
Favorable response to levodopa
Very slow disease progression
Postural instability
Neuropsychiatric symptoms are not common.
Often iron deposition is seen on brain imaging.
Onset is mostly in young adulthood/adulthood.
Slow disease progression
No neuropsychiatric features
Myoclonus of proximal limbs, dystonia (torticollis or writer's cramp), often responding to alcohol
Psychiatric features
Responsive to alcohol
Dystonia can be only manifestation.
Infantile-onset parkinsonism w/dystonia, poor fine motor skills, ataxia, limb hypertonia, autonomic dysfunction
Variable DD
Normal brain imaging
↑ levels of neurotransmitter metabolites & ↓ levels of norepinephrine & dopamine in urine analysis
Exacerbation of symptoms under levodopa, but symptom control under dopamine receptor agonists
Rigidity, tremor, dystonia, staring gaze, supranuclear gaze palsy
Seizures
Cognitive impairment
Seizures, mental deterioration, ataxia, myoclonus
Vision loss
Late infantile onset w/rapid deterioration
Multiple seizure types, refractory to treatment
EEG w/photoparoxysmal response at low-frequency photic stimulation
Cerebellar & cortical atrophy of predominantly the posterior region on brain MRI
Akineto-rigid syndrome, resting tremor
Dysautonomia
Cognitive impairment
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PARK = Parkinson disease
For a general review of the clinical characteristics and causes of monogenic Parkinson disease, see
Myoclonus-ataxia predominate phenotypes should further be differentiated from:
Myoclonus epilepsy syndromes (See
Neuraminidase deficiency (OMIM
Neuronal ceroid lipofuscinosis (OMIM Phenotypic Series:
• Juvenile onset
• Atypical parkinsonism
• Iron deposition in basal ganglia on brain MRI
• ID/DD, seizures, movement disorders (dystonia, spasticity, myoclonus)
• Neuropsychiatric features
• Onset of parkinsonism is between 2nd & 4th decade
• Nonresponsive to levodopa
• Loss of ambulation
• Tremor, rigidity, akinesia, scissor gait, hyperreflexia
• Mostly good responsiveness to levodopa
• Early-onset parkinsonism w/tremor, bradykinesia, loss of postural reflexes; asymmetric onset of symptoms
• Neuropsychiatric symptoms
• Age of onset is typically older than in
• Absence of multisystem involvement
• Rigidity, bradykinesia, postural instability, resting tremor, frozen gait, dystonia hyperreflexia w/asymmetric onset
• Favorable response to levodopa
• Very slow disease progression
• Postural instability
• Neuropsychiatric symptoms are not common.
• Often iron deposition is seen on brain imaging.
• Onset is mostly in young adulthood/adulthood.
• Slow disease progression
• No neuropsychiatric features
• Myoclonus of proximal limbs, dystonia (torticollis or writer's cramp), often responding to alcohol
• Psychiatric features
• Responsive to alcohol
• Dystonia can be only manifestation.
• Infantile-onset parkinsonism w/dystonia, poor fine motor skills, ataxia, limb hypertonia, autonomic dysfunction
• Variable DD
• Normal brain imaging
• ↑ levels of neurotransmitter metabolites & ↓ levels of norepinephrine & dopamine in urine analysis
• Exacerbation of symptoms under levodopa, but symptom control under dopamine receptor agonists
• Rigidity, tremor, dystonia, staring gaze, supranuclear gaze palsy
• Seizures
• Cognitive impairment
• Seizures, mental deterioration, ataxia, myoclonus
• Vision loss
• Late infantile onset w/rapid deterioration
• Multiple seizure types, refractory to treatment
• EEG w/photoparoxysmal response at low-frequency photic stimulation
• Cerebellar & cortical atrophy of predominantly the posterior region on brain MRI
• Akineto-rigid syndrome, resting tremor
• Dysautonomia
• Cognitive impairment
• Myoclonus epilepsy syndromes (See
• Neuraminidase deficiency (OMIM
•
• Neuronal ceroid lipofuscinosis (OMIM Phenotypic Series:
## Management
No clinical practice guidelines for WARS2 deficiency have been published.
The evaluations recommended to determine the extent of disease and needs of an individual diagnosed with
Assess functional neurologic status.
Brain imaging
EEG if seizures are suspected
Gross motor & fine motor skills
Equinovarus foot deformity, contractures, scoliosis if present
Need for adaptive devices
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval for GI dysmotility, aspiration risk, & nutritional status
Consider eval for gastrostomy tube placement to manage dysphagia &/or increased risk of aspiration.
Ptosis & strabismus
Visual acuity
Evidence of optic atrophy/pigmentary retinal changes
Community
Social work involvement for parental support;
Home nursing referral.
Assess health care decisions in the context of the best interest of the child & the values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider seeking further opinions from independent clinical teams.
GI = gastrointestinal; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Assess for best corrected visual acuity, nystagmus, & ptosis.
Consider referral for corrective measures incl prisms &/or surgery.
Community or
Social work involvement for parental support;
Home nursing referral.
IEP = individual educational plan; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale; UPDRS = Unified Parkinson's Disease Rating Scale
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
To date, there is no known cure for WARS2 deficiency.
To maintain muscle strength & mobility & to prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs need monitoring of levels.
Avoid use of valproate.
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
See
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
Physical & occupational therapy
Self-directed exercise
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).
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
1st drug of choice; diminishes myoclonus & frequency of generalized seizures
Should be given in low doses while monitoring liver enzymes, as a hepatopathy after use of valproic acid has been described.
Video esophagram may help define best food consistency.
Education re strategies to mitigate aspiration
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Tremor cannot be completely controlled by the dopaminergic treatment; a jerky dystonic hand tremor persists despite satisfactory control of the extrapyramidal manifestations [
In individuals with parkinsonism, side effects of the dopaminergic therapy can occur over time, with wearing-off phenomenon, "on-off" fluctuations, peak-dose dyskinesia, and retrocolic dystonic spasms.
The following information represents typical management recommendations for school-age 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.
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 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.
Because most infants and young children with
The recommendations regarding frequency of follow up in
Eval of seizure status by pediatric neurologist; to incl EEG & video EEG monitoring
Without seizure correlates, routine EEG is not indicated.
Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.
Assessment of feeding
Monitoring of stool frequency
Dietary assessment to maintain adequate nutrition & growth
OT = occupational therapy; PT = physical therapy
SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale; UPDRS = Unified Parkinson's Disease Rating Scale
Valproic acid can cause severe hepatopathy and neurologic deterioration, as reported in one individual with
See
Search
• Assess functional neurologic status.
• Brain imaging
• EEG if seizures are suspected
• Gross motor & fine motor skills
• Equinovarus foot deformity, contractures, scoliosis if present
• Need for adaptive devices
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval for GI dysmotility, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube placement to manage dysphagia &/or increased risk of aspiration.
• Ptosis & strabismus
• Visual acuity
• Evidence of optic atrophy/pigmentary retinal changes
• Community
• Social work involvement for parental support;
• Home nursing referral.
• Assess health care decisions in the context of the best interest of the child & the values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider seeking further opinions from independent clinical teams.
• Assess for best corrected visual acuity, nystagmus, & ptosis.
• Consider referral for corrective measures incl prisms &/or surgery.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• To maintain muscle strength & mobility & to prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs need monitoring of levels.
• Avoid use of valproate.
• 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.
• Physical & occupational therapy
• Self-directed exercise
• 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).
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
• 1st drug of choice; diminishes myoclonus & frequency of generalized seizures
• Should be given in low doses while monitoring liver enzymes, as a hepatopathy after use of valproic acid has been described.
• Video esophagram may help define best food consistency.
• Education re strategies to mitigate aspiration
• 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.
• 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 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 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 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.
• Eval of seizure status by pediatric neurologist; to incl EEG & video EEG monitoring
• Without seizure correlates, routine EEG is not indicated.
• Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.
• Assessment of feeding
• Monitoring of stool frequency
• Dietary assessment to maintain adequate nutrition & growth
## Evaluations Following Initial Diagnosis
The evaluations recommended to determine the extent of disease and needs of an individual diagnosed with
Assess functional neurologic status.
Brain imaging
EEG if seizures are suspected
Gross motor & fine motor skills
Equinovarus foot deformity, contractures, scoliosis if present
Need for adaptive devices
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval for GI dysmotility, aspiration risk, & nutritional status
Consider eval for gastrostomy tube placement to manage dysphagia &/or increased risk of aspiration.
Ptosis & strabismus
Visual acuity
Evidence of optic atrophy/pigmentary retinal changes
Community
Social work involvement for parental support;
Home nursing referral.
Assess health care decisions in the context of the best interest of the child & the values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider seeking further opinions from independent clinical teams.
GI = gastrointestinal; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Assess for best corrected visual acuity, nystagmus, & ptosis.
Consider referral for corrective measures incl prisms &/or surgery.
Community or
Social work involvement for parental support;
Home nursing referral.
IEP = individual educational plan; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale; UPDRS = Unified Parkinson's Disease Rating Scale
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess functional neurologic status.
• Brain imaging
• EEG if seizures are suspected
• Gross motor & fine motor skills
• Equinovarus foot deformity, contractures, scoliosis if present
• Need for adaptive devices
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval for GI dysmotility, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube placement to manage dysphagia &/or increased risk of aspiration.
• Ptosis & strabismus
• Visual acuity
• Evidence of optic atrophy/pigmentary retinal changes
• Community
• Social work involvement for parental support;
• Home nursing referral.
• Assess health care decisions in the context of the best interest of the child & the values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider seeking further opinions from independent clinical teams.
• Assess for best corrected visual acuity, nystagmus, & ptosis.
• Consider referral for corrective measures incl prisms &/or surgery.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
To date, there is no known cure for WARS2 deficiency.
To maintain muscle strength & mobility & to prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs need monitoring of levels.
Avoid use of valproate.
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
See
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
Physical & occupational therapy
Self-directed exercise
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).
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
1st drug of choice; diminishes myoclonus & frequency of generalized seizures
Should be given in low doses while monitoring liver enzymes, as a hepatopathy after use of valproic acid has been described.
Video esophagram may help define best food consistency.
Education re strategies to mitigate aspiration
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Tremor cannot be completely controlled by the dopaminergic treatment; a jerky dystonic hand tremor persists despite satisfactory control of the extrapyramidal manifestations [
In individuals with parkinsonism, side effects of the dopaminergic therapy can occur over time, with wearing-off phenomenon, "on-off" fluctuations, peak-dose dyskinesia, and retrocolic dystonic spasms.
• To maintain muscle strength & mobility & to prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs need monitoring of levels.
• Avoid use of valproate.
• 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.
• Physical & occupational therapy
• Self-directed exercise
• 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).
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
• 1st drug of choice; diminishes myoclonus & frequency of generalized seizures
• Should be given in low doses while monitoring liver enzymes, as a hepatopathy after use of valproic acid has been described.
• Video esophagram may help define best food consistency.
• Education re strategies to mitigate aspiration
## Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for school-age 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.
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 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.
• 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.
• 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 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 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 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
Because most infants and young children with
The recommendations regarding frequency of follow up in
Eval of seizure status by pediatric neurologist; to incl EEG & video EEG monitoring
Without seizure correlates, routine EEG is not indicated.
Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.
Assessment of feeding
Monitoring of stool frequency
Dietary assessment to maintain adequate nutrition & growth
OT = occupational therapy; PT = physical therapy
SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale; UPDRS = Unified Parkinson's Disease Rating Scale
• Eval of seizure status by pediatric neurologist; to incl EEG & video EEG monitoring
• Without seizure correlates, routine EEG is not indicated.
• Assess for new manifestations, e.g., seizures, changes in tone, movement disorders.
• Assessment of feeding
• Monitoring of stool frequency
• Dietary assessment to maintain adequate nutrition & growth
## Agents/Circumstances to Avoid
Valproic acid can cause severe hepatopathy and neurologic deterioration, as reported in one individual with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
WARS2 deficiency is inherited in an autosomal recessive manner. To date:
Most individuals with
Most individuals with
The parents of an affected individual 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 pathogenic variant or hypomorphic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the 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
Biallelic loss-of-function pathogenic variants are likely to have
A
One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
Neither of the familial
In all but one family, clinically significant intrafamilial clinical variability has not been observed among sibs who have the same biallelic
Note: Individuals who are homozygous for the hypomorphic
To date, individuals with
The offspring of an individual with 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 for reproductive partners of individuals known to be carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
Once the WARS2 deficiency-related 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.
• Most individuals with
• Most individuals with
• The parents of an affected individual 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 pathogenic variant or hypomorphic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the 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
• Biallelic loss-of-function pathogenic variants are likely to have
• A
• One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
• Neither of the familial
• Biallelic loss-of-function pathogenic variants are likely to have
• A
• One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
• Neither of the familial
• In all but one family, clinically significant intrafamilial clinical variability has not been observed among sibs who have the same biallelic
• Note: Individuals who are homozygous for the hypomorphic
• Biallelic loss-of-function pathogenic variants are likely to have
• A
• One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
• Neither of the familial
• To date, individuals with
• The offspring of an individual with 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 for reproductive partners of individuals known to be carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
## Mode of Inheritance
WARS2 deficiency is inherited in an autosomal recessive manner. To date:
Most individuals with
Most individuals with
• Most individuals with
• Most individuals with
## 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 the proband to confirm that both parents are heterozygous for a
If a pathogenic variant or hypomorphic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the 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
Biallelic loss-of-function pathogenic variants are likely to have
A
One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
Neither of the familial
In all but one family, clinically significant intrafamilial clinical variability has not been observed among sibs who have the same biallelic
Note: Individuals who are homozygous for the hypomorphic
To date, individuals with
The offspring of an individual with a
• The parents of an affected individual 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 pathogenic variant or hypomorphic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the 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
• Biallelic loss-of-function pathogenic variants are likely to have
• A
• One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
• Neither of the familial
• Biallelic loss-of-function pathogenic variants are likely to have
• A
• One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
• Neither of the familial
• In all but one family, clinically significant intrafamilial clinical variability has not been observed among sibs who have the same biallelic
• Note: Individuals who are homozygous for the hypomorphic
• Biallelic loss-of-function pathogenic variants are likely to have
• A
• One variant (either a pathogenic variant or a hypomorphic variant) are asymptomatic and are not at risk of developing WARS2 deficiency;
• Neither of the familial
• To date, individuals with
• The offspring of an individual with 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, are carriers, or are at risk of being carriers.
Carrier testing for reproductive partners of individuals known to be carriers should be considered, particularly if consanguinity is likely and/or 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 individuals known to be carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background.
## Prenatal Testing and Preimplantation Genetic Testing
Once the WARS2 deficiency-related 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
Australia
United Kingdom
United Kingdom
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• Australia
•
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• United Kingdom
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• United Kingdom
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## Molecular Genetics
WARS2 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for WARS2 Deficiency (
Aminoacyl-tRNA synthetases are nucleus-encoded mitochondrial enzymes involved in a broad range of cellular processes. Pathogenic variants involving aminoacyl-tRNA synthetases can affect several cellular mechanisms, mainly in tissues with a high energy demand such as the central nervous system (CNS). Accordingly, pathogenic variants in 17 of the 19 aminoacyl-tRNA synthetases have been associated with diseases of the CNS [
Functional data show that the hypomorphic p.Trp13Gly variant diminishes (but does not abolish) transport of WARS2 protein into mitochondria [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Aminoacyl-tRNA synthetases are nucleus-encoded mitochondrial enzymes involved in a broad range of cellular processes. Pathogenic variants involving aminoacyl-tRNA synthetases can affect several cellular mechanisms, mainly in tissues with a high energy demand such as the central nervous system (CNS). Accordingly, pathogenic variants in 17 of the 19 aminoacyl-tRNA synthetases have been associated with diseases of the CNS [
Functional data show that the hypomorphic p.Trp13Gly variant diminishes (but does not abolish) transport of WARS2 protein into mitochondria [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Contact Professor Henry Houlden (
12 October 2023 (bp) Review posted live
18 April 2023 (sn) Original submission
• 12 October 2023 (bp) Review posted live
• 18 April 2023 (sn) Original submission
## Author Notes
Contact Professor Henry Houlden (
## Revision History
12 October 2023 (bp) Review posted live
18 April 2023 (sn) Original submission
• 12 October 2023 (bp) Review posted live
• 18 April 2023 (sn) Original submission
## References
## Literature Cited
|
[] |
12/10/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
warsaw
|
warsaw
|
[
"Warsaw Breakage Syndrome (WABS)",
"Warsaw Syndrome",
"Warsaw Syndrome",
"Warsaw Breakage Syndrome (WABS)",
"ATP-dependent DNA helicase DDX11",
"DDX11",
"DDX11-Related Cohesinopathy"
] |
Ebba Alkhunaizi, Robert M Brosh, David Chitayat
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Congenital severe microcephaly
Prenatal and postnatal growth restriction
Congenital sensorineural hearing loss due to cochlear abnormalities (e.g., cochlear hypoplasia)
Additional clinical, imaging, and laboratory findings include the following.
Intellectual disability and developmental delay
Skeletal anomalies (e.g., proximal insertion of the thumbs, shortening of the thumbs and the first metacarpals, clinodactyly of the fifth finger, and overlapping toes)
Abnormal skin pigmentation (e.g., café au lait macules, cutis marmorata, hypo- or hyperpigmentation, livedo reticularis with telangiectasia)
Congenital cardiovascular malformations (e.g., patent ductus arteriosus, atrial septal defect, ventricular septal defect, tetralogy of Fallot)
Genitourinary malformations (e.g., hypoplastic scrotum, cryptorchidism, hypospadias, multicystic kidneys)
Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane (DEB) and mitomycin C (MMC) in some affected individuals
Note: The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers prefer using DEB while other centers use both DEB and MMC.
Premature chromatid separation (PCS) and premature centromere division (PCD) – separation of the sister chromatids and centromeres during metaphase rather than in anaphase visible on C-banding techniques (See
In many chromosomes, a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers
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
Note: Analysis of
For an introduction to multigene panels click
When the diagnosis of
Note: Analysis 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.
• Congenital severe microcephaly
• Prenatal and postnatal growth restriction
• Congenital sensorineural hearing loss due to cochlear abnormalities (e.g., cochlear hypoplasia)
• Intellectual disability and developmental delay
• Skeletal anomalies (e.g., proximal insertion of the thumbs, shortening of the thumbs and the first metacarpals, clinodactyly of the fifth finger, and overlapping toes)
• Abnormal skin pigmentation (e.g., café au lait macules, cutis marmorata, hypo- or hyperpigmentation, livedo reticularis with telangiectasia)
• Congenital cardiovascular malformations (e.g., patent ductus arteriosus, atrial septal defect, ventricular septal defect, tetralogy of Fallot)
• Genitourinary malformations (e.g., hypoplastic scrotum, cryptorchidism, hypospadias, multicystic kidneys)
• Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane (DEB) and mitomycin C (MMC) in some affected individuals
• Note: The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers prefer using DEB while other centers use both DEB and MMC.
• Premature chromatid separation (PCS) and premature centromere division (PCD) – separation of the sister chromatids and centromeres during metaphase rather than in anaphase visible on C-banding techniques (See
• In many chromosomes, a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers
• Note: Analysis of
• For an introduction to multigene panels click
## Suggestive Findings
Congenital severe microcephaly
Prenatal and postnatal growth restriction
Congenital sensorineural hearing loss due to cochlear abnormalities (e.g., cochlear hypoplasia)
Additional clinical, imaging, and laboratory findings include the following.
Intellectual disability and developmental delay
Skeletal anomalies (e.g., proximal insertion of the thumbs, shortening of the thumbs and the first metacarpals, clinodactyly of the fifth finger, and overlapping toes)
Abnormal skin pigmentation (e.g., café au lait macules, cutis marmorata, hypo- or hyperpigmentation, livedo reticularis with telangiectasia)
Congenital cardiovascular malformations (e.g., patent ductus arteriosus, atrial septal defect, ventricular septal defect, tetralogy of Fallot)
Genitourinary malformations (e.g., hypoplastic scrotum, cryptorchidism, hypospadias, multicystic kidneys)
Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane (DEB) and mitomycin C (MMC) in some affected individuals
Note: The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers prefer using DEB while other centers use both DEB and MMC.
Premature chromatid separation (PCS) and premature centromere division (PCD) – separation of the sister chromatids and centromeres during metaphase rather than in anaphase visible on C-banding techniques (See
In many chromosomes, a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers
• Congenital severe microcephaly
• Prenatal and postnatal growth restriction
• Congenital sensorineural hearing loss due to cochlear abnormalities (e.g., cochlear hypoplasia)
• Intellectual disability and developmental delay
• Skeletal anomalies (e.g., proximal insertion of the thumbs, shortening of the thumbs and the first metacarpals, clinodactyly of the fifth finger, and overlapping toes)
• Abnormal skin pigmentation (e.g., café au lait macules, cutis marmorata, hypo- or hyperpigmentation, livedo reticularis with telangiectasia)
• Congenital cardiovascular malformations (e.g., patent ductus arteriosus, atrial septal defect, ventricular septal defect, tetralogy of Fallot)
• Genitourinary malformations (e.g., hypoplastic scrotum, cryptorchidism, hypospadias, multicystic kidneys)
• Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane (DEB) and mitomycin C (MMC) in some affected individuals
• Note: The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers prefer using DEB while other centers use both DEB and MMC.
• Premature chromatid separation (PCS) and premature centromere division (PCD) – separation of the sister chromatids and centromeres during metaphase rather than in anaphase visible on C-banding techniques (See
• In many chromosomes, a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers
## 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
Note: Analysis of
For an introduction to multigene panels click
When the diagnosis of
Note: Analysis 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.
• Note: Analysis of
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of
Note: Analysis of
For an introduction to multigene panels click
• Note: Analysis of
• For an introduction to multigene panels click
## Option 2
When the diagnosis of
Note: Analysis 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.
## Clinical Characteristics
No clinically relevant genotype-phenotype correlations are known.
"Warsaw breakage syndrome" refers to the city of origin of the first reported individual and the elevated level of chromosome breakage, similar to Fanconi anemia, reported in some affected individuals [
The observation of inconsistent increased levels of chromosome breakage in individuals with this disorder led to the suggestion to change the name of the condition to Warsaw syndrome [
The designation "
## Clinical Description
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations are known.
## Nomenclature
"Warsaw breakage syndrome" refers to the city of origin of the first reported individual and the elevated level of chromosome breakage, similar to Fanconi anemia, reported in some affected individuals [
The observation of inconsistent increased levels of chromosome breakage in individuals with this disorder led to the suggestion to change the name of the condition to Warsaw syndrome [
The designation "
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic disorders of interest in the differential diagnosis of
Disorders to Consider in the Differential Diagnosis of
Microcephaly
Growth deficiency, prenatal &/or postnatal short stature, low birth weight
Abnormal skin pigmentation: generalized hyperpigmentation, café au lait macules, hypopigmentation
Skeletal malformations of upper & lower limbs
Hearing loss (10% of affected persons)
Chromosome instability (chromosome breakage induced by DEB & MMC)
Mild-to-severe prenatal growth restriction
Hand anomalies
Cytogenetic findings of premature centromere separations
Bilateral symmetric tetraphocomelia or hypomelia
Elbow & knee flexion contractures
Ear malformations
Corneal opacities
Not assoc w/SNHL
Microcephaly, progressive
Early growth deficiency (more pronounced from birth until age 2 years, w/mild improvement thereafter)
Chromosome instability (inversions & translocations involving chromosomes 7 & 14)
Immunodeficiency
Premature ovarian failure in females
↑ risk of malignancy (primarily lymphoma)
Not assoc w/SNHL
Pre- & postnatal growth deficiency
Severe microcephaly
Short stature
Growth deficiency is more severe; extremely short stature
Lack of cochlear hypoplasia
CNS vascular anomalies
Insulin resistance
Microcephaly
Short stature
↑ chromosome breakage rate
Hearing loss
Immunodeficiency, combined; pancytopenia & myelodysplastic syndrome
Predisposition to malignancy (mainly lymphoma & leukemia)
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DEB = diepoxybutane; MMC = mitomycin C; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked
Fanconi anemia (FA) is inherited in an autosomal recessive manner with the exception of
Unlike
• Microcephaly
• Growth deficiency, prenatal &/or postnatal short stature, low birth weight
• Abnormal skin pigmentation: generalized hyperpigmentation, café au lait macules, hypopigmentation
• Skeletal malformations of upper & lower limbs
• Hearing loss (10% of affected persons)
• Chromosome instability (chromosome breakage induced by DEB & MMC)
• Mild-to-severe prenatal growth restriction
• Hand anomalies
• Cytogenetic findings of premature centromere separations
• Bilateral symmetric tetraphocomelia or hypomelia
• Elbow & knee flexion contractures
• Ear malformations
• Corneal opacities
• Not assoc w/SNHL
• Microcephaly, progressive
• Early growth deficiency (more pronounced from birth until age 2 years, w/mild improvement thereafter)
• Chromosome instability (inversions & translocations involving chromosomes 7 & 14)
• Immunodeficiency
• Premature ovarian failure in females
• ↑ risk of malignancy (primarily lymphoma)
• Not assoc w/SNHL
• Pre- & postnatal growth deficiency
• Severe microcephaly
• Short stature
• Growth deficiency is more severe; extremely short stature
• Lack of cochlear hypoplasia
• CNS vascular anomalies
• Insulin resistance
• Microcephaly
• Short stature
• ↑ chromosome breakage rate
• Hearing loss
• Immunodeficiency, combined; pancytopenia & myelodysplastic syndrome
• Predisposition to malignancy (mainly lymphoma & leukemia)
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Assess speech development & intellectual abilities.
Assess for features of ADHD.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
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
Optimize nutrition in those w/poor weight gain.
Supplementary formulas &/or gastrostomy tube as needed
Hearing aids should be considered in those w/non-profound hearing loss.
Cochlear implantation, if cochlear nerve is present
Auditory brain stem implant (ABI) is an optional treatment.
Establish an appropriate system of communication & hearing habilitation immediately w/diagnosis of hearing loss; may include sign language in addition to auditory & speech therapy.
Offer educational programs designed for those w/hearing impairment.
Early intervention & educational support as needed
Ongoing PT, OT, & speech therapy to optimize developmental outcomes
ADHD = attention-deficit/hyperactivity disorder; 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
ADHD = attention-deficit/hyperactivity disorder
Although
See
Search
• Assess speech development & intellectual abilities.
• Assess for features of ADHD.
• Optimize nutrition in those w/poor weight gain.
• Supplementary formulas &/or gastrostomy tube as needed
• Hearing aids should be considered in those w/non-profound hearing loss.
• Cochlear implantation, if cochlear nerve is present
• Auditory brain stem implant (ABI) is an optional treatment.
• Establish an appropriate system of communication & hearing habilitation immediately w/diagnosis of hearing loss; may include sign language in addition to auditory & speech therapy.
• Offer educational programs designed for those w/hearing impairment.
• Early intervention & educational support as needed
• Ongoing PT, OT, & speech therapy to optimize developmental outcomes
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Assess speech development & intellectual abilities.
Assess for features of ADHD.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Assess speech development & intellectual abilities.
• Assess for features of ADHD.
## 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
Optimize nutrition in those w/poor weight gain.
Supplementary formulas &/or gastrostomy tube as needed
Hearing aids should be considered in those w/non-profound hearing loss.
Cochlear implantation, if cochlear nerve is present
Auditory brain stem implant (ABI) is an optional treatment.
Establish an appropriate system of communication & hearing habilitation immediately w/diagnosis of hearing loss; may include sign language in addition to auditory & speech therapy.
Offer educational programs designed for those w/hearing impairment.
Early intervention & educational support as needed
Ongoing PT, OT, & speech therapy to optimize developmental outcomes
ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy
• Optimize nutrition in those w/poor weight gain.
• Supplementary formulas &/or gastrostomy tube as needed
• Hearing aids should be considered in those w/non-profound hearing loss.
• Cochlear implantation, if cochlear nerve is present
• Auditory brain stem implant (ABI) is an optional treatment.
• Establish an appropriate system of communication & hearing habilitation immediately w/diagnosis of hearing loss; may include sign language in addition to auditory & speech therapy.
• Offer educational programs designed for those w/hearing impairment.
• Early intervention & educational support as needed
• Ongoing PT, OT, & speech therapy to optimize developmental outcomes
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
ADHD = attention-deficit/hyperactivity disorder
Although
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
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 not at risk of developing
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are not at risk of developing
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 the parents of affected children and young adults who are carriers or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with
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 not at risk of developing
• 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 not at risk of developing
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 affected children and young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with
## Mode of Inheritance
## 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 not at risk of developing
If both parents are known to be heterozygous for a
Heterozygotes (carriers) are not at risk of developing
• 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 not at risk of developing
• 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 not at risk of developing
## 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 the parents of affected children and young adults who are carriers or are at risk of being carriers.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected 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 the parents of affected children and young adults who are carriers or are at risk of being carriers.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with
## 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
•
•
•
•
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
DDX11-Related Cohesinopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for DDX11-Related Cohesinopathy (
DDX11 is a superfamily 2 DNA helicase belonging to the iron-sulfur (Fe-S) cluster family of DNA helicase proteins [
DDX11 is an ATP-dependent DNA helicase [
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
DDX11 is a superfamily 2 DNA helicase belonging to the iron-sulfur (Fe-S) cluster family of DNA helicase proteins [
DDX11 is an ATP-dependent DNA helicase [
Variants listed in the table have been provided by the authors.
## Chapter Notes
Ebba Alkhunaizi, MD (2019-present)Fowzan S Alkuraya, MD; Alfaisal University (2019-2025)Robert M Brosh, Jr, PhD (2019-present)David Chitayat, MD (2019-present)
5 June 2025 (sw) Comprehensive update posted live
6 June 2019 (sw) Review posted live
20 November 2018 (ea, dc) Original submission
• 5 June 2025 (sw) Comprehensive update posted live
• 6 June 2019 (sw) Review posted live
• 20 November 2018 (ea, dc) Original submission
## Author History
Ebba Alkhunaizi, MD (2019-present)Fowzan S Alkuraya, MD; Alfaisal University (2019-2025)Robert M Brosh, Jr, PhD (2019-present)David Chitayat, MD (2019-present)
## Revision History
5 June 2025 (sw) Comprehensive update posted live
6 June 2019 (sw) Review posted live
20 November 2018 (ea, dc) Original submission
• 5 June 2025 (sw) Comprehensive update posted live
• 6 June 2019 (sw) Review posted live
• 20 November 2018 (ea, dc) Original submission
## References
## Literature Cited
C-banding of metaphase chromosomes in two individuals with
A. Representative metaphase from untreated (0 dose) culture
B. Thymidine-synchronized culture
|
[] |
6/6/2019
|
5/6/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
was
|
was
|
[
"Wiskott-Aldrich Syndrome",
"X-Linked Thrombocytopenia (XLT)",
"X-Linked Neutropenia (XLN)",
"Actin nucleation-promoting factor WAS",
"WAS",
"WAS-Related Disorders"
] |
Sharat Chandra, Chinmayee B Nagaraj, Miao Sun, Shanmuganathan Chandrakasan, Kejian Zhang
|
Summary The Wiskott-Aldrich syndrome usually presents in infancy. Affected males have thrombocytopenia with intermittent mucosal bleeding, bloody diarrhea, and intermittent or chronic petechiae and purpura; recurrent bacterial, viral, fungal, and/or opportunistic infections; and eczema. Approximately 25%-40% of those who survive the early complications develop one or more autoimmune conditions including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, vasculitis, rheumatoid arthritis, and immune-mediated damage to the kidneys and liver. Individuals with a Males with XLT have small platelet volume and thrombocytopenia. Severe disease-related events include severe bleeding episodes (14%), autoimmunity (12%), life-threatening infections (7%), and malignancy (5%). Males with XLN typically have congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities. The diagnosis of a The diagnosis of a In those with XLN, treatment includes granulocyte colony-stimulating factor therapy; routine non-live immunizations; prompt evaluation and treatment for infection including empiric parenteral antibiotics and exhaustive search for source of infection; and treatment of myelodysplastic syndrome and acute myelogenous leukemia per hematologist/oncologist.
|
Wiskott-Aldrich syndrome
X-linked thrombocytopenia (XLT)
X-linked neutropenia (XLN)
For other genetic causes of these phenotypes see
• Wiskott-Aldrich syndrome
• X-linked thrombocytopenia (XLT)
• X-linked neutropenia (XLN)
## Diagnosis
Profound thrombocytopenia (<70,000 platelets/mm
Small platelet size (mean platelet volume >2 standard deviations [SD] below the mean for the laboratory)
Recurrent bacterial, viral, fungal, and/or other opportunistic infections in infancy or early childhood
Eczema
Autoimmune disorder, such as hemolytic anemia, vasculitis, rheumatoid arthritis, or glomerulonephritis
Increased risk of cancer, particularly lymphoma
Family history of one or more maternally related males with a
Absent or decreased Wiskott-Aldrich syndrome protein (WASP) in hematopoietic cells by flow cytometry or western blotting
Abnormal lymphocytes:
Decreased T-cell subsets, especially proportion and absolute number of CD8
Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
Absent isohemagglutinins
Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
Congenital thrombocytopenia (5,000-50,000 platelets/mm
Small platelet size (platelet volume <7.5 fL)
Absence of other clinical findings of Wiskott-Aldrich syndrome
Family history of one or more maternally related males with a
Decreased or absent WASP by flow cytometry or western blotting
Note: Some affected individuals have near-normal amounts of WASP.
