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[ "CPT II Deficiency", "CPT II Deficiency", "Carnitine O-palmitoyltransferase 2, mitochondrial", "CPT2", "Carnitine Palmitoyltransferase II Deficiency" ]
Carnitine Palmitoyltransferase II Deficiency
Thomas Wieser
Summary Carnitine palmitoyltransferase II (CPT II) deficiency is a disorder of long-chain fatty-acid oxidation. The three clinical presentations are lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form (which is usually mild and can manifest from infancy to adulthood). While the former two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria. Males are more likely to be affected than females. The diagnosis of CPT II deficiency is established in a proband by the finding of reduced CPT enzyme activity in muscle or the identification of biallelic pathogenic variants in CPT II deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are usually asymptomatic; however, manifesting carriers have been reported. Prenatal testing for a pregnancy at increased risk for one of the severe forms of the disease is possible either by molecular genetic testing of
## Diagnosis Carnitine palmitoyltransferase II (CPT II) deficiency Episodes of liver failure with hypoketotic hypoglycemia Cardiomyopathy Cardiac arrhythmias Seizures and coma after fasting or infection Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) Liver failure Cardiomyopathy Seizures Hypoketotic hypoglycemia Peripheral myopathy Attacks of abdominal pain and headache Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress Possible weakness during attacks Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks Note: CPT II deficiency cannot be excluded based on acylcarnitine quantification in dried blood spots alone and investigation of plasma is recommended [ Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ The diagnosis of CPT II 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 For an introduction to multigene panels click Molecular Genetic Testing Used in Carnitine Palmitoyltransferase II 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 The following pathogenic variants are found with the approximate stated frequency in individuals who have the myopathic form: The severe infantile hepatocardiomuscular form and the lethal neonatal form are associated with severe pathogenic variants including Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving The "radio isotope exchange assay" described by The "isotope forward assay" measures total CPT enzyme activity (CPT I and CPT II) by the incorporation of radio-labeled carnitine into palmitoylcarnitine [ CPT II activity can also be determined spectroscopically [ The lethal neonatal form and the severe infantile hepatocardiomuscular form are associated with less than 10% of normal CPT II enzyme activity in lymphoblasts and skeletal muscle. Although the CPT II enzyme defect in the myopathic form can be detected using other tissues (e.g., liver, fibroblasts, leukocytes), preparation of tissue for assay of CPT II enzyme activity is difficult, and comparison of CPT II enzyme activity in different tissues yields inconsistent results. Therefore, only muscle tissue is recommended for assay of enzyme activity for the myopathic form of CPT II deficiency. • Episodes of liver failure with hypoketotic hypoglycemia • Cardiomyopathy • Cardiac arrhythmias • Seizures and coma after fasting or infection • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) • Episodes of liver failure with hypoketotic hypoglycemia • Cardiomyopathy • Cardiac arrhythmias • Seizures and coma after fasting or infection • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) • Liver failure • Cardiomyopathy • Seizures • Hypoketotic hypoglycemia • Peripheral myopathy • Attacks of abdominal pain and headache • Liver failure • Cardiomyopathy • Seizures • Hypoketotic hypoglycemia • Peripheral myopathy • Attacks of abdominal pain and headache • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress • Possible weakness during attacks • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress • Possible weakness during attacks • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks • Episodes of liver failure with hypoketotic hypoglycemia • Cardiomyopathy • Cardiac arrhythmias • Seizures and coma after fasting or infection • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) • Liver failure • Cardiomyopathy • Seizures • Hypoketotic hypoglycemia • Peripheral myopathy • Attacks of abdominal pain and headache • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress • Possible weakness during attacks • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks • Note: CPT II deficiency cannot be excluded based on acylcarnitine quantification in dried blood spots alone and investigation of plasma is recommended [ • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ • For an introduction to multigene panels click • The "radio isotope exchange assay" described by • The "isotope forward assay" measures total CPT enzyme activity (CPT I and CPT II) by the incorporation of radio-labeled carnitine into palmitoylcarnitine [ • CPT II activity can also be determined spectroscopically [ ## Suggestive Findings Carnitine palmitoyltransferase II (CPT II) deficiency Episodes of liver failure with hypoketotic hypoglycemia Cardiomyopathy Cardiac arrhythmias Seizures and coma after fasting or infection Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) Liver failure Cardiomyopathy Seizures Hypoketotic hypoglycemia Peripheral myopathy Attacks of abdominal pain and headache Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress Possible weakness during attacks Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks Note: CPT II deficiency cannot be excluded based on acylcarnitine quantification in dried blood spots alone and investigation of plasma is recommended [ Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ • Episodes of liver failure with hypoketotic hypoglycemia • Cardiomyopathy • Cardiac arrhythmias • Seizures and coma after fasting or infection • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) • Episodes of liver failure with hypoketotic hypoglycemia • Cardiomyopathy • Cardiac arrhythmias • Seizures and coma after fasting or infection • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) • Liver failure • Cardiomyopathy • Seizures • Hypoketotic hypoglycemia • Peripheral myopathy • Attacks of abdominal pain and headache • Liver failure • Cardiomyopathy • Seizures • Hypoketotic hypoglycemia • Peripheral myopathy • Attacks of abdominal pain and headache • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress • Possible weakness during attacks • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress • Possible weakness during attacks • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks • Episodes of liver failure with hypoketotic hypoglycemia • Cardiomyopathy • Cardiac arrhythmias • Seizures and coma after fasting or infection • Facial abnormalities or structural malformations (e.g., cystic renal dysplasia, neuronal migration defects or brain dysgenisis) • Liver failure • Cardiomyopathy • Seizures • Hypoketotic hypoglycemia • Peripheral myopathy • Attacks of abdominal pain and headache • Recurrent attacks of myalgia accompanied by myoglobinuria precipitated by prolonged exercise (especially after fasting), cold exposure, or stress • Possible weakness during attacks • Usually no signs of myopathy (weakness, myalgia, elevation of serum creatine kinase [CK] concentration) between attacks • Note: CPT II deficiency cannot be excluded based on acylcarnitine quantification in dried blood spots alone and investigation of plasma is recommended [ • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ • Most individuals with the myopathic form of CPT II deficiency have normal serum CK concentration (<80 U/L) between attacks. • Permanent elevation of serum CK concentration (≤313 U/L) is observed in approximately 10% of affected individuals [ ## Establishing the Diagnosis The diagnosis of CPT II 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 For an introduction to multigene panels click Molecular Genetic Testing Used in Carnitine Palmitoyltransferase II 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 The following pathogenic variants are found with the approximate stated frequency in individuals who have the myopathic form: The severe infantile hepatocardiomuscular form and the lethal neonatal form are associated with severe pathogenic variants including Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving The "radio isotope exchange assay" described by The "isotope forward assay" measures total CPT enzyme activity (CPT I and CPT II) by the incorporation of radio-labeled carnitine into palmitoylcarnitine [ CPT II activity can also be determined spectroscopically [ The lethal neonatal form and the severe infantile hepatocardiomuscular form are associated with less than 10% of normal CPT II enzyme activity in lymphoblasts and skeletal muscle. Although the CPT II enzyme defect in the myopathic form can be detected using other tissues (e.g., liver, fibroblasts, leukocytes), preparation of tissue for assay of CPT II enzyme activity is difficult, and comparison of CPT II enzyme activity in different tissues yields inconsistent results. Therefore, only muscle tissue is recommended for assay of enzyme activity for the myopathic form of CPT II deficiency. • For an introduction to multigene panels click • The "radio isotope exchange assay" described by • The "isotope forward assay" measures total CPT enzyme activity (CPT I and CPT II) by the incorporation of radio-labeled carnitine into palmitoylcarnitine [ • CPT II activity can also be determined spectroscopically [ ## CPT II Enzyme Activity The "radio isotope exchange assay" described by The "isotope forward assay" measures total CPT enzyme activity (CPT I and CPT II) by the incorporation of radio-labeled carnitine into palmitoylcarnitine [ CPT II activity can also be determined spectroscopically [ The lethal neonatal form and the severe infantile hepatocardiomuscular form are associated with less than 10% of normal CPT II enzyme activity in lymphoblasts and skeletal muscle. Although the CPT II enzyme defect in the myopathic form can be detected using other tissues (e.g., liver, fibroblasts, leukocytes), preparation of tissue for assay of CPT II enzyme activity is difficult, and comparison of CPT II enzyme activity in different tissues yields inconsistent results. Therefore, only muscle tissue is recommended for assay of enzyme activity for the myopathic form of CPT II deficiency. • The "radio isotope exchange assay" described by • The "isotope forward assay" measures total CPT enzyme activity (CPT I and CPT II) by the incorporation of radio-labeled carnitine into palmitoylcarnitine [ • CPT II activity can also be determined spectroscopically [ ## Clinical Characteristics Three carnitine palmitoyltransferase II (CPT II) deficiency phenotypes are recognized: a lethal neonatal form; a severe infantile hepatocardiomuscular form; and a myopathic form, in which onset ranges from infancy to adulthood. Liver failure, hypoketotic hypoglycemia, cardiomyopathy, respiratory distress, and/or cardiac arrhythmias occur. Affected individuals have liver calcifications and cystic dysplastic kidneys [ Neuronal migration defects including cystic dysplasia of the basal ganglia have been reported [ Prognosis is poor. Death occurs within days to months. The lethal neonatal form is characterized by reduced CPT II enzyme activity in multiple organs, reduced serum concentrations of total and free carnitine, and increased serum concentrations of long-chain acylcarnitines and lipids. This form is characterized by hypoketotic hypoglycemia, liver failure, cardiomyopathy, and peripheral myopathy. Cardiac arrhythmias can result in sudden death during infancy [ The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. In vivo investigation of fatty acid oxidation in CPT2-deficient persons by indirect calorimetry and stable isotope methodology shows an impaired oxidation of long chain fatty acids during low-intensity exercise, with normal oxidation at rest [ Age at onset and age at diagnosis vary widely. Detailed clinical data obtained from 23 of 32 individuals with the myopathic form revealed age of onset ranging from one to 61 years; age at diagnosis ranged from seven to 62 years [ Exercise is the most common trigger of attacks, followed by infections (~50% of affected individuals) and fasting (~20%). The severity of exercise that triggers symptoms is highly variable. In some individuals, only long-term exercise induces symptoms, and in others, only mild exercise is necessary. Cold, general anesthesia, sleep deprivation, and conditions that are normally associated with an increased dependency of muscle on lipid metabolism are also reported as trigger factors. Most individuals are mildly affected; some are even serious athletes [ End-stage renal disease caused by interstitial nephritis with acute tubular necrosis requiring dialysis occasionally occurs [ The preponderance of affected males is notable. In the series of 32 individuals of A consistent genotype-phenotype correlation is found between In northern Europeans the pathogenic variants Histopathologic changes in asymptomatic carriers of CPT II deficiency (heterozygotes) and in affected individuals (homozygotes) are inconsistent. A recent study found histopathologic abnormalities quite frequently (in all but one heterozygote). Lipid accumulation, found in all homozygotes, was mild or absent in heterozygotes. Some twenty families with the lethal neonatal form [ Approximately 28 families with the severe infantile hepatocardiomuscular form have been described. Since the first description of the myopathic form of CPT II deficiency by ## Clinical Description Three carnitine palmitoyltransferase II (CPT II) deficiency phenotypes are recognized: a lethal neonatal form; a severe infantile hepatocardiomuscular form; and a myopathic form, in which onset ranges from infancy to adulthood. Liver failure, hypoketotic hypoglycemia, cardiomyopathy, respiratory distress, and/or cardiac arrhythmias occur. Affected individuals have liver calcifications and cystic dysplastic kidneys [ Neuronal migration defects including cystic dysplasia of the basal ganglia have been reported [ Prognosis is poor. Death occurs within days to months. The lethal neonatal form is characterized by reduced CPT II enzyme activity in multiple organs, reduced serum concentrations of total and free carnitine, and increased serum concentrations of long-chain acylcarnitines and lipids. This form is characterized by hypoketotic hypoglycemia, liver failure, cardiomyopathy, and peripheral myopathy. Cardiac arrhythmias can result in sudden death during infancy [ The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. In vivo investigation of fatty acid oxidation in CPT2-deficient persons by indirect calorimetry and stable isotope methodology shows an impaired oxidation of long chain fatty acids during low-intensity exercise, with normal oxidation at rest [ Age at onset and age at diagnosis vary widely. Detailed clinical data obtained from 23 of 32 individuals with the myopathic form revealed age of onset ranging from one to 61 years; age at diagnosis ranged from seven to 62 years [ Exercise is the most common trigger of attacks, followed by infections (~50% of affected individuals) and fasting (~20%). The severity of exercise that triggers symptoms is highly variable. In some individuals, only long-term exercise induces symptoms, and in others, only mild exercise is necessary. Cold, general anesthesia, sleep deprivation, and conditions that are normally associated with an increased dependency of muscle on lipid metabolism are also reported as trigger factors. Most individuals are mildly affected; some are even serious athletes [ End-stage renal disease caused by interstitial nephritis with acute tubular necrosis requiring dialysis occasionally occurs [ The preponderance of affected males is notable. In the series of 32 individuals of ## Lethal Neonatal Form Liver failure, hypoketotic hypoglycemia, cardiomyopathy, respiratory distress, and/or cardiac arrhythmias occur. Affected individuals have liver calcifications and cystic dysplastic kidneys [ Neuronal migration defects including cystic dysplasia of the basal ganglia have been reported [ Prognosis is poor. Death occurs within days to months. The lethal neonatal form is characterized by reduced CPT II enzyme activity in multiple organs, reduced serum concentrations of total and free carnitine, and increased serum concentrations of long-chain acylcarnitines and lipids. ## Severe Infantile Hepatocardiomuscular Form This form is characterized by hypoketotic hypoglycemia, liver failure, cardiomyopathy, and peripheral myopathy. Cardiac arrhythmias can result in sudden death during infancy [ ## Myopathic Form The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. In vivo investigation of fatty acid oxidation in CPT2-deficient persons by indirect calorimetry and stable isotope methodology shows an impaired oxidation of long chain fatty acids during low-intensity exercise, with normal oxidation at rest [ Age at onset and age at diagnosis vary widely. Detailed clinical data obtained from 23 of 32 individuals with the myopathic form revealed age of onset ranging from one to 61 years; age at diagnosis ranged from seven to 62 years [ Exercise is the most common trigger of attacks, followed by infections (~50% of affected individuals) and fasting (~20%). The severity of exercise that triggers symptoms is highly variable. In some individuals, only long-term exercise induces symptoms, and in others, only mild exercise is necessary. Cold, general anesthesia, sleep deprivation, and conditions that are normally associated with an increased dependency of muscle on lipid metabolism are also reported as trigger factors. Most individuals are mildly affected; some are even serious athletes [ End-stage renal disease caused by interstitial nephritis with acute tubular necrosis requiring dialysis occasionally occurs [ The preponderance of affected males is notable. In the series of 32 individuals of ## Genotype-Phenotype Correlations A consistent genotype-phenotype correlation is found between In northern Europeans the pathogenic variants Histopathologic changes in asymptomatic carriers of CPT II deficiency (heterozygotes) and in affected individuals (homozygotes) are inconsistent. A recent study found histopathologic abnormalities quite frequently (in all but one heterozygote). Lipid accumulation, found in all homozygotes, was mild or absent in heterozygotes. ## Prevalence Some twenty families with the lethal neonatal form [ Approximately 28 families with the severe infantile hepatocardiomuscular form have been described. Since the first description of the myopathic form of CPT II deficiency by ## Genetically Related (Allelic) Disorders One reported family presented with a slowly progressive mild myopathy characterized by progressive muscle weakness and myopathic symptoms caused by a heterozygous The polymorphism ## Differential Diagnosis Note: The differentiation of CACT deficiency from CPT II deficiency continues to be difficult using current acylcarnitine profiling techniques either from plasma or blood spots, or in the intact cell system (fibroblasts/amniocytes). Specific enzyme assays are required to unequivocally differentiate CACT enzyme activity from CPT II enzyme activity [ Alternatively, molecular genetic testing could be used to distinguish between these two conditions. The ratio of free-to-total carnitine in serum or plasma on a newborn screen bloodspot may be elevated in CPT1A deficiency. CPT1 enzyme activity on cultured skin fibroblasts is 1%-5% of normal in most affected individuals. In individuals with an enzymatically confirmed diagnosis of CPT1A deficiency, the The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. If clinical history is suggestive of a metabolic myopathy, routine laboratory tests including measurement of concentrations of lactate, pyruvate, creatine kinase, amino acids, and free acylcarnitine in blood should be performed. Careful family history should be taken. In early reports, elevation of acylcarnitines, notably C16 and C18:1, suggestive of a defect in mitochondrial β-oxidation, was detected by screening for acylcarnitines [ Excessive use of muscle force (e.g., sports, seizures, dystonia) Muscle damage (e.g., crush, cold, ischemia, embolism) Infections (bacterial/viral/fungal) Temperature changes Inflammatory myopathies (polymyositis, vasculitis) Induction of an autoimmune reaction (e.g., cyclosporine, penicillamine) Hypokalemia (amphotericin, caffeine) Membrane disruption (cemitidin, colchicine) Disturbance of Na/K ATPase (antidepressants, arsen, azathioprine, bezafibrates) Neuroleptic syndrome (all neuroleptics, lithium) Serotonergic syndrome (amphetamines, MAO-inhibitor, SSRI) Defects of glucose/glycogen metabolism (e.g., Defects of lipid metabolism (carnitine deficiency). Mitochondrial β-oxidation of long-chain fatty acids is a major source of energy production, particularly at times of stress or fasting. Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity. At rest or during prolonged low-intensity exercise, approximately 70% of the energy requirement is met by the oxidation of long-chain fatty acids. Two defects of lipid metabolism primarily affecting the skeletal muscle are known: carnitine palmitoyltransferase II deficiency and Defects of oxidative phosphorylation (complex II deficiency, complex III defect, cytochrome Malignant hyperthermia (See Myoadenylate deaminase deficiency (MAD) (OMIM • Excessive use of muscle force (e.g., sports, seizures, dystonia) • Muscle damage (e.g., crush, cold, ischemia, embolism) • Infections (bacterial/viral/fungal) • Temperature changes • Inflammatory myopathies (polymyositis, vasculitis) • Induction of an autoimmune reaction (e.g., cyclosporine, penicillamine) • Hypokalemia (amphotericin, caffeine) • Membrane disruption (cemitidin, colchicine) • Disturbance of Na/K ATPase (antidepressants, arsen, azathioprine, bezafibrates) • Neuroleptic syndrome (all neuroleptics, lithium) • Serotonergic syndrome (amphetamines, MAO-inhibitor, SSRI) • Defects of glucose/glycogen metabolism (e.g., • Defects of lipid metabolism (carnitine deficiency). Mitochondrial β-oxidation of long-chain fatty acids is a major source of energy production, particularly at times of stress or fasting. Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity. At rest or during prolonged low-intensity exercise, approximately 70% of the energy requirement is met by the oxidation of long-chain fatty acids. Two defects of lipid metabolism primarily affecting the skeletal muscle are known: carnitine palmitoyltransferase II deficiency and • Defects of oxidative phosphorylation (complex II deficiency, complex III defect, cytochrome • • Malignant hyperthermia (See • Myoadenylate deaminase deficiency (MAD) (OMIM ## Neonatal Form Note: The differentiation of CACT deficiency from CPT II deficiency continues to be difficult using current acylcarnitine profiling techniques either from plasma or blood spots, or in the intact cell system (fibroblasts/amniocytes). Specific enzyme assays are required to unequivocally differentiate CACT enzyme activity from CPT II enzyme activity [ Alternatively, molecular genetic testing could be used to distinguish between these two conditions. The ratio of free-to-total carnitine in serum or plasma on a newborn screen bloodspot may be elevated in CPT1A deficiency. CPT1 enzyme activity on cultured skin fibroblasts is 1%-5% of normal in most affected individuals. In individuals with an enzymatically confirmed diagnosis of CPT1A deficiency, the ## Myopathic Form The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and is the most frequent cause of hereditary myoglobinuria. If clinical history is suggestive of a metabolic myopathy, routine laboratory tests including measurement of concentrations of lactate, pyruvate, creatine kinase, amino acids, and free acylcarnitine in blood should be performed. Careful family history should be taken. In early reports, elevation of acylcarnitines, notably C16 and C18:1, suggestive of a defect in mitochondrial β-oxidation, was detected by screening for acylcarnitines [ Excessive use of muscle force (e.g., sports, seizures, dystonia) Muscle damage (e.g., crush, cold, ischemia, embolism) Infections (bacterial/viral/fungal) Temperature changes Inflammatory myopathies (polymyositis, vasculitis) Induction of an autoimmune reaction (e.g., cyclosporine, penicillamine) Hypokalemia (amphotericin, caffeine) Membrane disruption (cemitidin, colchicine) Disturbance of Na/K ATPase (antidepressants, arsen, azathioprine, bezafibrates) Neuroleptic syndrome (all neuroleptics, lithium) Serotonergic syndrome (amphetamines, MAO-inhibitor, SSRI) Defects of glucose/glycogen metabolism (e.g., Defects of lipid metabolism (carnitine deficiency). Mitochondrial β-oxidation of long-chain fatty acids is a major source of energy production, particularly at times of stress or fasting. Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity. At rest or during prolonged low-intensity exercise, approximately 70% of the energy requirement is met by the oxidation of long-chain fatty acids. Two defects of lipid metabolism primarily affecting the skeletal muscle are known: carnitine palmitoyltransferase II deficiency and Defects of oxidative phosphorylation (complex II deficiency, complex III defect, cytochrome Malignant hyperthermia (See Myoadenylate deaminase deficiency (MAD) (OMIM • Excessive use of muscle force (e.g., sports, seizures, dystonia) • Muscle damage (e.g., crush, cold, ischemia, embolism) • Infections (bacterial/viral/fungal) • Temperature changes • Inflammatory myopathies (polymyositis, vasculitis) • Induction of an autoimmune reaction (e.g., cyclosporine, penicillamine) • Hypokalemia (amphotericin, caffeine) • Membrane disruption (cemitidin, colchicine) • Disturbance of Na/K ATPase (antidepressants, arsen, azathioprine, bezafibrates) • Neuroleptic syndrome (all neuroleptics, lithium) • Serotonergic syndrome (amphetamines, MAO-inhibitor, SSRI) • Defects of glucose/glycogen metabolism (e.g., • Defects of lipid metabolism (carnitine deficiency). Mitochondrial β-oxidation of long-chain fatty acids is a major source of energy production, particularly at times of stress or fasting. Skeletal muscle can use carbohydrates or lipids as fuel, depending on the degree of activity. At rest or during prolonged low-intensity exercise, approximately 70% of the energy requirement is met by the oxidation of long-chain fatty acids. Two defects of lipid metabolism primarily affecting the skeletal muscle are known: carnitine palmitoyltransferase II deficiency and • Defects of oxidative phosphorylation (complex II deficiency, complex III defect, cytochrome • • Malignant hyperthermia (See • Myoadenylate deaminase deficiency (MAD) (OMIM ## Management To establish the extent of disease and needs in an individual diagnosed with carnitine palmitoyltransferase II (CPT II) deficiency, the following are recommended: Neurologic examination Strength testing Review of dietary association of symptoms Consultation with a clinical geneticist and/or genetic counselor Current treatment for long-chain fatty-acid oxidation disorders: Avoid known triggers. Reduce the amount of long-chain dietary fat while covering the need for essential fatty acids. Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines. Provide a large fraction of calories as carbohydrates to reduce body fat utilization and prevent hypoglycemia. Provide approximately one third of the calories as even-chain medium chain triglycerides (MCT). Metabolism of the eight to ten carbon fatty acids in MCT oil, for example, is independent of CPT I, carnitine-acylcarnitine translocase, CPT II, very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein, and long-chain hydroxy-acyl-CoA dehydrogenase deficiency (LCHAD) enzyme activities. Appropriate measures include the following: Infusions of glucose during intercurrent infections to prevent catabolism Note: Oral glucose cannot achieve this effect. High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis Frequent meals and avoidance of extended fasting Avoidance of prolonged exercise and other known triggers The most important aim while treating an individual with CPT II deficiency is to prevent renal failure during an episode of rhabdomyolysis and myoglobinuria. Therefore, sufficient hydration and, if necessary, dialysis must be performed immediately when renal failure is imminent. Annual or more frequent monitoring to regulate medication and diet is indicated. Extended fasting and prolonged exercise are to be avoided. Reports of medication-induced side effects in individuals with CPT II deficiency are rare. Relying mostly on case reports, the following agents should be avoided: Valproic acid [ General anesthesia Ibuprofen Diazepam in high doses [ It is appropriate to evaluate apparently asymptomatic at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and treatment. In addition, predictive testing for at-risk asymptomatic family members may be advisable before general anesthesia. Complications of general anesthesia (including rhabdomyolysis and suxamethonium hypersensitivity in individuals with a variety of neuromuscular diseases and renal post-anesthetic failure in individuals with CPT II deficiency in particular) have been observed [ Molecular genetic testing is appropriate if the pathogenic variants in the family are known. If the pathogenic variants in the family are not known, screening for alterations in acylcarnitines may be of use to identify other affected family members. See While a variety of maternal complications have been observed in association with other fatty acid oxidation disorders (severe preeclampsia; acute fatty liver of pregnancy; maternal liver disease; and hemolysis, elevated liver enzymes, and low platelets), none of these complications has been associated with CPT II deficiency [ Promising results have been obtained with treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using anaplerotic odd-chain triglycerides [ Fibrates are a class of hypolipidemic drugs that increase high-density lipoprotein levels by mRNA upregulation of many lipid-metabolism genes through interaction with the steroid/thyroid transcription factor PPARa. Studies have demonstrated that bezafibrate increases Search Carnitine supplementation is essentially a cure for the carnitine membrane transporter defect. While oral carnitine supplementation of 50 mg/kg/d is often prescribed in the treatment of other fat oxidation disorders, controlled trials of its effectiveness in CPT II deficiency are lacking. In addition, carnitine administration is controversial, given the possibility of accumulation of acyl-CoAs and consequent depletion of free CoA in the mitochondria [ • Neurologic examination • Strength testing • Review of dietary association of symptoms • Consultation with a clinical geneticist and/or genetic counselor • Avoid known triggers. • Reduce the amount of long-chain dietary fat while covering the need for essential fatty acids. • Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines. • Provide a large fraction of calories as carbohydrates to reduce body fat utilization and prevent hypoglycemia. • Provide approximately one third of the calories as even-chain medium chain triglycerides (MCT). Metabolism of the eight to ten carbon fatty acids in MCT oil, for example, is independent of CPT I, carnitine-acylcarnitine translocase, CPT II, very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein, and long-chain hydroxy-acyl-CoA dehydrogenase deficiency (LCHAD) enzyme activities. • Infusions of glucose during intercurrent infections to prevent catabolism • Note: Oral glucose cannot achieve this effect. • High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis • Frequent meals and avoidance of extended fasting • Avoidance of prolonged exercise and other known triggers • Valproic acid [ • General anesthesia • Ibuprofen • Diazepam in high doses [ • Molecular genetic testing is appropriate if the pathogenic variants in the family are known. • If the pathogenic variants in the family are not known, screening for alterations in acylcarnitines may be of use to identify other affected family members. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with carnitine palmitoyltransferase II (CPT II) deficiency, the following are recommended: Neurologic examination Strength testing Review of dietary association of symptoms Consultation with a clinical geneticist and/or genetic counselor • Neurologic examination • Strength testing • Review of dietary association of symptoms • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Current treatment for long-chain fatty-acid oxidation disorders: Avoid known triggers. Reduce the amount of long-chain dietary fat while covering the need for essential fatty acids. Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines. Provide a large fraction of calories as carbohydrates to reduce body fat utilization and prevent hypoglycemia. Provide approximately one third of the calories as even-chain medium chain triglycerides (MCT). Metabolism of the eight to ten carbon fatty acids in MCT oil, for example, is independent of CPT I, carnitine-acylcarnitine translocase, CPT II, very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein, and long-chain hydroxy-acyl-CoA dehydrogenase deficiency (LCHAD) enzyme activities. • Avoid known triggers. • Reduce the amount of long-chain dietary fat while covering the need for essential fatty acids. • Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines. • Provide a large fraction of calories as carbohydrates to reduce body fat utilization and prevent hypoglycemia. • Provide approximately one third of the calories as even-chain medium chain triglycerides (MCT). Metabolism of the eight to ten carbon fatty acids in MCT oil, for example, is independent of CPT I, carnitine-acylcarnitine translocase, CPT II, very long-chain acyl-CoA dehydrogenase (VLCAD), trifunctional protein, and long-chain hydroxy-acyl-CoA dehydrogenase deficiency (LCHAD) enzyme activities. ## Prevention of Primary Manifestations Appropriate measures include the following: Infusions of glucose during intercurrent infections to prevent catabolism Note: Oral glucose cannot achieve this effect. High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis Frequent meals and avoidance of extended fasting Avoidance of prolonged exercise and other known triggers • Infusions of glucose during intercurrent infections to prevent catabolism • Note: Oral glucose cannot achieve this effect. • High-carbohydrate (70%) and low-fat (<20%) diet to provide fuel for glycolysis • Frequent meals and avoidance of extended fasting • Avoidance of prolonged exercise and other known triggers ## Prevention of Secondary Complications The most important aim while treating an individual with CPT II deficiency is to prevent renal failure during an episode of rhabdomyolysis and myoglobinuria. Therefore, sufficient hydration and, if necessary, dialysis must be performed immediately when renal failure is imminent. ## Surveillance Annual or more frequent monitoring to regulate medication and diet is indicated. ## Agents/Circumstances to Avoid Extended fasting and prolonged exercise are to be avoided. Reports of medication-induced side effects in individuals with CPT II deficiency are rare. Relying mostly on case reports, the following agents should be avoided: Valproic acid [ General anesthesia Ibuprofen Diazepam in high doses [ • Valproic acid [ • General anesthesia • Ibuprofen • Diazepam in high doses [ ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and treatment. In addition, predictive testing for at-risk asymptomatic family members may be advisable before general anesthesia. Complications of general anesthesia (including rhabdomyolysis and suxamethonium hypersensitivity in individuals with a variety of neuromuscular diseases and renal post-anesthetic failure in individuals with CPT II deficiency in particular) have been observed [ Molecular genetic testing is appropriate if the pathogenic variants in the family are known. If the pathogenic variants in the family are not known, screening for alterations in acylcarnitines may be of use to identify other affected family members. See • Molecular genetic testing is appropriate if the pathogenic variants in the family are known. • If the pathogenic variants in the family are not known, screening for alterations in acylcarnitines may be of use to identify other affected family members. ## Pregnancy Management While a variety of maternal complications have been observed in association with other fatty acid oxidation disorders (severe preeclampsia; acute fatty liver of pregnancy; maternal liver disease; and hemolysis, elevated liver enzymes, and low platelets), none of these complications has been associated with CPT II deficiency [ ## Therapies Under Investigation Promising results have been obtained with treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using anaplerotic odd-chain triglycerides [ Fibrates are a class of hypolipidemic drugs that increase high-density lipoprotein levels by mRNA upregulation of many lipid-metabolism genes through interaction with the steroid/thyroid transcription factor PPARa. Studies have demonstrated that bezafibrate increases Search ## Other Carnitine supplementation is essentially a cure for the carnitine membrane transporter defect. While oral carnitine supplementation of 50 mg/kg/d is often prescribed in the treatment of other fat oxidation disorders, controlled trials of its effectiveness in CPT II deficiency are lacking. In addition, carnitine administration is controversial, given the possibility of accumulation of acyl-CoAs and consequent depletion of free CoA in the mitochondria [ ## Genetic Counseling Carnitine palmitoyltransferase II (CPT II) 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 generally asymptomatic; however, manifesting carriers for the At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are generally asymptomatic. No data regarding the use of MS/MS for carrier detection are available. Carriers can be detected by measuring enzyme activity in muscle homogenates. Two unaffected carriers (parents), each carrying the common 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. Differences in perspective may exist among medical professionals if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. 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., carriers of one • Heterozygotes (carriers) are generally asymptomatic; however, manifesting carriers for the • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are generally asymptomatic. • No data regarding the use of MS/MS for carrier detection are available. • Carriers can be detected by measuring enzyme activity in muscle homogenates. Two unaffected carriers (parents), each carrying the common • 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 Carnitine palmitoyltransferase II (CPT II) 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 generally asymptomatic; however, manifesting carriers for the At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are generally asymptomatic. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are generally asymptomatic; however, manifesting carriers for the • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are generally asymptomatic. ## Carrier (Heterozygote) Detection No data regarding the use of MS/MS for carrier detection are available. Carriers can be detected by measuring enzyme activity in muscle homogenates. Two unaffected carriers (parents), each carrying the common • No data regarding the use of MS/MS for carrier detection are available. • Carriers can be detected by measuring enzyme activity in muscle homogenates. Two unaffected carriers (parents), each carrying the common ## 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 Differences in perspective may exist among medical professionals if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom United Kingdom • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • • • United Kingdom • • • ## Molecular Genetics Carnitine Palmitoyltransferase II Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Carnitine Palmitoyltransferase II Deficiency ( The carnitine palmitoyltransferase enzyme system (CPT), in conjunction with acyl-CoA synthetase and carnitine-acylcarnitine translocase, mediates the entry of long-chain fatty acids (LCFA) into the mitochondrial matrix for β-oxidation. CPT II, encoded by A so-called "common" variant, p.Ser113Leu, is present in exon 3 of p.Lys414ThrfsTer7 was found in subsequent studies in eight affected individuals and is therefore the second-most common variant [ Interestingly, the p.Phe448Leu amino acid substitution alone has no functional consequence [ Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions The two sequence variants are on the same allele; the p.Phe448Leu variant has no known functional significance. The crystal structure of rat carnitine palmitoyltransferase II has led to new insights into possible pathologic mechanisms. It was shown that the overall structure shows similarity to other carnitine acyltransferases with structural differences in the active sites, which may have an effect on substrate selectivity. Regarding the most frequently mutated residue, serine-113, • A so-called "common" variant, p.Ser113Leu, is present in exon 3 of • p.Lys414ThrfsTer7 was found in subsequent studies in eight affected individuals and is therefore the second-most common variant [ • Interestingly, the p.Phe448Leu amino acid substitution alone has no functional consequence [ ## Molecular Pathogenesis The carnitine palmitoyltransferase enzyme system (CPT), in conjunction with acyl-CoA synthetase and carnitine-acylcarnitine translocase, mediates the entry of long-chain fatty acids (LCFA) into the mitochondrial matrix for β-oxidation. CPT II, encoded by A so-called "common" variant, p.Ser113Leu, is present in exon 3 of p.Lys414ThrfsTer7 was found in subsequent studies in eight affected individuals and is therefore the second-most common variant [ Interestingly, the p.Phe448Leu amino acid substitution alone has no functional consequence [ Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions The two sequence variants are on the same allele; the p.Phe448Leu variant has no known functional significance. The crystal structure of rat carnitine palmitoyltransferase II has led to new insights into possible pathologic mechanisms. It was shown that the overall structure shows similarity to other carnitine acyltransferases with structural differences in the active sites, which may have an effect on substrate selectivity. Regarding the most frequently mutated residue, serine-113, • A so-called "common" variant, p.Ser113Leu, is present in exon 3 of • p.Lys414ThrfsTer7 was found in subsequent studies in eight affected individuals and is therefore the second-most common variant [ • Interestingly, the p.Phe448Leu amino acid substitution alone has no functional consequence [ ## Chapter Notes 3 January 2019 (aa) Revision: 16 March 2017 (ma) Comprehensive update posted live 15 May 2014 (me) Comprehensive update posted live 6 October 2011 (me) Comprehensive update posted live 25 June 2009 (me) Comprehensive update posted live 30 November 2006 (me) Comprehensive update posted live 27 August 2004 (me) Review posted live 7 October 2003 (tw) Original submission • 3 January 2019 (aa) Revision: • 16 March 2017 (ma) Comprehensive update posted live • 15 May 2014 (me) Comprehensive update posted live • 6 October 2011 (me) Comprehensive update posted live • 25 June 2009 (me) Comprehensive update posted live • 30 November 2006 (me) Comprehensive update posted live • 27 August 2004 (me) Review posted live • 7 October 2003 (tw) Original submission ## Revision History 3 January 2019 (aa) Revision: 16 March 2017 (ma) Comprehensive update posted live 15 May 2014 (me) Comprehensive update posted live 6 October 2011 (me) Comprehensive update posted live 25 June 2009 (me) Comprehensive update posted live 30 November 2006 (me) Comprehensive update posted live 27 August 2004 (me) Review posted live 7 October 2003 (tw) Original submission • 3 January 2019 (aa) Revision: • 16 March 2017 (ma) Comprehensive update posted live • 15 May 2014 (me) Comprehensive update posted live • 6 October 2011 (me) Comprehensive update posted live • 25 June 2009 (me) Comprehensive update posted live • 30 November 2006 (me) Comprehensive update posted live • 27 August 2004 (me) Review posted live • 7 October 2003 (tw) Original submission ## References ## Literature Cited
[]
27/8/2004
16/3/2017
3/1/2019
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
cranio-md
cranio-md
[ "Mineralization regulator ANKH", "ANKH", "Autosomal Dominant Craniometaphyseal Dysplasia" ]
Autosomal Dominant Craniometaphyseal Dysplasia
Ernst Reichenberger, I-Ping Chen
Summary Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, fullness of the paranasal tissue, hypertelorism with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum. Diagnosis is based on clinical and radiographic findings that include diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible as well as widening and radiolucency of metaphyses in long bones. Identification of a heterozygous pathogenic variant in By definition, AD-CMD is inherited in an autosomal dominant manner. Most individuals diagnosed with AD-CMD have an affected parent. The proportion of individuals with AD-CMD caused by a
## Diagnosis Formal diagnostic criteria for autosomal dominant craniometaphyseal dysplasia (AD-CMD) have not been established. AD-CMD Obstruction of the nasal sinuses Characteristic facial features. Wide nasal bridge, fullness of the paranasal tissue, hypertelorism with an increase in bizygomatic width, and prominent mandible (See Dolichocephaly due to fronto-occipital hyperostosis Note: Findings are based on very limited data. Variability of the described parameters can be expected. Abnormal parameters may be transient. The diagnosis of AD-CMD 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 laboratory findings suggest the diagnosis of AD-CMD, 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 hyperostosis, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 AD-CMD occurs through a gain-of-function/dominant-negative mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant. Some simplex cases of CMD did not have identifiable pathogenic variants in • Obstruction of the nasal sinuses • Characteristic facial features. Wide nasal bridge, fullness of the paranasal tissue, hypertelorism with an increase in bizygomatic width, and prominent mandible (See • Dolichocephaly due to fronto-occipital hyperostosis • For an introduction to multigene panels click ## Suggestive Findings AD-CMD Obstruction of the nasal sinuses Characteristic facial features. Wide nasal bridge, fullness of the paranasal tissue, hypertelorism with an increase in bizygomatic width, and prominent mandible (See Dolichocephaly due to fronto-occipital hyperostosis Note: Findings are based on very limited data. Variability of the described parameters can be expected. Abnormal parameters may be transient. • Obstruction of the nasal sinuses • Characteristic facial features. Wide nasal bridge, fullness of the paranasal tissue, hypertelorism with an increase in bizygomatic width, and prominent mandible (See • Dolichocephaly due to fronto-occipital hyperostosis ## Establishing the Diagnosis The diagnosis of AD-CMD 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 laboratory findings suggest the diagnosis of AD-CMD, 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 hyperostosis, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 AD-CMD occurs through a gain-of-function/dominant-negative mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant. Some simplex cases of CMD did not have identifiable pathogenic variants in • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of AD-CMD, 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 hyperostosis, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Craniometaphyseal Dysplasia See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 AD-CMD occurs through a gain-of-function/dominant-negative mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant. Some simplex cases of CMD did not have identifiable pathogenic variants in ## Clinical Characteristics Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is often detected within the first few weeks of life because of breathing or feeding problems resulting from choanal stenosis (narrowing of nasal sinus) [ Early stages of AD-CMD can be radiographically recognized as sclerosis of the cranial base [ Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural) as cranial hyperostosis and sclerosis progress [ Associated Chiari I malformation can lead to severe headaches [ Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone [ Malocclusion and anterior cross-bite can be caused by jaw overgrowth [ No clinically relevant genotype-phenotype correlation has been reported. The phenotypic severity (expressivity) in AD-CMD is variable even among affected members of the same family. Penetrance is 100%. AD-CMD was previously referred to as "craniometaphyseal dysplasia-Jackson type." AD-CMD is very rare; there are likely only a few thousand affected individuals worldwide. ## Clinical Description Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is often detected within the first few weeks of life because of breathing or feeding problems resulting from choanal stenosis (narrowing of nasal sinus) [ Early stages of AD-CMD can be radiographically recognized as sclerosis of the cranial base [ Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural) as cranial hyperostosis and sclerosis progress [ Associated Chiari I malformation can lead to severe headaches [ Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone [ Malocclusion and anterior cross-bite can be caused by jaw overgrowth [ ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlation has been reported. The phenotypic severity (expressivity) in AD-CMD is variable even among affected members of the same family. ## Penetrance Penetrance is 100%. ## Nomenclature AD-CMD was previously referred to as "craniometaphyseal dysplasia-Jackson type." ## Prevalence AD-CMD is very rare; there are likely only a few thousand affected individuals worldwide. ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in AD = autosomal dominant; AD-CMD = autosomal dominant craniometaphyseal dysplasia; AR = autosomal recessive; MOI = mode of inheritance ## Differential Diagnosis Genetic Disorders of Interest in the Differential Diagnosis of Autosomal Dominant Craniometaphyseal Dysplasia Short stature Delayed closure of anterior fontanelle Micrognathia Linear striations in long bones of females Diffuse osteosclerosis No metaphyseal flaring Progressive overgrowth of craniofacial bones w/deafness, facial palsy, & visual disturbance due to nerve entrapment Choanal stenosis is a clinically significant complication. Radiologically, cranial & facial bones are hyperostotic. Progressive skeletal overgrowth in skull & mandible Bossing of forehead & mandibular overgrowth becomes apparent in early childhood w/progression into adulthood. Hyperostosis of skull leads to narrowing of foramina & entrapment of 7th cranial nerve (causing facial palsy) w/other, less common nerve entrapment syndromes. Hyperostosis of calvarium decreases intracranial volume. Sclerosis in spine & pelvis 2-3 finger syndactyly Nail dysplasia No metaphyseal flaring Tall stature Cranial hyperostosis Cranial nerve compression causing facial palsy & loss of vision or hearing. Osteosclerosis includes clavicles & ribs Hyperphosphatasemia Long bone fractures Osteosclerosis, osteopetrosis No metaphyseal flaring AD = autosomal dominant; AD-CMD = autosomal dominant craniometaphyseal dysplasia; AR = autosomal recessive; CMD = craniometaphyseal dysplasia; MOI = mode of inheritance; XL = X-linked • Short stature • Delayed closure of anterior fontanelle • Micrognathia • Linear striations in long bones of females • Diffuse osteosclerosis • No metaphyseal flaring • Progressive overgrowth of craniofacial bones w/deafness, facial palsy, & visual disturbance due to nerve entrapment • Choanal stenosis is a clinically significant complication. • Radiologically, cranial & facial bones are hyperostotic. • Progressive skeletal overgrowth in skull & mandible • Bossing of forehead & mandibular overgrowth becomes apparent in early childhood w/progression into adulthood. • Hyperostosis of skull leads to narrowing of foramina & entrapment of 7th cranial nerve (causing facial palsy) w/other, less common nerve entrapment syndromes. • Hyperostosis of calvarium decreases intracranial volume. • Sclerosis in spine & pelvis • 2-3 finger syndactyly • Nail dysplasia • No metaphyseal flaring • Tall stature • Cranial hyperostosis • Cranial nerve compression causing facial palsy & loss of vision or hearing. • Osteosclerosis includes clavicles & ribs • Hyperphosphatasemia • Long bone fractures • Osteosclerosis, osteopetrosis • No metaphyseal flaring ## Management No clinical practice guidelines for autosomal dominant craniometaphyseal dysplasia (AD-CMD) 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 AD-CMD, the evaluations summarized in Autosomal Dominant Craniometaphyseal Dysplasia: Recommended Evaluations Following Initial Diagnosis Radiographs of skull, hands, & knees CT to evaluate involvement of foramina & foramen magnum Measure serum phosphorus to assess for hypophosphatemia in infancy. Assess for radiographic features of Rickets in infancy. AD-CMD = autosomal dominant craniometaphyseal dysplasia; CTX = carboxy-terminal collagen crosslinks; MOI = mode of inheritance; P1NP = procollagen type 1 N-terminal propeptide Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for AD-CMD. 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 Autosomal Dominant Craniometaphyseal Dysplasia: Treatment of Manifestations Surgical procedures can be technically difficult & bone regrowth is common. As severe complications have occurred, surgery is considered for conservative purposes to relieve severe symptoms caused by cranial nerve compression. Surgery for optic nerve impaction Vision aids To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Autosomal Dominant Craniometaphyseal Dysplasia: Recommended Surveillance It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Early diagnosis of at-risk relatives may be beneficial for management of complications from progressive hyperostosis. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Clinical evaluation and cranial and long bone radiographs if the pathogenic variant in the family is not known. See Search Calcitonin has been thought to be effective because of its inhibitory effect on bone turnover. However, previous case reports found calcitonin therapy to be ineffective in treating hyperplasia of craniofacial bones in persons with CMD [ Calcitriol with a low-calcium diet to stimulate bone resorption by promoting osteoclast formation has been reported to improve facial paralysis but has no effect on metaphyseal deformity [ Acetazolamide has been suggested for treatment of disorders with increased bone mineral density. • Radiographs of skull, hands, & knees • CT to evaluate involvement of foramina & foramen magnum • Measure serum phosphorus to assess for hypophosphatemia in infancy. • Assess for radiographic features of Rickets in infancy. • Surgical procedures can be technically difficult & bone regrowth is common. • As severe complications have occurred, surgery is considered for conservative purposes to relieve severe symptoms caused by cranial nerve compression. • Surgery for optic nerve impaction • Vision aids • Molecular genetic testing if the pathogenic variant in the family is known; • Clinical evaluation and cranial and long bone radiographs 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 AD-CMD, the evaluations summarized in Autosomal Dominant Craniometaphyseal Dysplasia: Recommended Evaluations Following Initial Diagnosis Radiographs of skull, hands, & knees CT to evaluate involvement of foramina & foramen magnum Measure serum phosphorus to assess for hypophosphatemia in infancy. Assess for radiographic features of Rickets in infancy. AD-CMD = autosomal dominant craniometaphyseal dysplasia; CTX = carboxy-terminal collagen crosslinks; MOI = mode of inheritance; P1NP = procollagen type 1 N-terminal propeptide Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Radiographs of skull, hands, & knees • CT to evaluate involvement of foramina & foramen magnum • Measure serum phosphorus to assess for hypophosphatemia in infancy. • Assess for radiographic features of Rickets in infancy. ## Treatment of Manifestations There is no cure for AD-CMD. 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 Autosomal Dominant Craniometaphyseal Dysplasia: Treatment of Manifestations Surgical procedures can be technically difficult & bone regrowth is common. As severe complications have occurred, surgery is considered for conservative purposes to relieve severe symptoms caused by cranial nerve compression. Surgery for optic nerve impaction Vision aids • Surgical procedures can be technically difficult & bone regrowth is common. • As severe complications have occurred, surgery is considered for conservative purposes to relieve severe symptoms caused by cranial nerve compression. • Surgery for optic nerve impaction • Vision aids ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Autosomal Dominant Craniometaphyseal Dysplasia: Recommended Surveillance ## Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Early diagnosis of at-risk relatives may be beneficial for management of complications from progressive hyperostosis. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Clinical evaluation and cranial and long bone radiographs if the pathogenic variant in the family is not known. See • Molecular genetic testing if the pathogenic variant in the family is known; • Clinical evaluation and cranial and long bone radiographs if the pathogenic variant in the family is not known. ## Therapies Under Investigation Search ## Other Calcitonin has been thought to be effective because of its inhibitory effect on bone turnover. However, previous case reports found calcitonin therapy to be ineffective in treating hyperplasia of craniofacial bones in persons with CMD [ Calcitriol with a low-calcium diet to stimulate bone resorption by promoting osteoclast formation has been reported to improve facial paralysis but has no effect on metaphyseal deformity [ Acetazolamide has been suggested for treatment of disorders with increased bone mineral density. ## Genetic Counseling By definition, autosomal dominant craniometaphyseal dysplasia (AD-CMD) is inherited in an autosomal dominant manner. Most individuals diagnosed with AD-CMD have an affected parent. Some individuals diagnosed with AD-CMD 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 a molecular diagnosis has not been established in the proband, clinical evaluation and cranial and long bone radiographs are recommended for the parents of the proband. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members. Therefore, If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent (and parental identity testing has confirmed biological maternity and paternity), the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because penetrance of AD-CMD is 100%, sibs who inherit a pathogenic variant will develop the phenotype, although the severity of the phenotype may vary among affected family members. 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 still increased over that of the general population because of the possibility of parental gonadal mosaicism. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Once the AD-CMD-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. • Most individuals diagnosed with AD-CMD have an affected parent. • Some individuals diagnosed with AD-CMD 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 a molecular diagnosis has not been established in the proband, clinical evaluation and cranial and long bone radiographs are recommended for the parents of the proband. • Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members. Therefore, • If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent (and parental identity testing has confirmed biological maternity and paternity), the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because penetrance of AD-CMD is 100%, sibs who inherit a pathogenic variant will develop the phenotype, although the severity of the phenotype may vary among affected family members. • 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 still increased over that of the general population because of the possibility of parental gonadal mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance By definition, autosomal dominant craniometaphyseal dysplasia (AD-CMD) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with AD-CMD have an affected parent. Some individuals diagnosed with AD-CMD 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 a molecular diagnosis has not been established in the proband, clinical evaluation and cranial and long bone radiographs are recommended for the parents of the proband. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members. Therefore, If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent (and parental identity testing has confirmed biological maternity and paternity), the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because penetrance of AD-CMD is 100%, sibs who inherit a pathogenic variant will develop the phenotype, although the severity of the phenotype may vary among affected family members. 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 still increased over that of the general population because of the possibility of parental gonadal mosaicism. • Most individuals diagnosed with AD-CMD have an affected parent. • Some individuals diagnosed with AD-CMD 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 a molecular diagnosis has not been established in the proband, clinical evaluation and cranial and long bone radiographs are recommended for the parents of the proband. • Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members. Therefore, • If a molecular diagnosis has been established in the proband and the pathogenic variant identified in the proband is not identified in either parent (and parental identity testing has confirmed biological maternity and paternity), the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because penetrance of AD-CMD is 100%, sibs who inherit a pathogenic variant will develop the phenotype, although the severity of the phenotype may vary among affected family members. • 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 still increased over that of the general population because of the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 AD-CMD-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 United Kingdom • • • • • • United Kingdom • • • • • ## Molecular Genetics Autosomal Dominant Craniometaphyseal Dysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Autosomal Dominant Craniometaphyseal Dysplasia ( In previous literature, ANKH was described as a transporter of intracellular pyrophosphate, a regulator of matrix (bone) mineralization. ## Molecular Pathogenesis In previous literature, ANKH was described as a transporter of intracellular pyrophosphate, a regulator of matrix (bone) mineralization. ## Chapter Notes 14 August 2025 (sw) Comprehensive update posted live 11 June 2020 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 27 August 2007 (me) Review posted live 25 May 2007 (er) Original submission • 14 August 2025 (sw) Comprehensive update posted live • 11 June 2020 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 27 August 2007 (me) Review posted live • 25 May 2007 (er) Original submission ## Revision History 14 August 2025 (sw) Comprehensive update posted live 11 June 2020 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 27 August 2007 (me) Review posted live 25 May 2007 (er) Original submission • 14 August 2025 (sw) Comprehensive update posted live • 11 June 2020 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 27 August 2007 (me) Review posted live • 25 May 2007 (er) Original submission ## References ## Literature Cited Facial features of a girl age 13 years with AD-CMD Reprinted with permission from Increased thickness of craniofacial bones in a child age three years with AD-CMD Metaphyseal widening of long bones, specifically prominent at the knee joint
[]