Recurrent bacterial infections
Persistent neutropenia
Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome
Normal WASP expression by flow cytometry or western blotting
BOTH of the following:
Thrombocytopenia (<70,000 platelets/mm
Small platelets (platelet volume 2 SD below the mean for the laboratory)
AND at least ONE of the following:
Eczema
Recurrent bacterial, viral, and/or fungal infections
Autoimmune disease(s) (including vasculitis)
Malignancy
Reduced WASP expression in a fresh blood sample
Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
Positive maternal family history of a
AND a hemizygous
Note: (1) Females heterozygous for a
Molecular testing approaches can include a combination of
For an introduction to multigene panels click
When the diagnosis of a
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.
• Profound thrombocytopenia (<70,000 platelets/mm
• Small platelet size (mean platelet volume >2 standard deviations [SD] below the mean for the laboratory)
• Recurrent bacterial, viral, fungal, and/or other opportunistic infections in infancy or early childhood
• Eczema
• Autoimmune disorder, such as hemolytic anemia, vasculitis, rheumatoid arthritis, or glomerulonephritis
• Increased risk of cancer, particularly lymphoma
• Family history of one or more maternally related males with a
• Absent or decreased Wiskott-Aldrich syndrome protein (WASP) in hematopoietic cells by flow cytometry or western blotting
• Abnormal lymphocytes:
• Decreased T-cell subsets, especially proportion and absolute number of CD8
• Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
• Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
• Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
• Absent isohemagglutinins
• Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
• Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
• Decreased T-cell subsets, especially proportion and absolute number of CD8
• Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
• Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
• Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
• Absent isohemagglutinins
• Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
• Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
• Decreased T-cell subsets, especially proportion and absolute number of CD8
• Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
• Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
• Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
• Absent isohemagglutinins
• Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
• Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
• Congenital thrombocytopenia (5,000-50,000 platelets/mm
• Small platelet size (platelet volume <7.5 fL)
• Absence of other clinical findings of Wiskott-Aldrich syndrome
• Family history of one or more maternally related males with a
• Decreased or absent WASP by flow cytometry or western blotting
• Note: Some affected individuals have near-normal amounts of WASP.
• Recurrent bacterial infections
• Persistent neutropenia
• Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome
• Normal WASP expression by flow cytometry or western blotting
• BOTH of the following:
• Thrombocytopenia (<70,000 platelets/mm
• Small platelets (platelet volume 2 SD below the mean for the laboratory)
• Thrombocytopenia (<70,000 platelets/mm
• Small platelets (platelet volume 2 SD below the mean for the laboratory)
• AND at least ONE of the following:
• Eczema
• Recurrent bacterial, viral, and/or fungal infections
• Autoimmune disease(s) (including vasculitis)
• Malignancy
• Reduced WASP expression in a fresh blood sample
• Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
• Positive maternal family history of a
• Eczema
• Recurrent bacterial, viral, and/or fungal infections
• Autoimmune disease(s) (including vasculitis)
• Malignancy
• Reduced WASP expression in a fresh blood sample
• Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
• Positive maternal family history of a
• AND a hemizygous
• Thrombocytopenia (<70,000 platelets/mm
• Small platelets (platelet volume 2 SD below the mean for the laboratory)
• Eczema
• Recurrent bacterial, viral, and/or fungal infections
• Autoimmune disease(s) (including vasculitis)
• Malignancy
• Reduced WASP expression in a fresh blood sample
• Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
• Positive maternal family history of a
## Suggestive Findings
Profound thrombocytopenia (<70,000 platelets/mm
Small platelet size (mean platelet volume >2 standard deviations [SD] below the mean for the laboratory)
Recurrent bacterial, viral, fungal, and/or other opportunistic infections in infancy or early childhood
Eczema
Autoimmune disorder, such as hemolytic anemia, vasculitis, rheumatoid arthritis, or glomerulonephritis
Increased risk of cancer, particularly lymphoma
Family history of one or more maternally related males with a
Absent or decreased Wiskott-Aldrich syndrome protein (WASP) in hematopoietic cells by flow cytometry or western blotting
Abnormal lymphocytes:
Decreased T-cell subsets, especially proportion and absolute number of CD8
Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
Absent isohemagglutinins
Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
Congenital thrombocytopenia (5,000-50,000 platelets/mm
Small platelet size (platelet volume <7.5 fL)
Absence of other clinical findings of Wiskott-Aldrich syndrome
Family history of one or more maternally related males with a
Decreased or absent WASP by flow cytometry or western blotting
Note: Some affected individuals have near-normal amounts of WASP.
Recurrent bacterial infections
Persistent neutropenia
Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome
Normal WASP expression by flow cytometry or western blotting
• Profound thrombocytopenia (<70,000 platelets/mm
• Small platelet size (mean platelet volume >2 standard deviations [SD] below the mean for the laboratory)
• Recurrent bacterial, viral, fungal, and/or other opportunistic infections in infancy or early childhood
• Eczema
• Autoimmune disorder, such as hemolytic anemia, vasculitis, rheumatoid arthritis, or glomerulonephritis
• Increased risk of cancer, particularly lymphoma
• Family history of one or more maternally related males with a
• Absent or decreased Wiskott-Aldrich syndrome protein (WASP) in hematopoietic cells by flow cytometry or western blotting
• Abnormal lymphocytes:
• Decreased T-cell subsets, especially proportion and absolute number of CD8
• Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
• Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
• Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
• Absent isohemagglutinins
• Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
• Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
• Decreased T-cell subsets, especially proportion and absolute number of CD8
• Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
• Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
• Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
• Absent isohemagglutinins
• Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
• Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
• Decreased T-cell subsets, especially proportion and absolute number of CD8
• Decreased NK cell function. Lymphocyte subsets, mitogen responses, and other tests of cell-mediated immunity can vary among individuals, and over time in the same individual.
• Note: (1) Some individuals, particularly children, have normal lymphocyte numbers and normal function. (2) Although the proportion of CD8
• Abnormal immunoglobulin levels (decreased IgM, normal or decreased IgG, increased IgA, increased IgE)
• Absent isohemagglutinins
• Note: Interpretation of the significance of isohemagglutinin titers is unreliable in children younger than age 18 years.
• Absent or greatly decreased antibody responses to polysaccharide antigens (e.g., Pneumovax
• Congenital thrombocytopenia (5,000-50,000 platelets/mm
• Small platelet size (platelet volume <7.5 fL)
• Absence of other clinical findings of Wiskott-Aldrich syndrome
• Family history of one or more maternally related males with a
• Decreased or absent WASP by flow cytometry or western blotting
• Note: Some affected individuals have near-normal amounts of WASP.
• Recurrent bacterial infections
• Persistent neutropenia
• Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome
• Normal WASP expression by flow cytometry or western blotting
## Establishing the Diagnosis
BOTH of the following:
Thrombocytopenia (<70,000 platelets/mm
Small platelets (platelet volume 2 SD below the mean for the laboratory)
AND at least ONE of the following:
Eczema
Recurrent bacterial, viral, and/or fungal infections
Autoimmune disease(s) (including vasculitis)
Malignancy
Reduced WASP expression in a fresh blood sample
Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
Positive maternal family history of a
AND a hemizygous
Note: (1) Females heterozygous for a
Molecular testing approaches can include a combination of
For an introduction to multigene panels click
When the diagnosis of a
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.
• BOTH of the following:
• Thrombocytopenia (<70,000 platelets/mm
• Small platelets (platelet volume 2 SD below the mean for the laboratory)
• Thrombocytopenia (<70,000 platelets/mm
• Small platelets (platelet volume 2 SD below the mean for the laboratory)
• AND at least ONE of the following:
• Eczema
• Recurrent bacterial, viral, and/or fungal infections
• Autoimmune disease(s) (including vasculitis)
• Malignancy
• Reduced WASP expression in a fresh blood sample
• Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
• Positive maternal family history of a
• Eczema
• Recurrent bacterial, viral, and/or fungal infections
• Autoimmune disease(s) (including vasculitis)
• Malignancy
• Reduced WASP expression in a fresh blood sample
• Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
• Positive maternal family history of a
• AND a hemizygous
• Thrombocytopenia (<70,000 platelets/mm
• Small platelets (platelet volume 2 SD below the mean for the laboratory)
• Eczema
• Recurrent bacterial, viral, and/or fungal infections
• Autoimmune disease(s) (including vasculitis)
• Malignancy
• Reduced WASP expression in a fresh blood sample
• Abnormal antibody response to polysaccharide antigens and/or low isohemagglutinins
• Positive maternal family history of a
## Option 1
For an introduction to multigene panels click
## Option 2
When the diagnosis of a
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
The
XLN = X-linked neutropenia; XLT = X-linked thrombocytopenia
Thrombocytopenia may be reversed by splenectomy; however, recurrent thrombocytopenia associated with the development of immune thrombocytopenia purpura (ITP) is observed in some splenectomized individuals, more so in those with Wiskott-Aldrich syndrome compared to those with XLT [
The overall incidence of any severe infections is 0.11 per patient-year (0.10-0.13). About half of individuals with Wiskott-Aldrich syndrome have a severe infection by age 15 years, and severe infections contribute to 27% of the mortality in Wiskott-Aldrich syndrome [
High serum immunoglobulin (Ig) M concentration in young children prior to splenectomy may be a risk factor for the development of autoimmune hemolytic anemia [
The presence of an autoimmune disorder significantly increases the risk of developing lymphoma [
Allogeneic hematopoietic stem cell transplantation (HSCT) corrects autoimmunity in individuals with Wiskott-Aldrich syndrome [
The prognosis of individuals with Wiskott-Aldrich syndrome following conventional chemotherapy is poorer than that of age-matched normal controls. Individuals with Wiskott-Aldrich syndrome have a significant risk of relapse or development of a second
Only three other non-hematologic malignancies were reported in individuals with Wiskott-Aldrich syndrome, including glioma, acoustic neuroma, and testicular carcinoma. To date, it is unknown if the risk of non-hematologic malignancy is increased in individuals with Wiskott-Aldrich syndrome.
Males with XLT have small platelet volume and thrombocytopenia that may be intermittent.
Males with XLN typically present with congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities [
Females heterozygous for a
Individuals with Wiskott-Aldrich syndrome show remarkably variable expressivity of clinical findings.
At least 300 different disease-causing variants and six mutational hot spots in
Specific pathogenic variants are not universally associated with a specific clinical phenotype, and disease severity varies considerably within families, even between monozygotic twins [
XLN is caused by rare gain-of-function variants in the GTPase binding domain, which cause constitutive activation of WASP in tissues to compensate the reduced myelopoiesis and extremely low number of circulating neutrophil in peripheral blood. Therefore, individuals with XLN are generally not at high risk of infections and do not require permanent granulocyte colony-stimulating factor support. Disease severity varies considerably within families [
While predictions can sometimes be made based on groups of affected individuals or types of pathogenic variant, considerable caution must be exercised in assigning a phenotype to a young, newly diagnosed male based on genotype alone for the following reasons:
The phenotype of affected males in the same kindred can vary widely [
Splice site variants may allow production of multiple gene products, including normally spliced WASP [
Reversion of an inherited pathogenic variant to a benign variant in a subpopulation of cells with improvement of clinical symptoms has been reported [
It is likely that the clinical phenotype in
Some studies have focused on WASP expression as a better predictor of clinical severity of a
In one study, 74.2% of individuals who produced WASP had XLT, while 86.5% of individuals who produced no WASP had Wiskott-Aldrich syndrome [
As a group, individuals who expressed normal-sized mutated WASP were significantly less likely to develop autoimmune disease and/or malignancy than individuals who did not express WASP or who expressed only a truncated protein [
Penetrance is complete in males with a
The estimated prevalence of
• The phenotype of affected males in the same kindred can vary widely [
• Splice site variants may allow production of multiple gene products, including normally spliced WASP [
• Reversion of an inherited pathogenic variant to a benign variant in a subpopulation of cells with improvement of clinical symptoms has been reported [
• It is likely that the clinical phenotype in
• In one study, 74.2% of individuals who produced WASP had XLT, while 86.5% of individuals who produced no WASP had Wiskott-Aldrich syndrome [
• As a group, individuals who expressed normal-sized mutated WASP were significantly less likely to develop autoimmune disease and/or malignancy than individuals who did not express WASP or who expressed only a truncated protein [
## Clinical Description
The
XLN = X-linked neutropenia; XLT = X-linked thrombocytopenia
Thrombocytopenia may be reversed by splenectomy; however, recurrent thrombocytopenia associated with the development of immune thrombocytopenia purpura (ITP) is observed in some splenectomized individuals, more so in those with Wiskott-Aldrich syndrome compared to those with XLT [
The overall incidence of any severe infections is 0.11 per patient-year (0.10-0.13). About half of individuals with Wiskott-Aldrich syndrome have a severe infection by age 15 years, and severe infections contribute to 27% of the mortality in Wiskott-Aldrich syndrome [
High serum immunoglobulin (Ig) M concentration in young children prior to splenectomy may be a risk factor for the development of autoimmune hemolytic anemia [
The presence of an autoimmune disorder significantly increases the risk of developing lymphoma [
Allogeneic hematopoietic stem cell transplantation (HSCT) corrects autoimmunity in individuals with Wiskott-Aldrich syndrome [
The prognosis of individuals with Wiskott-Aldrich syndrome following conventional chemotherapy is poorer than that of age-matched normal controls. Individuals with Wiskott-Aldrich syndrome have a significant risk of relapse or development of a second
Only three other non-hematologic malignancies were reported in individuals with Wiskott-Aldrich syndrome, including glioma, acoustic neuroma, and testicular carcinoma. To date, it is unknown if the risk of non-hematologic malignancy is increased in individuals with Wiskott-Aldrich syndrome.
Males with XLT have small platelet volume and thrombocytopenia that may be intermittent.
Males with XLN typically present with congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities [
Females heterozygous for a
## Wiskott-Aldrich Syndrome
Thrombocytopenia may be reversed by splenectomy; however, recurrent thrombocytopenia associated with the development of immune thrombocytopenia purpura (ITP) is observed in some splenectomized individuals, more so in those with Wiskott-Aldrich syndrome compared to those with XLT [
The overall incidence of any severe infections is 0.11 per patient-year (0.10-0.13). About half of individuals with Wiskott-Aldrich syndrome have a severe infection by age 15 years, and severe infections contribute to 27% of the mortality in Wiskott-Aldrich syndrome [
High serum immunoglobulin (Ig) M concentration in young children prior to splenectomy may be a risk factor for the development of autoimmune hemolytic anemia [
The presence of an autoimmune disorder significantly increases the risk of developing lymphoma [
Allogeneic hematopoietic stem cell transplantation (HSCT) corrects autoimmunity in individuals with Wiskott-Aldrich syndrome [
The prognosis of individuals with Wiskott-Aldrich syndrome following conventional chemotherapy is poorer than that of age-matched normal controls. Individuals with Wiskott-Aldrich syndrome have a significant risk of relapse or development of a second
Only three other non-hematologic malignancies were reported in individuals with Wiskott-Aldrich syndrome, including glioma, acoustic neuroma, and testicular carcinoma. To date, it is unknown if the risk of non-hematologic malignancy is increased in individuals with Wiskott-Aldrich syndrome.
## X-Linked Thrombocytopenia (XLT)
Males with XLT have small platelet volume and thrombocytopenia that may be intermittent.
## X-Linked Neutropenia (XLN)
Males with XLN typically present with congenital neutropenia associated with myelodysplasia, hyperactive neutrophils, increased myeloid cell apoptosis, and lymphoid cell abnormalities [
## Heterozygous Females
Females heterozygous for a
## Genotype-Phenotype Correlations
Individuals with Wiskott-Aldrich syndrome show remarkably variable expressivity of clinical findings.
At least 300 different disease-causing variants and six mutational hot spots in
Specific pathogenic variants are not universally associated with a specific clinical phenotype, and disease severity varies considerably within families, even between monozygotic twins [
XLN is caused by rare gain-of-function variants in the GTPase binding domain, which cause constitutive activation of WASP in tissues to compensate the reduced myelopoiesis and extremely low number of circulating neutrophil in peripheral blood. Therefore, individuals with XLN are generally not at high risk of infections and do not require permanent granulocyte colony-stimulating factor support. Disease severity varies considerably within families [
While predictions can sometimes be made based on groups of affected individuals or types of pathogenic variant, considerable caution must be exercised in assigning a phenotype to a young, newly diagnosed male based on genotype alone for the following reasons:
The phenotype of affected males in the same kindred can vary widely [
Splice site variants may allow production of multiple gene products, including normally spliced WASP [
Reversion of an inherited pathogenic variant to a benign variant in a subpopulation of cells with improvement of clinical symptoms has been reported [
It is likely that the clinical phenotype in
Some studies have focused on WASP expression as a better predictor of clinical severity of a
In one study, 74.2% of individuals who produced WASP had XLT, while 86.5% of individuals who produced no WASP had Wiskott-Aldrich syndrome [
As a group, individuals who expressed normal-sized mutated WASP were significantly less likely to develop autoimmune disease and/or malignancy than individuals who did not express WASP or who expressed only a truncated protein [
• The phenotype of affected males in the same kindred can vary widely [
• Splice site variants may allow production of multiple gene products, including normally spliced WASP [
• Reversion of an inherited pathogenic variant to a benign variant in a subpopulation of cells with improvement of clinical symptoms has been reported [
• It is likely that the clinical phenotype in
• In one study, 74.2% of individuals who produced WASP had XLT, while 86.5% of individuals who produced no WASP had Wiskott-Aldrich syndrome [
• As a group, individuals who expressed normal-sized mutated WASP were significantly less likely to develop autoimmune disease and/or malignancy than individuals who did not express WASP or who expressed only a truncated protein [
## Penetrance
Penetrance is complete in males with a
## Prevalence
The estimated prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic disorders of interest in the differential diagnosis Wiskott-Aldrich syndrome include those listed in
Genetic Disorders of Interest in the Differential Diagnosis of Wiskott-Aldrich Syndrome
Recurrent infections, eczema, & thrombocytopenia
Low numbers of B & T cells, defective T-cell proliferation & chemotaxis, low NK cell function, & abnormal WASP
Consider In males who initially present w/
Note: Persistent thrombocytopenia is rarely, if ever, seen in these conditions.
Recurrent infections, neutropenia, thrombocytopenia, & hemolytic anemia
Dysfunction of B cells & defective T-cell activation (normal to low T-cell counts)
Risk for lymphomas & other malignancies
IgM normal or high
Serum IgG, IgA, & IgE severely deficient
Gastrointestinal complications & neurologic deterioration
Severe & persistent infections, diarrhea, & poor growth
T-B+NK-, nonfunctional B lymphocytes, & lymphocytopenia
AR = autosomal recessive; Ig = immunoglobulin; MOI = mode of inheritance; T-B+NK- = low numbers of T & natural killer cells, normal number of B cells; WASP = Wiskott-Aldrich syndrome protein; XL = X-linked
See
Human immunodeficiency virus (HIV) infection can also be considered in males who initially present with
The differential diagnosis for XLT includes
The differential diagnosis for XLN is broad and includes autoimmune neutropenia and benign ethnic neutropenia in addition to several novel genetic causes of severe congenital neutropenia. For detailed reviews of congenital neutropenia, see
• Recurrent infections, eczema, & thrombocytopenia
• Low numbers of B & T cells, defective T-cell proliferation & chemotaxis, low NK cell function, & abnormal WASP
• Consider In males who initially present w/
• Note: Persistent thrombocytopenia is rarely, if ever, seen in these conditions.
• Recurrent infections, neutropenia, thrombocytopenia, & hemolytic anemia
• Dysfunction of B cells & defective T-cell activation (normal to low T-cell counts)
• Risk for lymphomas & other malignancies
• IgM normal or high
• Serum IgG, IgA, & IgE severely deficient
• Gastrointestinal complications & neurologic deterioration
• Severe & persistent infections, diarrhea, & poor growth
• T-B+NK-, nonfunctional B lymphocytes, & lymphocytopenia
## Wiskott-Aldrich Syndrome
Genetic disorders of interest in the differential diagnosis Wiskott-Aldrich syndrome include those listed in
Genetic Disorders of Interest in the Differential Diagnosis of Wiskott-Aldrich Syndrome
Recurrent infections, eczema, & thrombocytopenia
Low numbers of B & T cells, defective T-cell proliferation & chemotaxis, low NK cell function, & abnormal WASP
Consider In males who initially present w/
Note: Persistent thrombocytopenia is rarely, if ever, seen in these conditions.
Recurrent infections, neutropenia, thrombocytopenia, & hemolytic anemia
Dysfunction of B cells & defective T-cell activation (normal to low T-cell counts)
Risk for lymphomas & other malignancies
IgM normal or high
Serum IgG, IgA, & IgE severely deficient
Gastrointestinal complications & neurologic deterioration
Severe & persistent infections, diarrhea, & poor growth
T-B+NK-, nonfunctional B lymphocytes, & lymphocytopenia
AR = autosomal recessive; Ig = immunoglobulin; MOI = mode of inheritance; T-B+NK- = low numbers of T & natural killer cells, normal number of B cells; WASP = Wiskott-Aldrich syndrome protein; XL = X-linked
See
Human immunodeficiency virus (HIV) infection can also be considered in males who initially present with
• Recurrent infections, eczema, & thrombocytopenia
• Low numbers of B & T cells, defective T-cell proliferation & chemotaxis, low NK cell function, & abnormal WASP
• Consider In males who initially present w/
• Note: Persistent thrombocytopenia is rarely, if ever, seen in these conditions.
• Recurrent infections, neutropenia, thrombocytopenia, & hemolytic anemia
• Dysfunction of B cells & defective T-cell activation (normal to low T-cell counts)
• Risk for lymphomas & other malignancies
• IgM normal or high
• Serum IgG, IgA, & IgE severely deficient
• Gastrointestinal complications & neurologic deterioration
• Severe & persistent infections, diarrhea, & poor growth
• T-B+NK-, nonfunctional B lymphocytes, & lymphocytopenia
## X-Linked Thrombocytopenia (XLT)
The differential diagnosis for XLT includes
## X-Linked Neutropenia (XLN)
The differential diagnosis for XLN is broad and includes autoimmune neutropenia and benign ethnic neutropenia in addition to several novel genetic causes of severe congenital neutropenia. For detailed reviews of congenital neutropenia, see
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
Platelet count & size
Assessment for complications assoc w/↑ bleeding
Referral to hematologist for periodic CBCs to monitor platelet counts & assess for anemia assoc w/bleeding
T-cell subsets
Ig levels
Vaccine titers
WASP expression
Community or
Social work involvement for parental support
Home nursing referral
CBC = complete blood count; Ig = immunoglobulin; ITP = idiopathic thrombocytopenic purpura; MOI = mode of inheritance; WASP = Wiskott-Aldrich syndrome protein
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment options vary based on the predicted disease burden in a particular individual. See
Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [
Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see
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
Wiskott-Aldrich Syndrome and X-Linked Thrombocytopenia: Treatment of Manifestations
The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see
Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).
IVIG & immune modulation w/steroids as first-line therapy
Rituximab as second-line therapy
Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.
Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.
Topical steroids
Antibiotics may be needed for chronic skin infections that worsen eczema.
Prophylaxis for
Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
Prompt eval & treatment for infection
Treatment w/empiric parenteral antibiotics is necessary in most persons.
Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
HSCT = hematopoietic stem cell transplantation; IVIG = Intravenous immunoglobulin; XLT = X-linked thrombocytopenia
X-Linked Neutropenia: Treatment of Manifestations
G-CSF therapy
Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
Prompt eval & treatment for infection
Treatment w/empiric parenteral antibiotics is necessary in most persons.
Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
G-CSF = granulocyte colony-stimulating factor
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
CBC incl platelet count & size
Assessment for complications assoc w/↑ bleeding
Circumcision of an at-risk newborn male should not be undertaken in the presence of thrombocytopenia.
The use of over-the-counter medications should be discussed with a physician, as some medications can interfere with platelet function.
When possible, elective surgical procedures should be deferred until after HSCT.
It is appropriate to clarify the genetic status of at-risk male relatives of an affected individual so that morbidity and mortality can be reduced by early diagnosis and treatment. Of note, evaluation of newborn at-risk males is recommended before any elective procedure such as circumcision.
Rapid screening of at-risk males may be accomplished by WASP staining using flow cytometry. Definitive testing requires molecular genetic testing for the familial
See
Search
• Platelet count & size
• Assessment for complications assoc w/↑ bleeding
• Referral to hematologist for periodic CBCs to monitor platelet counts & assess for anemia assoc w/bleeding
• T-cell subsets
• Ig levels
• Vaccine titers
• WASP expression
• Community or
• Social work involvement for parental support
• Home nursing referral
• Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [
• Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see
• The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see
• Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).
• IVIG & immune modulation w/steroids as first-line therapy
• Rituximab as second-line therapy
• Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.
• Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.
• Topical steroids
• Antibiotics may be needed for chronic skin infections that worsen eczema.
• Prophylaxis for
• Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
• IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
• Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
• Prompt eval & treatment for infection
• Treatment w/empiric parenteral antibiotics is necessary in most persons.
• Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
• G-CSF therapy
• Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
• Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
• Prompt eval & treatment for infection
• Treatment w/empiric parenteral antibiotics is necessary in most persons.
• Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
• CBC incl platelet count & size
• Assessment for complications assoc w/↑ bleeding
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Platelet count & size
Assessment for complications assoc w/↑ bleeding
Referral to hematologist for periodic CBCs to monitor platelet counts & assess for anemia assoc w/bleeding
T-cell subsets
Ig levels
Vaccine titers
WASP expression
Community or
Social work involvement for parental support
Home nursing referral
CBC = complete blood count; Ig = immunoglobulin; ITP = idiopathic thrombocytopenic purpura; MOI = mode of inheritance; WASP = Wiskott-Aldrich syndrome protein
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Platelet count & size
• Assessment for complications assoc w/↑ bleeding
• Referral to hematologist for periodic CBCs to monitor platelet counts & assess for anemia assoc w/bleeding
• T-cell subsets
• Ig levels
• Vaccine titers
• WASP expression
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Treatment options vary based on the predicted disease burden in a particular individual. See
Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [
Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see
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
Wiskott-Aldrich Syndrome and X-Linked Thrombocytopenia: Treatment of Manifestations
The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see
Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).
IVIG & immune modulation w/steroids as first-line therapy
Rituximab as second-line therapy
Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.
Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.
Topical steroids
Antibiotics may be needed for chronic skin infections that worsen eczema.
Prophylaxis for
Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
Prompt eval & treatment for infection
Treatment w/empiric parenteral antibiotics is necessary in most persons.
Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
HSCT = hematopoietic stem cell transplantation; IVIG = Intravenous immunoglobulin; XLT = X-linked thrombocytopenia
X-Linked Neutropenia: Treatment of Manifestations
G-CSF therapy
Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
Prompt eval & treatment for infection
Treatment w/empiric parenteral antibiotics is necessary in most persons.
Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
G-CSF = granulocyte colony-stimulating factor
• Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [
• Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see
• The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see
• Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).
• IVIG & immune modulation w/steroids as first-line therapy
• Rituximab as second-line therapy
• Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.
• Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.
• Topical steroids
• Antibiotics may be needed for chronic skin infections that worsen eczema.
• Prophylaxis for
• Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
• IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
• Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
• Prompt eval & treatment for infection
• Treatment w/empiric parenteral antibiotics is necessary in most persons.
• Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
• G-CSF therapy
• Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
• Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
• Prompt eval & treatment for infection
• Treatment w/empiric parenteral antibiotics is necessary in most persons.
• Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
## Targeted Therapy
Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [
Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see
• Myeloablative conditioning prior to transplantation is the most widely used approach, although busulfan-based reduced-intensity or sub-myeloblative regimens can also be used and result in donor myeloid chimerism >50%, which is essential for resolution of thrombocytopenia associated with Wiskott-Aldrich syndrome. Non-busulfan-based reduced-intensity conditioning regimens, however, are associated with increased risk of mixed chimerism and more likely to result in donor myeloid chimerism <50% or graft failure [
• Individuals with Wiskott-Aldrich syndrome who do not have a suitably matched donor but who experience life-threatening complications are candidates for gene therapy (see
## 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
Wiskott-Aldrich Syndrome and X-Linked Thrombocytopenia: Treatment of Manifestations
The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see
Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).
IVIG & immune modulation w/steroids as first-line therapy
Rituximab as second-line therapy
Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.
Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.
Topical steroids
Antibiotics may be needed for chronic skin infections that worsen eczema.
Prophylaxis for
Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
Prompt eval & treatment for infection
Treatment w/empiric parenteral antibiotics is necessary in most persons.
Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
HSCT = hematopoietic stem cell transplantation; IVIG = Intravenous immunoglobulin; XLT = X-linked thrombocytopenia
X-Linked Neutropenia: Treatment of Manifestations
G-CSF therapy
Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
Prompt eval & treatment for infection
Treatment w/empiric parenteral antibiotics is necessary in most persons.
Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
G-CSF = granulocyte colony-stimulating factor
• The mainstay of thrombocytopenia mgmt in Wiskott-Aldrich syndrome is early HSCT (see
• Platelet transfusions should be administered judiciously (e.g., for significant bleeding & surgical procedures).
• IVIG & immune modulation w/steroids as first-line therapy
• Rituximab as second-line therapy
• Splenectomy can also be considered for mgmt of XLT-related thrombocytopenia.
• Males who have had splenectomy must take antibiotics routinely for the rest of their lives because of ↑ risk for overwhelming infection.
• Topical steroids
• Antibiotics may be needed for chronic skin infections that worsen eczema.
• Prophylaxis for
• Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
• IVIG starting by age 6 mos administered every 3-4 wks or subcutaneously, usually on a weekly basis. IVIG is a highly purified blood derivative (a combination of many specific antimicrobial antibodies).
• Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
• Prompt eval & treatment for infection
• Treatment w/empiric parenteral antibiotics is necessary in most persons.
• Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
• G-CSF therapy
• Consider prophylactic antibiotics in persons w/recurrent bacterial sinopulmonary infections.
• Routine immunizations. "Non-live" vaccinations can be given safely to persons w/a
• Prompt eval & treatment for infection
• Treatment w/empiric parenteral antibiotics is necessary in most persons.
• Exhaustive eval for source of infection, which may incl invasive assessments; identification of offending organism is needed to guide therapy.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
CBC incl platelet count & size
Assessment for complications assoc w/↑ bleeding
• CBC incl platelet count & size
• Assessment for complications assoc w/↑ bleeding
## Agents/Circumstances to Avoid
Circumcision of an at-risk newborn male should not be undertaken in the presence of thrombocytopenia.
The use of over-the-counter medications should be discussed with a physician, as some medications can interfere with platelet function.
When possible, elective surgical procedures should be deferred until after HSCT.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of at-risk male relatives of an affected individual so that morbidity and mortality can be reduced by early diagnosis and treatment. Of note, evaluation of newborn at-risk males is recommended before any elective procedure such as circumcision.
Rapid screening of at-risk males may be accomplished by WASP staining using flow cytometry. Definitive testing requires molecular genetic testing for the familial
See
## Therapies Under Investigation
Search
## Genetic Counseling
The father of an affected male will not have a
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
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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 symptomatic. The clinical presentation of males with a
Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters, who will be carriers (see Clinical Description,
None of their sons.
Note: Molecular genetic testing may be able to identify the family member in whom a
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are typically asymptomatic (see Clinical Description,
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.
Note: There is no evidence that cesarean section reduces the risk of morbidity and mortality in males with Wiskott-Aldrich syndrome.
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 father of an affected male will not have a
• 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
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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 symptomatic. The clinical presentation of males with a
• Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
• Males who inherit the pathogenic variant will be symptomatic. The clinical presentation of males with a
• Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be symptomatic. The clinical presentation of males with a
• Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
• All of their daughters, who will be carriers (see Clinical Description,
• 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 carriers, or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The father of an affected male will not have a
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
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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 symptomatic. The clinical presentation of males with a
Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters, who will be carriers (see Clinical Description,
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 a
• 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
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier), 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 symptomatic. The clinical presentation of males with a
• Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
• Males who inherit the pathogenic variant will be symptomatic. The clinical presentation of males with a
• Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be symptomatic. The clinical presentation of males with a
• Females who inherit the pathogenic variant will be carriers and are typically asymptomatic due to random X-chromosome inactivation that results in sufficient normal Wiskott-Aldrich syndrome protein (WASP) expression. Mild thrombocytopenia is noted in a small proportion. Heterozygous females rarely present with typical features of Wiskott-Aldrich syndrome such as severe thrombocytopenia and/or immunologic dysfunction due to severe skewed X-chromosome inactivation with expression of the mutated
• All of their daughters, who will be carriers (see Clinical Description,
• None of their sons.
## Carrier Detection
Note: (1) Females who are heterozygous (carriers) for this X-linked disorder are typically asymptomatic (see Clinical Description,
## 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.
Note: There is no evidence that cesarean section reduces the risk of morbidity and mortality in males with Wiskott-Aldrich syndrome.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Canada
•
•
•
• Canada
•
•
•
•
•
•
•
•
•
## Molecular Genetics
WAS-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for WAS-Related Disorders (
Because the actin cytoskeleton plays an important role in cell adhesion and migration, T and B lymphocytes, neutrophils, macrophages, and dendritic cells of males with
## Molecular Pathogenesis
Because the actin cytoskeleton plays an important role in cell adhesion and migration, T and B lymphocytes, neutrophils, macrophages, and dendritic cells of males with
## Chapter Notes
Lucas Bronicki, PhD; University of Cincinnati College of Medicine (2016-2024)Sharat Chandra, MD (2016-present)Shanmuganathan Chandrakasan, MD (2024-present)Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2004-2016)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2004-2016)Chinmayee B Nagaraj, MS (2016-present)Miao Sun, PhD (2024-present)Kejian Zhang, MD, MBA (2004-present)
15 August 2024 (sw) Comprehensive update posted live
22 September 2016 (sw) Comprehensive update posted live
20 March 2014 (me) Comprehensive update posted live
28 July 2011 (me) Comprehensive update posted live
27 April 2007 (me) Comprehensive update posted live
30 September 2004 (me) Review posted live
1 October 2003 (jj) Original submission
• 15 August 2024 (sw) Comprehensive update posted live
• 22 September 2016 (sw) Comprehensive update posted live
• 20 March 2014 (me) Comprehensive update posted live
• 28 July 2011 (me) Comprehensive update posted live
• 27 April 2007 (me) Comprehensive update posted live
• 30 September 2004 (me) Review posted live
• 1 October 2003 (jj) Original submission
## Author Notes
## Author History
Lucas Bronicki, PhD; University of Cincinnati College of Medicine (2016-2024)Sharat Chandra, MD (2016-present)Shanmuganathan Chandrakasan, MD (2024-present)Alexandra H Filipovich, MD; Cincinnati Children's Hospital Medical Center (2004-2016)Judith Johnson, MS; Cincinnati Children's Hospital Medical Center (2004-2016)Chinmayee B Nagaraj, MS (2016-present)Miao Sun, PhD (2024-present)Kejian Zhang, MD, MBA (2004-present)
## Revision History
15 August 2024 (sw) Comprehensive update posted live
22 September 2016 (sw) Comprehensive update posted live
20 March 2014 (me) Comprehensive update posted live
28 July 2011 (me) Comprehensive update posted live
27 April 2007 (me) Comprehensive update posted live
30 September 2004 (me) Review posted live
1 October 2003 (jj) Original submission
• 15 August 2024 (sw) Comprehensive update posted live
• 22 September 2016 (sw) Comprehensive update posted live
• 20 March 2014 (me) Comprehensive update posted live
• 28 July 2011 (me) Comprehensive update posted live
• 27 April 2007 (me) Comprehensive update posted live
• 30 September 2004 (me) Review posted live
• 1 October 2003 (jj) Original submission
## References
## Literature Cited
|
[] |
30/9/2004
|
15/8/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
wdr26-id
|
wdr26-id
|
[
"WD repeat-containing protein 26",
"WDR26",
"WDR26-Related Intellectual Disability"
] |
Cara M Skraban, Katheryn L Grand, Matthew A Deardorff
|
Summary The diagnosis of
|
## Diagnosis
Formal diagnostic criteria for
Developmental delay or intellectual disability of variable degree
Characteristic facial features including coarse features, prominent eyes with large-appearing irises, prominent maxilla, broad nasal tip, protruding upper lip, prominent upper gingiva, and widely spaced teeth (
Central hypotonia
Autistic features
Seizures: both febrile and non-febrile
Abnormal wide-based, ataxic, and/or stiff-legged gait
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
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.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use include the 1q42region.
To date, no individuals with isolated deletions of
• Developmental delay or intellectual disability of variable degree
• Characteristic facial features including coarse features, prominent eyes with large-appearing irises, prominent maxilla, broad nasal tip, protruding upper lip, prominent upper gingiva, and widely spaced teeth (
• Central hypotonia
• Autistic features
• Seizures: both febrile and non-febrile
• Abnormal wide-based, ataxic, and/or stiff-legged gait
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Developmental delay or intellectual disability of variable degree
Characteristic facial features including coarse features, prominent eyes with large-appearing irises, prominent maxilla, broad nasal tip, protruding upper lip, prominent upper gingiva, and widely spaced teeth (
Central hypotonia
Autistic features
Seizures: both febrile and non-febrile
Abnormal wide-based, ataxic, and/or stiff-legged gait
• Developmental delay or intellectual disability of variable degree
• Characteristic facial features including coarse features, prominent eyes with large-appearing irises, prominent maxilla, broad nasal tip, protruding upper lip, prominent upper gingiva, and widely spaced teeth (
• Central hypotonia
• Autistic features
• Seizures: both febrile and non-febrile
• Abnormal wide-based, ataxic, and/or stiff-legged gait
## 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
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.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use include the 1q42region.
To date, no individuals with isolated deletions of
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Speech development is a relative weakness. All individuals have delayed speech. Although some begin to develop speech in the second year, others remain nonverbal through childhood.
Seizure types are generally mild and include febrile and non-febrile (tonic-clonic, absence, rolandic). Most are self limited or respond well to standard treatments.
Hypotonia, present in nine of 12 reported individuals; typically mild
Failure to thrive and infant feeding difficulties; reported in six of 15 individuals, with three requiring a gastrostomy tube at least temporarily
An abnormal gait, described as wide-based, ataxic, and/or stiff-legged
Structural brain anomalies, nearly all minor, noted in ten of 14 individuals; including the nonspecific findings (enlarged ventricles, thin corpus callosum, white matter volume loss, mild cerebellar hypoplasia, and pineal cyst) as well as a markedly abnormal left supratentorial hemisphere structure with pachygyria that required hemispherectomy (in 1 individual)
Microcephaly; noted in three of 14 individuals
Strabismus and/or amblyopia (in 9/14)
Congenital abducens paresis (in 1)
Marcus Gunn jaw winking (in 1)
Refractive errors, including myopia and hyperopia
Recurrent otitis media / eustachian tube dysfunction (5/15)
Cleft palate (1)
Mild contractures of the lower extremities (2)
Forefoot varus (1)
Hip dysplasia (1)
Osteopathia striata of the distal femurs (1)
Ventricular septal defect (1)
Right-sided aortic arch (1)
No genotype-phenotype correlations have been established.
• Hypotonia, present in nine of 12 reported individuals; typically mild
• Failure to thrive and infant feeding difficulties; reported in six of 15 individuals, with three requiring a gastrostomy tube at least temporarily
• An abnormal gait, described as wide-based, ataxic, and/or stiff-legged
• Structural brain anomalies, nearly all minor, noted in ten of 14 individuals; including the nonspecific findings (enlarged ventricles, thin corpus callosum, white matter volume loss, mild cerebellar hypoplasia, and pineal cyst) as well as a markedly abnormal left supratentorial hemisphere structure with pachygyria that required hemispherectomy (in 1 individual)
• Microcephaly; noted in three of 14 individuals
•
• Strabismus and/or amblyopia (in 9/14)
• Congenital abducens paresis (in 1)
• Marcus Gunn jaw winking (in 1)
• Refractive errors, including myopia and hyperopia
• Strabismus and/or amblyopia (in 9/14)
• Congenital abducens paresis (in 1)
• Marcus Gunn jaw winking (in 1)
• Refractive errors, including myopia and hyperopia
•
• Recurrent otitis media / eustachian tube dysfunction (5/15)
• Cleft palate (1)
• Recurrent otitis media / eustachian tube dysfunction (5/15)
• Cleft palate (1)
•
• Mild contractures of the lower extremities (2)
• Forefoot varus (1)
• Hip dysplasia (1)
• Osteopathia striata of the distal femurs (1)
• Mild contractures of the lower extremities (2)
• Forefoot varus (1)
• Hip dysplasia (1)
• Osteopathia striata of the distal femurs (1)
•
• Ventricular septal defect (1)
• Right-sided aortic arch (1)
• Ventricular septal defect (1)
• Right-sided aortic arch (1)
• Strabismus and/or amblyopia (in 9/14)
• Congenital abducens paresis (in 1)
• Marcus Gunn jaw winking (in 1)
• Refractive errors, including myopia and hyperopia
• Recurrent otitis media / eustachian tube dysfunction (5/15)
• Cleft palate (1)
• Mild contractures of the lower extremities (2)
• Forefoot varus (1)
• Hip dysplasia (1)
• Osteopathia striata of the distal femurs (1)
• Ventricular septal defect (1)
• Right-sided aortic arch (1)
## Clinical Description
Speech development is a relative weakness. All individuals have delayed speech. Although some begin to develop speech in the second year, others remain nonverbal through childhood.
Seizure types are generally mild and include febrile and non-febrile (tonic-clonic, absence, rolandic). Most are self limited or respond well to standard treatments.
Hypotonia, present in nine of 12 reported individuals; typically mild
Failure to thrive and infant feeding difficulties; reported in six of 15 individuals, with three requiring a gastrostomy tube at least temporarily
An abnormal gait, described as wide-based, ataxic, and/or stiff-legged
Structural brain anomalies, nearly all minor, noted in ten of 14 individuals; including the nonspecific findings (enlarged ventricles, thin corpus callosum, white matter volume loss, mild cerebellar hypoplasia, and pineal cyst) as well as a markedly abnormal left supratentorial hemisphere structure with pachygyria that required hemispherectomy (in 1 individual)
Microcephaly; noted in three of 14 individuals
Strabismus and/or amblyopia (in 9/14)
Congenital abducens paresis (in 1)
Marcus Gunn jaw winking (in 1)
Refractive errors, including myopia and hyperopia
Recurrent otitis media / eustachian tube dysfunction (5/15)
Cleft palate (1)
Mild contractures of the lower extremities (2)
Forefoot varus (1)
Hip dysplasia (1)
Osteopathia striata of the distal femurs (1)
Ventricular septal defect (1)
Right-sided aortic arch (1)
• Hypotonia, present in nine of 12 reported individuals; typically mild
• Failure to thrive and infant feeding difficulties; reported in six of 15 individuals, with three requiring a gastrostomy tube at least temporarily
• An abnormal gait, described as wide-based, ataxic, and/or stiff-legged
• Structural brain anomalies, nearly all minor, noted in ten of 14 individuals; including the nonspecific findings (enlarged ventricles, thin corpus callosum, white matter volume loss, mild cerebellar hypoplasia, and pineal cyst) as well as a markedly abnormal left supratentorial hemisphere structure with pachygyria that required hemispherectomy (in 1 individual)
• Microcephaly; noted in three of 14 individuals
•
• Strabismus and/or amblyopia (in 9/14)
• Congenital abducens paresis (in 1)
• Marcus Gunn jaw winking (in 1)
• Refractive errors, including myopia and hyperopia
• Strabismus and/or amblyopia (in 9/14)
• Congenital abducens paresis (in 1)
• Marcus Gunn jaw winking (in 1)
• Refractive errors, including myopia and hyperopia
•
• Recurrent otitis media / eustachian tube dysfunction (5/15)
• Cleft palate (1)
• Recurrent otitis media / eustachian tube dysfunction (5/15)
• Cleft palate (1)
•
• Mild contractures of the lower extremities (2)
• Forefoot varus (1)
• Hip dysplasia (1)
• Osteopathia striata of the distal femurs (1)
• Mild contractures of the lower extremities (2)
• Forefoot varus (1)
• Hip dysplasia (1)
• Osteopathia striata of the distal femurs (1)
•
• Ventricular septal defect (1)
• Right-sided aortic arch (1)
• Ventricular septal defect (1)
• Right-sided aortic arch (1)
• Strabismus and/or amblyopia (in 9/14)
• Congenital abducens paresis (in 1)
• Marcus Gunn jaw winking (in 1)
• Refractive errors, including myopia and hyperopia
• Recurrent otitis media / eustachian tube dysfunction (5/15)
• Cleft palate (1)
• Mild contractures of the lower extremities (2)
• Forefoot varus (1)
• Hip dysplasia (1)
• Osteopathia striata of the distal femurs (1)
• Ventricular septal defect (1)
• Right-sided aortic arch (1)
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been established.
## Nomenclature
## Prevalence
## Genetically Related (Allelic) Disorders
Of relevance,
## Differential Diagnosis
Developmental delay with delayed speech and febrile and/or non-febrile seizures, the most frequent features of
The following syndromes with significant phenotypic overlap with
Disorders with Developmental Delay / Intellectual Disability to Consider in the Differential Diagnosis of
Happy demeanor
Seizures
Abnormal gait
Widely spaced teeth
Inappropriate laughter/excitability
Microcephaly common
Seizures
Widely spaced teeth
Full lips
Episodic hyperventilation &/or breath-holding spells
Severe myopia
Hypotonia
Coarse facial features
Alpha-thalassemia & HbH inclusion bodies
Genital anomalies
Microcephaly common
Postnatal growth deficiency
Seizures
Hypotonia
Autistic features
Congenital malformations more common
Severe infections
AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of
Pitt-Hopkins syndrome is caused by haploinsufficiency of
• Happy demeanor
• Seizures
• Abnormal gait
• Widely spaced teeth
• Inappropriate laughter/excitability
• Microcephaly common
• Seizures
• Widely spaced teeth
• Full lips
• Episodic hyperventilation &/or breath-holding spells
• Severe myopia
• Hypotonia
• Coarse facial features
• Alpha-thalassemia & HbH inclusion bodies
• Genital anomalies
• Microcephaly common
• Postnatal growth deficiency
• Seizures
• Hypotonia
• Autistic features
• Congenital malformations more common
• Severe infections
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Recurrent otitis media
Cleft palate
Feeding difficulties, GERD, &/or FTT: assess swallowing, feeding, & nutritional status to determine safety of oral vs gastrostomy feeding
Constipation
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat; FTT = failure to thrive; GERD = gastroesophageal reflux disease
Treatment of Manifestations in Individuals with
ASMs= anti-seizure medications; FTT = failure to thrive
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
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 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.
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.
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 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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Recommended Surveillance for Individuals with
FTT = failure to thrive
See
Search
• Recurrent otitis media
• Cleft palate
• Feeding difficulties, GERD, &/or FTT: assess swallowing, feeding, & nutritional status to determine safety of oral vs gastrostomy feeding
• Constipation
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• 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.
• 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.
• 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.
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• 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 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).
## 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
Recurrent otitis media
Cleft palate
Feeding difficulties, GERD, &/or FTT: assess swallowing, feeding, & nutritional status to determine safety of oral vs gastrostomy feeding
Constipation
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat; FTT = failure to thrive; GERD = gastroesophageal reflux disease
• Recurrent otitis media
• Cleft palate
• Feeding difficulties, GERD, &/or FTT: assess swallowing, feeding, & nutritional status to determine safety of oral vs gastrostomy feeding
• Constipation
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
ASMs= anti-seizure medications; FTT = failure to thrive
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
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 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.
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.
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 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 (ADHD), 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 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.
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• 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.
• 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.
• 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.
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• 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 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 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.
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.
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.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• 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.
• 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.
• 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.
• An IEP provides specially designed instruction and related services to children who qualify
• 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.
• 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 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 Difficulties
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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
FTT = failure to thrive
## 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 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 probands reported to date 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 probands reported to date 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 probands reported to date 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
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
## Molecular Genetics
WDR26-Related Intellectual Disability: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for WDR26-Related Intellectual Disability (
See
The observation that core features of the 1q41q42 deletion syndrome consistently overlap those of
Domains WD1-WD7 (amino acids 1-353) comprise an N-terminal β propeller.
Domains WD8-WD14 (amino acids 354-645) comprise a C-terminal β propeller, which includes the conserved LisH (LIS1 homology) and CTLH (C-terminal LIS homology) domains.
Although specific cellular functions for WDR26 are unclear, many WD40 repeat proteins play key roles in cellular scaffolding [
• Domains WD1-WD7 (amino acids 1-353) comprise an N-terminal β propeller.
• Domains WD8-WD14 (amino acids 354-645) comprise a C-terminal β propeller, which includes the conserved LisH (LIS1 homology) and CTLH (C-terminal LIS homology) domains.
## Molecular Pathogenesis
See
The observation that core features of the 1q41q42 deletion syndrome consistently overlap those of
Domains WD1-WD7 (amino acids 1-353) comprise an N-terminal β propeller.
Domains WD8-WD14 (amino acids 354-645) comprise a C-terminal β propeller, which includes the conserved LisH (LIS1 homology) and CTLH (C-terminal LIS homology) domains.
Although specific cellular functions for WDR26 are unclear, many WD40 repeat proteins play key roles in cellular scaffolding [
• Domains WD1-WD7 (amino acids 1-353) comprise an N-terminal β propeller.
• Domains WD8-WD14 (amino acids 354-645) comprise a C-terminal β propeller, which includes the conserved LisH (LIS1 homology) and CTLH (C-terminal LIS homology) domains.
## Chapter Notes
Dr Skraban is a member of the faculty at the University of Pennsylvania Perelman School of Medicine and the Children's Hospital of Philadelphia. Dr Deardorff is a member of the faculty at the University of Southern California Keck School of Medicine and the Children's Hospital Los Angeles. They are working to further understand the clinical features and molecular pathogenesis associated with
We would like to thank the families who have agreed to participate, as well as the many clinical colleagues who have referred patients and collaborated in these efforts.
25 April 2019 (bp) Review posted live
10 May 2018 (cs) Original submission
• 25 April 2019 (bp) Review posted live
• 10 May 2018 (cs) Original submission
## Author Notes
Dr Skraban is a member of the faculty at the University of Pennsylvania Perelman School of Medicine and the Children's Hospital of Philadelphia. Dr Deardorff is a member of the faculty at the University of Southern California Keck School of Medicine and the Children's Hospital Los Angeles. They are working to further understand the clinical features and molecular pathogenesis associated with
## Acknowledgments
We would like to thank the families who have agreed to participate, as well as the many clinical colleagues who have referred patients and collaborated in these efforts.
## Revision History
25 April 2019 (bp) Review posted live
10 May 2018 (cs) Original submission
• 25 April 2019 (bp) Review posted live
• 10 May 2018 (cs) Original submission
## References
## Literature Cited
Four individuals with loss-of-function
Images published with permission of families
|
[
"PY Au, B Argiropoulos, JS Parboosingh, A Micheil Innes. Refinement of the critical region of 1q41q42 microdeletion syndrome identifies FBXO28 as a candidate causative gene for intellectual disability and seizures.. Am J Med Genet A. 2014;164A:441-8",
"C Balak, N Belnap, K Ramsey, S Joss, K Devriendt, M Naymik, W Jepsen, AL Siniard, S Szelinger, ME Parker, R Richholt, T Izatt, M Lafleur, P Terraf, L Llaci, M De Both, IS Piras, S Rangasamy, I Schrauwen, DW Craig, M Huentelman, V Narayanan. A novel FBXO28 frameshift mutation in a child with developmental delay, dysmorphic features, and intractable epilepsy: a second gene that may contribute to the 1q41-q42 deletion phenotype.. Am J Med Genet A. 2018;176:1549-58",
"M Cassina, C Rigon, A Casarin, V Vicenzi, L Salviati, M Clementi. FBXO28 is a critical gene of the 1q41q42 microdeletion syndrome.. Am J Med Genet A. 2015;167:1418-20",
"I Filges, B Rothlisberger, N Boesch, P Weber, F Wenzel, AR Huber, K Heinimann, P Miny. Interstitial deletion 1q42 in a patient with agenesis of corpus callosum: phenotype-genotype comparison to the 1q41q42 microdeletion suggests a contiguous 1q4 syndrome.. Am J Med Genet. 2010;152A:987-93",
"S Kantarci, KG Ackerman, MN Russell, M Longoni, C Sougnez, KM Noonan, E Hatchwell, X Zhang, RP Vanmarcke, K Anyane-Yeboa, P Dickerman, J Wilson, PK Donahoe, BR Pober. Characterization of the chromosome 1q41q42.12 region, and the candidate gene DISP1, in patients with CDH.. Am J Med Genet. 2010;152A:2493-504",
"JF Mazzeu, AC Krepischi-Santos, C Rosenbery, K Szuhai, J Knijnenburg, JMM Weiss, I Kerkis, Z Mustacchi, G Colin, R Mombach, RCM Pavanello, PA Otto, AM Vianna-Morgante. Chromosome abnormalities in two patients with features of autosomal dominant Robinow syndrome.. Am J Med Genet. 2007;143A:1790-5",
"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",
"GM Rice, Z Qi, R Selzer, T Richmond, K Thompson, RM Pauli, J Yu. Microdissection-based high resolution genomic array analysis of two patients with cytogenetically identical interstitial deletion of chromosome 1q but distinct clinical phenotypes.. Am J Med Genet. 2006;140:1637-43",
"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",
"JA Rosenfeld, Y Lacassie, D El-Khechen, LF Escobar, J Reggin, C Hueur, E Chen, LS Jenkins, AT Collins, S Zinner, M Babcock, B Morrow, RA Schultz, BS Torchia, BC Ballif, KD Tsuchiya, LG Shaffer. New cases and refinement of the critical region in the 1q41q42 microdeletion syndrome.. Eur J Med Genet. 2011;54:42-9",
"LG Shaffer, A Theisen, BA Bejjani, BC Ballif, AS Aylsworth, C Lim, M Mcdonald, JW Ellison, D Kostiner, S Saitta, T Shaikh. The discovery of microdeletion syndromes in the post-genomic era: review of the methodology and characterization of a new 1q41q42 microdeletion syndrome.. Genet Med. 2007;9:607-16",
"CM Skraban, CF Wells, P Markose, MT Cho, AI Nesbitt, PYB Au, A Begtrup, JA Bernat, LM Bird, K Cao, APM de Brouwer, EH Denenberg, G Douglas, KM Gibson, K Grand, A Goldenberg, AM Innes, J Juusola, M Kempers, E Kinning, DM Markie, MM Owens, K Payne, R Person, R Pfundt, A Stocco, CLS Turner, NE Verbeek, LE Walsh, TC Warner, PG Wheeler, D Wieczorek, AB Wilkens, E Zonneveld-Huijssoon, T Kleefstra, SP Robertson, A Santani, KLI van Gassen, MA Deardorff. WDR26 haploinsufficiency causes a recognizable syndrome of intellectual disability, seizures, abnormal gait, and distinctive facial features.. Am J Hum Genet. 2017;101:139-48",
"AM Slavotinek, A Moshrefi, N Lopenjimenez, R Chao, A Mendell, GM Shaw, LA Pennacchio, MD Bates. Sequence variants in the HLX gene at chromosome 1q41-1q42 in patients with diaphragmatic hernia.. Clin Genet. 2009;75:429-39",
"CU Stirnimann, E Petsalaki, RB Russell, CW Muller. WD40 proteins propel cellular networks.. Trends Biochem Sci. 2010;35:565-74",
"Z Sun, AV Smrcka, S Chen. WDR26 functions as a scaffolding protein to promote Gbetagamma-mediated phospholipase C beta2 (PLCbeta2) activation in leukocytes.. J Biol Chem. 2013;288:16715-25",
"MJ Wat, D Veenma, J Hogue, AM Holder, Z Yu, J Wat, N Hanchard, OA Shchelochkov, CJ Fernandes, A Johnson, KP Lally, A Slavotinek, O Danhaive, T Schaible, SW Cheung, KA Rauen, VS Tonk, D Tibboel, A De Klein, DA Scott. Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia.. J Med Genet. 2011;48:299-307",
"T Yanagishita, K Yamamoto-Shimojima, S Nakano, T Sasaki, H Shigematsu, K Imai, T. Yamamoto. Phenotypic features of 1q41q42 microdeletion including WDR26 and FBXO28 are clinically recognizable: the first case from Japan.. Brain Dev. 2019;41:452-5",
"Y Zhu, Y Wang, C Xia, D Li, Y Li, W Zeng, W Yuan, H Liu, C Zhu, X Wu, M. Liu. WDR26: a novel Gbeta-like protein, suppresses MAPK signaling pathway.. J Cell Biochem. 2004;93:579-87"
] |
25/4/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
wdr62-pm
|
wdr62-pm
|
[
"Autosomal Recessive Primary Microcephaly 2 With or Without Cortical Malformations",
"MCPH2",
"Autosomal Recessive Primary Microcephaly 2 With or Without Cortical Malformations",
"MCPH2",
"WD repeat-containing protein 62",
"WDR62",
"WDR62 Primary Microcephaly"
] |
Alain Verloes, Lyse Ruaud, Séverine Drunat, Sandrine Passemard
|
Summary In The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Microcephaly, usually congenital (identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth. In some instances, microcephaly may occur after birth, but within the first year of life.
Normal or delayed motor development
Mild-to-severe intellectual disability
Epilepsy
Behavior disorders
Pyramidal signs (from hemiplegia or quadriplegia to spasticity or brisk deep-tendon reflexes)
Ataxia
Absence of intrauterine growth restriction and other congenital anomalies
Including pachygyria, simplified gyral pattern, and severe malformations of cortical development
Including polymicrogyria, schizencephaly, lissencephaly, and neuronal heterotopia
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
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 intragenic deletion has been reported to date [
• Microcephaly, usually congenital (identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth. In some instances, microcephaly may occur after birth, but within the first year of life.
• Normal or delayed motor development
• Mild-to-severe intellectual disability
• Epilepsy
• Behavior disorders
• Pyramidal signs (from hemiplegia or quadriplegia to spasticity or brisk deep-tendon reflexes)
• Ataxia
• Absence of intrauterine growth restriction and other congenital anomalies
## Suggestive Findings
Microcephaly, usually congenital (identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth. In some instances, microcephaly may occur after birth, but within the first year of life.
Normal or delayed motor development
Mild-to-severe intellectual disability
Epilepsy
Behavior disorders
Pyramidal signs (from hemiplegia or quadriplegia to spasticity or brisk deep-tendon reflexes)
Ataxia
Absence of intrauterine growth restriction and other congenital anomalies
Including pachygyria, simplified gyral pattern, and severe malformations of cortical development
Including polymicrogyria, schizencephaly, lissencephaly, and neuronal heterotopia
• Microcephaly, usually congenital (identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth. In some instances, microcephaly may occur after birth, but within the first year of life.
• Normal or delayed motor development
• Mild-to-severe intellectual disability
• Epilepsy
• Behavior disorders
• Pyramidal signs (from hemiplegia or quadriplegia to spasticity or brisk deep-tendon reflexes)
• Ataxia
• Absence of intrauterine growth restriction and other congenital anomalies
## 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
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.
One intragenic deletion has been reported to date [
## 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
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 intragenic deletion has been reported to date [
## Clinical Characteristics
To date, 153 individuals have been reported with
Normal: 6/17 w/independent walking < age 18 mos
Delayed: 9/17 w/independent walking < age 3.5 yrs
Nonambulatory: 2/17 at age 16 yrs
Normal: 4/17
Delayed language w/speech disorders:11/17
No language: 2/17
Hyperkinesia: 4/21
Self-injury: 5/21
Aggressiveness: 15/21
Confusion: 2/21
ID = intellectual disability; NA = not available; OFC = occipitofrontal circumference
Defined as 4 standard deviations (SD) (±1.5 SD) below the mean at last examination (mean age: 12 years, 4 months)
Defined as 6.3 SD (±2.4 SD) below the mean at last examination (mean age: 12 years, 10 months)
Including hyperkinesia, aggressiveness, hypersociability, poor concentration, and disinhibition
In two other individuals, progressive cerebellar involvement was noted. In one individual, progressive motor decline associated with tremor and ataxia appeared in the second decade without cerebellar atrophy on brain MRI. In the other individual, ataxia manifesting as truncal hypotonia and inability to sit without support at age 20 years was associated with cerebellar atrophy on MRI.
Of the five individuals who had severe malformations of cortical development (i.e., polymicrogyria, schizencephaly, lissencephaly, and neuronal heterotopia), all five had epilepsy (see
Of 11 individuals who had a normal MRI or pachygyria and/or simplified gyral pattern, six had epilepsy.
Comparable information on epilepsy is not available for Cohort 2; however, it is notable that the proportion of individuals with severe cortical malformations in the two cohorts is similar (see
Infantile spasms and focal and generalized seizures occurred mostly within the first two years. All types of generalized seizures were reported (tonic, clonic, atonic, myoclonic, and absences).