27/8/2007
14/8/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
craniosynostosis
craniosynostosis
[ "FGFR Acrocephalosyndactyly", "FGFR Acrocephalosyndactyly", "FGFR2-Related Craniosynostosis", "FGFR1-Related Craniosynostosis", "FGFR3-Related Craniosynostosis", "Fibroblast growth factor receptor 1", "Fibroblast growth factor receptor 2", "Fibroblast growth factor receptor 3", "FGFR1", "FGFR2", "FGFR3", "FGFR Craniosynostosis Syndromes", "Overview" ]
Tara Wenger, Danny Miller, Kelly Evans
Summary The purpose of this overview is to: Describe the Review the Provide an Summarize current Inform
## Clinical Characteristics of To date, more than 500 individuals with an Apert syndrome Beare-Stevenson cutis gyrata syndrome Bent bone dysplasia Crouzon syndrome Crouzon syndrome with acanthosis nigricans Jackson-Weiss syndrome Muenke syndrome Pfeiffer syndrome Isolated coronal synostosis Considerable phenotypic overlap notwithstanding, discriminating features can aid in the specific diagnosis (see Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) Ovarian dysgerminoma (1 individual) [ Intellect. Normal Craniofacial. Unilateral or bilateral coronal synostosis, asymmetric brachycephaly and/or orbital hypertelorism Extremities. Normal Distinguishing Characteristics of Midface retrusion, proptosis Cleft palate CHL Dental anomalies Multilevel airway obstruction Soft tissue & bony syndactyly w/or w/o polydactyly of fingers & toes Synonychia ID (~50%) Stable ventriculomegaly (>50%) Chiari I, absent septum pellucidum, agenesis corpus callosum Vertebral fusions (often C5-C6) Hyperhidrosis Acne Nail dystrophy Severe midface retrusion w/proptosis Cleft palate CHL Natal teeth Multilevel airway obstruction ID (100%) Hydrocephalus Chiari I High rate of neonatal death Cutis gyrata Acanthosis nigricans Hirsutism Open metopic suture Hypertelorism Midface hypoplasia Prenatal teeth Low-set ears Brachydactyly Bony nodules on phalanges & metacarpals Hepatosplenomegaly Clitoromegaly Hirsutism Variable midface retrusion & proptosis ↑ w/age. CHL & SNHL ± airway obstruction Hydrocephalus Chiari I ID uncommon Variable midface retrusion & proptosis ↑ w/age. CHL & SNHL ± airway obstruction Hydrocephalus Chiari I ID uncommon Proptosis CHL ± multilevel airway obstruction Broad medially deviated great toes, 2/3 syndactyly, tarsal &/or metatarsal fusion Normal hands Variable midface retrusion & proptosis SNHL Brachydactyly Carpal & tarsal fusions DD (66%) ID (36%) ADHD (24%) Seizures (20%) Most w/ moderate to severe midface retrusion & proptosis CHL ± multilevel airway obstruction Broad medially deviated thumbs & great toes ± brachydactyly Hydrocephalus Chiari I ID 1 ± fusions at elbows and knees ± sacral appendage Proptosis if bicoronal craniosynostosis Variable midface retrusion ADHD = attention-deficit/hyperactivity disorder; CHL = conductive hearing loss; DD = developmental delay; ID = intellectual disability; SNHL = sensorineural hearing loss Intellectual disability is common in those with severe craniosynostosis but may be lessened with aggressive medical and surgical management of cephalocranial disproportion and sleep apnea. Infants with Common complications that affect medical management for Unicoronal craniosynostosis results in asymmetric forehead with nasal twist and harlequin eye deformity. Bicoronal craniosynostosis results in turribrachycephaly. Multisuture craniosynostosis results in a variable head shape determined by the involved sutures, presence of hydrocephalus, and timing of premature fusion. The shape of the skull results from the pressure of the developing brain expanding outwards into the space allowed by the skull. There is typically expansion perpendicular to the fused suture. When multiple sutures are fused, expansion occurs into the portion of the skull with least resistance, resulting in predictable head shapes. Prenatal pansynostosis results in a cloverleaf ( Palatal anomalies affecting the quality of suck (e.g., high arched palate, narrow palate, cleft palate) Respiratory difficulties due to airway obstruction (e.g., choanal stenosis, choanal atresia, tracheomalacia, laryngomalacia). Infants with choanal stenosis or atresia attempt to latch but abruptly unlatch to breathe through their mouth. The degree of narrowing of the bony passage correlates with the amount of time an infant can attempt to suck before unlatching. Ascending and/or descending aspiration Coordination difficulties with sucking, swallowing, and breathing, which may be seen without other signs of neurologic dysfunction Severe neurologic dysfunction (e.g., severe hydrocephalus, symptomatic Chiari I malformation) Gastrointestinal issues (e.g., pyloric stenosis, malrotation, volvulus) Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis. For infants with choanal stenosis respiratory difficulty can increase over time as the bony passage remains relatively stable but the lung tidal volumes increase with growth. Infants with choanal stenosis may gradually require more time to finish a smaller volume. Nasal flaring, retractions, and repeated unlatching during a feeding with mouth breathing can be seen. Tongue-based airway obstruction, which may be exacerbated in infants with cleft palate after palate repair Tracheal anomalies including fused rings and tracheal cartilaginous sleeves. Tracheal cartilaginous sleeves are often asymptomatic but pose a significant risk of sudden death caused by obstruction of the airway with mucous during illness. Tracheal cartilaginous sleeves can be identified during operative airway evaluation, as recommended for all children with a multisuture craniosynostosis syndrome [ Airway inflammation as a result of chronic aspiration Central sleep apnea is more common in children with Chiari I malformation and/or significant hydrocephalus. Children with Pfeiffer syndrome as a result of Individuals with mild involvement of the bony orbit may have downslanted palpebral fissures. Other ophthalmologic abnormalities include strabismus, refractive error, anisometropia, iris hypoplasia, and posterior embryotoxon [ In individuals with increased intracranial pressure – particularly if there is not prompt and aggressive intervention – papilledema can occur, leading to optic atrophy and loss of vision. Structural brain anomalies are more common in individuals with Apert syndrome, including abnormalities of the corpus callosum, absent septum pellucidum, posterior fossa arachnoid cyst, and limbic malformations. Chiari I malformations and/or low-lying cerebellar tonsils can be seen, and 73% of those with Crouzon syndrome have been reported to have chronic tonsillar herniation. This is in stark contrast to Apert syndrome, where only 2% have chronic tonsillar herniation. Craniosynostosis can be primary or secondary. In primary craniosynostosis, abnormal biology of the suture causes premature suture closure, as in In secondary craniosynostosis, the suture biology is normal, but abnormal external forces result in premature suture closure. Single-suture craniosynostosis results in recognizable head shapes: metopic (trigonocephaly), sagittal (scaphocephaly), lambdoid (posterior asymmetric flattening with vertical displacement of one ear and tilt of skull base), unicoronal (asymmetric forehead with nasal twist and harlequin eye deformity), and bicoronal (turribrachycephaly). Among 204 individuals with apparently nonsyndromic and nonfamilial single-suture craniosynostosis, the likelihood of finding an underlying genetic difference varied by suture involvement [ Note: (1) Those with apparently isolated synostosis of the lambdoid, sagittal, or metopic sutures had no pathogenic variants identified [ Craniosynostosis is a finding in more than 150 genetic disorders. Additional syndromes that should be considered are included in Syndromes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked See • Apert syndrome • Beare-Stevenson cutis gyrata syndrome • Bent bone dysplasia • Crouzon syndrome • Crouzon syndrome with acanthosis nigricans • Jackson-Weiss syndrome • Muenke syndrome • Pfeiffer syndrome • Isolated coronal synostosis • • Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 • Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) • Ovarian dysgerminoma (1 individual) [ • Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 • Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) • Ovarian dysgerminoma (1 individual) [ • Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 • Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) • Ovarian dysgerminoma (1 individual) [ • Intellect. Normal • Craniofacial. Unilateral or bilateral coronal synostosis, asymmetric brachycephaly and/or orbital hypertelorism • Extremities. Normal • Midface retrusion, proptosis • Cleft palate • CHL • Dental anomalies • Multilevel airway obstruction • Soft tissue & bony syndactyly w/or w/o polydactyly of fingers & toes • Synonychia • ID (~50%) • Stable ventriculomegaly (>50%) • Chiari I, absent septum pellucidum, agenesis corpus callosum • Vertebral fusions (often C5-C6) • Hyperhidrosis • Acne • Nail dystrophy • Severe midface retrusion w/proptosis • Cleft palate • CHL • Natal teeth • Multilevel airway obstruction • ID (100%) • Hydrocephalus • Chiari I • High rate of neonatal death • Cutis gyrata • Acanthosis nigricans • Hirsutism • Open metopic suture • Hypertelorism • Midface hypoplasia • Prenatal teeth • Low-set ears • Brachydactyly • Bony nodules on phalanges & metacarpals • Hepatosplenomegaly • Clitoromegaly • Hirsutism • Variable midface retrusion & proptosis ↑ w/age. • CHL & SNHL • ± airway obstruction • Hydrocephalus • Chiari I • ID uncommon • Variable midface retrusion & proptosis ↑ w/age. • CHL & SNHL • ± airway obstruction • Hydrocephalus • Chiari I • ID uncommon • Proptosis • CHL • ± multilevel airway obstruction • Broad medially deviated great toes, 2/3 syndactyly, tarsal &/or metatarsal fusion • Normal hands • Variable midface retrusion & proptosis • SNHL • Brachydactyly • Carpal & tarsal fusions • DD (66%) • ID (36%) • ADHD (24%) • Seizures (20%) • Most w/ moderate to severe midface retrusion & proptosis • CHL • ± multilevel airway obstruction • Broad medially deviated thumbs & great toes • ± brachydactyly • Hydrocephalus • Chiari I • ID 1 • ± fusions at elbows and knees • ± sacral appendage • Proptosis if bicoronal craniosynostosis • Variable midface retrusion • Palatal anomalies affecting the quality of suck (e.g., high arched palate, narrow palate, cleft palate) • Respiratory difficulties due to airway obstruction (e.g., choanal stenosis, choanal atresia, tracheomalacia, laryngomalacia). Infants with choanal stenosis or atresia attempt to latch but abruptly unlatch to breathe through their mouth. The degree of narrowing of the bony passage correlates with the amount of time an infant can attempt to suck before unlatching. • Ascending and/or descending aspiration • Coordination difficulties with sucking, swallowing, and breathing, which may be seen without other signs of neurologic dysfunction • Severe neurologic dysfunction (e.g., severe hydrocephalus, symptomatic Chiari I malformation) • Gastrointestinal issues (e.g., pyloric stenosis, malrotation, volvulus) • Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis. For infants with choanal stenosis respiratory difficulty can increase over time as the bony passage remains relatively stable but the lung tidal volumes increase with growth. Infants with choanal stenosis may gradually require more time to finish a smaller volume. Nasal flaring, retractions, and repeated unlatching during a feeding with mouth breathing can be seen. • Tongue-based airway obstruction, which may be exacerbated in infants with cleft palate after palate repair • Tracheal anomalies including fused rings and tracheal cartilaginous sleeves. Tracheal cartilaginous sleeves are often asymptomatic but pose a significant risk of sudden death caused by obstruction of the airway with mucous during illness. Tracheal cartilaginous sleeves can be identified during operative airway evaluation, as recommended for all children with a multisuture craniosynostosis syndrome [ • Airway inflammation as a result of chronic aspiration ## Clinical Description To date, more than 500 individuals with an Apert syndrome Beare-Stevenson cutis gyrata syndrome Bent bone dysplasia Crouzon syndrome Crouzon syndrome with acanthosis nigricans Jackson-Weiss syndrome Muenke syndrome Pfeiffer syndrome Isolated coronal synostosis Considerable phenotypic overlap notwithstanding, discriminating features can aid in the specific diagnosis (see Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) Ovarian dysgerminoma (1 individual) [ Intellect. Normal Craniofacial. Unilateral or bilateral coronal synostosis, asymmetric brachycephaly and/or orbital hypertelorism Extremities. Normal Distinguishing Characteristics of Midface retrusion, proptosis Cleft palate CHL Dental anomalies Multilevel airway obstruction Soft tissue & bony syndactyly w/or w/o polydactyly of fingers & toes Synonychia ID (~50%) Stable ventriculomegaly (>50%) Chiari I, absent septum pellucidum, agenesis corpus callosum Vertebral fusions (often C5-C6) Hyperhidrosis Acne Nail dystrophy Severe midface retrusion w/proptosis Cleft palate CHL Natal teeth Multilevel airway obstruction ID (100%) Hydrocephalus Chiari I High rate of neonatal death Cutis gyrata Acanthosis nigricans Hirsutism Open metopic suture Hypertelorism Midface hypoplasia Prenatal teeth Low-set ears Brachydactyly Bony nodules on phalanges & metacarpals Hepatosplenomegaly Clitoromegaly Hirsutism Variable midface retrusion & proptosis ↑ w/age. CHL & SNHL ± airway obstruction Hydrocephalus Chiari I ID uncommon Variable midface retrusion & proptosis ↑ w/age. CHL & SNHL ± airway obstruction Hydrocephalus Chiari I ID uncommon Proptosis CHL ± multilevel airway obstruction Broad medially deviated great toes, 2/3 syndactyly, tarsal &/or metatarsal fusion Normal hands Variable midface retrusion & proptosis SNHL Brachydactyly Carpal & tarsal fusions DD (66%) ID (36%) ADHD (24%) Seizures (20%) Most w/ moderate to severe midface retrusion & proptosis CHL ± multilevel airway obstruction Broad medially deviated thumbs & great toes ± brachydactyly Hydrocephalus Chiari I ID 1 ± fusions at elbows and knees ± sacral appendage Proptosis if bicoronal craniosynostosis Variable midface retrusion ADHD = attention-deficit/hyperactivity disorder; CHL = conductive hearing loss; DD = developmental delay; ID = intellectual disability; SNHL = sensorineural hearing loss Intellectual disability is common in those with severe craniosynostosis but may be lessened with aggressive medical and surgical management of cephalocranial disproportion and sleep apnea. Infants with • Apert syndrome • Beare-Stevenson cutis gyrata syndrome • Bent bone dysplasia • Crouzon syndrome • Crouzon syndrome with acanthosis nigricans • Jackson-Weiss syndrome • Muenke syndrome • Pfeiffer syndrome • Isolated coronal synostosis • • Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 • Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) • Ovarian dysgerminoma (1 individual) [ • Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 • Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) • Ovarian dysgerminoma (1 individual) [ • Fused cervical and/or thoracic vertebrae (68%), usually C5-C6 • Cardiac anomalies (10%) (e.g., ventricular septal defect, overriding aorta) • Ovarian dysgerminoma (1 individual) [ • Intellect. Normal • Craniofacial. Unilateral or bilateral coronal synostosis, asymmetric brachycephaly and/or orbital hypertelorism • Extremities. Normal • Midface retrusion, proptosis • Cleft palate • CHL • Dental anomalies • Multilevel airway obstruction • Soft tissue & bony syndactyly w/or w/o polydactyly of fingers & toes • Synonychia • ID (~50%) • Stable ventriculomegaly (>50%) • Chiari I, absent septum pellucidum, agenesis corpus callosum • Vertebral fusions (often C5-C6) • Hyperhidrosis • Acne • Nail dystrophy • Severe midface retrusion w/proptosis • Cleft palate • CHL • Natal teeth • Multilevel airway obstruction • ID (100%) • Hydrocephalus • Chiari I • High rate of neonatal death • Cutis gyrata • Acanthosis nigricans • Hirsutism • Open metopic suture • Hypertelorism • Midface hypoplasia • Prenatal teeth • Low-set ears • Brachydactyly • Bony nodules on phalanges & metacarpals • Hepatosplenomegaly • Clitoromegaly • Hirsutism • Variable midface retrusion & proptosis ↑ w/age. • CHL & SNHL • ± airway obstruction • Hydrocephalus • Chiari I • ID uncommon • Variable midface retrusion & proptosis ↑ w/age. • CHL & SNHL • ± airway obstruction • Hydrocephalus • Chiari I • ID uncommon • Proptosis • CHL • ± multilevel airway obstruction • Broad medially deviated great toes, 2/3 syndactyly, tarsal &/or metatarsal fusion • Normal hands • Variable midface retrusion & proptosis • SNHL • Brachydactyly • Carpal & tarsal fusions • DD (66%) • ID (36%) • ADHD (24%) • Seizures (20%) • Most w/ moderate to severe midface retrusion & proptosis • CHL • ± multilevel airway obstruction • Broad medially deviated thumbs & great toes • ± brachydactyly • Hydrocephalus • Chiari I • ID 1 • ± fusions at elbows and knees • ± sacral appendage • Proptosis if bicoronal craniosynostosis • Variable midface retrusion ## Clinical Complications Common complications that affect medical management for Unicoronal craniosynostosis results in asymmetric forehead with nasal twist and harlequin eye deformity. Bicoronal craniosynostosis results in turribrachycephaly. Multisuture craniosynostosis results in a variable head shape determined by the involved sutures, presence