Individuals with mild-to-moderate ID had significant autonomy in daily life and good social interactions (based on Vineland Adaptive Behavior Scales). Regardless of the degree of ID, autonomy in daily life scores were higher than communication scores in affected individuals.
No genotype-phenotype correlations have been identified [
A review of the literature in 2021 identified 153 individuals with
• Normal: 6/17 w/independent walking < age 18 mos
• Delayed: 9/17 w/independent walking < age 3.5 yrs
• Nonambulatory: 2/17 at age 16 yrs
• Normal: 4/17
• Delayed language w/speech disorders:11/17
• No language: 2/17
• Hyperkinesia: 4/21
• Self-injury: 5/21
• Aggressiveness: 15/21
• Confusion: 2/21
• Of the five individuals who had severe malformations of cortical development (i.e., polymicrogyria, schizencephaly, lissencephaly, and neuronal heterotopia), all five had epilepsy (see
• Of 11 individuals who had a normal MRI or pachygyria and/or simplified gyral pattern, six had epilepsy.
## Clinical Description
To date, 153 individuals have been reported with
Normal: 6/17 w/independent walking < age 18 mos
Delayed: 9/17 w/independent walking < age 3.5 yrs
Nonambulatory: 2/17 at age 16 yrs
Normal: 4/17
Delayed language w/speech disorders:11/17
No language: 2/17
Hyperkinesia: 4/21
Self-injury: 5/21
Aggressiveness: 15/21
Confusion: 2/21
ID = intellectual disability; NA = not available; OFC = occipitofrontal circumference
Defined as 4 standard deviations (SD) (±1.5 SD) below the mean at last examination (mean age: 12 years, 4 months)
Defined as 6.3 SD (±2.4 SD) below the mean at last examination (mean age: 12 years, 10 months)
Including hyperkinesia, aggressiveness, hypersociability, poor concentration, and disinhibition
In two other individuals, progressive cerebellar involvement was noted. In one individual, progressive motor decline associated with tremor and ataxia appeared in the second decade without cerebellar atrophy on brain MRI. In the other individual, ataxia manifesting as truncal hypotonia and inability to sit without support at age 20 years was associated with cerebellar atrophy on MRI.
Of the five individuals who had severe malformations of cortical development (i.e., polymicrogyria, schizencephaly, lissencephaly, and neuronal heterotopia), all five had epilepsy (see
Of 11 individuals who had a normal MRI or pachygyria and/or simplified gyral pattern, six had epilepsy.
Comparable information on epilepsy is not available for Cohort 2; however, it is notable that the proportion of individuals with severe cortical malformations in the two cohorts is similar (see
Infantile spasms and focal and generalized seizures occurred mostly within the first two years. All types of generalized seizures were reported (tonic, clonic, atonic, myoclonic, and absences).
Individuals with mild-to-moderate ID had significant autonomy in daily life and good social interactions (based on Vineland Adaptive Behavior Scales). Regardless of the degree of ID, autonomy in daily life scores were higher than communication scores in affected individuals.
• Normal: 6/17 w/independent walking < age 18 mos
• Delayed: 9/17 w/independent walking < age 3.5 yrs
• Nonambulatory: 2/17 at age 16 yrs
• Normal: 4/17
• Delayed language w/speech disorders:11/17
• No language: 2/17
• Hyperkinesia: 4/21
• Self-injury: 5/21
• Aggressiveness: 15/21
• Confusion: 2/21
• Of the five individuals who had severe malformations of cortical development (i.e., polymicrogyria, schizencephaly, lissencephaly, and neuronal heterotopia), all five had epilepsy (see
• Of 11 individuals who had a normal MRI or pachygyria and/or simplified gyral pattern, six had epilepsy.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified [
## Nomenclature
## Prevalence
A review of the literature in 2021 identified 153 individuals with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The primary microcephalies are a group of rare, phenotypically and etiologically heterogeneous disorders of brain growth characterized by (1) a head circumference close to or greater than 2 SD below the mean at birth and greater than 3 SD below the mean by age one year, and (2) mild-to-severe intellectual disability. Additional clinical or neuroimaging features can be associated. Most primary microcephalies are inherited in an autosomal recessive manner. To date, pathogenic variants in more than 100 genes are known to cause primary microcephaly (for review, see
* MCPH and Seckel syndrome may be further subdivided by the presence of cortical malformations and/or chorioretinopathy.
Selected genes associated with isolated primary microcephaly, primary microcephaly with short stature, and syndromic primary microcephaly (excluding those with a true clinically recognizable "syndromic gestalt," such as
OMIM phenotypic series referenced in
Disorders with Congenital Microcephaly to Consider in the Differential Diagnosis of
Chorioretinopathy (inconstant)
AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; IUGR = intrauterine growth restriction; MCPH = microcephaly, primary hereditary; MOI = mode of inheritance; PS = phenotypic series; PVNH = periventricular nodular heterotopia
Disorders are associated with intellectual disability unless otherwise noted.
MCPH associated with the listed genes is inherited in an autosomal recessive manner with the exception of
Cortical dysplasia, complex, with other brain malformations (CDCBM) associated with the listed genes is inherited in an autosomal dominant manner with the exception of
• * MCPH and Seckel syndrome may be further subdivided by the presence of cortical malformations and/or chorioretinopathy.
• Chorioretinopathy (inconstant)
## 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
Consider EEG;
Evaluate for malformations of cortical development (e.g., polymicrogyria, lissencephaly, schizencephaly, neuronal heterotopia), which are known to be assoc w/epilepsy.
Incl motor, adaptive, cognitive & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
Possible progression of ataxia.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is symptomatic. Care by a multidisciplinary team, often including a pediatric neurologist, developmental pediatrician, speech-language pathologist, occupational and physical therapist, medical geneticist, and social work team, is recommended to address individual needs.
Treatment of Manifestations in Individuals with
Lamotrigine, levetiracetam, sodium valproate, vigabatrin, oxcarbazepine, & sulthiame have been mostly effective as monotherapy.
Multitherapy may be required; some seizures may resist treatment w/2 or 3 ASMs.
Education of parents/caregivers is helpful.
Spasticity: stretching to ↑ mobility; antispastic treatment (baclofen) &/or botulinum toxin treatment may be required.
Ataxia: no medications improve ataxia.
Mobility: use of a walker &/or wheelchair may eventually be required.
AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Applied behavior analysis (ABA) therapy is therapy targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses; it is typically performed one on one with a board-certified behavior analyst.
Authors, personal observation
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 (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 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
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 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.
Consider evaluation for alternative means of communication (e.g.,
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 those w/seizures as clinically indicated.
Assess for new manifestations such as new-onset seizures, spasticity, contractures, & ataxia.
Ancillary behavior assessment for anxiety, attention, & aggressive or self-injurious behavior
Refer for formal eval if concern exists.
OT = occupational therapy; PT = physical therapy
See
The authors' research project on
Search
• Consider EEG;
• Evaluate for malformations of cortical development (e.g., polymicrogyria, lissencephaly, schizencephaly, neuronal heterotopia), which are known to be assoc w/epilepsy.
• Incl motor, adaptive, cognitive & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
• Possible progression of ataxia.
• Community or
• Social work involvement for parental support.
• Lamotrigine, levetiracetam, sodium valproate, vigabatrin, oxcarbazepine, & sulthiame have been mostly effective as monotherapy.
• Multitherapy may be required; some seizures may resist treatment w/2 or 3 ASMs.
• Education of parents/caregivers is helpful.
• Spasticity: stretching to ↑ mobility; antispastic treatment (baclofen) &/or botulinum toxin treatment may be required.
• Ataxia: no medications improve ataxia.
• Mobility: use of a walker &/or wheelchair may eventually be required.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• 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 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 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as new-onset seizures, spasticity, contractures, & ataxia.
• Ancillary behavior assessment for anxiety, attention, & aggressive or self-injurious behavior
• Refer for formal eval if concern exists.
## 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
Consider EEG;
Evaluate for malformations of cortical development (e.g., polymicrogyria, lissencephaly, schizencephaly, neuronal heterotopia), which are known to be assoc w/epilepsy.
Incl motor, adaptive, cognitive & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
Possible progression of ataxia.
Community or
Social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Consider EEG;
• Evaluate for malformations of cortical development (e.g., polymicrogyria, lissencephaly, schizencephaly, neuronal heterotopia), which are known to be assoc w/epilepsy.
• Incl motor, adaptive, cognitive & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills);
• Possible progression of ataxia.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment is symptomatic. Care by a multidisciplinary team, often including a pediatric neurologist, developmental pediatrician, speech-language pathologist, occupational and physical therapist, medical geneticist, and social work team, is recommended to address individual needs.
Treatment of Manifestations in Individuals with
Lamotrigine, levetiracetam, sodium valproate, vigabatrin, oxcarbazepine, & sulthiame have been mostly effective as monotherapy.
Multitherapy may be required; some seizures may resist treatment w/2 or 3 ASMs.
Education of parents/caregivers is helpful.
Spasticity: stretching to ↑ mobility; antispastic treatment (baclofen) &/or botulinum toxin treatment may be required.
Ataxia: no medications improve ataxia.
Mobility: use of a walker &/or wheelchair may eventually be required.
AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; OT = occupational therapy; PT = physical therapy
Applied behavior analysis (ABA) therapy is therapy targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses; it is typically performed one on one with a board-certified behavior analyst.
Authors, personal observation
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 (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 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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
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 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.
Consider evaluation for alternative means of communication (e.g.,
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.
• Lamotrigine, levetiracetam, sodium valproate, vigabatrin, oxcarbazepine, & sulthiame have been mostly effective as monotherapy.
• Multitherapy may be required; some seizures may resist treatment w/2 or 3 ASMs.
• Education of parents/caregivers is helpful.
• Spasticity: stretching to ↑ mobility; antispastic treatment (baclofen) &/or botulinum toxin treatment may be required.
• Ataxia: no medications improve ataxia.
• Mobility: use of a walker &/or wheelchair may eventually be required.
• IEP services:
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• 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 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 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
## 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.
IEP services:
An IEP provides specially designed instruction and related services to children who qualify.
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.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
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 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 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
• 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 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 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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.
## Communication Issues
Consider evaluation for alternative means of communication (e.g.,
## Social/Behavioral Concerns
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 those w/seizures as clinically indicated.
Assess for new manifestations such as new-onset seizures, spasticity, contractures, & ataxia.
Ancillary behavior assessment for anxiety, attention, & aggressive or self-injurious behavior
Refer for formal eval if concern exists.
OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as new-onset seizures, spasticity, contractures, & ataxia.
• Ancillary behavior assessment for anxiety, attention, & aggressive or self-injurious behavior
• Refer for formal eval if concern exists.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
The authors' research project on
Search
## Genetic Counseling
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
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.
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 and preimplantation genetic testing. While most health care professionals 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
• 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.
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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
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
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.
• 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
• 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.
• 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.
## 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
## Molecular Genetics
WDR62 Primary Microcephaly: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for WDR62 Primary Microcephaly (
WDR62 is a microtubule minus-end mitotic spindle pole protein, located in dividing neural progenitors in humans. WDR62 is highly expressed in rodent and human forebrain during neurogenesis, especially in the ventricular and sub-ventricular zones. It plays a crucial role in spindle pole organization and orientation, and is involved in brain development during embryonic neurogenesis. In rodent models and human brain organoids, WDR62 depletion leads to fewer neural progenitors [
## Molecular Pathogenesis
WDR62 is a microtubule minus-end mitotic spindle pole protein, located in dividing neural progenitors in humans. WDR62 is highly expressed in rodent and human forebrain during neurogenesis, especially in the ventricular and sub-ventricular zones. It plays a crucial role in spindle pole organization and orientation, and is involved in brain development during embryonic neurogenesis. In rodent models and human brain organoids, WDR62 depletion leads to fewer neural progenitors [
## Chapter Notes
Our research group in the child neurology and genetic departments at APHP-Robert Debré University Hospital is interested in understanding the natural history of primary microcephalies including
We thank the families who have put their trust in us.
This study was supported by the Microfanc project (
17 February 2022 (bp) Review posted live
23 February 2021 (sp) Original submission
• 17 February 2022 (bp) Review posted live
• 23 February 2021 (sp) Original submission
## Author Notes
Our research group in the child neurology and genetic departments at APHP-Robert Debré University Hospital is interested in understanding the natural history of primary microcephalies including
## Acknowledgments
We thank the families who have put their trust in us.
This study was supported by the Microfanc project (
## Revision History
17 February 2022 (bp) Review posted live
23 February 2021 (sp) Original submission
• 17 February 2022 (bp) Review posted live
• 23 February 2021 (sp) Original submission
## References
## Literature Cited
|
[] |
17/2/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
weaver
|
weaver
|
[
"EZH2-Related Weaver Syndrome",
"EZH2-Associated Weaver Syndrome",
"Histone-lysine N-methyltransferase EZH2",
"EZH2",
"EZH2-Related Overgrowth"
] |
Sharon Ocansey, Katrina Tatton-Brown
|
Summary The diagnosis of
|
The scope of this
## Diagnosis
Tall stature (height or length ≥2 standard deviations [SD] above the mean)
Macrocephaly (head circumference ≥2 SD above the mean)
Intellectual disability
Characteristic facial appearance (See
In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
The characteristic facial appearance (which is most distinctive at a younger age) evolves over time; therefore, review of younger childhood photographs may help the clinician reach a clinical diagnosis.
Poor coordination
Soft, doughy skin
Excessive loose skin
Camptodactyly of the fingers and/or toes (See
Umbilical hernia (that is occasionally significant enough to require surgical reduction)
Abnormal tone (central hypotonia and/or peripheral hypertonia) (See
Hoarse, low-pitched cry (sometimes described as a quiet cry)
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
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
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, only a few individuals have been reported with large deletions encompassing
Pathogenic variants in
Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1)
• Tall stature (height or length ≥2 standard deviations [SD] above the mean)
• Macrocephaly (head circumference ≥2 SD above the mean)
• Intellectual disability
• Characteristic facial appearance (See
• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
• The characteristic facial appearance (which is most distinctive at a younger age) evolves over time; therefore, review of younger childhood photographs may help the clinician reach a clinical diagnosis.
• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
• Poor coordination
• Soft, doughy skin
• Excessive loose skin
• Camptodactyly of the fingers and/or toes (See
• Umbilical hernia (that is occasionally significant enough to require surgical reduction)
• Abnormal tone (central hypotonia and/or peripheral hypertonia) (See
• Hoarse, low-pitched cry (sometimes described as a quiet cry)
• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
## Suggestive Findings
Tall stature (height or length ≥2 standard deviations [SD] above the mean)
Macrocephaly (head circumference ≥2 SD above the mean)
Intellectual disability
Characteristic facial appearance (See
In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
The characteristic facial appearance (which is most distinctive at a younger age) evolves over time; therefore, review of younger childhood photographs may help the clinician reach a clinical diagnosis.
Poor coordination
Soft, doughy skin
Excessive loose skin
Camptodactyly of the fingers and/or toes (See
Umbilical hernia (that is occasionally significant enough to require surgical reduction)
Abnormal tone (central hypotonia and/or peripheral hypertonia) (See
Hoarse, low-pitched cry (sometimes described as a quiet cry)
• Tall stature (height or length ≥2 standard deviations [SD] above the mean)
• Macrocephaly (head circumference ≥2 SD above the mean)
• Intellectual disability
• Characteristic facial appearance (See
• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
• The characteristic facial appearance (which is most distinctive at a younger age) evolves over time; therefore, review of younger childhood photographs may help the clinician reach a clinical diagnosis.
• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
• Poor coordination
• Soft, doughy skin
• Excessive loose skin
• Camptodactyly of the fingers and/or toes (See
• Umbilical hernia (that is occasionally significant enough to require surgical reduction)
• Abnormal tone (central hypotonia and/or peripheral hypertonia) (See
• Hoarse, low-pitched cry (sometimes described as a quiet cry)
• In children younger than age three years: retrognathia, large, fleshy ears, and a "stuck on" appearance of the chin associated with a horizontal skin crease and sometimes a central dimple
• In affected individuals of all ages, additional features include broad forehead (increased bifrontal diameter), round face, widely spaced eyes, almond-shaped palpebral fissures, and long or prominent philtrum
## 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
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
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, only a few individuals have been reported with large deletions encompassing
Pathogenic variants in
Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1)
## Option 1
When the phenotypic findings suggest the diagnosis of
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
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, only a few individuals have been reported with large deletions encompassing
## Epigenetic Signature Analysis / Methylation Array
Pathogenic variants in
Epigenetic signature analysis of a peripheral blood sample or DNA banked from a blood sample can therefore be considered to clarify the diagnosis in individuals with: (1)
## Clinical Characteristics
Primary phenotypic features associated with
The phenotypic spectrum associated with germline
To date, at least 70 individuals have been identified with a pathogenic variant in
Mild ID: 58%
Moderate ID: 22%
Severe ID: 5%
Unclassified ID: 15%
Neuroblastoma & acute lymphoblastic leukemia
Lymphoma
Acute myeloid leukemia
ID = intellectual disability
Each with one individual reported
Tall stature is a near-consistent finding: height in 59 of 65 individuals was at least two SD above the mean (ages 1-70 years). Of note, three of four individuals with a height less than two SD above the mean had been tall as young children. The mean postnatal height was 3.5 SD above the mean.
Of 59 individuals for whom information is available, 27 had a head circumference less than two SD above the mean and 32 had macrocephaly (>2 SD above the mean), with a head circumference reaching up to 5.5 SD above the mean. Head circumferences at birth were at least two SD above the mean in 5 of 6 infants for whom data is available [
Intellectual disability in those with a brain MRI abnormality was:
Mild in seven individuals (ventriculomegaly [5 individuals], periventricular leukomalacia [1 individual], and cerebellar hypoplasia [1 individual]);
Moderate in three individuals (periventricular leukomalacia with ventriculomegaly [1 individual] and isolated ventriculomegaly [2 individuals]);
Severe in two individuals with polymicrogyria and pachygyria [
Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly.
Several reported individuals with
Hypotonia (predominantly central) was reported in 22 of 47 individuals.
Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 14 of 51 individuals.
Note: Three of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia [
Tumor Types Reported in Individuals with
This individual was diagnosed with both neuroblastoma and acute lymphoblastic leukaemia at age 13 months [
Café au lait macules (2 individuals), hemangioma (4 individuals), pigmented nevi (3 individuals)
Large hands and feet (1 individual)
Hypermetropia (hyperopia; 3 individuals), strabismus (3 individuals), myopia (1 individual)
Hydrocele (2 individuals), cryptorchidism (1 individual), hypospadias (1 individual)
Cleft palate (3 individuals)
Hearing loss (conductive and sensorineural; 3 individuals)
Cardiac anomalies (4 individuals), including mitral valve prolapse (1 individual), ventricular septal defect (2 individuals), and patent ductus arteriosus (1 individual)
Gastroesophageal reflux (1 individual), hiatal hernia (1 individual)
Neonatal hypoglycemia (2 individuals)
Neonatal hypocalcemia (2 individual)
No genotype-phenotype correlations are evident among individuals reported with
Data are currently insufficient to determine the penetrance of
Weaver syndrome is named after David Weaver, who reported two boys with accelerated osseous maturation, unusual facies, and camptodactyly [
As individuals with a mild phenotype may escape clinical diagnosis, it is currently difficult to estimate the prevalence of
• Mild ID: 58%
• Moderate ID: 22%
• Severe ID: 5%
• Unclassified ID: 15%
• Neuroblastoma & acute lymphoblastic leukemia
• Lymphoma
• Acute myeloid leukemia
• Mild in seven individuals (ventriculomegaly [5 individuals], periventricular leukomalacia [1 individual], and cerebellar hypoplasia [1 individual]);
• Moderate in three individuals (periventricular leukomalacia with ventriculomegaly [1 individual] and isolated ventriculomegaly [2 individuals]);
• Severe in two individuals with polymicrogyria and pachygyria [
• Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly.
• Hypotonia (predominantly central) was reported in 22 of 47 individuals.
• Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 14 of 51 individuals.
• Note: Three of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia [
• Café au lait macules (2 individuals), hemangioma (4 individuals), pigmented nevi (3 individuals)
• Large hands and feet (1 individual)
• Hypermetropia (hyperopia; 3 individuals), strabismus (3 individuals), myopia (1 individual)
• Hydrocele (2 individuals), cryptorchidism (1 individual), hypospadias (1 individual)
• Cleft palate (3 individuals)
• Hearing loss (conductive and sensorineural; 3 individuals)
• Cardiac anomalies (4 individuals), including mitral valve prolapse (1 individual), ventricular septal defect (2 individuals), and patent ductus arteriosus (1 individual)
• Gastroesophageal reflux (1 individual), hiatal hernia (1 individual)
• Neonatal hypoglycemia (2 individuals)
• Neonatal hypocalcemia (2 individual)
## Clinical Description
Primary phenotypic features associated with
The phenotypic spectrum associated with germline
To date, at least 70 individuals have been identified with a pathogenic variant in
Mild ID: 58%
Moderate ID: 22%
Severe ID: 5%
Unclassified ID: 15%
Neuroblastoma & acute lymphoblastic leukemia
Lymphoma
Acute myeloid leukemia
ID = intellectual disability
Each with one individual reported
Tall stature is a near-consistent finding: height in 59 of 65 individuals was at least two SD above the mean (ages 1-70 years). Of note, three of four individuals with a height less than two SD above the mean had been tall as young children. The mean postnatal height was 3.5 SD above the mean.
Of 59 individuals for whom information is available, 27 had a head circumference less than two SD above the mean and 32 had macrocephaly (>2 SD above the mean), with a head circumference reaching up to 5.5 SD above the mean. Head circumferences at birth were at least two SD above the mean in 5 of 6 infants for whom data is available [
Intellectual disability in those with a brain MRI abnormality was:
Mild in seven individuals (ventriculomegaly [5 individuals], periventricular leukomalacia [1 individual], and cerebellar hypoplasia [1 individual]);
Moderate in three individuals (periventricular leukomalacia with ventriculomegaly [1 individual] and isolated ventriculomegaly [2 individuals]);
Severe in two individuals with polymicrogyria and pachygyria [
Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly.
Several reported individuals with
Hypotonia (predominantly central) was reported in 22 of 47 individuals.
Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 14 of 51 individuals.
Note: Three of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia [
Tumor Types Reported in Individuals with
This individual was diagnosed with both neuroblastoma and acute lymphoblastic leukaemia at age 13 months [
Café au lait macules (2 individuals), hemangioma (4 individuals), pigmented nevi (3 individuals)
Large hands and feet (1 individual)
Hypermetropia (hyperopia; 3 individuals), strabismus (3 individuals), myopia (1 individual)
Hydrocele (2 individuals), cryptorchidism (1 individual), hypospadias (1 individual)
Cleft palate (3 individuals)
Hearing loss (conductive and sensorineural; 3 individuals)
Cardiac anomalies (4 individuals), including mitral valve prolapse (1 individual), ventricular septal defect (2 individuals), and patent ductus arteriosus (1 individual)
Gastroesophageal reflux (1 individual), hiatal hernia (1 individual)
Neonatal hypoglycemia (2 individuals)
Neonatal hypocalcemia (2 individual)
• Mild ID: 58%
• Moderate ID: 22%
• Severe ID: 5%
• Unclassified ID: 15%
• Neuroblastoma & acute lymphoblastic leukemia
• Lymphoma
• Acute myeloid leukemia
• Mild in seven individuals (ventriculomegaly [5 individuals], periventricular leukomalacia [1 individual], and cerebellar hypoplasia [1 individual]);
• Moderate in three individuals (periventricular leukomalacia with ventriculomegaly [1 individual] and isolated ventriculomegaly [2 individuals]);
• Severe in two individuals with polymicrogyria and pachygyria [
• Note: The degree of intellectual disability was not reported for one individual with ventriculomegaly.
• Hypotonia (predominantly central) was reported in 22 of 47 individuals.
• Hypertonia (predominantly peripheral manifesting as stiffness in the limbs with brisk reflexes) was reported in 14 of 51 individuals.
• Note: Three of the individuals presenting with peripheral hypertonia were also reported to have central hypotonia [
• Café au lait macules (2 individuals), hemangioma (4 individuals), pigmented nevi (3 individuals)
• Large hands and feet (1 individual)
• Hypermetropia (hyperopia; 3 individuals), strabismus (3 individuals), myopia (1 individual)
• Hydrocele (2 individuals), cryptorchidism (1 individual), hypospadias (1 individual)
• Cleft palate (3 individuals)
• Hearing loss (conductive and sensorineural; 3 individuals)
• Cardiac anomalies (4 individuals), including mitral valve prolapse (1 individual), ventricular septal defect (2 individuals), and patent ductus arteriosus (1 individual)
• Gastroesophageal reflux (1 individual), hiatal hernia (1 individual)
• Neonatal hypoglycemia (2 individuals)
• Neonatal hypocalcemia (2 individual)
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are evident among individuals reported with
## Penetrance
Data are currently insufficient to determine the penetrance of
## Nomenclature
Weaver syndrome is named after David Weaver, who reported two boys with accelerated osseous maturation, unusual facies, and camptodactyly [
## Prevalence
As individuals with a mild phenotype may escape clinical diagnosis, it is currently difficult to estimate the prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Sporadic tumors (including hematopoietic malignancies) occurring in the absence of any other findings of
## Differential Diagnosis
Significant overlap in findings is observed between
Additional disorders of interest in the differential diagnosis of
Disorders to Consider in the Differential Diagnosis of
Pre- & postnatal overgrowth
Variable ID
Similar (but distinctive) facial appearance
Advanced bone age
Scoliosis
Joint hypermobility
Prominent chin, malar flushing in children
Most easily distinguishable from
Overgrowth
Macrocephaly
Hypertelorism, round face, "stuck on" chin
Advanced bone age
Scoliosis
Umbilical hernia
Joint hypermobility
ID is usually more prominent (variable in
Camptodactyly/clinodactyly tends to affect fingers only (not toes).
Cryptorchidism
No tumors have been reported.
Cervical spine anomalies
Congenital heart defects
There are too few cases of Cohen-Gibson syndrome to clarify which clinical features might distinguish them from
Overgrowth
Macrocephaly
Hypertelorism
Variable ID
Scoliosis
Joint hypermobility
Hypertrichosis
Normal skin texture
No tumors have been reported.
There are too few cases of Imagawa-Matsumoto syndrome to clarify which clinical features might distinguish them from
↑ birth weight
Tall stature (not as frequent in BWS as other conditions in the differential diagnosis)
Umbilical hernia
Macroglossia
Earlobe creases/pits
Omphalocele
Visceromegaly
Usually normal intellect
Neonatal hypoglycemia
Polyhydramnios
Predisposition to embryonal tumors, esp Wilms tumor
Tall stature
Variable ID
Autism spectrum disorder
Scoliosis
Joint hypermobility
Facial appearance (round, heavy; w/horizontal eyebrows & narrow palpebral fissures) most recognizable in early teen / adult yrs.
↑ weight
Neuropsychiatric issues
Tall stature
Scoliosis
Joint hypermobility
Cognitive abilities are usually normal.
Ocular findings (myopia & lens dislocation)
Cardiovascular findings (dilatation of aorta; mitral & tricuspid valve prolapse)
Pectus abnormalities are common.
Tall stature
Scoliosis
Camptodactyly
Cognitive abilities are usually normal.
Cardiovascular findings (dilatation of aorta; mitral & tricuspid valve prolapse)
Crumpled appearance to top of ear
Pectus abnormalities are common.
↑ birth weight
Tall stature
Variable ID
Characteristic facial appearance
Supernumerary nipples
Polydactyly
Diastasis recti
Sotos syndrome-like condition
Tall stature
Variable ID
Ophthalmologic abnormalities are common.
Growth frequently normalizes in teenagers & young adults.
AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
Pathogenic variants in
More than 95% of individuals have a
Beckwith-Wiedemann syndrome (BWS) (without multilocus imprinting disturbances) is associated with abnormal expression of imprinted genes in the BWS critical region. Abnormal expression of imprinted genes can be caused by an epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous maternally inherited
Simpson-Golabi-Behmel syndrome type 1 is caused by a hemizygous pathogenic variant in
• Pre- & postnatal overgrowth
• Variable ID
• Similar (but distinctive) facial appearance
• Advanced bone age
• Scoliosis
• Joint hypermobility
• Prominent chin, malar flushing in children
• Most easily distinguishable from
• Overgrowth
• Macrocephaly
• Hypertelorism, round face, "stuck on" chin
• Advanced bone age
• Scoliosis
• Umbilical hernia
• Joint hypermobility
• ID is usually more prominent (variable in
• Camptodactyly/clinodactyly tends to affect fingers only (not toes).
• Cryptorchidism
• No tumors have been reported.
• Cervical spine anomalies
• Congenital heart defects
• There are too few cases of Cohen-Gibson syndrome to clarify which clinical features might distinguish them from
• Overgrowth
• Macrocephaly
• Hypertelorism
• Variable ID
• Scoliosis
• Joint hypermobility
• Hypertrichosis
• Normal skin texture
• No tumors have been reported.
• There are too few cases of Imagawa-Matsumoto syndrome to clarify which clinical features might distinguish them from
• ↑ birth weight
• Tall stature (not as frequent in BWS as other conditions in the differential diagnosis)
• Umbilical hernia
• Macroglossia
• Earlobe creases/pits
• Omphalocele
• Visceromegaly
• Usually normal intellect
• Neonatal hypoglycemia
• Polyhydramnios
• Predisposition to embryonal tumors, esp Wilms tumor
• Tall stature
• Variable ID
• Autism spectrum disorder
• Scoliosis
• Joint hypermobility
• Facial appearance (round, heavy; w/horizontal eyebrows & narrow palpebral fissures) most recognizable in early teen / adult yrs.
• ↑ weight
• Neuropsychiatric issues
• Tall stature
• Scoliosis
• Joint hypermobility
• Cognitive abilities are usually normal.
• Ocular findings (myopia & lens dislocation)
• Cardiovascular findings (dilatation of aorta; mitral & tricuspid valve prolapse)
• Pectus abnormalities are common.
• Tall stature
• Scoliosis
• Camptodactyly
• Cognitive abilities are usually normal.
• Cardiovascular findings (dilatation of aorta; mitral & tricuspid valve prolapse)
• Crumpled appearance to top of ear
• Pectus abnormalities are common.
• ↑ birth weight
• Tall stature
• Variable ID
• Characteristic facial appearance
• Supernumerary nipples
• Polydactyly
• Diastasis recti
• Sotos syndrome-like condition
• Tall stature
• Variable ID
• Ophthalmologic abnormalities are common.
• Growth frequently normalizes in teenagers & young adults.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Consider brain MRI scan if progressive macrocephaly or unexplained neurologic features are present.
Consider EEG if seizures are suspected.
Gross motor & fine motor skills
Scoliosis, camptodactyly, &/or ligamentous laxity
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
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
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.
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
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 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
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitoring by pediatrician for resolution/improvement of camptodactyly &/or hypotonia
If scoliosis is present, monitor per orthopedist.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
In older children / teenagers who do not have medical complications, the clinician may wish to review less frequently than in younger children.
Current data suggest a slightly increased relative risk for the development of neuroblastoma in individuals with heterozygous germline
Histone-lysine N-methyltransferase EZH2 (EZH2), encoded by
See
In general, pregnancies in which the mother and/or fetus has a heterozygous
See
Search
• Consider brain MRI scan if progressive macrocephaly or unexplained neurologic features are present.
• Consider EEG if seizures are suspected.
• Gross motor & fine motor skills
• Scoliosis, camptodactyly, &/or ligamentous laxity
• 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
• 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: 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 children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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 those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitoring by pediatrician for resolution/improvement of camptodactyly &/or hypotonia
• If scoliosis is present, monitor per orthopedist.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Consider brain MRI scan if progressive macrocephaly or unexplained neurologic features are present.
Consider EEG if seizures are suspected.
Gross motor & fine motor skills
Scoliosis, camptodactyly, &/or ligamentous laxity
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
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
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Consider brain MRI scan if progressive macrocephaly or unexplained neurologic features are present.
• Consider EEG if seizures are suspected.
• Gross motor & fine motor skills
• Scoliosis, camptodactyly, &/or ligamentous laxity
• 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
• 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.
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
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 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 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: 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 children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitoring by pediatrician for resolution/improvement of camptodactyly &/or hypotonia
If scoliosis is present, monitor per orthopedist.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
In older children / teenagers who do not have medical complications, the clinician may wish to review less frequently than in younger children.
Current data suggest a slightly increased relative risk for the development of neuroblastoma in individuals with heterozygous germline
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitoring by pediatrician for resolution/improvement of camptodactyly &/or hypotonia
• If scoliosis is present, monitor per orthopedist.
## Agents/Circumstances to Avoid
Histone-lysine N-methyltransferase EZH2 (EZH2), encoded by
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In general, pregnancies in which the mother and/or fetus has a heterozygous
See
## Therapies Under Investigation
Search
## Genetic Counseling
Some individuals diagnosed with
Some individuals diagnosed with
Of 70 individuals with
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 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 family history of some individuals diagnosed with
If a parent of the proband is known to have 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.
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 can be helpful.
• Some individuals diagnosed with
• Some individuals diagnosed with
• Of 70 individuals with
• 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 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.
• 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 known to have 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
## Risk to Family Members
Some individuals diagnosed with
Some individuals diagnosed with
Of 70 individuals with
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 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 family history of some individuals diagnosed with
If a parent of the proband is known to have the
If the
If the parents have not been tested for the
• Some individuals diagnosed with
• Some individuals diagnosed with
• Of 70 individuals with
• 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 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.
• 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 known to have the
• 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 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 can be helpful.
## Resources
United Kingdom
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
EZH2-Related Overgrowth: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for EZH2-Related Overgrowth (
Histone-lysine N-methyltransferase EZH2 (EZH2) is a histone methyltransferase with a critical SET (su(var)3-9, enhancer of zeste, trithorax) domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains [
Epigenetic mutational signature analysis has shown that
Further functional studies are needed to determine the precise mechanism of disease causation in
Variants listed in the table have been provided by the authors.
See
## Molecular Pathogenesis
Histone-lysine N-methyltransferase EZH2 (EZH2) is a histone methyltransferase with a critical SET (su(var)3-9, enhancer of zeste, trithorax) domain, a pre-SET CXC domain, and two additional SANT (Sw13, Ada2, N-cor TFIIIB) domains [
Epigenetic mutational signature analysis has shown that
Further functional studies are needed to determine the precise mechanism of disease causation in
Variants listed in the table have been provided by the authors.
See
## Chapter Notes
Sharon Ocansey, MBBS, BSc, MSc (2024-present)Nazneen Rahman, BM BCh, PhD; Institute of Cancer Research (2013-2024)Katrina Tatton-Brown, BM BCh, MD (2013-present)
26 June 2025 (gm) Revision: neuroblastoma guidelines updated
21 March 2024 (gm) Comprehensive update posted live
2 August 2018 (bp) Comprehensive update posted live
6 August 2015 (me) Comprehensive update posted live
18 July 2013 (me) Review posted live
23 January 2013 (ktb) Original submission
• 26 June 2025 (gm) Revision: neuroblastoma guidelines updated
• 21 March 2024 (gm) Comprehensive update posted live
• 2 August 2018 (bp) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 18 July 2013 (me) Review posted live
• 23 January 2013 (ktb) Original submission
## Author History
Sharon Ocansey, MBBS, BSc, MSc (2024-present)Nazneen Rahman, BM BCh, PhD; Institute of Cancer Research (2013-2024)Katrina Tatton-Brown, BM BCh, MD (2013-present)
## Revision History
26 June 2025 (gm) Revision: neuroblastoma guidelines updated
21 March 2024 (gm) Comprehensive update posted live
2 August 2018 (bp) Comprehensive update posted live
6 August 2015 (me) Comprehensive update posted live
18 July 2013 (me) Review posted live
23 January 2013 (ktb) Original submission
• 26 June 2025 (gm) Revision: neuroblastoma guidelines updated
• 21 March 2024 (gm) Comprehensive update posted live
• 2 August 2018 (bp) Comprehensive update posted live
• 6 August 2015 (me) Comprehensive update posted live
• 18 July 2013 (me) Review posted live
• 23 January 2013 (ktb) Original submission
## References
## Literature Cited
Retrognathia present in younger children with
Mild hyperextension of the distal interphalangeal joints and flexion of the proximal interphalangeal joints in a woman age 22 years with a heterozygous
|
[] |
18/7/2013
|
21/3/2024
|
26/6/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
weill-ms
|
weill-ms
|
[
"A disintegrin and metalloproteinase with thrombospondin motifs 10",
"A disintegrin and metalloproteinase with thrombospondin motifs 17",
"Fibrillin-1",
"Latent-transforming growth factor beta-binding protein 2",
"ADAMTS10",
"ADAMTS17",
"FBN1",
"LTBP2",
"Weill-Marchesani Syndrome"
] |
Weill-Marchesani Syndrome
|
Pauline Marzin, Valérie Cormier-Daire, Ekaterini Tsilou
|
Summary Weill-Marchesani syndrome (WMS) is a connective tissue disorder characterized by abnormalities of the lens of the eye, short stature, brachydactyly, joint stiffness, and cardiovascular defects. The ocular problems, typically recognized in childhood, include microspherophakia (small spherical lens), myopia secondary to the abnormal shape of the lens, ectopia lentis (abnormal position of the lens), and glaucoma, which can lead to blindness. Height of adult males is 142-169 cm; height of adult females is 130-157 cm. Autosomal recessive WMS cannot be distinguished from autosomal dominant WMS by clinical findings alone. The diagnosis WMS is established in a proband with characteristic clinical features. Identification of biallelic pathogenic variants in Prenatal and preimplantation genetic testing are possible once the WMS-related pathogenic variant(s) have been identified in an affected family member.
|
## Diagnosis
No consensus clinical diagnostic criteria for Weill-Marchesani syndrome (WMS) have been published.
WMS
Eye anomalies including microspherophakia and ectopia lentis
Short stature
Brachydactyly
Progressive joint stiffness
Thickened skin
Pseudomuscular build
Cardiovascular defects (e.g., patent ductus arteriosus, pulmonary stenosis, thoracic aortic aneurysm, cervical artery dissection, prolonged QTc)
Shortened long tubular bones
Delayed bone age
Broad proximal phalanges
The diagnosis of WMS can be
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 phenotype is indistinguishable from many other inherited disorders characterized by connective tissue abnormalities,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Weill-Marchesani Syndrome (WMS)
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.
A whole-gene deletion has been reported as a founder variant in the Amish population [
• Eye anomalies including microspherophakia and ectopia lentis
• Short stature
• Brachydactyly
• Progressive joint stiffness
• Thickened skin
• Pseudomuscular build
• Cardiovascular defects (e.g., patent ductus arteriosus, pulmonary stenosis, thoracic aortic aneurysm, cervical artery dissection, prolonged QTc)
• Shortened long tubular bones
• Delayed bone age
• Broad proximal phalanges
## Suggestive Findings
WMS
Eye anomalies including microspherophakia and ectopia lentis
Short stature
Brachydactyly
Progressive joint stiffness
Thickened skin
Pseudomuscular build
Cardiovascular defects (e.g., patent ductus arteriosus, pulmonary stenosis, thoracic aortic aneurysm, cervical artery dissection, prolonged QTc)
Shortened long tubular bones
Delayed bone age
Broad proximal phalanges
• Eye anomalies including microspherophakia and ectopia lentis
• Short stature
• Brachydactyly
• Progressive joint stiffness
• Thickened skin
• Pseudomuscular build
• Cardiovascular defects (e.g., patent ductus arteriosus, pulmonary stenosis, thoracic aortic aneurysm, cervical artery dissection, prolonged QTc)
• Shortened long tubular bones
• Delayed bone age
• Broad proximal phalanges
## Establishing the Diagnosis
The diagnosis of WMS can be
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 phenotype is indistinguishable from many other inherited disorders characterized by connective tissue abnormalities,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Weill-Marchesani Syndrome (WMS)
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.
A whole-gene deletion has been reported as a founder variant in the Amish population [
## Option 1
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by connective tissue abnormalities,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Weill-Marchesani Syndrome (WMS)
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.
A whole-gene deletion has been reported as a founder variant in the Amish population [
## Clinical Characteristics
Weill-Marchesani syndrome (WMS) is a connective tissue disorder that usually presents in childhood with short stature and/or ocular problems. The autosomal recessive and autosomal dominant forms of WMS share clinical manifestations in the following systems [
Lenticular myopia is usually the first ophthalmologic finding.
Ectopia lentis usually results in downward displacement of the lens.
Glaucoma is the most serious complication because it can lead to blindness. In most individuals glaucoma results from pupillary block resulting from forward movement of the lens or dislocation of the lens into the anterior chamber. Increased central corneal thickness has been recognized as a pathologic feature of WMS that may lead to overestimation of intraocular pressure by applanation tonometers [
Loss of vision occurs earlier in WMS and is more severe than in other lens dislocation syndromes. In some individuals, lens dislocation and pupillary block appear after blunt trauma to the eye weakens the zonular fibers.
Presenile vitreous liquefaction has been described in a large family with autosomal dominant WMS [
Retinal vascular tortuosity in the absence of congenital heart disease has been described in one affected individual [
Retinitis pigmentosa has been reported in an affected female age 14 years [
Advanced glaucoma and corneal endothelial dysfunction have recently been reported in an affected female age 30 years [
Weill-Marchesani Syndrome Phenotype Correlations by Gene
ID = intellectual disability
Given the limited number of individuals with WMS in the literature, no genotype-phenotype correlations for
The penetrance in those with autosomal recessive and dominant WMS is thought to be 100%. Intrafamilial and interfamilial variable expressivity is observed in WMS.
Other terms previously used to refer to Weill-Marchesani syndrome:
Spherophakia-brachymorphia syndrome
Mesodermal dysmorphodystrophy, congenital
WMS is described as being very rare. Prevalence has been estimated at 1:100,000 population.
• Lenticular myopia is usually the first ophthalmologic finding.
• Ectopia lentis usually results in downward displacement of the lens.
• Glaucoma is the most serious complication because it can lead to blindness. In most individuals glaucoma results from pupillary block resulting from forward movement of the lens or dislocation of the lens into the anterior chamber. Increased central corneal thickness has been recognized as a pathologic feature of WMS that may lead to overestimation of intraocular pressure by applanation tonometers [
• Spherophakia-brachymorphia syndrome
• Mesodermal dysmorphodystrophy, congenital
## Clinical Description
Weill-Marchesani syndrome (WMS) is a connective tissue disorder that usually presents in childhood with short stature and/or ocular problems. The autosomal recessive and autosomal dominant forms of WMS share clinical manifestations in the following systems [
Lenticular myopia is usually the first ophthalmologic finding.
Ectopia lentis usually results in downward displacement of the lens.
Glaucoma is the most serious complication because it can lead to blindness. In most individuals glaucoma results from pupillary block resulting from forward movement of the lens or dislocation of the lens into the anterior chamber. Increased central corneal thickness has been recognized as a pathologic feature of WMS that may lead to overestimation of intraocular pressure by applanation tonometers [
Loss of vision occurs earlier in WMS and is more severe than in other lens dislocation syndromes. In some individuals, lens dislocation and pupillary block appear after blunt trauma to the eye weakens the zonular fibers.
Presenile vitreous liquefaction has been described in a large family with autosomal dominant WMS [
Retinal vascular tortuosity in the absence of congenital heart disease has been described in one affected individual [
Retinitis pigmentosa has been reported in an affected female age 14 years [
Advanced glaucoma and corneal endothelial dysfunction have recently been reported in an affected female age 30 years [
• Lenticular myopia is usually the first ophthalmologic finding.
• Ectopia lentis usually results in downward displacement of the lens.
• Glaucoma is the most serious complication because it can lead to blindness. In most individuals glaucoma results from pupillary block resulting from forward movement of the lens or dislocation of the lens into the anterior chamber. Increased central corneal thickness has been recognized as a pathologic feature of WMS that may lead to overestimation of intraocular pressure by applanation tonometers [
## Phenotype Correlations by Gene
Weill-Marchesani Syndrome Phenotype Correlations by Gene
ID = intellectual disability
## Genotype-Phenotype Correlations
Given the limited number of individuals with WMS in the literature, no genotype-phenotype correlations for
## Penetrance
The penetrance in those with autosomal recessive and dominant WMS is thought to be 100%. Intrafamilial and interfamilial variable expressivity is observed in WMS.
## Nomenclature
Other terms previously used to refer to Weill-Marchesani syndrome:
Spherophakia-brachymorphia syndrome
Mesodermal dysmorphodystrophy, congenital
• Spherophakia-brachymorphia syndrome
• Mesodermal dysmorphodystrophy, congenital
## Prevalence
WMS is described as being very rare. Prevalence has been estimated at 1:100,000 population.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Other phenotypes associated with pathogenic variants in
Allelic Disorders to Consider in the Differential Diagnosis of Weill-Marchesani Syndrome
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Other Allelic Disorders
MASS =
## Differential Diagnosis
Ectopia lentis may occur in the conditions listed in
Other Genes and Disorders Associated with Ectopia Lentis
DD/ID
Tall & slender w/asthenic habitus ("marfanoid")
Biochemical features
Thromboembolism
Skeletal manifestations: bone overgrowth & joint laxity; extremities disproportionately long for trunk size (dolichostenomelia)
Cardiovascular manifestations: dilatation of aorta at the level of sinuses of Valsalva, predisposition for aortic tear & rupture, mitral valve prolapse w/or w/o regurgitation, tricuspid valve prolapse, & enlargement of proximal pulmonary artery
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
Homocystinuria 1 is a metabolic disorder caused by cystathionine β-synthase deficiency. The cardinal biochemical features of homocystinuria are markedly increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase (CBS) enzyme activity.
The acromelic dysplasia group includes four rare disorders: Weill-Marchesani syndrome,
Other Acromelic Dysplasias to Consider in the Differential Diagnosis of Weill-Marchesani Syndrome (WMS)
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance
All probands with Myhre syndrome reported to date have had a
• DD/ID
• Tall & slender w/asthenic habitus ("marfanoid")
• Biochemical features
• Thromboembolism
• Skeletal manifestations: bone overgrowth & joint laxity; extremities disproportionately long for trunk size (dolichostenomelia)
• Cardiovascular manifestations: dilatation of aorta at the level of sinuses of Valsalva, predisposition for aortic tear & rupture, mitral valve prolapse w/or w/o regurgitation, tricuspid valve prolapse, & enlargement of proximal pulmonary artery
## Ectopia Lentis
Ectopia lentis may occur in the conditions listed in
Other Genes and Disorders Associated with Ectopia Lentis
DD/ID
Tall & slender w/asthenic habitus ("marfanoid")
Biochemical features
Thromboembolism
Skeletal manifestations: bone overgrowth & joint laxity; extremities disproportionately long for trunk size (dolichostenomelia)
Cardiovascular manifestations: dilatation of aorta at the level of sinuses of Valsalva, predisposition for aortic tear & rupture, mitral valve prolapse w/or w/o regurgitation, tricuspid valve prolapse, & enlargement of proximal pulmonary artery
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance
Homocystinuria 1 is a metabolic disorder caused by cystathionine β-synthase deficiency. The cardinal biochemical features of homocystinuria are markedly increased concentrations of plasma homocystine, total homocysteine, and methionine; increased concentration of urine homocystine; and reduced cystathionine β-synthase (CBS) enzyme activity.
• DD/ID
• Tall & slender w/asthenic habitus ("marfanoid")
• Biochemical features
• Thromboembolism
• Skeletal manifestations: bone overgrowth & joint laxity; extremities disproportionately long for trunk size (dolichostenomelia)
• Cardiovascular manifestations: dilatation of aorta at the level of sinuses of Valsalva, predisposition for aortic tear & rupture, mitral valve prolapse w/or w/o regurgitation, tricuspid valve prolapse, & enlargement of proximal pulmonary artery
## Acromelic Dysplasia
The acromelic dysplasia group includes four rare disorders: Weill-Marchesani syndrome,
Other Acromelic Dysplasias to Consider in the Differential Diagnosis of Weill-Marchesani Syndrome (WMS)
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; IUGR = intrauterine growth restriction; MOI = mode of inheritance
All probands with Myhre syndrome reported to date have had a
## Management
To establish the extent of disease in an individual diagnosed with Weill-Marchesani syndrome (WMS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Weill-Marchesani Syndrome
Growth assessment
Assessment of joint range of motion by orthopedist/PT
Echocardiography
Electrocardiogram
Patent ductus arteriosus, valvular stenosis, &/or arterial narrowing
Prolonged QT
MOI = mode of inheritance; PT = physical therapist
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
The medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics.
A peripheral iridectomy should be performed to prevent or relieve pupillary block [
Lens extraction and/or trabeculectomy may be necessary in some persons with advanced chronic angle closure glaucoma [
Individuals with WMS were recently reported to have increased central corneal thickness, which needs to be considered in the diagnosis and follow up of glaucoma because increased central corneal thickness may lead to overestimation of intraocular pressure by applanation tonometers [
Treatment of Manifestations in Individuals with Weill-Marchesani Syndrome (WMS)
PT = physical therapy
Recommended Surveillance for Individuals with Weill-Marchesani Syndrome
Echocardiogram for evidence of valvular stenosis, arterial narrowing, &/or aneurysm
Electrocardiography to evaluate QT interval
Use of ophthalmic miotics and mydriatics should be avoided as they can induce pupillary block.
Potential increased risk of WMS-related ocular complications associated with contact sports should be discussed with the ophthalmologist.
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 pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from ophthalmology and cardiology evaluations. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist if the pathogenic variant in the family is not known.
See
Search
• Growth assessment
• Assessment of joint range of motion by orthopedist/PT
• Echocardiography
• Electrocardiogram
• Patent ductus arteriosus, valvular stenosis, &/or arterial narrowing
• Prolonged QT
• The medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics.
• A peripheral iridectomy should be performed to prevent or relieve pupillary block [
• Lens extraction and/or trabeculectomy may be necessary in some persons with advanced chronic angle closure glaucoma [
• Individuals with WMS were recently reported to have increased central corneal thickness, which needs to be considered in the diagnosis and follow up of glaucoma because increased central corneal thickness may lead to overestimation of intraocular pressure by applanation tonometers [
• Echocardiogram for evidence of valvular stenosis, arterial narrowing, &/or aneurysm
• Electrocardiography to evaluate QT interval
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with Weill-Marchesani syndrome (WMS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Weill-Marchesani Syndrome
Growth assessment
Assessment of joint range of motion by orthopedist/PT
Echocardiography
Electrocardiogram
Patent ductus arteriosus, valvular stenosis, &/or arterial narrowing
Prolonged QT
MOI = mode of inheritance; PT = physical therapist
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• Growth assessment
• Assessment of joint range of motion by orthopedist/PT
• Echocardiography
• Electrocardiogram
• Patent ductus arteriosus, valvular stenosis, &/or arterial narrowing
• Prolonged QT
## Treatment of Manifestations
The medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics.
A peripheral iridectomy should be performed to prevent or relieve pupillary block [
Lens extraction and/or trabeculectomy may be necessary in some persons with advanced chronic angle closure glaucoma [
Individuals with WMS were recently reported to have increased central corneal thickness, which needs to be considered in the diagnosis and follow up of glaucoma because increased central corneal thickness may lead to overestimation of intraocular pressure by applanation tonometers [
Treatment of Manifestations in Individuals with Weill-Marchesani Syndrome (WMS)
PT = physical therapy
• The medical treatment of glaucoma is difficult because of paradoxic response to miotics and mydriatics.
• A peripheral iridectomy should be performed to prevent or relieve pupillary block [
• Lens extraction and/or trabeculectomy may be necessary in some persons with advanced chronic angle closure glaucoma [
• Individuals with WMS were recently reported to have increased central corneal thickness, which needs to be considered in the diagnosis and follow up of glaucoma because increased central corneal thickness may lead to overestimation of intraocular pressure by applanation tonometers [
## Surveillance
Recommended Surveillance for Individuals with Weill-Marchesani Syndrome
Echocardiogram for evidence of valvular stenosis, arterial narrowing, &/or aneurysm
Electrocardiography to evaluate QT interval
• Echocardiogram for evidence of valvular stenosis, arterial narrowing, &/or aneurysm
• Electrocardiography to evaluate QT interval
## Agents/Circumstances to Avoid
Use of ophthalmic miotics and mydriatics should be avoided as they can induce pupillary block.
Potential increased risk of WMS-related ocular complications associated with contact sports should be discussed with the ophthalmologist.
## 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 pathogenic variant(s) in the family in order to identify as early as possible those who would benefit from ophthalmology and cardiology evaluations. Evaluations can include:
Molecular genetic testing if the pathogenic variant(s) in the family are known;
Ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist if the pathogenic variant in the family is not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Weill-Marchesani syndrome (WMS) caused by pathogenic variants in
WMS caused by pathogenic variants
Most individuals diagnosed with autosomal dominant WMS have an affected parent.
A proband with autosomal dominant WMS may have the disorder as the result of a
If the proband appears to be the only affected family member, molecular genetic testing (if a molecular diagnosis has been established in the proband) is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. Recommendations may also include ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist.
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
If a parent of the proband is affected and/or is known to have the
If the proband has a known WMS-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 [
If the parents have not been tested for the
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 is recommended for the parents to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Intrafamilial variable expressivity is observed in WMS.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing of at-risk relatives is possible if the WMS-related pathogenic variants have been identified in the family.
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 WMS-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.
• Most individuals diagnosed with autosomal dominant WMS have an affected parent.
• A proband with autosomal dominant WMS may have the disorder as the result of a
• If the proband appears to be the only affected family member, molecular genetic testing (if a molecular diagnosis has been established in the proband) is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. Recommendations may also include ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist.
• 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 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 is affected and/or is known to have the
• If the proband has a known WMS-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 [
• If the parents have not been tested for the
• 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 is recommended for the parents to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Intrafamilial variable expressivity is observed in WMS.
• 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
Weill-Marchesani syndrome (WMS) caused by pathogenic variants in
WMS caused by pathogenic variants
## Autosomal Dominant Inheritance ‒ Risk to Family Members
Most individuals diagnosed with autosomal dominant WMS have an affected parent.
A proband with autosomal dominant WMS may have the disorder as the result of a
If the proband appears to be the only affected family member, molecular genetic testing (if a molecular diagnosis has been established in the proband) is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. Recommendations may also include ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist.
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
If a parent of the proband is affected and/or is known to have the
If the proband has a known WMS-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 [
If the parents have not been tested for the
• Most individuals diagnosed with autosomal dominant WMS have an affected parent.
• A proband with autosomal dominant WMS may have the disorder as the result of a
• If the proband appears to be the only affected family member, molecular genetic testing (if a molecular diagnosis has been established in the proband) is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. Recommendations may also include ophthalmologic examination for detection of possible microspherophakia and detailed examination by a clinical geneticist.
• 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 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 is affected and/or is known to have the
• If the proband has a known WMS-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 [
• If the parents have not been tested for the
## Autosomal Recessive Inheritance ‒ 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 is recommended for the parents to confirm that both parents are heterozygous for an
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for an
Intrafamilial variable expressivity is observed in WMS.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing of at-risk relatives is possible if the WMS-related pathogenic variants have been identified in the family.
• 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 is recommended for the parents to confirm that both parents are heterozygous for an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Intrafamilial variable expressivity is observed in WMS.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Carrier testing of at-risk relatives is possible if the WMS-related pathogenic variants have been identified in the family.
## 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 WMS-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
•
•
•
•
•
•
•
•
•
•
## Molecular Genetics
Weill-Marchesani Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Weill-Marchesani Syndrome (
Weill-Marchesani syndrome (WMS) is a genetic disorder of the connective tissue caused by pathogenic variants in four genes,
A direct interaction between the protein products encoded by
Latent transforming growth factor beta-binding protein 2 (LTBP2) is an extracellular matrix protein that associates with fibrillin-1 containing microfibrils.
## Molecular Pathogenesis
Weill-Marchesani syndrome (WMS) is a genetic disorder of the connective tissue caused by pathogenic variants in four genes,
A direct interaction between the protein products encoded by
Latent transforming growth factor beta-binding protein 2 (LTBP2) is an extracellular matrix protein that associates with fibrillin-1 containing microfibrils.
## Chapter Notes
Valérie Cormier-Daire, MD, PhD (2020-present)Ian M MacDonald, MDCM; University of Alberta (2007-2020)Pauline Marzin, MD (2020-present)Ekaterini Tsilou, MD (2007-present)
10 December 2020 (sw) Comprehensive update posted live
14 February 2013 (me) Comprehensive update posted live
1 November 2007 (me) Review posted live
3 August 2007 (et) Original submission
• 10 December 2020 (sw) Comprehensive update posted live
• 14 February 2013 (me) Comprehensive update posted live
• 1 November 2007 (me) Review posted live
• 3 August 2007 (et) Original submission
## Author History
Valérie Cormier-Daire, MD, PhD (2020-present)Ian M MacDonald, MDCM; University of Alberta (2007-2020)Pauline Marzin, MD (2020-present)Ekaterini Tsilou, MD (2007-present)
## Revision History
10 December 2020 (sw) Comprehensive update posted live
14 February 2013 (me) Comprehensive update posted live
1 November 2007 (me) Review posted live
3 August 2007 (et) Original submission
• 10 December 2020 (sw) Comprehensive update posted live
• 14 February 2013 (me) Comprehensive update posted live
• 1 November 2007 (me) Review posted live
• 3 August 2007 (et) Original submission
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"C Evereklioglu, IF Hepsen, H Er. Weill-Marchesani syndrome in three generations.. Eye 1999;13:773-7",
"L Faivre, H Dollfus, S Lyonnet, Y Alembik, A Mégarbané, J Samples, RJ Gorlin, A Alswaid, J Feingold, M Le Merrer, A Munnich, V Cormier-Daire. Clinical homogeneity and genetic heterogeneity in Weill-Marchesani syndrome.. Am J Med Genet A. 2003a;123A:204-7",
"L Faivre, RJ Gorlin, MK Wirtz, M Godfrey, N Dagoneau, JR Samples, M Le Merrer, G Collod-Béroud, C Boileau, A Munnich, V Cormier-Daire. In frame fibrillin-1 gene deletion in autosomal dominant Weill-Marchesani syndrome.. J Med Genet 2003b;40:34-6",
"K Gallagher, T Salam, B Sin, S Gupta, H Zambarakji. Retinal vascular tortuosity in a patient with Weill-Marchesani syndrome.. Case Rep Ophthalmol Med. 2011;2011",
"KA Groth, Y Von Kodolitsch, K Kutsche, M Gaustadnes, K Thorsen, NH Andersen, CH Gravholt. Evaluating the quality of Marfan genotype-phenotype correlations in existing FBN1 databases.. Genet Med. 2017;19:772-7",
"H Guo, X Wu, K Cai, Z Qiao. Weill-Marchesani syndrome with advanced glaucoma and corneal endothelial dysfunction: a case report and literature review.. BMC Ophthalmol. 2015;15:3",
"R Haji-Seyed-Javadi, S Jelodari-Mamaghani, SH Paylakhi, S Yazdani, N Nilforushan, JB Fan, B Klotzle, MJ Mahmoudi, MJ Ebrahimian, N Chelich, E Taghiabadi, K Kamyab, C Boileau, C Paisan-Ruiz, M Ronaghi, E Elahi. LTBP2 mutations cause Weill-Marchesani and Weill-Marchesani-like syndrome and affect disruptions in the extracellular matrix.. Hum Mutat 2012;33:1182-7",
"P Harasymowycz, R Wilson. Surgical treatment of advanced chronic angle closure glaucoma in Weill-Marchesani syndrome.. J Pediatr Ophthalmol Strabismus. 2004;41:295-9",
"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",
"J Jethani, A Mishra, S Shetty, P Vijayalakshmi. Weill-Marchesani syndrome associated with retinitis pigmentosa.. Indian J Ophthalmol 2007;55:142-3",
"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",
"L Karabiyik. Airway management of a patient with Weill-Marchesani syndrome.. J Clin Anesth 2003;15:214-6",
"SZ Karoulias, A Beyens, Z Balic, S Symoens, A Vandersteen, AL Rideout, J Dickinson, B Callewaert, D Hubmacher. A novel ADAMTS17 variant that causes Weill-Marchesani syndrome 4 alters fibrillin-1 and collagen type I deposition in the extracellular matrix.. Matrix Biol. 2020;88:1-18",
"J Kojuri, MR Razeghinejad, A Aslani. Cardiac findings in Weill–Marchesani syndrome.. Am J Med Genet Part A 2007;143A:2062-4",
"A Kumar, MR Duvvari, VC Prabhakaran, JS Shetty, GJ Murthy, SH Blanton. A homozygous mutation in LTBP2 causes isolated microspherophakia.. Hum Genet 2010;128:365-71",
"WE Kutz, LW Wang, HL Bader, AK Majors, K Iwata, EI Traboulsi, LY Sakai, DR Keene, SS Apte. ADAMTS10 protein interacts with fibrillin-1 and promotes its deposition in extracellular matrix of cultured fibroblasts.. J Biol Chem 2011;286:17156-67",
"JP Lerner-Ellis, SH Aldubayan, AL Hernandez, MA Kelly, AJ Stuenkel, J Walsh, VA Joshi. The spectrum of FBN1, TGFbetaR1, TGFbetaR2 and ACTA2 variants in 594 individuals with suspected Marfan syndrome, Loeys-Dietz syndrome or thoracic aortic aneurysms and dissections (TAAD).. Mol Genet Metab. 2014;112:171-6",
"J Li, X Jia, S Li, S Fang, X Guo. Mutation survey of candidate genes in 40 Chinese patients with congenital ectopia lentis.. Mol Vis. 2014;20:1017-24",
"AM McInerney-Leo, C Le Goff, PJ Leo, TJ Kenna, P Keith, JE Harris, R Steer, C Bole-Feysot, P Nitschke, C Kielty, MA Brown, A Zankl, EL Duncan, V Cormier-Daire. Mutations in LTBP3 cause acromicric dysplasia and geleophysic dysplasia.. J Med Genet. 2016;53:457-64",
"J Morales, L Al-Sharif, DS Khalil, JM Shinwari, P Bavi, RA Al-Mahrouqi, A Al-Rajhi, FS Alkuraya, BF Meyer, N Al Tassan. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature.. Am J Hum Genet 2009;85:558-68",
"K Newell, W Smith, B Ghoshhajra, E Isselbacher, A Lin, ME Lindsay. Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill-Marchesani syndrome.. Am J Med Genet A. 2017;173:2551-6",
"AL Pimienta, WR Wilcox, E Reinstein. More than meets the eye: the evolving phenotype of Weill-Marchesani syndrome-diagnostic confusion with geleophysic dysplasia.. Am J Med Genet A. 2013;161A:3126-9",
"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",
"MR Razeghinejad, H Safavian. Central corneal thickness in patients with Weill-Marchesani syndrome.. Am J Ophthalmol. 2006;142:507-8",
"W Riad, M Abouammoh, M Fathy. Anesthetic characteristics and airway evaluation of patients with Weill-Marchesani syndrome.. Middle East J Anesthesiol 2006;18:725-31",
"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",
"R Ritch, BM Chang, JM Liebmann. Angle closure in younger patients.. Ophthalmology 2003;110:1880-9",
"G Sengle, K Tsutsui, DR Keene, SF Tufa, EJ Carlson, NL Charbonneau, RN Ono, T Sasaki, MK Wirtz, JR Samples, LI Fessler, JH Fessler, K Sekiguchi, SJ Hayflick, LY Sakai. Microenvironmental regulation by fibrillin-1.. PLoS Genet. 2012;8",
"MH Shah, V Bhat, JS Shetty, A Kumar. Whole exome sequencing identifies a novel splice-site mutation in ADAMTS17 in an Indian family with Weill-Marchesani syndrome.. Mol Vis. 2014;20:790-6",
"KA Strauss, EG Puffenberger. Genetics, medicine, and the Plain people.. Annu Rev Genomics Hum Genet. 2009;10:513-36",
"Y Wang, H Zhang, J Ye, L Han, X. Gu. Three novel mutations of the FBN1 gene in Chinese children with acromelic dysplasia.. J Hum Genet. 2014;59:563-7",
"H Yi, X Zha, Y Zhu, J Lv, S Hu, Y Kong, G Wu, Y Yang, Y. He. A novel nonsense mutation in ADAMTS17 caused autosomal recessive inheritance Weill-Marchesani syndrome from a Chinese family.. J Hum Genet. 2019;64:681-7"
] |
1/11/2007
|
10/12/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
weiss-kruszka
|
weiss-kruszka
|
[
"ZNF462 Disorder",
"ZNF462 Disorder",
"Zinc finger protein 462",
"ZNF462",
"Weiss-Kruszka Syndrome"
] |
Weiss-Kruszka Syndrome
|
Paul Kruszka
|
Summary Weiss-Kruszka syndrome is characterized by metopic ridging or synostosis, ptosis, nonspecific dysmorphic features, developmental delay, and autistic features. Brain imaging may identify abnormalities of the corpus callosum. Developmental delay can present as global delay, motor delay, or speech delay. Affected individuals may also have ear anomalies, feeding difficulties (sometimes requiring placement of a gastrostomy tube), and congenital heart defects. There is significant variability in the clinical features, even between affected members of the same family. The diagnosis of Weiss-Kruszka syndrome is established in a proband with suggestive features and by identification of a heterozygous pathogenic variant in Weiss-Kruszka syndrome is inherited in an autosomal dominant manner. Approximately 95% of affected individuals have Weiss-Kruszka syndrome as the result of an apparently
|
## Diagnosis
Formal diagnostic criteria for Weiss-Kruszka syndrome have not been established.
Weiss-Kruszka syndrome
Metopic ridging or synostosis
Ptosis
Nonspecific dysmorphic features (see
Developmental delay and/or autistic features
The diagnosis of Weiss-Kruszka syndrome
A heterozygous pathogenic variant involving
A heterozygous deletion of 9q31.2 involving
Note: Chromosome rearrangements that disrupt
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 Weiss-Kruszka syndrome is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of Weiss-Kruszka 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 intellectual disability and nonspecific dysmorphic features,
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 Weiss-Kruszka 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. 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Metopic ridging or synostosis
• Ptosis
• Nonspecific dysmorphic features (see
• Developmental delay and/or autistic features
• A heterozygous pathogenic variant involving
• A heterozygous deletion of 9q31.2 involving
## Suggestive Findings
Weiss-Kruszka syndrome
Metopic ridging or synostosis
Ptosis
Nonspecific dysmorphic features (see
Developmental delay and/or autistic features
• Metopic ridging or synostosis
• Ptosis
• Nonspecific dysmorphic features (see
• Developmental delay and/or autistic features
## Establishing the Diagnosis
The diagnosis of Weiss-Kruszka syndrome
A heterozygous pathogenic variant involving
A heterozygous deletion of 9q31.2 involving
Note: Chromosome rearrangements that disrupt
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 Weiss-Kruszka syndrome is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of Weiss-Kruszka 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 intellectual disability and nonspecific dysmorphic features,
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 Weiss-Kruszka 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. 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• A heterozygous pathogenic variant involving
• A heterozygous deletion of 9q31.2 involving
## Option 1
When the phenotypic findings suggest the diagnosis of Weiss-Kruszka syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability and nonspecific dysmorphic features,
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 Weiss-Kruszka 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. 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
## Clinical Characteristics
To date, 24 individuals from 21 families are have been identified with a pathogenic variant in
Note: The reports by
Ptosis (20/24; 83%)
Downslanted palpebral fissures (13/24; 54%)
Exaggerated Cupid's Bow (13/24; 54%)
Arched eyebrows (12/24; 50%)
Epicanthal folds (11/24; 46%)
Short upturned nose with bulbous tip (11/24; 46%)
Fewer than half of affected individuals have metopic ridging or craniosynostosis involving the metopic or lambdoid suture (9/24; 38%).
Speech delay is the most common finding, occurring in 42%.
Motor delay is the second most common, occurring in 38%.
Hypotonia is a contributor to motor delay, with 50% of individuals having decreased muscle tone.
A third (8 of the known 24 affected individuals) have an autism spectrum disorder.
Low-set ears in six (25%) of the 24 affected individuals
Ear malformations in 12/24 affected individuals, including horizontal crux helix, prominent ears, ear pits, cupped ears, and overfolded ears
Hearing loss of varying severity in three of the 24 affected individuals
Gastroesophageal reflux requiring Nissen fundoplication
Laryngomalacia leading to respiratory difficulty during oral feeding attempts
Dysphagia
Eosinophilic esophagitis
Problems chewing
Three have single palmar creases (13%)
Three have fifth-finger clinodactyly (13%)
One individual was reported to have proximally implanted thumbs, although this individual has a balanced translocation involving
No genotype-phenotype correlations have been identified.
This disorder is rare and the prevalence is unknown. Only 24 affected individuals from 21 families are known [
• Ptosis (20/24; 83%)
• Downslanted palpebral fissures (13/24; 54%)
• Exaggerated Cupid's Bow (13/24; 54%)
• Arched eyebrows (12/24; 50%)
• Epicanthal folds (11/24; 46%)
• Short upturned nose with bulbous tip (11/24; 46%)
• Speech delay is the most common finding, occurring in 42%.
• Motor delay is the second most common, occurring in 38%.
• Hypotonia is a contributor to motor delay, with 50% of individuals having decreased muscle tone.
• Low-set ears in six (25%) of the 24 affected individuals
• Ear malformations in 12/24 affected individuals, including horizontal crux helix, prominent ears, ear pits, cupped ears, and overfolded ears
• Hearing loss of varying severity in three of the 24 affected individuals
• Gastroesophageal reflux requiring Nissen fundoplication
• Laryngomalacia leading to respiratory difficulty during oral feeding attempts
• Dysphagia
• Eosinophilic esophagitis
• Problems chewing
• Three have single palmar creases (13%)
• Three have fifth-finger clinodactyly (13%)
• One individual was reported to have proximally implanted thumbs, although this individual has a balanced translocation involving
## Clinical Description
To date, 24 individuals from 21 families are have been identified with a pathogenic variant in
Note: The reports by
Ptosis (20/24; 83%)
Downslanted palpebral fissures (13/24; 54%)
Exaggerated Cupid's Bow (13/24; 54%)
Arched eyebrows (12/24; 50%)
Epicanthal folds (11/24; 46%)
Short upturned nose with bulbous tip (11/24; 46%)
Fewer than half of affected individuals have metopic ridging or craniosynostosis involving the metopic or lambdoid suture (9/24; 38%).
Speech delay is the most common finding, occurring in 42%.
Motor delay is the second most common, occurring in 38%.
Hypotonia is a contributor to motor delay, with 50% of individuals having decreased muscle tone.
A third (8 of the known 24 affected individuals) have an autism spectrum disorder.
Low-set ears in six (25%) of the 24 affected individuals
Ear malformations in 12/24 affected individuals, including horizontal crux helix, prominent ears, ear pits, cupped ears, and overfolded ears
Hearing loss of varying severity in three of the 24 affected individuals
Gastroesophageal reflux requiring Nissen fundoplication
Laryngomalacia leading to respiratory difficulty during oral feeding attempts
Dysphagia
Eosinophilic esophagitis
Problems chewing
Three have single palmar creases (13%)
Three have fifth-finger clinodactyly (13%)
One individual was reported to have proximally implanted thumbs, although this individual has a balanced translocation involving
• Ptosis (20/24; 83%)
• Downslanted palpebral fissures (13/24; 54%)
• Exaggerated Cupid's Bow (13/24; 54%)
• Arched eyebrows (12/24; 50%)
• Epicanthal folds (11/24; 46%)
• Short upturned nose with bulbous tip (11/24; 46%)
• Speech delay is the most common finding, occurring in 42%.
• Motor delay is the second most common, occurring in 38%.
• Hypotonia is a contributor to motor delay, with 50% of individuals having decreased muscle tone.
• Low-set ears in six (25%) of the 24 affected individuals
• Ear malformations in 12/24 affected individuals, including horizontal crux helix, prominent ears, ear pits, cupped ears, and overfolded ears
• Hearing loss of varying severity in three of the 24 affected individuals
• Gastroesophageal reflux requiring Nissen fundoplication
• Laryngomalacia leading to respiratory difficulty during oral feeding attempts
• Dysphagia
• Eosinophilic esophagitis
• Problems chewing
• Three have single palmar creases (13%)
• Three have fifth-finger clinodactyly (13%)
• One individual was reported to have proximally implanted thumbs, although this individual has a balanced translocation involving
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
This disorder is rare and the prevalence is unknown. Only 24 affected individuals from 21 families are known [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders with Intellectual Disability to Consider in the Differential Diagnosis of Weiss-Kruszka Syndrome
Ptosis
Ear anomalies
Arched eyebrows
Blepharophimosis
Epicanthus inversus
Microphthalmia
Strabismus
Ptosis
Low set ears
Congenital heart disease
Widely spaced eyes
DD is less common than in Weiss-Kruszka syndrome
Short stature
Webbed neck
XL inheritance
Brain, craniofacial, & heart malformations absent
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked
Autosomal recessive inheritance of
• Ptosis
• Ear anomalies
• Arched eyebrows
• Blepharophimosis
• Epicanthus inversus
• Microphthalmia
• Strabismus
• Ptosis
• Low set ears
• Congenital heart disease
• Widely spaced eyes
• DD is less common than in Weiss-Kruszka syndrome
• Short stature
• Webbed neck
• XL inheritance
• Brain, craniofacial, & heart malformations absent
## Management
To establish the extent of disease and needs in an individual diagnosed with Weiss-Kruszka syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Weiss-Kruszka Syndrome
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support.
ASD = autism spectrum disorder
Treatment of Manifestations in Individuals with Weiss-Kruszka Syndrome
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Care coordination to manage multiple sub-specialty appointments, equipment, medications, & supplies
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
DD = delvelopmental delay; ID = 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.
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).
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.
Recommended Surveillance for Individuals with Weiss-Kruszka Syndrome
See
Search
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Care coordination to manage multiple sub-specialty appointments, equipment, medications, & supplies
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• 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).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Weiss-Kruszka syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Weiss-Kruszka Syndrome
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Community or
Social work involvement for parental support.
ASD = autism spectrum disorder
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Weiss-Kruszka Syndrome
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Care coordination to manage multiple sub-specialty appointments, equipment, medications, & supplies
Ongoing assessment of need for palliative care involvement &/or home nursing
Consider involvement in adaptive sports or Special Olympics.
DD = delvelopmental delay; ID = 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.
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).
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.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Care coordination to manage multiple sub-specialty appointments, equipment, medications, & supplies
• Ongoing assessment of need for palliative care involvement &/or home nursing
• Consider involvement in adaptive sports or Special Olympics.
• 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).
## Developmental Delay / Intellectual Disability Management Issues
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).
• Physical therapy is recommended to maximize mobility.
• Consider use of durable medical equipment 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.
## Surveillance
Recommended Surveillance for Individuals with Weiss-Kruszka Syndrome
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Weiss-Kruszka syndrome is inherited in an autosomal dominant manner.
95% of individuals diagnosed with Weiss-Kruszka syndrome have the disorder as the result of a
5% of individuals diagnosed with Weiss-Kruszka syndrome have an affected parent. Clinical variability is reported in families; the phenotype in affected family members can range from isolated ptosis to agenesis of the corpus callosum and metopic craniosynostosis [
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 Weiss-Kruszka syndrome may appear to be negative because of failure to recognize the disorder in more mildly affected 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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected.
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.
• 95% of individuals diagnosed with Weiss-Kruszka syndrome have the disorder as the result of a
• 5% of individuals diagnosed with Weiss-Kruszka syndrome have an affected parent. Clinical variability is reported in families; the phenotype in affected family members can range from isolated ptosis to agenesis of the corpus callosum and metopic craniosynostosis [
• 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 Weiss-Kruszka syndrome may appear to be negative because of failure to recognize the disorder in more mildly affected 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
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected.
## Mode of Inheritance
Weiss-Kruszka syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
95% of individuals diagnosed with Weiss-Kruszka syndrome have the disorder as the result of a
5% of individuals diagnosed with Weiss-Kruszka syndrome have an affected parent. Clinical variability is reported in families; the phenotype in affected family members can range from isolated ptosis to agenesis of the corpus callosum and metopic craniosynostosis [
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 Weiss-Kruszka syndrome may appear to be negative because of failure to recognize the disorder in more mildly affected 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
• 95% of individuals diagnosed with Weiss-Kruszka syndrome have the disorder as the result of a
• 5% of individuals diagnosed with Weiss-Kruszka syndrome have an affected parent. Clinical variability is reported in families; the phenotype in affected family members can range from isolated ptosis to agenesis of the corpus callosum and metopic craniosynostosis [
• 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 Weiss-Kruszka syndrome may appear to be negative because of failure to recognize the disorder in more mildly affected 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
## 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 mildly 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 mildly affected.
## 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
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
## Molecular Genetics
Weiss-Kruszka Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Weiss-Kruszka Syndrome (
## References
## Literature Cited
## Chapter Notes
31 October 2019 (ma) Review posted live
27 February 2019 (pk) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 31 October 2019 (ma) Review posted live
• 27 February 2019 (pk) Original submission
## Revision History
31 October 2019 (ma) Review posted live
27 February 2019 (pk) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 31 October 2019 (ma) Review posted live
• 27 February 2019 (pk) Original submission
These four individuals demonstrate the most common facial characteristics of Weiss-Kruszka syndrome including ptosis, downslanted palpebral fissures, exaggerated Cupid's bow, and arched eyebrows.
Images published with permission
|
[
"YS Chang, A Stoykova, K Chowdhury, P Gruss. Graded expression of Zfp462 in the embryonic mouse cerebral cortex.. Gene Expr Patterns. 2007;7:405-12",
"N Cosemans, L Vandenhove, J Maljaars, H Van Esch, K Devriendt, A Baldwin, JP Fryns, I Noens, H Peeters. ZNF462 and KLF12 are disrupted by a de novo translocation in a patient with syndromic intellectual disability and autism spectrum disorder.. Eur J Med Genet. 2018;61:376-83",
"HC Eberl, CG Spruijt, CD Kelstrup, M Vermeulen, M Mann. A map of general and specialized chromatin readers in mouse tissues generated by label-free interaction proteomics.. Mol Cell. 2013;49:368-78",
"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",
"JJ Johnston, JJ van der Smagt, JA Rosenfeld, AT Pagnamenta, A Alswaid, EH Baker, E Blair, G Borck, J Brinkmann, W Craigen, VC Dung, L Emrick, DB Everman, KL van Gassen, S Gulsuner, MH Harr, M Jain, A Kuechler, KA Leppig, DM McDonald-McGinn, NTB Can, A Peleg, ER Roeder, RC Rogers, L Sagi-Dain, JC Sapp, AA Schäffer, D Schanze, H Stewart, JC Taylor, NE Verbeek, MA Walkiewicz, EH Zackai, C Zweier, M Zenker, B Lee, LG Biesecker. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.. Genet Med. 2018;20:1175-85",
"P Kruszka, T Hu, S Hong, R Signer, B Cogné, B Isidor, SE Mazzola, JC Giltay, KLI Van Gassen, EM England, L Pais, CW Ockeloen, PA Sanchez-Lara, E Kinning, DJ Adams, K Treat, W Torres-Martinez, MF Bedeschi, M Iascone, S Blaney, O Bell, TY Tan, MA Delrue, J Jurgens, BJ Barry, EC Engle, SK Savage, N Fleischer, JA Martinez-Agosto, K Boycott, EH Zackai, M Muenke. Phenotype delineation of ZNF462 related syndrome.. Am J Med Genet A. 2019;179:2075-82",
"A Laurent, J Massé, F Omilli, S Deschamps, L Richard-Parpaillon, I Chartrain, I. Pellerin. ZFPIP/Zfp462 is maternally required for proper early Xenopus laevis development.. Dev Biol. 2009;327:169-76",
"J Massé, A Laurent, B Nicol, D Guerrier, I Pellerin, S. Deschamps. Involvement of ZFPIP/Zfp462 in chromatin integrity and survival of P19 pluripotent cells.. Exp Cell Res. 2010;316:1190-201",
"MB Ramocki, J Dowling, I Grinberg, VE Kimonis, C Cardoso, A Gross, J Chung, CL Martin, DH Ledbetter, WB Dobyns, KJ Millen. Reciprocal fusion transcripts of two novel Zn-finger genes in a female with absence of the corpus callosum, ocular colobomas and a balanced translocation between chromosomes 2p24 and 9q32.. Eur J Hum Genet. 2003;11:527-34",
"A Talisetti, SR Forrester, D Gregory, L Johnson, MC Schneider, VE Kimonis. Temtamy-like syndrome associated with translocation of 2p24 and 9q32.. Clin Dysmorphol. 2003;12:175-7",
"K Weiss, K Wigby, M Fannemel, LB Henderson, N Beck, N Ghali, BM Anderlid, J Lundin, A Hamosh, MC Jones, S Ghedia, M Muenke, P Kruszka. Haploinsufficiency of ZNF462 is associated with craniofacial anomalies, corpus callosum dysgenesis, ptosis, and developmental delay.. Eur J Hum Genet. 2017;25:946-51"
] |
31/10/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
werner
|
werner
|
[
"Bifunctional 3'-5' exonuclease/ATP-dependent helicase WRN",
"WRN",
"Werner Syndrome"
] |
Werner Syndrome
|
Junko Oshima, George M Martin, Fuki M Hisama
|
Summary Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death; the mean age of death in individuals with Werner syndrome is 54 years. The diagnosis of Werner syndrome is established in a proband with the following cardinal signs: bilateral ocular cataracts, premature graying and/or thinning of scalp hair, characteristic dermatologic pathology, and short stature. Identification of biallelic Werner syndrome 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 neither affected nor a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.
|
## Diagnosis
The diagnosis of Werner syndrome
Bilateral ocular cataracts (present in 99%) *
Premature graying and/or thinning of scalp hair (100%)
Characteristic dermatologic pathology (96%)
Short stature (95%)
Approximately 91% of affected individuals have all four cardinal signs.
The clinical diagnosis may be further supported by the presence of the following
Thin limbs (present in 98%)
Pinched facial features (96%)
Osteoporosis (91%)
Voice change (89%)
Hypogonadism (80%)
Type 2 diabetes mellitus (71%)
Soft tissue calcification (67%)
Neoplasm(s) (44%)
Skin ulcers, usually of distal legs (40%)
Atherosclerosis (30%)
* Note: Percent frequencies are derived from individuals with a diagnosis of Werner syndrome confirmed by molecular testing.
The clinical diagnosis of Werner syndrome
Similar diagnostic criteria have been proposed by
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Werner 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
Sequence analysis of the
Deep intronic pathogenic variants that affect splicing [
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.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
When sequencing identifies only one pathogenic variant known not to produce WRN. If protein analysis failed to detect any WRN protein, it may be inferred that the second unidentified pathogenic allele produced no or unstable WRN, thereby providing strong evidence for a diagnosis of Werner syndrome.
When compound heterozygosity is identified, where one pathogenic allele is known to confer WRN absence but a second missense variant is of uncertain clinical significance
If protein analysis implicates a missense variant of uncertain significance in conferring protein instability, which would suggest that it is a pathogenic allele. Such instances are rare.
• Bilateral ocular cataracts (present in 99%) *
• Premature graying and/or thinning of scalp hair (100%)
• Characteristic dermatologic pathology (96%)
• Short stature (95%)
• Thin limbs (present in 98%)
• Pinched facial features (96%)
• Osteoporosis (91%)
• Voice change (89%)
• Hypogonadism (80%)
• Type 2 diabetes mellitus (71%)
• Soft tissue calcification (67%)
• Neoplasm(s) (44%)
• Skin ulcers, usually of distal legs (40%)
• Atherosclerosis (30%)
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• When sequencing identifies only one pathogenic variant known not to produce WRN. If protein analysis failed to detect any WRN protein, it may be inferred that the second unidentified pathogenic allele produced no or unstable WRN, thereby providing strong evidence for a diagnosis of Werner syndrome.
• When compound heterozygosity is identified, where one pathogenic allele is known to confer WRN absence but a second missense variant is of uncertain clinical significance
• If protein analysis implicates a missense variant of uncertain significance in conferring protein instability, which would suggest that it is a pathogenic allele. Such instances are rare.
## Suggestive Findings
The diagnosis of Werner syndrome
Bilateral ocular cataracts (present in 99%) *
Premature graying and/or thinning of scalp hair (100%)
Characteristic dermatologic pathology (96%)
Short stature (95%)
Approximately 91% of affected individuals have all four cardinal signs.
The clinical diagnosis may be further supported by the presence of the following
Thin limbs (present in 98%)
Pinched facial features (96%)
Osteoporosis (91%)
Voice change (89%)
Hypogonadism (80%)
Type 2 diabetes mellitus (71%)
Soft tissue calcification (67%)
Neoplasm(s) (44%)
Skin ulcers, usually of distal legs (40%)
Atherosclerosis (30%)
* Note: Percent frequencies are derived from individuals with a diagnosis of Werner syndrome confirmed by molecular testing.
• Bilateral ocular cataracts (present in 99%) *
• Premature graying and/or thinning of scalp hair (100%)
• Characteristic dermatologic pathology (96%)
• Short stature (95%)
• Thin limbs (present in 98%)
• Pinched facial features (96%)
• Osteoporosis (91%)
• Voice change (89%)
• Hypogonadism (80%)
• Type 2 diabetes mellitus (71%)
• Soft tissue calcification (67%)
• Neoplasm(s) (44%)
• Skin ulcers, usually of distal legs (40%)
• Atherosclerosis (30%)
## Establishing the Diagnosis
The clinical diagnosis of Werner syndrome
Similar diagnostic criteria have been proposed by
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Werner 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
Sequence analysis of the
Deep intronic pathogenic variants that affect splicing [
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.
Data derived from the subscription-based professional view of Human Gene Mutation Database [
When sequencing identifies only one pathogenic variant known not to produce WRN. If protein analysis failed to detect any WRN protein, it may be inferred that the second unidentified pathogenic allele produced no or unstable WRN, thereby providing strong evidence for a diagnosis of Werner syndrome.
When compound heterozygosity is identified, where one pathogenic allele is known to confer WRN absence but a second missense variant is of uncertain clinical significance
If protein analysis implicates a missense variant of uncertain significance in conferring protein instability, which would suggest that it is a pathogenic allele. Such instances are rare.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
• When sequencing identifies only one pathogenic variant known not to produce WRN. If protein analysis failed to detect any WRN protein, it may be inferred that the second unidentified pathogenic allele produced no or unstable WRN, thereby providing strong evidence for a diagnosis of Werner syndrome.
• When compound heterozygosity is identified, where one pathogenic allele is known to confer WRN absence but a second missense variant is of uncertain clinical significance
• If protein analysis implicates a missense variant of uncertain significance in conferring protein instability, which would suggest that it is a pathogenic allele. Such instances are rare.
## Clinical Characteristics
Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years.
Symptoms typically start in the 20s. Initial findings include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Median age of diagnosis ranges from late 30s to 40s [
The chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific
The specific cell type in which cancer develops may depend on the type of
The
An older term for Werner syndrome was "progeria of the adult" (to distinguish it from the
The prevalence of Werner syndrome varies with the level of consanguinity in populations.
Apparent
Based on the population allele frequency of the most common pathogenic variant,
## Clinical Description
Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years.
Symptoms typically start in the 20s. Initial findings include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Median age of diagnosis ranges from late 30s to 40s [
## Genotype-Phenotype Correlations
The chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific
The specific cell type in which cancer develops may depend on the type of
The
## Nomenclature
An older term for Werner syndrome was "progeria of the adult" (to distinguish it from the
## Prevalence
The prevalence of Werner syndrome varies with the level of consanguinity in populations.
Apparent
Based on the population allele frequency of the most common pathogenic variant,
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis depends on the presenting symptoms and age of onset.
Genetic Disorders in the Differential Diagnosis of Werner Syndrome
AD = autosomal dominant; AR = autosomal recessive; FTT = failure to thrive; MOI = mode of inheritance; SHORT =
A small subset of persons in the Werner Syndrome Registry have normal WRN protein and some signs and symptoms that sufficiently overlap with Werner syndrome. Among this group, approximately 15% had novel heterozygous pathogenic missense variants in
Classic Hutchinson-Gilford progeria syndrome is defined by the presence of the pathogenic variant c.1824C>T.
## Management
To establish the extent of disease and needs in an individual diagnosed with Werner syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Werner Syndrome
Use of a 10-yr risk calculator & assessment of risk factors
Lipid profile
Blood pressure
Screening for type 2 diabetes mellitus by standard clinical assays incl fasting glucose level, hemoglobin A1c, or oral glucose tolerance test
Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism.
Bone mineral density screening
Encourage adequate intake of calcium, vitamin D.
Counsel on fall prevention & weight-bearing exercise.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Werner Syndrome
Use of cholesterol-lowering drugs if lipid profile is abnormal w/statin treatment for those w/LDL cholesterol levels >190 mg/dL
Primary prevention per current guidelines [
Evaluate stable angina w/cardiac stress testing per current guidelines.
LDL = low-density lipoprotein
Recommended Surveillance for Individuals with Werner Syndrome
Use of a 10-yr risk calculator
Lipid profile
Blood pressure
Lifestyle counseling: diet rich in fruits & vegetables, tobacco avoidance, regular exercise, healthy weight
Std clinical assessment for atherosclerosis risk, signs/symptoms of angina, & peripheral or cerebrovascular disease
Physical exam for malignancies common in Werner syndrome
Incl neurologic assessment for signs/symptoms of intracranial tumors.
Smoking and obesity increase the risk of atherosclerosis.
Smoking and alcohol ingestion increase the risk of osteoporosis and cataracts.
Falls resulting in fracture can be prevented or reduced by adding grab bars in the bathroom, eliminating slippery surfaces and tripping hazards, and providing adequate lighting.
Avoid trauma to the extremities and prolonged pressure to the elbows, feet, and ankles, where ulcers commonly form.
Avoidance of excessive sun exposure, use of sunscreen, protective clothing, and UV blocking sunglasses may reduce the risk of skin cancer (including melanoma) and cataracts.
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband/at-risk relatives 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 pathogenic variants in the family are known;
Clinical examination including growth assessment, skin examination, and ophthalmology evaluation including slit lamp examination if the pathogenic variants in the family are not known.
See
In one study of individuals with Werner syndrome, signs of hypogonadism were reported in 80%; however, approximately half of those had children and showed signs of hypogonadism after age 30 years [
The use of assisted reproductive technologies such as in vitro fertilization and egg donation has not been reported in women with Werner syndrome.
Search
• Use of a 10-yr risk calculator & assessment of risk factors
• Lipid profile
• Blood pressure
• Screening for type 2 diabetes mellitus by standard clinical assays incl fasting glucose level, hemoglobin A1c, or oral glucose tolerance test
• Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism.
• Bone mineral density screening
• Encourage adequate intake of calcium, vitamin D.
• Counsel on fall prevention & weight-bearing exercise.
• Use of cholesterol-lowering drugs if lipid profile is abnormal w/statin treatment for those w/LDL cholesterol levels >190 mg/dL
• Primary prevention per current guidelines [
• Evaluate stable angina w/cardiac stress testing per current guidelines.
• Use of a 10-yr risk calculator
• Lipid profile
• Blood pressure
• Lifestyle counseling: diet rich in fruits & vegetables, tobacco avoidance, regular exercise, healthy weight
• Std clinical assessment for atherosclerosis risk, signs/symptoms of angina, & peripheral or cerebrovascular disease
• Physical exam for malignancies common in Werner syndrome
• Incl neurologic assessment for signs/symptoms of intracranial tumors.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Clinical examination including growth assessment, skin examination, and ophthalmology evaluation including slit lamp examination if the pathogenic variants in the family are not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Werner syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Werner Syndrome
Use of a 10-yr risk calculator & assessment of risk factors
Lipid profile
Blood pressure
Screening for type 2 diabetes mellitus by standard clinical assays incl fasting glucose level, hemoglobin A1c, or oral glucose tolerance test
Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism.
Bone mineral density screening
Encourage adequate intake of calcium, vitamin D.
Counsel on fall prevention & weight-bearing exercise.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Use of a 10-yr risk calculator & assessment of risk factors
• Lipid profile
• Blood pressure
• Screening for type 2 diabetes mellitus by standard clinical assays incl fasting glucose level, hemoglobin A1c, or oral glucose tolerance test
• Ask about menstrual cycle (women) or sexual dysfunction (men) to screen for hypogonadism.
• Bone mineral density screening
• Encourage adequate intake of calcium, vitamin D.
• Counsel on fall prevention & weight-bearing exercise.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Werner Syndrome
Use of cholesterol-lowering drugs if lipid profile is abnormal w/statin treatment for those w/LDL cholesterol levels >190 mg/dL
Primary prevention per current guidelines [
Evaluate stable angina w/cardiac stress testing per current guidelines.
LDL = low-density lipoprotein
• Use of cholesterol-lowering drugs if lipid profile is abnormal w/statin treatment for those w/LDL cholesterol levels >190 mg/dL
• Primary prevention per current guidelines [
• Evaluate stable angina w/cardiac stress testing per current guidelines.
## Surveillance
Recommended Surveillance for Individuals with Werner Syndrome
Use of a 10-yr risk calculator
Lipid profile
Blood pressure
Lifestyle counseling: diet rich in fruits & vegetables, tobacco avoidance, regular exercise, healthy weight
Std clinical assessment for atherosclerosis risk, signs/symptoms of angina, & peripheral or cerebrovascular disease
Physical exam for malignancies common in Werner syndrome
Incl neurologic assessment for signs/symptoms of intracranial tumors.
• Use of a 10-yr risk calculator
• Lipid profile
• Blood pressure
• Lifestyle counseling: diet rich in fruits & vegetables, tobacco avoidance, regular exercise, healthy weight
• Std clinical assessment for atherosclerosis risk, signs/symptoms of angina, & peripheral or cerebrovascular disease
• Physical exam for malignancies common in Werner syndrome
• Incl neurologic assessment for signs/symptoms of intracranial tumors.
## Agents/Circumstances to Avoid
Smoking and obesity increase the risk of atherosclerosis.
Smoking and alcohol ingestion increase the risk of osteoporosis and cataracts.
Falls resulting in fracture can be prevented or reduced by adding grab bars in the bathroom, eliminating slippery surfaces and tripping hazards, and providing adequate lighting.
Avoid trauma to the extremities and prolonged pressure to the elbows, feet, and ankles, where ulcers commonly form.
Avoidance of excessive sun exposure, use of sunscreen, protective clothing, and UV blocking sunglasses may reduce the risk of skin cancer (including melanoma) and cataracts.
## Evaluation of Relatives at Risk
It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband/at-risk relatives 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 pathogenic variants in the family are known;
Clinical examination including growth assessment, skin examination, and ophthalmology evaluation including slit lamp examination if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Clinical examination including growth assessment, skin examination, and ophthalmology evaluation including slit lamp examination if the pathogenic variants in the family are not known.
## Pregnancy Management
In one study of individuals with Werner syndrome, signs of hypogonadism were reported in 80%; however, approximately half of those had children and showed signs of hypogonadism after age 30 years [
The use of assisted reproductive technologies such as in vitro fertilization and egg donation has not been reported in women with Werner syndrome.
## Therapies Under Investigation
Search
## Genetic Counseling
Werner syndrome 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
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.
Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.
If both parents are known to be heterozygous for a
Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.
The offspring of an individual with Werner syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous.
In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.
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 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.
• Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased 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 systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.
• The offspring of an individual with Werner syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
• Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous.
• In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Werner syndrome 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
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.
Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.
If both parents are known to be heterozygous for a
Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.
The offspring of an individual with Werner syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous.
In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.
• 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.
• Although systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased 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 systematic clinical studies have not been reported, heterozygotes (carriers) are asymptomatic and do not appear to be at increased risk of developing the disorder.
• The offspring of an individual with Werner syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
• Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous.
• In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.
## 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
University of Washington School of Medicine, Department of Pathology
Box 357470
Seattle WA 98195-7470
•
•
•
•
•
•
•
• University of Washington School of Medicine, Department of Pathology
• Box 357470
• Seattle WA 98195-7470
•
## Molecular Genetics
Werner Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Werner Syndrome (
Studies suggest that WRN protein is involved in DNA repair, recombination, replication, and transcription as well as combined functions such as DNA repair during replication. WRN protein can potentially unwind or digest aberrant DNA structures accidentally generated during various DNA metabolic processes and can also regulate DNA recombination and repair processes by unwinding or digesting intermediate DNA structures. WRN protein is also involved in the maintenance of telomeres. These findings are consistent with the notion that WRN plays a role in maintenance of genomic stability [
More than 90 different
Notable
Variants listed in the table have been provided by the authors.
Creates a new exon between exons 18 and 19 that introduces a stop codon and alters the length of the protein [
Results in exon 26 skipping
Results in exon 30 deletion
## Molecular Pathogenesis
Studies suggest that WRN protein is involved in DNA repair, recombination, replication, and transcription as well as combined functions such as DNA repair during replication. WRN protein can potentially unwind or digest aberrant DNA structures accidentally generated during various DNA metabolic processes and can also regulate DNA recombination and repair processes by unwinding or digesting intermediate DNA structures. WRN protein is also involved in the maintenance of telomeres. These findings are consistent with the notion that WRN plays a role in maintenance of genomic stability [
More than 90 different
Notable
Variants listed in the table have been provided by the authors.
Creates a new exon between exons 18 and 19 that introduces a stop codon and alters the length of the protein [
Results in exon 26 skipping
Results in exon 30 deletion
## Chapter Notes
Nancy Hanson, MS, CGC; University of Washington (2002-2011)Fuki M Hisama, MD (2011-present)Dru F Leistritz, MS, CGC; University of Washington (2002-2011)George M Martin, MD (2002-present)Junko Oshima, MD, PhD (2002-present)
13 May 2021 (sw) Comprehensive update posted live
29 September 2016 (sw) Comprehensive update posted live
27 March 2014 (me) Comprehensive update posted live
13 December 2012 (cd) Revision: prenatal testing available clinically
1 November 2012 (cd) Revision: deletion/duplication analysis available clinically
9 February 2012 (cd) Revision: protein analysis clinically available
29 December 2011 (cd) Revision: sequence analysis and carrier testing available clinically
17 November 2011 (me) Comprehensive update posted live
8 March 2007 (me) Comprehensive update posted live
13 January 2005 (me) Comprehensive update posted live
16 March 2004 (nh) Revision: Normal allelic variants
2 December 2002 (me) Review posted live
30 July 2002 (nh) Original submission
• 13 May 2021 (sw) Comprehensive update posted live
• 29 September 2016 (sw) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 13 December 2012 (cd) Revision: prenatal testing available clinically
• 1 November 2012 (cd) Revision: deletion/duplication analysis available clinically
• 9 February 2012 (cd) Revision: protein analysis clinically available
• 29 December 2011 (cd) Revision: sequence analysis and carrier testing available clinically
• 17 November 2011 (me) Comprehensive update posted live
• 8 March 2007 (me) Comprehensive update posted live
• 13 January 2005 (me) Comprehensive update posted live
• 16 March 2004 (nh) Revision: Normal allelic variants
• 2 December 2002 (me) Review posted live
• 30 July 2002 (nh) Original submission
## Author Notes
## Author History
Nancy Hanson, MS, CGC; University of Washington (2002-2011)Fuki M Hisama, MD (2011-present)Dru F Leistritz, MS, CGC; University of Washington (2002-2011)George M Martin, MD (2002-present)Junko Oshima, MD, PhD (2002-present)
## Revision History
13 May 2021 (sw) Comprehensive update posted live
29 September 2016 (sw) Comprehensive update posted live
27 March 2014 (me) Comprehensive update posted live
13 December 2012 (cd) Revision: prenatal testing available clinically
1 November 2012 (cd) Revision: deletion/duplication analysis available clinically
9 February 2012 (cd) Revision: protein analysis clinically available
29 December 2011 (cd) Revision: sequence analysis and carrier testing available clinically
17 November 2011 (me) Comprehensive update posted live
8 March 2007 (me) Comprehensive update posted live
13 January 2005 (me) Comprehensive update posted live
16 March 2004 (nh) Revision: Normal allelic variants
2 December 2002 (me) Review posted live
30 July 2002 (nh) Original submission
• 13 May 2021 (sw) Comprehensive update posted live
• 29 September 2016 (sw) Comprehensive update posted live
• 27 March 2014 (me) Comprehensive update posted live
• 13 December 2012 (cd) Revision: prenatal testing available clinically
• 1 November 2012 (cd) Revision: deletion/duplication analysis available clinically
• 9 February 2012 (cd) Revision: protein analysis clinically available
• 29 December 2011 (cd) Revision: sequence analysis and carrier testing available clinically
• 17 November 2011 (me) Comprehensive update posted live
• 8 March 2007 (me) Comprehensive update posted live
• 13 January 2005 (me) Comprehensive update posted live
• 16 March 2004 (nh) Revision: Normal allelic variants
• 2 December 2002 (me) Review posted live
• 30 July 2002 (nh) Original submission
## References
## Literature Cited
|
[
"DK Arnett, RS Blumenthal, MA Albert, AB Buroker, ZD Goldberger, EJ Hahn, CD Himmelfarb, A Khera, D Lloyd-Jones, JW McEvoy, ED Michos, MD Miedema, D Munoz, SC Smith, SS Virani, KA Williams, J Yeboah, B Ziaeian. ACC/AHA guideline on the primary prevention of cardiovascular disease (2019). Circulation 2019;140:e596-e646",
"F Cosman, SJ de Beur, MS LeBoff, EM Lewiecki, B Tanner, S Randall, R Lindsay. Clinician's guide to prevention and treatment of osteoporosis.. Osteoporos Int 2014;25:2359-81",
"DL Croteau, V Popuri, PL Opresko, VA Bohr. Human RecQ helicases in DNA repair, recombination, and replication.. Annu Rev Biochem 2014;83:519-52",
"N De Stefano, MT Dotti, C Battisti, F Sicurelli, ML Stromillo, M Mortilla, A Federico. MR evidence of structural and metabolic changes in brains of patients with Werner's syndrome.. J Neurol 2003;250:1169-73",
"M Goto. Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing.. Mech Ageing Dev 1997;98:239-54",
"M Goto, Y Ishikawa, M Sugimoto, Y Furuichi. Werner syndrome: a changing pattern of clinical manifestations in Japan (1917~2008).. Biosci Trends 2013;7:13-22",
"Y Ishikawa, H Sugano, T Matsumoto, Y Furuichi, RW Miller, M Goto. Unusual features of thyroid carcinomas in Japanese patients with Werner syndrome and possible genotype-phenotype relations to cell type and race.. Cancer 1999;85:1345-52",
"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",
"AS Kamath-Loeb, DG Zavala-van Rankin, J Flores-Morales, MJ Emond, JM Sidorova, A Carnevale, M del Carmen Cardenas-Cortes, TH Norwood, RJ Monnat, LA Loeb, GE Mercado-Celis. Homozygosity for the WRN helicase-inactivating variant, R834C, does not confer a Werner syndrome clinical phenotype.. Scientific Reports 2017;7:44081",
"Y Kubota, M Takemoto, T Taniguchi, S Motegi, A Taniguchi, H Nakagami, Y Maezawa, M Koshizaka, H Kato, S Mori, K Tsukamoto, M Kuzuya, K Yokote. Management guideline for Werner syndrome 2020.6. Skin ulcers associated with Werner syndrome: prevention and non-surgical and surgical treatment.. Geriatr Gerontol Int. 2021;21:153-9",
"JM Lauper, A Krause, TL Vaughan, RJ Monnat. Spectrum and risk of neoplasia in Werner syndrome: a systematic review.. PLoS One 2013;8",
"C Lyons, D Gallagher, T McSwiney, E McElnea, F Kinsella. The ophthalmic diagnosis and management of four siblings with Werner syndrome.. Int Ophthal 2019;39:1371-8",
"M Matucci-Cerinic, CP Denton, DE Furst, MD Mayes, VM Hsu, P Carpentier, FM Wigley, CM Black, BJ Fessler, PA Merkel, JE Pope, NJ Sweiss, MK Doyle, B Hellmich, TA Medsger, A Morganti, F Kramer, JH Korn, JR Seibold. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial.. Ann Rheum Dis 2011;70:32-8",
"S Mori, M Takemoto, Y Kubota, T Taniguchi, SI Motegi, A Taniguchi, H Nakagami, Y Maezawa, M Koshizaka, H Kato, K Tsukamoto, M Kuzuya, K Yokote. Management guideline for Werner syndrome 2020. 4. Osteoporosis associated with Werner syndrome.. Geriatr Gerontol Int. 2021;21:146-9",
"J Oshima, FM Hisama. Search and insights into novel genetic alterations leading to classical and atypical Werner syndrome.. Gerontology 2014;60:239-46",
"J Oshima, JM Sidorova, RJ Monnat. Werner syndrome: clinical features, pathogenesis and potential therapeutic interventions.. Ageing Res Rev 2017;33:105-114",
"J Sołek-Pastuszka, E Zagrodnik-Ułan, T Płonka, M Wylot, J Biernawska, R Bohatyrewicz, W Kos, M Zukowski, Z Celewicz. Pregnancy complicated by Werner syndrome.. Acta Obstet Gynecol Scand 2011;90:201-2",
"PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77",
"M Takemoto, Y Kubota, T Taniguchi, S Motegi, A Tanoguchi, H Nakagami, Y Maezawa, M Koshizaka, H Kato, K Tsukamoto, S Mori, M Kuzuya, K Yokote. Management guideline for Werner syndrome 2020.3. diabetes associated with Werner syndrome.. Geriatr Gerontol Int 2021;21:142-5",
"M Takemoto, S Mori, M Kuzuya, S Yoshimoto, A Shimamoto, M Igarashi, Y Tanaka, T Miki, K Yokote. Diagnostic criteria for Werner syndrome based on Japanese nationwide epidemiological survey.. Geriatr Gerontol Int 2013;13:475-81",
"K Tsukamoto, M Takemoto, T Taniguchi, S Motegi, A Taniguchi, H Nakagami, Y Maezawa, M Koshizaka, H Kato, S Mori, M Kuzuya, K Yokote. Management guideline for Werner syndrome 2020.1. dyslipidemia and fatty liver associated with Werner syndrome.. Geriatr Gerontol Int 2021;21:133-8",
"K Watanabe, K Kobayashi, M Takemoto, R Ishibashi, M Yamaga, H Kawamura, M Fujimoto, T Ishikawa, S Onishi, E Okabe, P He, K Yokote. Sitagliptin improves postprandial hyperglycemia by inhibiting glucagon secretion in Werner syndrome with diabetes.. Diabetes Care. 2013;36",
"K Yokote, S Chanprasert, L Lee, K Eirich, M Takemoto, A Watanabe, N Koizumi, D Lessel, T Mori, FM Hisama, PD Ladd, B Angle, H Baris, K Cefle, S Palanduz, S Ozturk, A Chateau, K Deguchi, TKM Easwar, A Federico, A Fox, TA Grebe, B Hay, S Nampoothiri, K Seitner, E Streeten, RE Pina-Aguilar, G Poke, M Poot, R Posmyk, GM Martin, C Kubisch, D Schindler, J Oshima. WRN mutation update: mutation spectrum, patient registries, and translational prospects.. Hum Mutat 2017;38:7-15",
"CE Yu, J Oshima, YH Fu, EM Wijsman, F Hisama, R Alisch, S Matthews, J Nakura, T Miki, S Ouais, GM Martin, J Mulligan, GD Schellenberg. Positional cloning of the Werner's syndrome gene.. Science 1996;272:258-62"
] |
2/12/2002
|
13/5/2021
|
13/12/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
wfs
|
wfs
|
[
"Wolfram Syndrome-Like Disease",
"DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness",
"Wolfram Syndrome Type 1",
"Wolframin",
"WFS1",
"WFS1 Spectrum Disorder"
] |
Timothy Barrett, Lisbeth Tranebjærg, Rajat Gupta, Liam McCarthy, Nanna Dahl Rendtorff, Denise Williams, Benjamin Wright, Renuka Dias
|
Summary There is no cure for
|
This
Evaluate an individual with one or two
Provide genetic counseling based on each family's genetic finding.
Wolfram syndrome type 1
DIDMOAD (
AD = autosomal dominant; AR = autosomal recessive
Includes isolated autosomal dominant
• Evaluate an individual with one or two
• Provide genetic counseling based on each family's genetic finding.
• Wolfram syndrome type 1
• DIDMOAD (
## Diagnosis
Classic
Diabetes mellitus (onset age usually <16 years)
Optic atrophy (onset age usually <16 years)
Additional clinical findings may include one or more of the following:
High-tone sensorineural hearing impairment
Cerebellar ataxia
Psychiatric illness
Neurogenic bladder (overactive or underactive)
Other endocrine findings:
Central diabetes insipidus
Delayed puberty, particularly in males, associated with hypogonadism
Non-autoimmune hypothyroidism
Structural congenital heart defects
Nonclassic
Diabetes mellitus (onset age usually >16 years)
Optic atrophy (onset age usually >16 years)
Low-tone sensorineural hearing impairment including profound hearing loss in infancy
Neonatal diabetes, congenital deafness, and/or cataracts
The diagnosis of
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
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.
Three intragenic deletions of one or more exons have been described [
• Diabetes mellitus (onset age usually <16 years)
• Optic atrophy (onset age usually <16 years)
• High-tone sensorineural hearing impairment
• Cerebellar ataxia
• Psychiatric illness
• Neurogenic bladder (overactive or underactive)
• Other endocrine findings:
• Central diabetes insipidus
• Delayed puberty, particularly in males, associated with hypogonadism
• Non-autoimmune hypothyroidism
• Central diabetes insipidus
• Delayed puberty, particularly in males, associated with hypogonadism
• Non-autoimmune hypothyroidism
• Structural congenital heart defects
• Central diabetes insipidus
• Delayed puberty, particularly in males, associated with hypogonadism
• Non-autoimmune hypothyroidism
• Diabetes mellitus (onset age usually >16 years)
• Optic atrophy (onset age usually >16 years)
• Low-tone sensorineural hearing impairment including profound hearing loss in infancy
• Neonatal diabetes, congenital deafness, and/or cataracts
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings – Classic
Classic
Diabetes mellitus (onset age usually <16 years)
Optic atrophy (onset age usually <16 years)
Additional clinical findings may include one or more of the following:
High-tone sensorineural hearing impairment
Cerebellar ataxia
Psychiatric illness
Neurogenic bladder (overactive or underactive)
Other endocrine findings:
Central diabetes insipidus
Delayed puberty, particularly in males, associated with hypogonadism
Non-autoimmune hypothyroidism
Structural congenital heart defects
• Diabetes mellitus (onset age usually <16 years)
• Optic atrophy (onset age usually <16 years)
• High-tone sensorineural hearing impairment
• Cerebellar ataxia
• Psychiatric illness
• Neurogenic bladder (overactive or underactive)
• Other endocrine findings:
• Central diabetes insipidus
• Delayed puberty, particularly in males, associated with hypogonadism
• Non-autoimmune hypothyroidism
• Central diabetes insipidus
• Delayed puberty, particularly in males, associated with hypogonadism
• Non-autoimmune hypothyroidism
• Structural congenital heart defects
• Central diabetes insipidus
• Delayed puberty, particularly in males, associated with hypogonadism
• Non-autoimmune hypothyroidism
## Suggestive Findings – Nonclassic
Nonclassic
Diabetes mellitus (onset age usually >16 years)
Optic atrophy (onset age usually >16 years)
Low-tone sensorineural hearing impairment including profound hearing loss in infancy
Neonatal diabetes, congenital deafness, and/or cataracts
• Diabetes mellitus (onset age usually >16 years)
• Optic atrophy (onset age usually >16 years)
• Low-tone sensorineural hearing impairment including profound hearing loss in infancy
• Neonatal diabetes, congenital deafness, and/or cataracts
## Establishing the Diagnosis of
The diagnosis of
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
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.
Three intragenic deletions of one or more exons have been described [
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Classic
Select Features Associated with Classic
Based on data from
Both functional (neurogenic bladder) and structural (upper urinary tract dilatation)
A comprehensive review of classic
Classic
The natural history of classic
Very rarely,
A longitudinal study of 40 individuals showed that high-frequency hearing loss worsened and speech intelligibility index worsened over time, but the change over one year was subclinical, suggesting gradual progression over years [
Current experience indicates the presence of symptomatic neurologic findings by the fourth decade, with presymptomatic onset typically between the first and second decades.
Neurologic findings were progressive and resulted from general brain atrophy with brain stem and cranial nerve involvement [
Truncal or gait ataxia was found in 15 of 45 individuals [
Episodes of central apnea, a serious manifestation, occurred in five of 45 individuals [
A significantly increased risk of psychiatric illness including suicidal behavior has been reported [
Intellectual disability is not a common feature.
Absent or diminished posterior pituitary bright spot (first visit, 53%; last visit, 70%)
T
Optic nerve atrophy (first visit, 30%; last visit, 80%)
White matter T
Cerebellar atrophy (first visit, 23%; last visit, 70%)
Nonclassic
Most affected individuals have isolated optic atrophy and congenital deafness. Some families also have diabetes mellitus that is isolated or in combination with optic atrophy and deafness. Although published data on follow up are limited, the findings appear to be non-progressive, with a milder phenotype than classic
Additionally, five probands were reported with neonatal diabetes mellitus, congenital cataracts, and sensorineural deafness [
In a family of Dutch origin, three affected members from two generations had childhood-onset optic atrophy and hearing impairment [
Eight families from the UK, US, and Sweden also had autosomal dominantly inherited optic atrophy and sensorineural deafness. Optic atrophy, which presented in childhood or adulthood, was very slowly progressive. Early-childhood-onset sensorineural hearing loss was profound; several family members required cochlear implants.
No genotype-phenotype correlations have been identified for classic
Recent epidemiologic studies based on molecularly confirmed classic
1:54,478 in the Messina district of northeast Sicily [
1:1,351,000 in Italy [
1:805,000 in northern India [
• Truncal or gait ataxia was found in 15 of 45 individuals [
• Episodes of central apnea, a serious manifestation, occurred in five of 45 individuals [
• A significantly increased risk of psychiatric illness including suicidal behavior has been reported [
• Intellectual disability is not a common feature.
• Absent or diminished posterior pituitary bright spot (first visit, 53%; last visit, 70%)
• T
• Optic nerve atrophy (first visit, 30%; last visit, 80%)
• White matter T
• Cerebellar atrophy (first visit, 23%; last visit, 70%)
• 1:54,478 in the Messina district of northeast Sicily [
• 1:1,351,000 in Italy [
• 1:805,000 in northern India [
## Clinical Description – Classic
Classic
Select Features Associated with Classic
Based on data from
Both functional (neurogenic bladder) and structural (upper urinary tract dilatation)
A comprehensive review of classic
Classic
The natural history of classic
Very rarely,
A longitudinal study of 40 individuals showed that high-frequency hearing loss worsened and speech intelligibility index worsened over time, but the change over one year was subclinical, suggesting gradual progression over years [
Current experience indicates the presence of symptomatic neurologic findings by the fourth decade, with presymptomatic onset typically between the first and second decades.
Neurologic findings were progressive and resulted from general brain atrophy with brain stem and cranial nerve involvement [
Truncal or gait ataxia was found in 15 of 45 individuals [
Episodes of central apnea, a serious manifestation, occurred in five of 45 individuals [
A significantly increased risk of psychiatric illness including suicidal behavior has been reported [
Intellectual disability is not a common feature.
Absent or diminished posterior pituitary bright spot (first visit, 53%; last visit, 70%)
T
Optic nerve atrophy (first visit, 30%; last visit, 80%)
White matter T
Cerebellar atrophy (first visit, 23%; last visit, 70%)
• Truncal or gait ataxia was found in 15 of 45 individuals [
• Episodes of central apnea, a serious manifestation, occurred in five of 45 individuals [
• A significantly increased risk of psychiatric illness including suicidal behavior has been reported [
• Intellectual disability is not a common feature.
• Absent or diminished posterior pituitary bright spot (first visit, 53%; last visit, 70%)
• T
• Optic nerve atrophy (first visit, 30%; last visit, 80%)
• White matter T
• Cerebellar atrophy (first visit, 23%; last visit, 70%)
## Clinical Description – Nonclassic
Nonclassic
Most affected individuals have isolated optic atrophy and congenital deafness. Some families also have diabetes mellitus that is isolated or in combination with optic atrophy and deafness. Although published data on follow up are limited, the findings appear to be non-progressive, with a milder phenotype than classic
Additionally, five probands were reported with neonatal diabetes mellitus, congenital cataracts, and sensorineural deafness [
In a family of Dutch origin, three affected members from two generations had childhood-onset optic atrophy and hearing impairment [
Eight families from the UK, US, and Sweden also had autosomal dominantly inherited optic atrophy and sensorineural deafness. Optic atrophy, which presented in childhood or adulthood, was very slowly progressive. Early-childhood-onset sensorineural hearing loss was profound; several family members required cochlear implants.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified for classic
## Prevalence
Recent epidemiologic studies based on molecularly confirmed classic
1:54,478 in the Messina district of northeast Sicily [
1:1,351,000 in Italy [
1:805,000 in northern India [
• 1:54,478 in the Messina district of northeast Sicily [
• 1:1,351,000 in Italy [
• 1:805,000 in northern India [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Families of Palestinian Arab origin have been described with juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired kidney function, hypogonadism, and severe gastrointestinal ulcer and bleeding [
Diabetes insipidus, psychiatric abnormalities, and variable degrees of optic atrophy have been reported in individuals from Italy and Morocco [
Note: A novel
Monogenic Diabetes Syndromes in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DM = diabetes mellitus; DM1 = myotonic dystrophy type 1; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; OA = optic atrophy; SNHL = sensorineural hearing loss
Listed genes represent the more commonly associated genes; at least 26 genes are associated with Bardet-Biedl syndrome (see
Disorders with Optic Atrophy Associated with Hearing Impairment in the Differential Diagnosis of
AD = autosomal dominant; MOI = mode of inheritance; OA = optic atrophy; SNHL = sensorineural hearing loss; XL = X-linked
Identified by specific audiologic testing only
The diagnosis of deafness-dystonia-optic neuronopathy syndrome is established in either a male proband with a hemizygous
• Families of Palestinian Arab origin have been described with juvenile-onset diabetes mellitus, optic atrophy, high-frequency sensorineural hearing impairment, urinary tract dilatation, impaired kidney function, hypogonadism, and severe gastrointestinal ulcer and bleeding [
• Diabetes insipidus, psychiatric abnormalities, and variable degrees of optic atrophy have been reported in individuals from Italy and Morocco [
## Other Genetic Causes of Features Seen in
Monogenic Diabetes Syndromes in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DM = diabetes mellitus; DM1 = myotonic dystrophy type 1; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; OA = optic atrophy; SNHL = sensorineural hearing loss
Listed genes represent the more commonly associated genes; at least 26 genes are associated with Bardet-Biedl syndrome (see
Disorders with Optic Atrophy Associated with Hearing Impairment in the Differential Diagnosis of
AD = autosomal dominant; MOI = mode of inheritance; OA = optic atrophy; SNHL = sensorineural hearing loss; XL = X-linked
Identified by specific audiologic testing only
The diagnosis of deafness-dystonia-optic neuronopathy syndrome is established in either a male proband with a hemizygous
## Management
To establish the extent of disease and needs in an individual diagnosed with classic or nonclassic
See also
Recommended Evaluations Following Initial Diagnosis in Individuals with Classic or Nonclassic
Assess extraocular movement, best corrected visual acuity, visual evoked potentials.
Perform color vision testing, visual field testing, optical coherence tomography, fundus exam.
Audiologic exam
Eval by speech-language therapist
Auditory brain stem responses to confirm pathology & provide baseline
Evoked otoacoustic emissions to identify type of hearing impairment
Audiogram
Speech discrimination tests
Assessment for hearing aids; children w/profound infancy-onset deafness may require cochlear implant.
Motor system: coordination, balance, ataxia
Sensory system: peripheral neuropathy
Cranial nerves: anosmia, ability to taste, dysarthria, swallowing/choking difficulties, apneic episodes
Autonomic system: hypotensive episodes, abnormal temperature regulation &/or sweating episodes
Central apnea can occur secondary to brain stem atrophy.
Sleep disturbance is common & multicausal.
Consider anxiety, depression eval. Although reported, psychoses are rare.
Refer to urologist.
Consider urodynamic eval, imaging of urinary tract & kidneys for dilated ureters, & assessment of kidney function.
Contact w/patient advocacy organization
Assess need for social work involvement for caregiver support.
Assess need for help coordinating multidisciplinary care.
Assess need for community resources &
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Management is focused on supportive care, often provided by multidisciplinary specialists in diabetic care, endocrinology, ophthalmology and low-vision clinics, audiology, speech-language therapy, neurology, pulmonology, psychiatry / psychology / mental health, urology, gastroenterology, social work, and medical genetics (see
See also
Treatment of Manifestations in Individuals with Classic or Nonclassic
Diabetic ketoacidosis is rare.
Because episodes of severe hypoglycemia are common,
Continuous glucose monitoring w/hypoglycemia alarm is recommended due to risk for hypoglycemic episodes.
Other hypoglycemic agents are not licensed for use in
Evaluate for visual aids.
Community vision services through early intervention or school district
To support tasks incl mobility & ADL
To assist w/household modifications if needed
Determine exact cause of swallowing malfunction.
Modify food types & consistency, head positioning during swallowing, & exercises to ensure safe swallow.
Anticholinergic drugs
Clean intermittent self-catheterization or indwelling catheter
Treatment of recurrent urinary tract infections
Detrusor muscle dyssynergia may require pharmacologic relaxants or stimulants at different stages.
Ensure central diabetes insipidus is screened for & treated.
Start from early in 2nd decade.
Involve young person as well as care providers in planned transfer to adult services.
Ensure appropriate social services involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; DM = diabetes mellitus; SNHL = sensorineural hearing loss; WFS1-SD = WFS1 spectrum disorder
See
An individualzed education plan (IEP) provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in 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.
In the US, families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
See also
To monitor existing manifestations, the response of an individual with classic
Recommended Surveillance for Individuals with Classic
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Need for low-vision aids
Urodynamic exam & assessment of bladder emptying
Routine urine cultures when there is bladder dysfunction &/or other urinary tract abnormality
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the response of an individual with nonclassic
Recommended Surveillance for Individuals with Nonclassic
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Need for low-vision aids
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
OT = occupational therapy; PT = physical therapy
It is appropriate to clarify the genetic status of apparently asymptomatic relatives at risk in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of
See
Pregnant women with insulin-dependent diabetes mellitus, a characteristic of both classic and nonclassic
Because women with classic
See
For a review of current and future therapeutic strategies, see
Search
• Assess extraocular movement, best corrected visual acuity, visual evoked potentials.
• Perform color vision testing, visual field testing, optical coherence tomography, fundus exam.
• Audiologic exam
• Eval by speech-language therapist
• Auditory brain stem responses to confirm pathology & provide baseline
• Evoked otoacoustic emissions to identify type of hearing impairment
• Audiogram
• Speech discrimination tests
• Assessment for hearing aids; children w/profound infancy-onset deafness may require cochlear implant.
• Motor system: coordination, balance, ataxia
• Sensory system: peripheral neuropathy
• Cranial nerves: anosmia, ability to taste, dysarthria, swallowing/choking difficulties, apneic episodes
• Autonomic system: hypotensive episodes, abnormal temperature regulation &/or sweating episodes
• Central apnea can occur secondary to brain stem atrophy.
• Sleep disturbance is common & multicausal.
• Consider anxiety, depression eval. Although reported, psychoses are rare.
• Refer to urologist.
• Consider urodynamic eval, imaging of urinary tract & kidneys for dilated ureters, & assessment of kidney function.
• Contact w/patient advocacy organization
• Assess need for social work involvement for caregiver support.
• Assess need for help coordinating multidisciplinary care.
• Assess need for community resources &
• Diabetic ketoacidosis is rare.
• Because episodes of severe hypoglycemia are common,
• Continuous glucose monitoring w/hypoglycemia alarm is recommended due to risk for hypoglycemic episodes.
• Other hypoglycemic agents are not licensed for use in
• Evaluate for visual aids.
• Community vision services through early intervention or school district
• To support tasks incl mobility & ADL
• To assist w/household modifications if needed
• Determine exact cause of swallowing malfunction.
• Modify food types & consistency, head positioning during swallowing, & exercises to ensure safe swallow.
• Anticholinergic drugs
• Clean intermittent self-catheterization or indwelling catheter
• Treatment of recurrent urinary tract infections
• Detrusor muscle dyssynergia may require pharmacologic relaxants or stimulants at different stages.
• Ensure central diabetes insipidus is screened for & treated.
• Start from early in 2nd decade.
• Involve young person as well as care providers in planned transfer to adult services.
• Ensure appropriate social services involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• An individualzed education plan (IEP) provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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.
• In the US, families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Need for low-vision aids
• Urodynamic exam & assessment of bladder emptying
• Routine urine cultures when there is bladder dysfunction &/or other urinary tract abnormality
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Need for low-vision aids
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with classic or nonclassic
See also
Recommended Evaluations Following Initial Diagnosis in Individuals with Classic or Nonclassic
Assess extraocular movement, best corrected visual acuity, visual evoked potentials.
Perform color vision testing, visual field testing, optical coherence tomography, fundus exam.
Audiologic exam
Eval by speech-language therapist
Auditory brain stem responses to confirm pathology & provide baseline
Evoked otoacoustic emissions to identify type of hearing impairment
Audiogram
Speech discrimination tests
Assessment for hearing aids; children w/profound infancy-onset deafness may require cochlear implant.
Motor system: coordination, balance, ataxia
Sensory system: peripheral neuropathy
Cranial nerves: anosmia, ability to taste, dysarthria, swallowing/choking difficulties, apneic episodes
Autonomic system: hypotensive episodes, abnormal temperature regulation &/or sweating episodes
Central apnea can occur secondary to brain stem atrophy.
Sleep disturbance is common & multicausal.
Consider anxiety, depression eval. Although reported, psychoses are rare.
Refer to urologist.
Consider urodynamic eval, imaging of urinary tract & kidneys for dilated ureters, & assessment of kidney function.
Contact w/patient advocacy organization
Assess need for social work involvement for caregiver support.
Assess need for help coordinating multidisciplinary care.
Assess need for community resources &
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assess extraocular movement, best corrected visual acuity, visual evoked potentials.
• Perform color vision testing, visual field testing, optical coherence tomography, fundus exam.
• Audiologic exam
• Eval by speech-language therapist
• Auditory brain stem responses to confirm pathology & provide baseline
• Evoked otoacoustic emissions to identify type of hearing impairment
• Audiogram
• Speech discrimination tests
• Assessment for hearing aids; children w/profound infancy-onset deafness may require cochlear implant.
• Motor system: coordination, balance, ataxia
• Sensory system: peripheral neuropathy
• Cranial nerves: anosmia, ability to taste, dysarthria, swallowing/choking difficulties, apneic episodes
• Autonomic system: hypotensive episodes, abnormal temperature regulation &/or sweating episodes
• Central apnea can occur secondary to brain stem atrophy.
• Sleep disturbance is common & multicausal.
• Consider anxiety, depression eval. Although reported, psychoses are rare.
• Refer to urologist.
• Consider urodynamic eval, imaging of urinary tract & kidneys for dilated ureters, & assessment of kidney function.
• Contact w/patient advocacy organization
• Assess need for social work involvement for caregiver support.
• Assess need for help coordinating multidisciplinary care.
• Assess need for community resources &
## Treatment of Manifestations
There is no cure for
Management is focused on supportive care, often provided by multidisciplinary specialists in diabetic care, endocrinology, ophthalmology and low-vision clinics, audiology, speech-language therapy, neurology, pulmonology, psychiatry / psychology / mental health, urology, gastroenterology, social work, and medical genetics (see
See also
Treatment of Manifestations in Individuals with Classic or Nonclassic
Diabetic ketoacidosis is rare.
Because episodes of severe hypoglycemia are common,
Continuous glucose monitoring w/hypoglycemia alarm is recommended due to risk for hypoglycemic episodes.
Other hypoglycemic agents are not licensed for use in
Evaluate for visual aids.
Community vision services through early intervention or school district
To support tasks incl mobility & ADL
To assist w/household modifications if needed
Determine exact cause of swallowing malfunction.
Modify food types & consistency, head positioning during swallowing, & exercises to ensure safe swallow.
Anticholinergic drugs
Clean intermittent self-catheterization or indwelling catheter
Treatment of recurrent urinary tract infections
Detrusor muscle dyssynergia may require pharmacologic relaxants or stimulants at different stages.
Ensure central diabetes insipidus is screened for & treated.
Start from early in 2nd decade.
Involve young person as well as care providers in planned transfer to adult services.
Ensure appropriate social services involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
ADL = activities of daily living; DM = diabetes mellitus; SNHL = sensorineural hearing loss; WFS1-SD = WFS1 spectrum disorder
See
An individualzed education plan (IEP) provides specially designed instruction and related services to children who qualify.
IEP services will be reviewed annually to determine whether any changes are needed.
Special education law requires that children participating in 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.
In the US, families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
• Diabetic ketoacidosis is rare.
• Because episodes of severe hypoglycemia are common,
• Continuous glucose monitoring w/hypoglycemia alarm is recommended due to risk for hypoglycemic episodes.
• Other hypoglycemic agents are not licensed for use in
• Evaluate for visual aids.
• Community vision services through early intervention or school district
• To support tasks incl mobility & ADL
• To assist w/household modifications if needed
• Determine exact cause of swallowing malfunction.
• Modify food types & consistency, head positioning during swallowing, & exercises to ensure safe swallow.
• Anticholinergic drugs
• Clean intermittent self-catheterization or indwelling catheter
• Treatment of recurrent urinary tract infections
• Detrusor muscle dyssynergia may require pharmacologic relaxants or stimulants at different stages.
• Ensure central diabetes insipidus is screened for & treated.
• Start from early in 2nd decade.
• Involve young person as well as care providers in planned transfer to adult services.
• Ensure appropriate social services involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• An individualzed education plan (IEP) provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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.
• In the US, families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
## Surveillance
See also
To monitor existing manifestations, the response of an individual with classic
Recommended Surveillance for Individuals with Classic
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Need for low-vision aids
Urodynamic exam & assessment of bladder emptying
Routine urine cultures when there is bladder dysfunction &/or other urinary tract abnormality
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
OT = occupational therapy; PT = physical therapy
To monitor existing manifestations, the response of an individual with nonclassic
Recommended Surveillance for Individuals with Nonclassic
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Need for low-vision aids
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
OT = occupational therapy; PT = physical therapy
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Need for low-vision aids
• Urodynamic exam & assessment of bladder emptying
• Routine urine cultures when there is bladder dysfunction &/or other urinary tract abnormality
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Need for low-vision aids
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
## Classic
To monitor existing manifestations, the response of an individual with classic
Recommended Surveillance for Individuals with Classic
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Need for low-vision aids
Urodynamic exam & assessment of bladder emptying
Routine urine cultures when there is bladder dysfunction &/or other urinary tract abnormality
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
OT = occupational therapy; PT = physical therapy
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Need for low-vision aids
• Urodynamic exam & assessment of bladder emptying
• Routine urine cultures when there is bladder dysfunction &/or other urinary tract abnormality
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
## Nonclassic
To monitor existing manifestations, the response of an individual with nonclassic
Recommended Surveillance for Individuals with Nonclassic
Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
Need for low-vision aids
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
OT = occupational therapy; PT = physical therapy
• Eye exam (visual acuity, color vision testing, slit lamp exam for cataracts, fundoscopy, visual fields)
• Need for low-vision aids
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Assess need for follow-up genetic counseling if new questions arise (e.g., family planning).
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic relatives at risk in order to identify as early as possible those who would benefit from prompt initiation of treatment for the earliest manifestations of
See
## Pregnancy Management
Pregnant women with insulin-dependent diabetes mellitus, a characteristic of both classic and nonclassic
Because women with classic
See
## Therapies Under Investigation
For a review of current and future therapeutic strategies, see
Search
## Genetic Counseling
Classic
Nonclassic
The parents of a child with classic
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.
There is no conclusive evidence that the heterozygous parents of a child with
If both parents are known to be heterozygous for a
The clinical course of classic
There is no conclusive evidence that the heterozygous sibs of a proband with
Most individuals diagnosed with nonclassic
Some individuals diagnosed with nonclassic
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.
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with nonclassic WFS1-SD 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 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 of inheriting the pathogenic variant is 50%. Clinical variability may be observed between affected family members with the same
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 with
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 a child with classic
• 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.
• There is no conclusive evidence that the heterozygous parents of a child with
• 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 clinical course of classic
• There is no conclusive evidence that the heterozygous sibs of a proband with
• Most individuals diagnosed with nonclassic
• Some individuals diagnosed with nonclassic
• 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.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with nonclassic WFS1-SD 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 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.
• 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 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%. Clinical variability may be observed between affected family members with the same
• 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 with
## Mode of Inheritance
Classic
Nonclassic
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with classic
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.
There is no conclusive evidence that the heterozygous parents of a child with
If both parents are known to be heterozygous for a
The clinical course of classic
There is no conclusive evidence that the heterozygous sibs of a proband with
• The parents of a child with classic
• 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.
• There is no conclusive evidence that the heterozygous parents of a child with
• 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 clinical course of classic
• There is no conclusive evidence that the heterozygous sibs of a proband with
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with nonclassic
Some individuals diagnosed with nonclassic
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.
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with nonclassic WFS1-SD 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 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 of inheriting the pathogenic variant is 50%. Clinical variability may be observed between affected family members with the same
If the
If the parents have not been tested for the
• Most individuals diagnosed with nonclassic
• Some individuals diagnosed with nonclassic
• 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.
• * 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 and will not detect a pathogenic variant that is present in the germ cells only.
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with nonclassic WFS1-SD 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 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.
• 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 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%. Clinical variability may be observed between affected family members with the same
• 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 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 young adults with
## 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
France
United Kingdom
United Kingdom
NY
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• France
•
•
•
•
• United Kingdom
•
•
•
•
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•
•
•
• United Kingdom
•
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• NY
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## Molecular Genetics
WFS1 Spectrum Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for WFS1 Spectrum Disorder (
Wolframin is widely expressed, including in retinal ganglion cells and optic nerve glia in monkeys.
There is some in vitro evidence that
## Molecular Pathogenesis
Wolframin is widely expressed, including in retinal ganglion cells and optic nerve glia in monkeys.
There is some in vitro evidence that
## Chapter Notes
Professor Timothy Barrett is based at the Institute of Cancer and Genomic Sciences, University of Birmingham, and Honorary Consultant in Pædiatric Endocrinology and Diabetes at Birmingham Women's and Children's Hospital. He has published more than 200 research papers in scientific journals as well as reviews and book chapters in the fields of pediatrics, diabetes, and genetics of childhood diabetes syndromes. His research interests include functional genetics, rare diabetes syndromes, and translational research to early-phase clinical trials in rare disease.
The Audiogenetic Research Group, headed by Lisbeth Tranebjærg, receives financial support from Widex AS and other research grants.
Timothy Barrett is supported by UK Medical Research Council grant "Development of a Novel Repurposed Drug Treatment for the Neurodegeneration and Diabetes in Wolfram Syndrome" (MR/P007732/1); NIHR Wellcome Clinical Research Facility (Birmingham); and NIHR Programme Grant "Improving Outcomes for Children and Young People with Diabetes from Socio-Economically Deprived and/or Ethnic Minority Populations" (NIHR202358). He holds an NIHR Senior Investigator award.
1 December 2022 (bp) Comprehensive update posted live
9 April 2020 (bp) Comprehensive update posted live
19 December 2013 (me) Comprehensive update posted live
24 February 2009 (me) Review posted live
12 August 2008 (lt) Original submission
• 1 December 2022 (bp) Comprehensive update posted live
• 9 April 2020 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 24 February 2009 (me) Review posted live
• 12 August 2008 (lt) Original submission
## Author Notes
Professor Timothy Barrett is based at the Institute of Cancer and Genomic Sciences, University of Birmingham, and Honorary Consultant in Pædiatric Endocrinology and Diabetes at Birmingham Women's and Children's Hospital. He has published more than 200 research papers in scientific journals as well as reviews and book chapters in the fields of pediatrics, diabetes, and genetics of childhood diabetes syndromes. His research interests include functional genetics, rare diabetes syndromes, and translational research to early-phase clinical trials in rare disease.
## Acknowledgments
The Audiogenetic Research Group, headed by Lisbeth Tranebjærg, receives financial support from Widex AS and other research grants.
Timothy Barrett is supported by UK Medical Research Council grant "Development of a Novel Repurposed Drug Treatment for the Neurodegeneration and Diabetes in Wolfram Syndrome" (MR/P007732/1); NIHR Wellcome Clinical Research Facility (Birmingham); and NIHR Programme Grant "Improving Outcomes for Children and Young People with Diabetes from Socio-Economically Deprived and/or Ethnic Minority Populations" (NIHR202358). He holds an NIHR Senior Investigator award.
## Revision History
1 December 2022 (bp) Comprehensive update posted live
9 April 2020 (bp) Comprehensive update posted live
19 December 2013 (me) Comprehensive update posted live
24 February 2009 (me) Review posted live
12 August 2008 (lt) Original submission
• 1 December 2022 (bp) Comprehensive update posted live
• 9 April 2020 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 24 February 2009 (me) Review posted live
• 12 August 2008 (lt) Original submission
## References
## Literature Cited
|
[] |
24/2/2009
|
1/12/2022
|
2/6/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
white-sutton
|
white-sutton
|
[
"POGZ-Related Intellectual Disability Syndrome",
"POGZ-Related Intellectual Disability Syndrome",
"Pogo transposable element with ZNF domain",
"POGZ",
"White-Sutton Syndrome"
] |
White-Sutton Syndrome
|
Nurit Assia Batzir, Janson White, V Reid Sutton
|
Summary White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females. The diagnosis of White-Sutton syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in White-Sutton syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for White-Sutton syndrome have been published.
White-Sutton syndrome
Mild-to-severe developmental delay, intellectual disability, or learning difficulties
Speech delay
AND
Any of the following features presenting in infancy or childhood:
Motor delay
Generalized hypotonia
Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
Autism / autism spectrum disorder
Microcephaly
Infant feeding difficulties that may require tube feeding or gastrostomy
Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
Tendency toward being overweight
Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
Sensorineural hearing impairment / cochlear dysfunction
Sleep-disordered breathing
Congenital diaphragmatic hernia
Mild male genital anomalies such as cryptorchidism or micropenis
Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
Recurrent infections
Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
While some facial features are frequently observed, the authors believe that this syndrome cannot be definitively diagnosed clinically based on facial or other phenotypic features alone (see
The diagnosis of White-Sutton 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 [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in White-Sutton 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.
• Mild-to-severe developmental delay, intellectual disability, or learning difficulties
• Speech delay
• Any of the following features presenting in infancy or childhood:
•
• Motor delay
• Generalized hypotonia
• Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
• Autism / autism spectrum disorder
• Microcephaly
• Infant feeding difficulties that may require tube feeding or gastrostomy
• Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
• Tendency toward being overweight
•
• Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
• Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
• Sensorineural hearing impairment / cochlear dysfunction
• Sleep-disordered breathing
• Congenital diaphragmatic hernia
• Mild male genital anomalies such as cryptorchidism or micropenis
• Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
• Recurrent infections
• Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
• Motor delay
• Generalized hypotonia
• Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
• Autism / autism spectrum disorder
• Microcephaly
• Infant feeding difficulties that may require tube feeding or gastrostomy
• Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
• Tendency toward being overweight
• Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
• Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
• Sensorineural hearing impairment / cochlear dysfunction
• Sleep-disordered breathing
• Congenital diaphragmatic hernia
• Mild male genital anomalies such as cryptorchidism or micropenis
• Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
• Recurrent infections
• Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
• Motor delay
• Generalized hypotonia
• Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
• Autism / autism spectrum disorder
• Microcephaly
• Infant feeding difficulties that may require tube feeding or gastrostomy
• Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
• Tendency toward being overweight
• Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
• Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
• Sensorineural hearing impairment / cochlear dysfunction
• Sleep-disordered breathing
• Congenital diaphragmatic hernia
• Mild male genital anomalies such as cryptorchidism or micropenis
• Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
• Recurrent infections
• Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
White-Sutton syndrome
Mild-to-severe developmental delay, intellectual disability, or learning difficulties
Speech delay
AND
Any of the following features presenting in infancy or childhood:
Motor delay
Generalized hypotonia
Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
Autism / autism spectrum disorder
Microcephaly
Infant feeding difficulties that may require tube feeding or gastrostomy
Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
Tendency toward being overweight
Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
Sensorineural hearing impairment / cochlear dysfunction
Sleep-disordered breathing
Congenital diaphragmatic hernia
Mild male genital anomalies such as cryptorchidism or micropenis
Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
Recurrent infections
Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
While some facial features are frequently observed, the authors believe that this syndrome cannot be definitively diagnosed clinically based on facial or other phenotypic features alone (see
• Mild-to-severe developmental delay, intellectual disability, or learning difficulties
• Speech delay
• Any of the following features presenting in infancy or childhood:
•
• Motor delay
• Generalized hypotonia
• Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
• Autism / autism spectrum disorder
• Microcephaly
• Infant feeding difficulties that may require tube feeding or gastrostomy
• Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
• Tendency toward being overweight
•
• Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
• Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
• Sensorineural hearing impairment / cochlear dysfunction
• Sleep-disordered breathing
• Congenital diaphragmatic hernia
• Mild male genital anomalies such as cryptorchidism or micropenis
• Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
• Recurrent infections
• Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
• Motor delay
• Generalized hypotonia
• Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
• Autism / autism spectrum disorder
• Microcephaly
• Infant feeding difficulties that may require tube feeding or gastrostomy
• Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
• Tendency toward being overweight
• Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
• Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
• Sensorineural hearing impairment / cochlear dysfunction
• Sleep-disordered breathing
• Congenital diaphragmatic hernia
• Mild male genital anomalies such as cryptorchidism or micropenis
• Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
• Recurrent infections
• Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
• Motor delay
• Generalized hypotonia
• Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
• Autism / autism spectrum disorder
• Microcephaly
• Infant feeding difficulties that may require tube feeding or gastrostomy
• Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
• Tendency toward being overweight
• Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
• Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
• Sensorineural hearing impairment / cochlear dysfunction
• Sleep-disordered breathing
• Congenital diaphragmatic hernia
• Mild male genital anomalies such as cryptorchidism or micropenis
• Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
• Recurrent infections
• Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula
## Establishing the Diagnosis
The diagnosis of White-Sutton 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 [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in White-Sutton 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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), and autism spectrum disorder (ASD) as well as other behavioral problems. Additional features commonly reported include hypotonia, gastrointestinal problems, seizures, microcephaly, sensorineural hearing loss, strabismus, short stature, tendency towards obesity, and sleep disturbance (particularly sleep apnea).
To date, more than 90 individuals have been identified with a pathogenic variant in
Select Features of White-Sutton Syndrome
LD in 5/19 persons
Mild ID in 8/19
Moderate ID in 3/19
Severe ID in 3/19
GTC, partial seizures, drop attacks, absence
Plus 2 addl persons w/paroxysmal nonepileptic episodes
Based on
ASD = autism spectrum disorder; CVS = cyclic vomiting syndrome; GTC = generalized tonic-clonic; ID = intellectual disability; LD = learning difficulties
Based on
"Occlusion" as appears in
Although information on cognitive function in adults is limited, adults may be able to work and care for themselves, and in some instances raise children [
Additional causes for motor delays include medical issues such as complex abdominal surgery and lower limb spasticity. Gait abnormalities including clumsiness and difficulty with coordination have also been reported.
Although a movement disorder is not frequently seen, paroxysmal nonepileptic events have been described in at least two individuals [
ASD was observed in up to 50% of individuals reported in the literature. Repetitive behaviors [
While onset of seizures ranges from infancy to adolescence, it is typically between ages one and four years. Seizures are generally controlled either by monotherapy or with multiple anti-seizure medications, and may resolve with age. Status epilepticus has not been reported.
Information on EEG patterns is limited. Findings may include epileptic abnormalities localized to the frontal region or bitemporal sharp waves and are not specific to this disorder [
Sleep apnea is known to occur; a sleep disorder survey completed for 12 individuals revealed features suggestive of obstructive sleep apnea in four [
Vomiting is common. Some individuals experience recurring episodes of vomiting in childhood with or without a cyclical pattern. Vomiting tends to improve or resolve with age; some parents report that nausea and vomiting appear to respond to therapies for "abdominal migraines" [
Gastrointestinal manifestations requiring surgery can include intestinal malrotation, ventral and inguinal hernia, and rectal prolapse.
Congenital diaphragmatic hernia, although infrequently described, is a recurring finding [
Height and weight range from below the third percentile to above average. Short stature or failure to gain weight have been reported in approximately 15% of individuals [
Despite initial problems with feeding, a significant proportion of children become overweight, as early as the first years of life [
Microcephaly (head circumference <3rd percentile) is common.
While no clear genotype-phenotype correlations have been identified, the following are general observations:
Missense variants are not clearly associated with cognitive problems but appear to be associated with behavioral issues including ASD or autistic-like behaviors [
In 20 individuals with White-Sutton syndrome with nonsense, frameshift, or copy number variants in
Behavioral problems, sleep disorders, gastrointestinal manifestations, and microcephaly were more frequently associated with variants in the DDE domain of the protein (encoded by part of exon 19), whereas central nervous system and genitourinary malformations occurred more often with variants affecting other protein domains [
To date, more than 90 individuals with White-Sutton syndrome have been reported.
Exome sequencing of 9,206 individuals with neurodevelopmental disorders identified pathogenic or likely pathogenic variants in
Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
To date, when parental data were available, all reported instances of loss-of-function variants in
The penetrance of missense
• LD in 5/19 persons
• Mild ID in 8/19
• Moderate ID in 3/19
• Severe ID in 3/19
• GTC, partial seizures, drop attacks, absence
• Plus 2 addl persons w/paroxysmal nonepileptic episodes
• Missense variants are not clearly associated with cognitive problems but appear to be associated with behavioral issues including ASD or autistic-like behaviors [
• In 20 individuals with White-Sutton syndrome with nonsense, frameshift, or copy number variants in
• Behavioral problems, sleep disorders, gastrointestinal manifestations, and microcephaly were more frequently associated with variants in the DDE domain of the protein (encoded by part of exon 19), whereas central nervous system and genitourinary malformations occurred more often with variants affecting other protein domains [
## Clinical Description
White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), and autism spectrum disorder (ASD) as well as other behavioral problems. Additional features commonly reported include hypotonia, gastrointestinal problems, seizures, microcephaly, sensorineural hearing loss, strabismus, short stature, tendency towards obesity, and sleep disturbance (particularly sleep apnea).
To date, more than 90 individuals have been identified with a pathogenic variant in
Select Features of White-Sutton Syndrome
LD in 5/19 persons
Mild ID in 8/19
Moderate ID in 3/19
Severe ID in 3/19
GTC, partial seizures, drop attacks, absence
Plus 2 addl persons w/paroxysmal nonepileptic episodes
Based on
ASD = autism spectrum disorder; CVS = cyclic vomiting syndrome; GTC = generalized tonic-clonic; ID = intellectual disability; LD = learning difficulties
Based on
"Occlusion" as appears in
Although information on cognitive function in adults is limited, adults may be able to work and care for themselves, and in some instances raise children [
Additional causes for motor delays include medical issues such as complex abdominal surgery and lower limb spasticity. Gait abnormalities including clumsiness and difficulty with coordination have also been reported.
Although a movement disorder is not frequently seen, paroxysmal nonepileptic events have been described in at least two individuals [
ASD was observed in up to 50% of individuals reported in the literature. Repetitive behaviors [
While onset of seizures ranges from infancy to adolescence, it is typically between ages one and four years. Seizures are generally controlled either by monotherapy or with multiple anti-seizure medications, and may resolve with age. Status epilepticus has not been reported.
Information on EEG patterns is limited. Findings may include epileptic abnormalities localized to the frontal region or bitemporal sharp waves and are not specific to this disorder [
Sleep apnea is known to occur; a sleep disorder survey completed for 12 individuals revealed features suggestive of obstructive sleep apnea in four [
Vomiting is common. Some individuals experience recurring episodes of vomiting in childhood with or without a cyclical pattern. Vomiting tends to improve or resolve with age; some parents report that nausea and vomiting appear to respond to therapies for "abdominal migraines" [
Gastrointestinal manifestations requiring surgery can include intestinal malrotation, ventral and inguinal hernia, and rectal prolapse.
Congenital diaphragmatic hernia, although infrequently described, is a recurring finding [
Height and weight range from below the third percentile to above average. Short stature or failure to gain weight have been reported in approximately 15% of individuals [
Despite initial problems with feeding, a significant proportion of children become overweight, as early as the first years of life [
Microcephaly (head circumference <3rd percentile) is common.
• LD in 5/19 persons
• Mild ID in 8/19
• Moderate ID in 3/19
• Severe ID in 3/19
• GTC, partial seizures, drop attacks, absence
• Plus 2 addl persons w/paroxysmal nonepileptic episodes
## Genotype-Phenotype Correlations
While no clear genotype-phenotype correlations have been identified, the following are general observations:
Missense variants are not clearly associated with cognitive problems but appear to be associated with behavioral issues including ASD or autistic-like behaviors [
In 20 individuals with White-Sutton syndrome with nonsense, frameshift, or copy number variants in
Behavioral problems, sleep disorders, gastrointestinal manifestations, and microcephaly were more frequently associated with variants in the DDE domain of the protein (encoded by part of exon 19), whereas central nervous system and genitourinary malformations occurred more often with variants affecting other protein domains [
• Missense variants are not clearly associated with cognitive problems but appear to be associated with behavioral issues including ASD or autistic-like behaviors [
• In 20 individuals with White-Sutton syndrome with nonsense, frameshift, or copy number variants in
• Behavioral problems, sleep disorders, gastrointestinal manifestations, and microcephaly were more frequently associated with variants in the DDE domain of the protein (encoded by part of exon 19), whereas central nervous system and genitourinary malformations occurred more often with variants affecting other protein domains [
## Prevalence
To date, more than 90 individuals with White-Sutton syndrome have been reported.
Exome sequencing of 9,206 individuals with neurodevelopmental disorders identified pathogenic or likely pathogenic variants in
Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
## Penetrance
To date, when parental data were available, all reported instances of loss-of-function variants in
The penetrance of missense
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with White-Sutton syndrome are not sufficient to diagnose this condition, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See
Note:
## Management
No clinical practice guidelines for White-Sutton syndrome have been published.
To establish the extent of disease and needs in an individual diagnosed with White-Sutton syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with White-Sutton 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)
Consider need for augmentative communication.
Assess for palatal abnormalities.
Consider brain MRI.
Consider EEG if seizures are a concern.
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
Community or online
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CAKUT = congenital anomalies of the kidney and/or urinary tract; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with White-Sutton Syndrome
PT/OT for muscle strengthening, stretching to help avoid contractures & falls
Orthopedics / physical medicine & rehab as needed
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Melatonin has improved quality of sleep in some persons.
Standardized treatment for obstructive sleep apnea
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 Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; 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.
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.
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.
Recommended Surveillance for Individuals with White-Sutton Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
See
Following studies in mice that suggested a role for the oxytocin system in autism spectrum disorders,
Behavioral abnormalities in a mouse model of White-Sutton syndrome improved when treated with the anti-seizure medication perampanel [
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)
• Consider need for augmentative communication.
• Assess for palatal abnormalities.
• Consider brain MRI.
• Consider EEG if seizures are a concern.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
• PT/OT for muscle strengthening, stretching to help avoid contractures & falls
• Orthopedics / physical medicine & rehab as needed
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Melatonin has improved quality of sleep in some persons.
• Standardized treatment for obstructive sleep apnea
• 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 Special Olympics.
• 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.
• 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
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with White-Sutton syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with White-Sutton 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)
Consider need for augmentative communication.
Assess for palatal abnormalities.
Consider brain MRI.
Consider EEG if seizures are a concern.
To incl eval of aspiration risk & nutritional status
Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
Community or online
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; CAKUT = congenital anomalies of the kidney and/or urinary tract; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist
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)
• Consider need for augmentative communication.
• Assess for palatal abnormalities.
• Consider brain MRI.
• Consider EEG if seizures are a concern.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
• Community or online
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with White-Sutton Syndrome
PT/OT for muscle strengthening, stretching to help avoid contractures & falls
Orthopedics / physical medicine & rehab as needed
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Melatonin has improved quality of sleep in some persons.
Standardized treatment for obstructive sleep apnea
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 Special Olympics.
ASM = anti-seizure medication; DD = developmental delay; FTT = failure to thrive; 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.
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.
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.
• PT/OT for muscle strengthening, stretching to help avoid contractures & falls
• Orthopedics / physical medicine & rehab as needed
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Melatonin has improved quality of sleep in some persons.
• Standardized treatment for obstructive sleep apnea
• 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 Special Olympics.
• 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.
• 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.
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.
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.
• 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.
• 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
Recommended Surveillance for Individuals with White-Sutton Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Following studies in mice that suggested a role for the oxytocin system in autism spectrum disorders,
Behavioral abnormalities in a mouse model of White-Sutton syndrome improved when treated with the anti-seizure medication perampanel [
Search
## Genetic Counseling
White-Sutton syndrome is an autosomal dominant disorder typically caused by a
Most probands reported to date with White-Sutton syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
Rarely, individuals diagnosed with White-Sutton syndrome 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.
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 young adults who are affected and to the 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.
• Most probands reported to date with White-Sutton syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
• Rarely, individuals diagnosed with White-Sutton syndrome 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 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 young adults who are affected and to the parents of affected individuals.
## Mode of Inheritance
White-Sutton syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
Most probands reported to date with White-Sutton syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
Rarely, individuals diagnosed with White-Sutton syndrome 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.
If a parent of the proband is known to have the
If the
• Most probands reported to date with White-Sutton syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a
• Rarely, individuals diagnosed with White-Sutton syndrome 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 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 young adults who are affected and to the 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 young adults who are affected and to the 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
PO Box 591
Broken Arrow OK 74103
•
• PO Box 591
• Broken Arrow OK 74103
•
## Molecular Genetics
White-Sutton Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for White-Sutton Syndrome (
The majority of pathogenic variants reported thus far create premature termination codons, although many are located in the final exon and are thus not expected to undergo nonsense-mediated decay. In addition, some single-nucleotide missense variants have demonstrated functional defects, such as impaired DNA binding [
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The majority of pathogenic variants reported thus far create premature termination codons, although many are located in the final exon and are thus not expected to undergo nonsense-mediated decay. In addition, some single-nucleotide missense variants have demonstrated functional defects, such as impaired DNA binding [
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
V Reid Sutton's website:
We would like to acknowledge James Lupski, Christine Beck, Tamar Harel, and Jennifer Posey, who were instrumental in the initial description of White-Sutton syndrome. The work that led to the initial description was supported by the US National Human Genome Research Institute (NHGRI) / National Heart Lung and Blood Institute (NHLBI) Grant No. HG006542 to the Baylor-Hopkins Center for Mendelian Genomics. We would also like to thank the White-Sutton Syndrome Foundation and families for their continued support in our research endeavors.
16 September 2021 (bp) Review posted live
2 July 2021 (vrs) Original submission
• 16 September 2021 (bp) Review posted live
• 2 July 2021 (vrs) Original submission
## Author Notes
V Reid Sutton's website:
## Acknowledgments
We would like to acknowledge James Lupski, Christine Beck, Tamar Harel, and Jennifer Posey, who were instrumental in the initial description of White-Sutton syndrome. The work that led to the initial description was supported by the US National Human Genome Research Institute (NHGRI) / National Heart Lung and Blood Institute (NHLBI) Grant No. HG006542 to the Baylor-Hopkins Center for Mendelian Genomics. We would also like to thank the White-Sutton Syndrome Foundation and families for their continued support in our research endeavors.
## Revision History
16 September 2021 (bp) Review posted live
2 July 2021 (vrs) Original submission
• 16 September 2021 (bp) Review posted live
• 2 July 2021 (vrs) Original submission
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"X Du, X Gao, X Liu, L Shen, K Wang, Y Fan, Y Sun, X Luo, H Liu, L Wang, Y Wang, Z Gong, J Wang, Y Yu, F. Li. Genetic diagnostic evaluation of trio-based whole exome sequencing among children with diagnosed or suspected autism spectrum disorder.. Front Genet. 2018;9:594",
"A Ferretti, S Barresi, M Trivisano, A Ciolfi, ML Dentici, FC Radio, F Vigevano, M Tartaglia, N Specchio. POGZ-related epilepsy: case report and review of the literature.. Am J Med Genet A. 2019;179:1631-6",
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] |
16/9/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
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