of hydrocephalus, and timing of premature fusion. The shape of the skull results from the pressure of the developing brain expanding outwards into the space allowed by the skull. There is typically expansion perpendicular to the fused suture. When multiple sutures are fused, expansion occurs into the portion of the skull with least resistance, resulting in predictable head shapes. Prenatal pansynostosis results in a cloverleaf ( Palatal anomalies affecting the quality of suck (e.g., high arched palate, narrow palate, cleft palate) Respiratory difficulties due to airway obstruction (e.g., choanal stenosis, choanal atresia, tracheomalacia, laryngomalacia). Infants with choanal stenosis or atresia attempt to latch but abruptly unlatch to breathe through their mouth. The degree of narrowing of the bony passage correlates with the amount of time an infant can attempt to suck before unlatching. Ascending and/or descending aspiration Coordination difficulties with sucking, swallowing, and breathing, which may be seen without other signs of neurologic dysfunction Severe neurologic dysfunction (e.g., severe hydrocephalus, symptomatic Chiari I malformation) Gastrointestinal issues (e.g., pyloric stenosis, malrotation, volvulus) Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis. For infants with choanal stenosis respiratory difficulty can increase over time as the bony passage remains relatively stable but the lung tidal volumes increase with growth. Infants with choanal stenosis may gradually require more time to finish a smaller volume. Nasal flaring, retractions, and repeated unlatching during a feeding with mouth breathing can be seen. Tongue-based airway obstruction, which may be exacerbated in infants with cleft palate after palate repair Tracheal anomalies including fused rings and tracheal cartilaginous sleeves. Tracheal cartilaginous sleeves are often asymptomatic but pose a significant risk of sudden death caused by obstruction of the airway with mucous during illness. Tracheal cartilaginous sleeves can be identified during operative airway evaluation, as recommended for all children with a multisuture craniosynostosis syndrome [ Airway inflammation as a result of chronic aspiration Central sleep apnea is more common in children with Chiari I malformation and/or significant hydrocephalus. Children with Pfeiffer syndrome as a result of Individuals with mild involvement of the bony orbit may have downslanted palpebral fissures. Other ophthalmologic abnormalities include strabismus, refractive error, anisometropia, iris hypoplasia, and posterior embryotoxon [ In individuals with increased intracranial pressure – particularly if there is not prompt and aggressive intervention – papilledema can occur, leading to optic atrophy and loss of vision. Structural brain anomalies are more common in individuals with Apert syndrome, including abnormalities of the corpus callosum, absent septum pellucidum, posterior fossa arachnoid cyst, and limbic malformations. Chiari I malformations and/or low-lying cerebellar tonsils can be seen, and 73% of those with Crouzon syndrome have been reported to have chronic tonsillar herniation. This is in stark contrast to Apert syndrome, where only 2% have chronic tonsillar herniation. • Palatal anomalies affecting the quality of suck (e.g., high arched palate, narrow palate, cleft palate) • Respiratory difficulties due to airway obstruction (e.g., choanal stenosis, choanal atresia, tracheomalacia, laryngomalacia). Infants with choanal stenosis or atresia attempt to latch but abruptly unlatch to breathe through their mouth. The degree of narrowing of the bony passage correlates with the amount of time an infant can attempt to suck before unlatching. • Ascending and/or descending aspiration • Coordination difficulties with sucking, swallowing, and breathing, which may be seen without other signs of neurologic dysfunction • Severe neurologic dysfunction (e.g., severe hydrocephalus, symptomatic Chiari I malformation) • Gastrointestinal issues (e.g., pyloric stenosis, malrotation, volvulus) • Narrowed nasal passages as a result of bony atresia or stenosis, including choanal atresia or stenosis. For infants with choanal stenosis respiratory difficulty can increase over time as the bony passage remains relatively stable but the lung tidal volumes increase with growth. Infants with choanal stenosis may gradually require more time to finish a smaller volume. Nasal flaring, retractions, and repeated unlatching during a feeding with mouth breathing can be seen. • Tongue-based airway obstruction, which may be exacerbated in infants with cleft palate after palate repair • Tracheal anomalies including fused rings and tracheal cartilaginous sleeves. Tracheal cartilaginous sleeves are often asymptomatic but pose a significant risk of sudden death caused by obstruction of the airway with mucous during illness. Tracheal cartilaginous sleeves can be identified during operative airway evaluation, as recommended for all children with a multisuture craniosynostosis syndrome [ • Airway inflammation as a result of chronic aspiration ## Differential Diagnosis Craniosynostosis can be primary or secondary. In primary craniosynostosis, abnormal biology of the suture causes premature suture closure, as in In secondary craniosynostosis, the suture biology is normal, but abnormal external forces result in premature suture closure. Single-suture craniosynostosis results in recognizable head shapes: metopic (trigonocephaly), sagittal (scaphocephaly), lambdoid (posterior asymmetric flattening with vertical displacement of one ear and tilt of skull base), unicoronal (asymmetric forehead with nasal twist and harlequin eye deformity), and bicoronal (turribrachycephaly). Among 204 individuals with apparently nonsyndromic and nonfamilial single-suture craniosynostosis, the likelihood of finding an underlying genetic difference varied by suture involvement [ Note: (1) Those with apparently isolated synostosis of the lambdoid, sagittal, or metopic sutures had no pathogenic variants identified [ Craniosynostosis is a finding in more than 150 genetic disorders. Additional syndromes that should be considered are included in Syndromes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked See ## Isolated Primary Craniosynostosis Single-suture craniosynostosis results in recognizable head shapes: metopic (trigonocephaly), sagittal (scaphocephaly), lambdoid (posterior asymmetric flattening with vertical displacement of one ear and tilt of skull base), unicoronal (asymmetric forehead with nasal twist and harlequin eye deformity), and bicoronal (turribrachycephaly). Among 204 individuals with apparently nonsyndromic and nonfamilial single-suture craniosynostosis, the likelihood of finding an underlying genetic difference varied by suture involvement [ Note: (1) Those with apparently isolated synostosis of the lambdoid, sagittal, or metopic sutures had no pathogenic variants identified [ ## Syndromic Primary Craniosynostosis Craniosynostosis is a finding in more than 150 genetic disorders. Additional syndromes that should be considered are included in Syndromes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked See ## Causes of Three genes, Molecular Genetics of Craniosynostosis Syndromes It is unclear whether individuals reported to have ## Evaluation Strategies to Identify the Genetic Cause of an An Establishing a specific genetic cause of an Can aid in discussions of prognosis (which are beyond the scope of this Is based on clinical and radiologic findings and the identification of a pathogenic variant in Note: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing. An A physical examination should include standard growth parameters (height, weight, head circumference) and address the following key issues: Abnormal head shape to evaluate for craniosynostosis as well as bulging fontanelle, which could suggest increased intracranial pressure Orbital protection and particular attention to whether the lids fully cover the eyes during sleep Nasal flaring, retractions or other signs of obstructive breathing, or inability to pass a nasogastric tube or suction catheter, suggestive of choanal stenosis/atresia Careful examination of hands and feet for polysyndactyly or thumb anomalies Range of motion of elbows and knees to evaluate for radioulnar synostosis and/or joint contractures Genitourinary exam for sacral appendage or other anomalies A three-generation family history should be taken, with attention to relatives with clinical and radiographic manifestations of an Approaches include 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 • Is based on clinical and radiologic findings and the identification of a pathogenic variant in • Note: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing. • Abnormal head shape to evaluate for craniosynostosis as well as bulging fontanelle, which could suggest increased intracranial pressure • Orbital protection and particular attention to whether the lids fully cover the eyes during sleep • Nasal flaring, retractions or other signs of obstructive breathing, or inability to pass a nasogastric tube or suction catheter, suggestive of choanal stenosis/atresia • Careful examination of hands and feet for polysyndactyly or thumb anomalies • Range of motion of elbows and knees to evaluate for radioulnar synostosis and/or joint contractures • Genitourinary exam for sacral appendage or other anomalies ## Medical History An ## Physical Examination A physical examination should include standard growth parameters (height, weight, head circumference) and address the following key issues: Abnormal head shape to evaluate for craniosynostosis as well as bulging fontanelle, which could suggest increased intracranial pressure Orbital protection and particular attention to whether the lids fully cover the eyes during sleep Nasal flaring, retractions or other signs of obstructive breathing, or inability to pass a nasogastric tube or suction catheter, suggestive of choanal stenosis/atresia Careful examination of hands and feet for polysyndactyly or thumb anomalies Range of motion of elbows and knees to evaluate for radioulnar synostosis and/or joint contractures Genitourinary exam for sacral appendage or other anomalies • Abnormal head shape to evaluate for craniosynostosis as well as bulging fontanelle, which could suggest increased intracranial pressure • Orbital protection and particular attention to whether the lids fully cover the eyes during sleep • Nasal flaring, retractions or other signs of obstructive breathing, or inability to pass a nasogastric tube or suction catheter, suggestive of choanal stenosis/atresia • Careful examination of hands and feet for polysyndactyly or thumb anomalies • Range of motion of elbows and knees to evaluate for radioulnar synostosis and/or joint contractures • Genitourinary exam for sacral appendage or other anomalies ## Family History A three-generation family history should be taken, with attention to relatives with clinical and radiographic manifestations of an ## Molecular Genetic Testing Approaches include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click ## Management of Individuals with an To establish the extent of disease and needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis in Individuals with CNS = central nervous system Individuals with an Treatment of Manifestations in Individuals with Typically in childhood or adolescence Early midface advancement may be pursued to treat airway obstruction. Specific airway management depends on level & severity of obstruction. Residual OSA after soft tissue & skeletal procedures is common. Placement of nasal stents Endotracheal intubation Tracheotomy OSA = obstructive sleep apnea Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased intracranial pressure and reduce progressive abnormal craniofacial development. Several techniques including endoscopic strip craniectomy, advancement through posterior distraction, and traditional cranioplasty are in current use. It is important to delay traditional anterior cranial fronto-orbital advancement until as late as possible in syndromic cases because of a high rate of relapse when done at early ages. Thus, early posterior cranial expansion can be used early in life to minimize progression of the anterior deformity. Early distraction osteogenesis can be a temporizing measure to allow subsequent traditional surgeries to be performed at a favorable age [ Early surgery may be performed to reduce intracranial pressure; however, young infants with Apert syndrome may have minimal physiologic reserve, which may affect surgical outcomes. Later surgeries tend to lead to a more stable bony correction [ A staged approach to increase intracranial volume and protect the globes is often pursued, and most children with bicoronal craniosynostosis benefit from a fronto-orbital advancement. The goals of craniofacial surgery are to provide adequate intracranial volume to allow brain development and to improve head shape. The timing and sequence of surgical interventions are dependent on the individual's functional, aesthetic, and psychological needs [ Timing of jaw surgery is guided by the affected individual's occlusion and degree of airway obstruction. Compared with Le Fort III distraction, Le Fort II distraction with simultaneous repositioning of the zygomas improves the facial and orbital relationships for older children with Apert syndrome [ Serious caution must be taken in the placement and care of tracheostomies in individuals with tracheal cartilaginous sleeves because of abnormal tissue healing and granulation tissue formation [ Recent studies describe novel techniques to improve aesthetic outcomes in children with complex syndactylies [ Evidence suggests that oral isotretinoin may be more effective than standard therapies, and biologic models support a role for isotretinoin in regulating androgens and Suggested areas of focus include the parents' and family's emotional, social, and financial needs; the child's neurocognitive development and educational needs; and potential barriers to care [ Note: (1) For recommended surveillance for Muenke syndrome, see Recommended Surveillance for Individuals with Close monitoring of head circumference / head growth Eval for signs of ↑ intracranial pressure (e.g., headaches, vomiting) Consider cervical spine CT when head CT is obtained. Consider radiographs at age 3-4 yrs to evaluate for progressive C-spine fusion. At age ~18 mos, then annually Additional speech assessments before & after midface surgeries Individuals with cervical spine anomalies may be at risk for spinal cord injury with hyperextension and may require fiberoptic intubation and/or sports restrictions for activities that pose a risk for head/neck injury. Individuals with exophthalmos may require protective eyewear during activities with risk of eye injury (e.g., ball sports). It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from who would benefit from early surveillance and intervention. Evaluations can include the following: Molecular genetic testing if the Assessment based on clinical and radiographic criteria (Note: Manifestations may not be readily evident in all affected individuals.) See Pregnant women carrying fetuses affected by See Search • Typically in childhood or adolescence • Early midface advancement may be pursued to treat airway obstruction. • Specific airway management depends on level & severity of obstruction. • Residual OSA after soft tissue & skeletal procedures is common. • Placement of nasal stents • Endotracheal intubation • Tracheotomy • Close monitoring of head circumference / head growth • Eval for signs of ↑ intracranial pressure (e.g., headaches, vomiting) • Consider cervical spine CT when head CT is obtained. • Consider radiographs at age 3-4 yrs to evaluate for progressive C-spine fusion. • At age ~18 mos, then annually • Additional speech assessments before & after midface surgeries • Molecular genetic testing if the • Assessment based on clinical and radiographic criteria (Note: Manifestations may not be readily evident in all affected individuals.) ## 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 CNS = central nervous system ## Treatment of Manifestations Individuals with an Treatment of Manifestations in Individuals with Typically in childhood or adolescence Early midface advancement may be pursued to treat airway obstruction. Specific airway management depends on level & severity of obstruction. Residual OSA after soft tissue & skeletal procedures is common. Placement of nasal stents Endotracheal intubation Tracheotomy OSA = obstructive sleep apnea Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased intracranial pressure and reduce progressive abnormal craniofacial development. Several techniques including endoscopic strip craniectomy, advancement through posterior distraction, and traditional cranioplasty are in current use. It is important to delay traditional anterior cranial fronto-orbital advancement until as late as possible in syndromic cases because of a high rate of relapse when done at early ages. Thus, early posterior cranial expansion can be used early in life to minimize progression of the anterior deformity. Early distraction osteogenesis can be a temporizing measure to allow subsequent traditional surgeries to be performed at a favorable age [ Early surgery may be performed to reduce intracranial pressure; however, young infants with Apert syndrome may have minimal physiologic reserve, which may affect surgical outcomes. Later surgeries tend to lead to a more stable bony correction [ A staged approach to increase intracranial volume and protect the globes is often pursued, and most children with bicoronal craniosynostosis benefit from a fronto-orbital advancement. The goals of craniofacial surgery are to provide adequate intracranial volume to allow brain development and to improve head shape. The timing and sequence of surgical interventions are dependent on the individual's functional, aesthetic, and psychological needs [ Timing of jaw surgery is guided by the affected individual's occlusion and degree of airway obstruction. Compared with Le Fort III distraction, Le Fort II distraction with simultaneous repositioning of the zygomas improves the facial and orbital relationships for older children with Apert syndrome [ Serious caution must be taken in the placement and care of tracheostomies in individuals with tracheal cartilaginous sleeves because of abnormal tissue healing and granulation tissue formation [ Recent studies describe novel techniques to improve aesthetic outcomes in children with complex syndactylies [ Evidence suggests that oral isotretinoin may be more effective than standard therapies, and biologic models support a role for isotretinoin in regulating androgens and Suggested areas of focus include the parents' and family's emotional, social, and financial needs; the child's neurocognitive development and educational needs; and potential barriers to care [ • Typically in childhood or adolescence • Early midface advancement may be pursued to treat airway obstruction. • Specific airway management depends on level & severity of obstruction. • Residual OSA after soft tissue & skeletal procedures is common. • Placement of nasal stents • Endotracheal intubation • Tracheotomy ## Surveillance Note: (1) For recommended surveillance for Muenke syndrome, see Recommended Surveillance for Individuals with Close monitoring of head circumference / head growth Eval for signs of ↑ intracranial pressure (e.g., headaches, vomiting) Consider cervical spine CT when head CT is obtained. Consider radiographs at age 3-4 yrs to evaluate for progressive C-spine fusion. At age ~18 mos, then annually Additional speech assessments before & after midface surgeries • Close monitoring of head circumference / head growth • Eval for signs of ↑ intracranial pressure (e.g., headaches, vomiting) • Consider cervical spine CT when head CT is obtained. • Consider radiographs at age 3-4 yrs to evaluate for progressive C-spine fusion. • At age ~18 mos, then annually • Additional speech assessments before & after midface surgeries ## Agents/Circumstances to Avoid Individuals with cervical spine anomalies may be at risk for spinal cord injury with hyperextension and may require fiberoptic intubation and/or sports restrictions for activities that pose a risk for head/neck injury. Individuals with exophthalmos may require protective eyewear during activities with risk of eye injury (e.g., ball sports). ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from who would benefit from early surveillance and intervention. Evaluations can include the following: Molecular genetic testing if the Assessment based on clinical and radiographic criteria (Note: Manifestations may not be readily evident in all affected individuals.) See • Molecular genetic testing if the • Assessment based on clinical and radiographic criteria (Note: Manifestations may not be readily evident in all affected individuals.) ## Pregnancy Management Pregnant women carrying fetuses affected by See ## Therapies Under Investigation Search ## Genetic Risk Assessment The An individual with an With a milder phenotype – as can be seen in Molecular genetic testing and clinical and radiographic evaluations are recommended for the 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 an If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be asymptomatic or mildly/minimally affected. To date, Crouzon syndrome is the only Note: Advanced paternal age has been shown clinically to be associated with If a parent 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 Significant differences in clinical severity of a given type of If the If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for an This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. 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 finding of an The long-term prognosis of individuals with syndromes previously associated with poor outcomes is difficult to predict as advances in surgical management have dramatically changed expected outcomes from those suggested by historical data in the literature. For example, Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most health care centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • An individual with an • With a milder phenotype – as can be seen in • With a milder phenotype – as can be seen in • Molecular genetic testing and clinical and radiographic evaluations are recommended for the 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 an • If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be asymptomatic or mildly/minimally affected. To date, Crouzon syndrome is the only • Note: Advanced paternal age has been shown clinically to be associated with • With a milder phenotype – as can be seen in • If a parent 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 • Significant differences in clinical severity of a given type of • The • Significant differences in clinical severity of a given type of • If the • If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for an • This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. • For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. • This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. • For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. • The • Significant differences in clinical severity of a given type of • This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. • For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 finding of an • The long-term prognosis of individuals with syndromes previously associated with poor outcomes is difficult to predict as advances in surgical management have dramatically changed expected outcomes from those suggested by historical data in the literature. For example, ## Mode of Inheritance The ## Risk to Family Members An individual with an With a milder phenotype – as can be seen in Molecular genetic testing and clinical and radiographic evaluations are recommended for the 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 an If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be asymptomatic or mildly/minimally affected. To date, Crouzon syndrome is the only Note: Advanced paternal age has been shown clinically to be associated with If a parent 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 Significant differences in clinical severity of a given type of If the If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for an This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. • An individual with an • With a milder phenotype – as can be seen in • With a milder phenotype – as can be seen in • Molecular genetic testing and clinical and radiographic evaluations are recommended for the 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 an • If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be asymptomatic or mildly/minimally affected. To date, Crouzon syndrome is the only • Note: Advanced paternal age has been shown clinically to be associated with • With a milder phenotype – as can be seen in • If a parent 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 • Significant differences in clinical severity of a given type of • The • Significant differences in clinical severity of a given type of • If the • If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for an • This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. • For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. • This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. • For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. • The • Significant differences in clinical severity of a given type of • This risk appears to be low for Apert, Beare-Stevenson cutis gyrata, bent bone dysplasia, and Pfeiffer syndromes. • For Crouzon and Muenke syndromes, variable expressivity between family members necessitates careful clinical evaluation of apparently unaffected relatives as affected parents with mild manifestations (e.g., mild hearing loss, prominent eyes) may be unaware that they have features of the condition. ## 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 The finding of an The long-term prognosis of individuals with syndromes previously associated with poor outcomes is difficult to predict as advances in surgical management have dramatically changed expected outcomes from those suggested by historical data in the literature. For example, Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most health care centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The finding of an • The long-term prognosis of individuals with syndromes previously associated with poor outcomes is difficult to predict as advances in surgical management have dramatically changed expected outcomes from those suggested by historical data in the literature. For example, ## Resources United Kingdom • • • • • • • • United Kingdom • • • ## Chapter Notes Kelly Evans, MD (2020-present)Marnie J Falk, MD; Children's Hospital of Philadelphia (1998-2020)Chad R Haldeman-Englert, MD; Fullerton Genetics Center (2007-2020)Danny Miller, MD, PhD (2020-present)Nathaniel H Robin, MD; University of Alabama at Birmingham (1998-2020)Tara Wenger, MD, PhD (2020-present) 30 April 2020 (tw) Revision: clarification regarding syndactyly/polydactyly in Apert syndrome 16 April 2020 (sw) Comprehensive update posted live 7 June 2011 (me) Comprehensive update posted live 27 September 2007 (me) Comprehensive update posted live 18 April 2005 (me) Comprehensive update posted live 13 February 2003 (me) Comprehensive update posted live 20 October 1998 (pb) Review posted live March 1998 (nr) Original submission • 30 April 2020 (tw) Revision: clarification regarding syndactyly/polydactyly in Apert syndrome • 16 April 2020 (sw) Comprehensive update posted live • 7 June 2011 (me) Comprehensive update posted live • 27 September 2007 (me) Comprehensive update posted live • 18 April 2005 (me) Comprehensive update posted live • 13 February 2003 (me) Comprehensive update posted live • 20 October 1998 (pb) Review posted live • March 1998 (nr) Original submission ## Author History Kelly Evans, MD (2020-present)Marnie J Falk, MD; Children's Hospital of Philadelphia (1998-2020)Chad R Haldeman-Englert, MD; Fullerton Genetics Center (2007-2020)Danny Miller, MD, PhD (2020-present)Nathaniel H Robin, MD; University of Alabama at Birmingham (1998-2020)Tara Wenger, MD, PhD (2020-present) ## Revision History 30 April 2020 (tw) Revision: clarification regarding syndactyly/polydactyly in Apert syndrome 16 April 2020 (sw) Comprehensive update posted live 7 June 2011 (me) Comprehensive update posted live 27 September 2007 (me) Comprehensive update posted live 18 April 2005 (me) Comprehensive update posted live 13 February 2003 (me) Comprehensive update posted live 20 October 1998 (pb) Review posted live March 1998 (nr) Original submission • 30 April 2020 (tw) Revision: clarification regarding syndactyly/polydactyly in Apert syndrome • 16 April 2020 (sw) Comprehensive update posted live • 7 June 2011 (me) Comprehensive update posted live • 27 September 2007 (me) Comprehensive update posted live • 18 April 2005 (me) Comprehensive update posted live • 13 February 2003 (me) Comprehensive update posted live • 20 October 1998 (pb) Review posted live • March 1998 (nr) Original submission ## References ## Literature Cited
[]
20/10/1998
16/4/2020
30/4/2020
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
creatine
creatine
[ "Cerebral Creatine Deficiency Disorders", "Cerebral Creatine Deficiency Disorders", "Guanidinoacetate Methyltransferase (GAMT) Deficiency", "Creatine Transporter (CRTR) Deficiency", "L-Arginine:Glycine Amidinotransferase (AGAT) Deficiency", "Glycine amidinotransferase, mitochondrial", "Guanidinoacetate N-methyltransferase", "Sodium- and chloride-dependent creatine transporter 1", "GAMT", "GATM", "SLC6A8", "Creatine Deficiency Disorders" ]
Creatine Deficiency Disorders
Saadet Mercimek-Andrews, Gajja S Salomons
Summary The creatine deficiency disorders (CDDs), inborn errors of creatine metabolism and transport, comprise three disorders: the creatine biosynthesis disorders guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency; and creatine transporter (CRTR) deficiency. Developmental delay and cognitive dysfunction or intellectual disability and speech-language disorder are common to all three CDDs. Onset of clinical manifestations of GAMT deficiency (reported in ~130 individuals) is between ages three months and two years; in addition to developmental delays, the majority of individuals have epilepsy and develop a behavior disorder (e.g., hyperactivity, autism, or self-injurious behavior), and about 30% have movement disorder. AGAT deficiency has been reported in 16 individuals; none have had epilepsy or movement disorders. Clinical findings of CRTR deficiency in affected males (reported in ~130 individuals) in addition to developmental delays include epilepsy (variable seizure types and may be intractable) and behavior disorders (e.g., attention deficit and/or hyperactivity, autistic features, impulsivity, social anxiety), hypotonia, and (less commonly) a movement disorder. Poor weight gain with constipation and prolonged QTc on EKG have been reported. While mild-to-moderate intellectual disability is commonly observed up to age four years, the majority of adult males with CRTR deficiency have been reported to have severe intellectual disability. Females heterozygous for CRTR deficiency are typically either asymptomatic or have mild intellectual disability, although a more severe phenotype resembling the male phenotype has been reported. The diagnosis of a CDD is established in a proband with suggestive findings and biallelic pathogenic variants in GAMT deficiency (caused by pathogenic variants in
Guanidinoacetate methyltransferase (GAMT) deficiency L-arginine:glycine amidinotransferase (AGAT) deficiency Creatine transporter (CRTR) deficiency • Guanidinoacetate methyltransferase (GAMT) deficiency • L-arginine:glycine amidinotransferase (AGAT) deficiency • Creatine transporter (CRTR) deficiency ## Diagnosis The creatine deficiency disorders (CDDs) are inborn errors of creatine metabolism and transport that comprise: Two creatine biosynthesis defects (both inherited in an autosomal recessive manner): Guanidinoacetate methyltransferase (GAMT) deficiency L-arginine:glycine amidinotransferase (AGAT) deficiency One creatine transporter defect (inherited in an X-linked manner): creatine transporter (CRTR) deficiency A CDD Developmental delay Cognitive dysfunction or intellectual disability Hypotonia Seizures or refractory epilepsy Movement disorders (e.g., chorea-athetosis, dystonia) Behavior problems (e.g., attention-deficit/hyperactivity disorder, autism spectrum disorder, aggressive behavior) The diagnosis of a CDD 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 based on the biochemical and imaging findings, whereas genomic testing does not. Individuals with the distinctive biochemical or imaging findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Creatine Deficiency Disorder Genes are listed in alphabetic order. See Percentages are based on number of families in authors' own databases / LOVD ( 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. • Two creatine biosynthesis defects (both inherited in an autosomal recessive manner): • Guanidinoacetate methyltransferase (GAMT) deficiency • L-arginine:glycine amidinotransferase (AGAT) deficiency • Guanidinoacetate methyltransferase (GAMT) deficiency • L-arginine:glycine amidinotransferase (AGAT) deficiency • One creatine transporter defect (inherited in an X-linked manner): creatine transporter (CRTR) deficiency • Guanidinoacetate methyltransferase (GAMT) deficiency • L-arginine:glycine amidinotransferase (AGAT) deficiency • Developmental delay • Cognitive dysfunction or intellectual disability • Hypotonia • Seizures or refractory epilepsy • Movement disorders (e.g., chorea-athetosis, dystonia) • Behavior problems (e.g., attention-deficit/hyperactivity disorder, autism spectrum disorder, aggressive behavior) ## Suggestive Findings A CDD Developmental delay Cognitive dysfunction or intellectual disability Hypotonia Seizures or refractory epilepsy Movement disorders (e.g., chorea-athetosis, dystonia) Behavior problems (e.g., attention-deficit/hyperactivity disorder, autism spectrum disorder, aggressive behavior) • Developmental delay • Cognitive dysfunction or intellectual disability • Hypotonia • Seizures or refractory epilepsy • Movement disorders (e.g., chorea-athetosis, dystonia) • Behavior problems (e.g., attention-deficit/hyperactivity disorder, autism spectrum disorder, aggressive behavior) ## Establishing the Diagnosis The diagnosis of a CDD 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 based on the biochemical and imaging findings, whereas genomic testing does not. Individuals with the distinctive biochemical or imaging findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Creatine Deficiency Disorder Genes are listed in alphabetic order. See Percentages are based on number of families in authors' own databases / LOVD ( 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. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Creatine Deficiency Disorder Genes are listed in alphabetic order. See Percentages are based on number of families in authors' own databases / LOVD ( 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. ## Clinical Characteristics Developmental delay, cognitive dysfunction, and intellectual disability are common to all three creatine deficiency disorders (CDDs). See Creatine Deficiency Disorders: Comparison of Phenotypes by Select Features ●●● = all; ●● = common; ● = infrequent; AGAT = L-arginine:glycine amidinotransferase; CRTR = creatine transporter; DD = developmental delay; GAMT = guanidinoacetate methyltransferase; NR = not reported Note that individuals diagnosed and treated from the newborn period or infancy with good treatment adherence may have normal developmental milestones, cognitive functions, and IQ. To date, about 130 individuals have been identified with biallelic pathogenic variants in To date, 16 individuals have been identified with biallelic pathogenic variants in To date, about 130 individuals have been identified with a pathogenic variant in A neuropsychological profile in four affected boys from two unrelated families from the Netherlands revealed a semantic-pragmatic language disorder (difficulty in understanding the meaning of words) with oral dyspraxia [ Females heterozygous for their family-specific No clinically relevant genotype-phenotype correlations for any of the CDDs have been identified. The estimated incidence of GAMT deficiency in the general population ranges from 1:2,640,000 to 1:250,000 [ The estimated incidence of GAMT deficiency in the Utah and New York newborn population was 1:405,655 [ Smaller studies of individuals with neurologic disease or severe intellectual disability found GAMT deficiency present in 1.1% [ ## Clinical Description Developmental delay, cognitive dysfunction, and intellectual disability are common to all three creatine deficiency disorders (CDDs). See Creatine Deficiency Disorders: Comparison of Phenotypes by Select Features ●●● = all; ●● = common; ● = infrequent; AGAT = L-arginine:glycine amidinotransferase; CRTR = creatine transporter; DD = developmental delay; GAMT = guanidinoacetate methyltransferase; NR = not reported Note that individuals diagnosed and treated from the newborn period or infancy with good treatment adherence may have normal developmental milestones, cognitive functions, and IQ. To date, about 130 individuals have been identified with biallelic pathogenic variants in To date, 16 individuals have been identified with biallelic pathogenic variants in To date, about 130 individuals have been identified with a pathogenic variant in A neuropsychological profile in four affected boys from two unrelated families from the Netherlands revealed a semantic-pragmatic language disorder (difficulty in understanding the meaning of words) with oral dyspraxia [ Females heterozygous for their family-specific ## GAMT Deficiency To date, about 130 individuals have been identified with biallelic pathogenic variants in ## AGAT Deficiency To date, 16 individuals have been identified with biallelic pathogenic variants in ## CRTR Deficiency ‒ Affected Males To date, about 130 individuals have been identified with a pathogenic variant in A neuropsychological profile in four affected boys from two unrelated families from the Netherlands revealed a semantic-pragmatic language disorder (difficulty in understanding the meaning of words) with oral dyspraxia [ ## CRTR Deficiency ‒ Heterozygous Females Females heterozygous for their family-specific ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations for any of the CDDs have been identified. ## Prevalence The estimated incidence of GAMT deficiency in the general population ranges from 1:2,640,000 to 1:250,000 [ The estimated incidence of GAMT deficiency in the Utah and New York newborn population was 1:405,655 [ Smaller studies of individuals with neurologic disease or severe intellectual disability found GAMT deficiency present in 1.1% [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders summarized in Disorders of Interest in the Differential Diagnosis of Creatine Deficiency Disorders ## Management No clinical practice guidelines for creatine deficiency disorders (CDDs) have been published. Some of the references list management recommendations for GAMT and CRTR deficiencies [ To establish the extent of disease and needs in an individual diagnosed with a CDD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Creatine Deficiency Disorders Brain EEG if any clinical seizures or suspicion of seizures Incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Eval of cognitive functions w/objective tests to measure IQ Orthopedics / physical medicine & rehab / PT/OT eval Video documentation of mvmt disorder 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) Behavior concerns Sleep disturbances ADHD Anxiety Findings suggestive of ASD Blood urea Blood creatinine Urinalysis If any abnormal kidney function, measure GFR or eGFR. EKG Echocardiography 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; CDD = creatine deficiency disorder; eGFR = estimated glomerular filtration rate; GFR = glomerular filtration rate; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Not typically present in those with GATM deficiency A concern for those with CRTR deficiency Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The general treatment of CDDs of any cause is presented in Medical treatment specific to the type of CDD follows in Treatment of Manifestations in Individuals with Creatine Deficiency Disorders Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Medications to treat mvmt disorder Deep brain stimulation if no response to medical mgmt ASM = anti-seizure medication; DD = developmental 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. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in 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 of Manifestations in Individuals with GAMT Deficiency Supplementation w/creatine monohydrate Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Only 1 person achieved normal development or cognitive functions on treatment; all showed some improvement. Seizure freedom achieved in ~50% Mvmt disorder resolved in 50% Normal neurodevelopmental outcome reported in 3 persons w/GAMT deficiency who were diagnosed & treated in neonatal period based on positive family history of disorder in older sib Supplementation w/ornithine Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Dietary restriction of arginine to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake To prevent protein malnutrition, essential amino acid medical formula should be supplemented (0.5-0.8 g/kg/day). bw = body weight; GAA = guanidinoacetate Because of the challenges involved in understanding arginine restriction, reading dietary labels, and calculating arginine intake (particularly since arginine content is not always indicated), many centers use protein restriction instead. Available databases (e.g., the US Department of Agriculture National Nutrient Database) can be used to determine exact arginine content of foods to allow precise calculation of daily arginine intake in individuals with GAMT deficiency. Treatment of Manifestations in Individuals with AGAT Deficiency Supplementation w/creatine monohydrate Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Muscle weakness was improved in all persons. No improvement in cognitive function or ID if initiation of treatment was > age 10 yrs Normal cognitive function reported when treatment was initiated < age 2 yrs in 2 persons. Normal neurodevelopment at age 18 mos when treatment started at age 4 mos in asymptomatic sib. bw = body weight; ID = intellectual disability Treatment of Manifestations in Individuals with CRTR Deficiency Creatine monohydrate 100-200 mg/kg bw/day in 3 doses Arginine (hydrochloride or base) 400 mg/kg bw/day in 3 doses Glycine 150 mg/kg bw/day in 3 doses The authors recommend that all 3 supplements be started together in newly diagnosed persons – esp in early childhood – to slow disease progression. Clinical effectiveness of treatment w/3 supplements not confirmed, but improvements noted bw = body weight See Surveillance recommendations for CDDs are summarized in Recommended Surveillance for Individuals with Creatine Deficiency Disorders For those w/GAMT or AGAT deficiency: to monitor cerebral creatine levels during creatine supplementation therapy For those w/CRTR deficiency: to monitor cerebral creatine levels for assessment of treatment outcome Growth & nutritional status; Plasma GAA levels, plasma amino acids, ammonia, protein, albumin, pre-albumin levels. GAA = guanidinoacetate; GFR = glomerular filtration rate High-dose arginine and glycine supplementation can result in increased GAA levels. It is appropriate to evaluate neonates at risk for a creatine deficiency disorder to allow for early diagnosis and treatment. (Note: It is not proven that early treatment of CRTR deficiency would change the outcome.) Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Biochemical genetic testing if the pathogenic variants in the family are not known. See Pregnancy management has been reported in a single individual with AGAT deficiency. The fetal growth and head circumference declined by 20 weeks of pregnancy during monitoring. Creatine levels were low in the pregnant woman. Daily creatine dose was increased in the pregnant woman, and the baby was normal at delivery and was not affected with AGAT deficiency [ There are no current clinical trials for any of the CDDs. Some pharmacotherapies are being investigated in cell lines or animal models of CRTR deficiency: Swiss mice brain hippocampal slices were treated with diacetyl creatine ethyl ester (DAC) after creatine transporter was blocked using guanidinopropionic acid. The study showed an increase in intracellular creatine, and DAC was metabolized to creatine. Authors concluded that further research is needed to fully elucidate their hypotheses [ Dodecyl creatine ester was administered intranasally and intracerebroventricularly in 4-phenylbutyrate (4-PBA) was shown to increase creatine uptake in transfected HEK293 cells expressing pathogenic variants in Cyclocreatine was used in a CRTR deficiency mouse model and was effective in treating cognitive functions, epilepsy, and behavioral features [ Search • Brain • EEG if any clinical seizures or suspicion of seizures • Incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Eval of cognitive functions w/objective tests to measure IQ • Orthopedics / physical medicine & rehab / PT/OT eval • Video documentation of mvmt disorder • 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) • Behavior concerns • Sleep disturbances • ADHD • Anxiety • Findings suggestive of ASD • Blood urea • Blood creatinine • Urinalysis • If any abnormal kidney function, measure GFR or eGFR. • EKG • Echocardiography • 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 • Medications to treat mvmt disorder • Deep brain stimulation if no response to medical mgmt • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 • Supplementation w/creatine monohydrate • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Only 1 person achieved normal development or cognitive functions on treatment; all showed some improvement. • Seizure freedom achieved in ~50% • Mvmt disorder resolved in 50% • Normal neurodevelopmental outcome reported in 3 persons w/GAMT deficiency who were diagnosed & treated in neonatal period based on positive family history of disorder in older sib • Supplementation w/ornithine • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Dietary restriction of arginine to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake • To prevent protein malnutrition, essential amino acid medical formula should be supplemented (0.5-0.8 g/kg/day). • Supplementation w/creatine monohydrate • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Muscle weakness was improved in all persons. • No improvement in cognitive function or ID if initiation of treatment was > age 10 yrs • Normal cognitive function reported when treatment was initiated < age 2 yrs in 2 persons. • Normal neurodevelopment at age 18 mos when treatment started at age 4 mos in asymptomatic sib. • Creatine monohydrate 100-200 mg/kg bw/day in 3 doses • Arginine (hydrochloride or base) 400 mg/kg bw/day in 3 doses • Glycine 150 mg/kg bw/day in 3 doses • The authors recommend that all 3 supplements be started together in newly diagnosed persons – esp in early childhood – to slow disease progression. • Clinical effectiveness of treatment w/3 supplements not confirmed, but improvements noted • For those w/GAMT or AGAT deficiency: to monitor cerebral creatine levels during creatine supplementation therapy • For those w/CRTR deficiency: to monitor cerebral creatine levels for assessment of treatment outcome • Growth & nutritional status; • Plasma GAA levels, plasma amino acids, ammonia, protein, albumin, pre-albumin levels. • Molecular genetic testing if the pathogenic variants in the family are known; • Biochemical genetic testing if the pathogenic variants in the family are not known. • Swiss mice brain hippocampal slices were treated with diacetyl creatine ethyl ester (DAC) after creatine transporter was blocked using guanidinopropionic acid. The study showed an increase in intracellular creatine, and DAC was metabolized to creatine. Authors concluded that further research is needed to fully elucidate their hypotheses [ • Dodecyl creatine ester was administered intranasally and intracerebroventricularly in • 4-phenylbutyrate (4-PBA) was shown to increase creatine uptake in transfected HEK293 cells expressing pathogenic variants in • Cyclocreatine was used in a CRTR deficiency mouse model and was effective in treating cognitive functions, epilepsy, and behavioral features [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a CDD, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Creatine Deficiency Disorders Brain EEG if any clinical seizures or suspicion of seizures Incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Eval of cognitive functions w/objective tests to measure IQ Orthopedics / physical medicine & rehab / PT/OT eval Video documentation of mvmt disorder 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) Behavior concerns Sleep disturbances ADHD Anxiety Findings suggestive of ASD Blood urea Blood creatinine Urinalysis If any abnormal kidney function, measure GFR or eGFR. EKG Echocardiography 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; CDD = creatine deficiency disorder; eGFR = estimated glomerular filtration rate; GFR = glomerular filtration rate; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Not typically present in those with GATM deficiency A concern for those with CRTR deficiency Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Brain • EEG if any clinical seizures or suspicion of seizures • Incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Eval of cognitive functions w/objective tests to measure IQ • Orthopedics / physical medicine & rehab / PT/OT eval • Video documentation of mvmt disorder • 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) • Behavior concerns • Sleep disturbances • ADHD • Anxiety • Findings suggestive of ASD • Blood urea • Blood creatinine • Urinalysis • If any abnormal kidney function, measure GFR or eGFR. • EKG • Echocardiography • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations The general treatment of CDDs of any cause is presented in Medical treatment specific to the type of CDD follows in Treatment of Manifestations in Individuals with Creatine Deficiency Disorders Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Medications to treat mvmt disorder Deep brain stimulation if no response to medical mgmt ASM = anti-seizure medication; DD = developmental 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. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in 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 of Manifestations in Individuals with GAMT Deficiency Supplementation w/creatine monohydrate Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Only 1 person achieved normal development or cognitive functions on treatment; all showed some improvement. Seizure freedom achieved in ~50% Mvmt disorder resolved in 50% Normal neurodevelopmental outcome reported in 3 persons w/GAMT deficiency who were diagnosed & treated in neonatal period based on positive family history of disorder in older sib Supplementation w/ornithine Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Dietary restriction of arginine to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake To prevent protein malnutrition, essential amino acid medical formula should be supplemented (0.5-0.8 g/kg/day). bw = body weight; GAA = guanidinoacetate Because of the challenges involved in understanding arginine restriction, reading dietary labels, and calculating arginine intake (particularly since arginine content is not always indicated), many centers use protein restriction instead. Available databases (e.g., the US Department of Agriculture National Nutrient Database) can be used to determine exact arginine content of foods to allow precise calculation of daily arginine intake in individuals with GAMT deficiency. Treatment of Manifestations in Individuals with AGAT Deficiency Supplementation w/creatine monohydrate Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Muscle weakness was improved in all persons. No improvement in cognitive function or ID if initiation of treatment was > age 10 yrs Normal cognitive function reported when treatment was initiated < age 2 yrs in 2 persons. Normal neurodevelopment at age 18 mos when treatment started at age 4 mos in asymptomatic sib. bw = body weight; ID = intellectual disability Treatment of Manifestations in Individuals with CRTR Deficiency Creatine monohydrate 100-200 mg/kg bw/day in 3 doses Arginine (hydrochloride or base) 400 mg/kg bw/day in 3 doses Glycine 150 mg/kg bw/day in 3 doses The authors recommend that all 3 supplements be started together in newly diagnosed persons – esp in early childhood – to slow disease progression. Clinical effectiveness of treatment w/3 supplements not confirmed, but improvements noted bw = body weight • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Medications to treat mvmt disorder • Deep brain stimulation if no response to medical mgmt • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 • Supplementation w/creatine monohydrate • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Only 1 person achieved normal development or cognitive functions on treatment; all showed some improvement. • Seizure freedom achieved in ~50% • Mvmt disorder resolved in 50% • Normal neurodevelopmental outcome reported in 3 persons w/GAMT deficiency who were diagnosed & treated in neonatal period based on positive family history of disorder in older sib • Supplementation w/ornithine • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Dietary restriction of arginine to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake • To prevent protein malnutrition, essential amino acid medical formula should be supplemented (0.5-0.8 g/kg/day). • Supplementation w/creatine monohydrate • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Muscle weakness was improved in all persons. • No improvement in cognitive function or ID if initiation of treatment was > age 10 yrs • Normal cognitive function reported when treatment was initiated < age 2 yrs in 2 persons. • Normal neurodevelopment at age 18 mos when treatment started at age 4 mos in asymptomatic sib. • Creatine monohydrate 100-200 mg/kg bw/day in 3 doses • Arginine (hydrochloride or base) 400 mg/kg bw/day in 3 doses • Glycine 150 mg/kg bw/day in 3 doses • The authors recommend that all 3 supplements be started together in newly diagnosed persons – esp in early childhood – to slow disease progression. • Clinical effectiveness of treatment w/3 supplements not confirmed, but improvements noted ## 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. Treatment of Manifestations in Individuals with GAMT Deficiency Supplementation w/creatine monohydrate Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Only 1 person achieved normal development or cognitive functions on treatment; all showed some improvement. Seizure freedom achieved in ~50% Mvmt disorder resolved in 50% Normal neurodevelopmental outcome reported in 3 persons w/GAMT deficiency who were diagnosed & treated in neonatal period based on positive family history of disorder in older sib Supplementation w/ornithine Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Dietary restriction of arginine to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake To prevent protein malnutrition, essential amino acid medical formula should be supplemented (0.5-0.8 g/kg/day). bw = body weight; GAA = guanidinoacetate Because of the challenges involved in understanding arginine restriction, reading dietary labels, and calculating arginine intake (particularly since arginine content is not always indicated), many centers use protein restriction instead. Available databases (e.g., the US Department of Agriculture National Nutrient Database) can be used to determine exact arginine content of foods to allow precise calculation of daily arginine intake in individuals with GAMT deficiency. Treatment of Manifestations in Individuals with AGAT Deficiency Supplementation w/creatine monohydrate Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses Muscle weakness was improved in all persons. No improvement in cognitive function or ID if initiation of treatment was > age 10 yrs Normal cognitive function reported when treatment was initiated < age 2 yrs in 2 persons. Normal neurodevelopment at age 18 mos when treatment started at age 4 mos in asymptomatic sib. bw = body weight; ID = intellectual disability Treatment of Manifestations in Individuals with CRTR Deficiency Creatine monohydrate 100-200 mg/kg bw/day in 3 doses Arginine (hydrochloride or base) 400 mg/kg bw/day in 3 doses Glycine 150 mg/kg bw/day in 3 doses The authors recommend that all 3 supplements be started together in newly diagnosed persons – esp in early childhood – to slow disease progression. Clinical effectiveness of treatment w/3 supplements not confirmed, but improvements noted bw = body weight • Supplementation w/creatine monohydrate • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Only 1 person achieved normal development or cognitive functions on treatment; all showed some improvement. • Seizure freedom achieved in ~50% • Mvmt disorder resolved in 50% • Normal neurodevelopmental outcome reported in 3 persons w/GAMT deficiency who were diagnosed & treated in neonatal period based on positive family history of disorder in older sib • Supplementation w/ornithine • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Dietary restriction of arginine to 15-25 mg/kg/day that corresponds to 0.4-0.7 g/kg/day protein intake • To prevent protein malnutrition, essential amino acid medical formula should be supplemented (0.5-0.8 g/kg/day). • Supplementation w/creatine monohydrate • Oral doses of 400-800 mg/kg bw/day in 3-6 divided doses • Muscle weakness was improved in all persons. • No improvement in cognitive function or ID if initiation of treatment was > age 10 yrs • Normal cognitive function reported when treatment was initiated < age 2 yrs in 2 persons. • Normal neurodevelopment at age 18 mos when treatment started at age 4 mos in asymptomatic sib. • Creatine monohydrate 100-200 mg/kg bw/day in 3 doses • Arginine (hydrochloride or base) 400 mg/kg bw/day in 3 doses • Glycine 150 mg/kg bw/day in 3 doses • The authors recommend that all 3 supplements be started together in newly diagnosed persons – esp in early childhood – to slow disease progression. • Clinical effectiveness of treatment w/3 supplements not confirmed, but improvements noted ## Prevention of Primary Manifestations See ## Surveillance Surveillance recommendations for CDDs are summarized in Recommended Surveillance for Individuals with Creatine Deficiency Disorders For those w/GAMT or AGAT deficiency: to monitor cerebral creatine levels during creatine supplementation therapy For those w/CRTR deficiency: to monitor cerebral creatine levels for assessment of treatment outcome Growth & nutritional status; Plasma GAA levels, plasma amino acids, ammonia, protein, albumin, pre-albumin levels. GAA = guanidinoacetate; GFR = glomerular filtration rate High-dose arginine and glycine supplementation can result in increased GAA levels. • For those w/GAMT or AGAT deficiency: to monitor cerebral creatine levels during creatine supplementation therapy • For those w/CRTR deficiency: to monitor cerebral creatine levels for assessment of treatment outcome • Growth & nutritional status; • Plasma GAA levels, plasma amino acids, ammonia, protein, albumin, pre-albumin levels. ## Evaluation of Relatives at Risk It is appropriate to evaluate neonates at risk for a creatine deficiency disorder to allow for early diagnosis and treatment. (Note: It is not proven that early treatment of CRTR deficiency would change the outcome.) Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Biochemical genetic testing if the pathogenic variants in the family are not known. See • Molecular genetic testing if the pathogenic variants in the family are known; • Biochemical genetic testing if the pathogenic variants in the family are not known. ## Pregnancy Management Pregnancy management has been reported in a single individual with AGAT deficiency. The fetal growth and head circumference declined by 20 weeks of pregnancy during monitoring. Creatine levels were low in the pregnant woman. Daily creatine dose was increased in the pregnant woman, and the baby was normal at delivery and was not affected with AGAT deficiency [ ## Therapies Under Investigation There are no current clinical trials for any of the CDDs. Some pharmacotherapies are being investigated in cell lines or animal models of CRTR deficiency: Swiss mice brain hippocampal slices were treated with diacetyl creatine ethyl ester (DAC) after creatine transporter was blocked using guanidinopropionic acid. The study showed an increase in intracellular creatine, and DAC was metabolized to creatine. Authors concluded that further research is needed to fully elucidate their hypotheses [ Dodecyl creatine ester was administered intranasally and intracerebroventricularly in 4-phenylbutyrate (4-PBA) was shown to increase creatine uptake in transfected HEK293 cells expressing pathogenic variants in Cyclocreatine was used in a CRTR deficiency mouse model and was effective in treating cognitive functions, epilepsy, and behavioral features [ Search • Swiss mice brain hippocampal slices were treated with diacetyl creatine ethyl ester (DAC) after creatine transporter was blocked using guanidinopropionic acid. The study showed an increase in intracellular creatine, and DAC was metabolized to creatine. Authors concluded that further research is needed to fully elucidate their hypotheses [ • Dodecyl creatine ester was administered intranasally and intracerebroventricularly in • 4-phenylbutyrate (4-PBA) was shown to increase creatine uptake in transfected HEK293 cells expressing pathogenic variants in • Cyclocreatine was used in a CRTR deficiency mouse model and was effective in treating cognitive functions, epilepsy, and behavioral features [ ## Genetic Counseling Guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency are inherited in an autosomal recessive manner. Creatine transporter (CRTR) deficiency is inherited in an X-linked manner. The parents of a child with GAMT or AGAT deficiency are presumed to be heterozygous for a Molecular genetic testing 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. Note: Because biochemical testing is normal in carriers for GAMT and AGAT deficiencies, identification of carriers requires molecular genetic testing for the familial The father of a male with CRTR deficiency will not have the disorder nor will he be hemizygous for the In a family with more than one affected child, 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, the mother may be a heterozygote, the affected male may have a 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Heterozygous mothers may have a history of learning disability or mild intellectual disability or seizures [ 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 heterozygous and may develop clinical findings related to the disorder (see Clinical Description, If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Because heterozygous females may have a normal creatine-to-creatinine ratio in urine and normal creatine content on brain 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 heterozygous or are at risk of being heterozygous. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of a child with GAMT or AGAT deficiency are presumed to be heterozygous for a • Molecular genetic testing 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 father of a male with CRTR deficiency will not have the disorder nor will he be hemizygous for the • In a family with more than one affected child, 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, the mother may be a heterozygote, the affected male may have a • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • Heterozygous mothers may have a history of learning disability or mild intellectual disability or seizures [ • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ • 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 heterozygous and may develop clinical findings related to the disorder (see Clinical Description, • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may develop clinical findings related to the disorder (see Clinical Description, • 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 affected; • Females who inherit the pathogenic variant will be heterozygous and may develop clinical findings related to the disorder (see Clinical Description, • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous. ## Mode of Inheritance Guanidinoacetate methyltransferase (GAMT) deficiency and L-arginine:glycine amidinotransferase (AGAT) deficiency are inherited in an autosomal recessive manner. Creatine transporter (CRTR) deficiency is inherited in an X-linked manner. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with GAMT or AGAT deficiency are presumed to be heterozygous for a Molecular genetic testing 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. Note: Because biochemical testing is normal in carriers for GAMT and AGAT deficiencies, identification of carriers requires molecular genetic testing for the familial • The parents of a child with GAMT or AGAT deficiency are presumed to be heterozygous for a • Molecular genetic testing 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. ## X-Linked Inheritance – Risk to Family Members The father of a male with CRTR deficiency will not have the disorder nor will he be hemizygous for the In a family with more than one affected child, 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, the mother may be a heterozygote, the affected male may have a 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. Heterozygous mothers may have a history of learning disability or mild intellectual disability or seizures [ 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 heterozygous and may develop clinical findings related to the disorder (see Clinical Description, If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Note: Because heterozygous females may have a normal creatine-to-creatinine ratio in urine and normal creatine content on brain • The father of a male with CRTR deficiency will not have the disorder nor will he be hemizygous for the • In a family with more than one affected child, 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, the mother may be a heterozygote, the affected male may have a • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • Heterozygous mothers may have a history of learning disability or mild intellectual disability or seizures [ • 7% of mothers in a retrospective study of 85 families had somatic/germline mosaicism [ • 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 heterozygous and may develop clinical findings related to the disorder (see Clinical Description, • Males who inherit the pathogenic variant will be affected; • Females who inherit the pathogenic variant will be heterozygous and may develop clinical findings related to the disorder (see Clinical Description, • 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 affected; • Females who inherit the pathogenic variant will be heterozygous and may develop clinical findings related to the disorder (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 heterozygous or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are heterozygous or are at risk of being heterozygous. ## 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 1024 Bayside Drive Suite 532 Newport Beach CA 92660 United Kingdom • • 1024 Bayside Drive • Suite 532 • Newport Beach CA 92660 • • • • • • • • • • • • • • • United Kingdom • • • ## Molecular Genetics Creatine Deficiency Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Creatine Deficiency Disorders ( Creatine is synthesized by two enzymatic reactions: Transfer of the amidino group from arginine to glycine, yielding guanidinoacetic acid (GAA) and catalyzed by L-arginine:glycine amidinotransferase (also known as glycine amidinotransferase, mitochondrial, AGAT, or GATM) Methylation of the amidino group in the GAA molecule by S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (also known as guanidinoacetate N-methyltransferase or GAMT) Creatine is synthesized primarily in the kidney and pancreas, which have high AGAT activity, and in the liver, which has high GAMT activity. Both genes and enzymes have been detected in the brain as well [ Synthesized creatine is transported via the bloodstream to the organs of utilization (mainly muscle and brain), where it is taken up via sodium- and chloride-dependent creatine transporter 1 (SLC6A8 protein) ( Biallelic pathogenic variants in either A hemizygous (or heterozygous) pathogenic variant in A paralogous copy of For ClinGen variant interpretation guidelines, see • Transfer of the amidino group from arginine to glycine, yielding guanidinoacetic acid (GAA) and catalyzed by L-arginine:glycine amidinotransferase (also known as glycine amidinotransferase, mitochondrial, AGAT, or GATM) • Methylation of the amidino group in the GAA molecule by S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (also known as guanidinoacetate N-methyltransferase or GAMT) • Biallelic pathogenic variants in either • A hemizygous (or heterozygous) pathogenic variant in • A paralogous copy of • For ClinGen variant interpretation guidelines, see ## Molecular Pathogenesis Creatine is synthesized by two enzymatic reactions: Transfer of the amidino group from arginine to glycine, yielding guanidinoacetic acid (GAA) and catalyzed by L-arginine:glycine amidinotransferase (also known as glycine amidinotransferase, mitochondrial, AGAT, or GATM) Methylation of the amidino group in the GAA molecule by S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (also known as guanidinoacetate N-methyltransferase or GAMT) Creatine is synthesized primarily in the kidney and pancreas, which have high AGAT activity, and in the liver, which has high GAMT activity. Both genes and enzymes have been detected in the brain as well [ Synthesized creatine is transported via the bloodstream to the organs of utilization (mainly muscle and brain), where it is taken up via sodium- and chloride-dependent creatine transporter 1 (SLC6A8 protein) ( Biallelic pathogenic variants in either A hemizygous (or heterozygous) pathogenic variant in A paralogous copy of For ClinGen variant interpretation guidelines, see • Transfer of the amidino group from arginine to glycine, yielding guanidinoacetic acid (GAA) and catalyzed by L-arginine:glycine amidinotransferase (also known as glycine amidinotransferase, mitochondrial, AGAT, or GATM) • Methylation of the amidino group in the GAA molecule by S-adenosyl-L-methionine:N-guanidinoacetate methyltransferase (also known as guanidinoacetate N-methyltransferase or GAMT) • Biallelic pathogenic variants in either • A hemizygous (or heterozygous) pathogenic variant in • A paralogous copy of • For ClinGen variant interpretation guidelines, see ## Chapter Notes We would like to thank Dr Sylvia Stöckler (Stöckler-Ipsiroglu), who discovered the first two creatine biosynthesis defects, GAMT deficiency and AGAT deficiency. We would like to thank Dr DeGrauw and Dr Salomons, who discovered CRTR deficiency. We would like to thank Dr Schulze, who discovered the high-dose ornithine supplementation combined with an arginine- and protein-restricted diet for the treatment of GAMT deficiency. Saadet Mercimek-Andrews, MD, PhD, FCCMG, FRCPC (2008-present)Gaija S Salomons, PhD (2008-present)Sylvia Stöckler-Ipsiroglu, MD, PhD, MBA, FRCPC; University of British Columbia (2008-2015) 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines 10 February 2022 (ha) Comprehensive update posted live 10 December 2015 (me) Comprehensive update posted live 18 August 2011 (me) Comprehensive update posted live 15 January 2009 (me) Review posted live 24 July 2008 (smm) Original submission • 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines • 10 February 2022 (ha) Comprehensive update posted live • 10 December 2015 (me) Comprehensive update posted live • 18 August 2011 (me) Comprehensive update posted live • 15 January 2009 (me) Review posted live • 24 July 2008 (smm) Original submission ## Author Notes ## Acknowledgments We would like to thank Dr Sylvia Stöckler (Stöckler-Ipsiroglu), who discovered the first two creatine biosynthesis defects, GAMT deficiency and AGAT deficiency. We would like to thank Dr DeGrauw and Dr Salomons, who discovered CRTR deficiency. We would like to thank Dr Schulze, who discovered the high-dose ornithine supplementation combined with an arginine- and protein-restricted diet for the treatment of GAMT deficiency. ## Author History Saadet Mercimek-Andrews, MD, PhD, FCCMG, FRCPC (2008-present)Gaija S Salomons, PhD (2008-present)Sylvia Stöckler-Ipsiroglu, MD, PhD, MBA, FRCPC; University of British Columbia (2008-2015) ## Revision History 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines 10 February 2022 (ha) Comprehensive update posted live 10 December 2015 (me) Comprehensive update posted live 18 August 2011 (me) Comprehensive update posted live 15 January 2009 (me) Review posted live 24 July 2008 (smm) Original submission • 7 August 2025 (aa) Revision: ClinGen variant interpretation guidelines • 10 February 2022 (ha) Comprehensive update posted live • 10 December 2015 (me) Comprehensive update posted live • 18 August 2011 (me) Comprehensive update posted live • 15 January 2009 (me) Review posted live • 24 July 2008 (smm) Original submission ## References ## Literature Cited Algorithm for diagnosis of the creatine deficiency disorders. Note: Urinary creatine-to-creatinine ratio and creatine uptake studies in cultured skin fibroblasts are often not informative in females with SLC6A8 deficiency; hence, molecular genetic testing is the preferred method of diagnosis of females with this disorder [ GAA = guanidinoacetate Schema illustrating (1) CREATINE SYNTHESIS that occurs mainly in liver, pancreas, and kidney; (2) CREATINE UPTAKE into cells (especially for high energy-requiring organs such as muscles and the brain by the creatine transporter (CRTR); and (3) non-enzymatic conversion of creatine to creatinine for CREATININE EXCRETION in the urine
[]
15/1/2009
10/2/2022
7/8/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
csc-dys
csc-dys
[ "Decorin", "DCN", "Congenital Stromal Corneal Dystrophy" ]
Congenital Stromal Corneal Dystrophy
Eyvind Rødahl, Per M Knappskog, Cecilie Bredrup, Helge Boman
Summary Congenital stromal corneal dystrophy is characterized by the presence of bilateral corneal opacities that can be seen at or shortly after birth. The surface of the cornea is normal or slightly irregular; small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance. Strabismus is common. Nystagmus is uncommon. Amblyopia can develop in children. The diagnosis of congenital stromal corneal dystrophy is established in an individual with bilateral corneal opacities and characteristic findings on transmission electron microscopy. Identification of a heterozygous pathogenic variant in Congenital stromal corneal dystrophy is inherited in an autosomal dominant manner. Most individuals diagnosed with congenital stromal corneal dystrophy have an affected parent. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. If the variant has been identified in an affected family member, prenatal testing for a pregnancy at risk is possible.
## Diagnosis Congenital stromal corneal dystrophy (CSCD) The surface of the cornea is normal or slightly irregular. Small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance. The thickness of the cornea (as measured by ultrasonic pachymetry) is increased. Note: This finding may help distinguish CSCD from other disorders that have normal corneal thickness. Intraocular pressure is normal. The diagnosis of congenital stromal corneal dystrophy (CSCD) 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. The phenotype of CSCD is relatively characteristic, and individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of CSCD, 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 congenital corneal opacification, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Congenital Stromal Corneal Dystrophy 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 stromal corneal dystrophy is caused by aggregation or deposition of a truncated form of decorin. It is not clear if this is a gain-of-function mechanism (see • The surface of the cornea is normal or slightly irregular. • Small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance. • The thickness of the cornea (as measured by ultrasonic pachymetry) is increased. Note: This finding may help distinguish CSCD from other disorders that have normal corneal thickness. • Intraocular pressure is normal. • For an introduction to multigene panels click ## Suggestive Findings Congenital stromal corneal dystrophy (CSCD) The surface of the cornea is normal or slightly irregular. Small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance. The thickness of the cornea (as measured by ultrasonic pachymetry) is increased. Note: This finding may help distinguish CSCD from other disorders that have normal corneal thickness. Intraocular pressure is normal. • The surface of the cornea is normal or slightly irregular. • Small opacities are seen throughout the stroma of the entire cornea and give the cornea a cloudy appearance. • The thickness of the cornea (as measured by ultrasonic pachymetry) is increased. Note: This finding may help distinguish CSCD from other disorders that have normal corneal thickness. • Intraocular pressure is normal. ## Establishing the Diagnosis The diagnosis of congenital stromal corneal dystrophy (CSCD) 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. The phenotype of CSCD is relatively characteristic, and individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of CSCD, 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 congenital corneal opacification, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Congenital Stromal Corneal Dystrophy 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 stromal corneal dystrophy is caused by aggregation or deposition of a truncated form of decorin. It is not clear if this is a gain-of-function mechanism (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of CSCD, 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 congenital corneal opacification, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Congenital Stromal Corneal Dystrophy 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 stromal corneal dystrophy is caused by aggregation or deposition of a truncated form of decorin. It is not clear if this is a gain-of-function mechanism (see ## Clinical Characteristics Only seven families with the characteristic findings of congenital stromal corneal dystrophy (CSCD) have been reported in the literature [ In a Norwegian family with 11 affected individuals, bilateral corneal opacities were observed at or slightly after birth [ Affected individuals reported deterioration in visual acuity with increasing age; opacities tended to increase with age. Penetrating keratoplasty was performed in 18 out of 22 eyes at a mean age of 20 years. The grafts remained clear in 56% of the eyes, and in an additional 33% only minimal opacities were seen within an observation period of three to 36 (mean: 19.5) years. Some affected individuals in other studies reported photophobia [ No findings in other organ systems have been noted. Because of limited data, no genotype-phenotype correlations are evident. In one family reported by Penetrance is complete in the described families. Other names by which congenital stromal corneal dystrophy has been known: Dystrophia corneae parenchymatosa congenita Congenital stromal dystrophy of the cornea Congenital hereditary stromal dystrophy of the cornea Decorin-associated congenital stromal corneal dystrophy CSCD is probably very rare. Seven families with a similar phenotype have been described. In four of these, molecular analyses have revealed • Dystrophia corneae parenchymatosa congenita • Congenital stromal dystrophy of the cornea • Congenital hereditary stromal dystrophy of the cornea • Decorin-associated congenital stromal corneal dystrophy ## Clinical Description Only seven families with the characteristic findings of congenital stromal corneal dystrophy (CSCD) have been reported in the literature [ In a Norwegian family with 11 affected individuals, bilateral corneal opacities were observed at or slightly after birth [ Affected individuals reported deterioration in visual acuity with increasing age; opacities tended to increase with age. Penetrating keratoplasty was performed in 18 out of 22 eyes at a mean age of 20 years. The grafts remained clear in 56% of the eyes, and in an additional 33% only minimal opacities were seen within an observation period of three to 36 (mean: 19.5) years. Some affected individuals in other studies reported photophobia [ No findings in other organ systems have been noted. ## Genotype-Phenotype Correlations Because of limited data, no genotype-phenotype correlations are evident. In one family reported by ## Penetrance Penetrance is complete in the described families. ## Nomenclature Other names by which congenital stromal corneal dystrophy has been known: Dystrophia corneae parenchymatosa congenita Congenital stromal dystrophy of the cornea Congenital hereditary stromal dystrophy of the cornea Decorin-associated congenital stromal corneal dystrophy • Dystrophia corneae parenchymatosa congenita • Congenital stromal dystrophy of the cornea • Congenital hereditary stromal dystrophy of the cornea • Decorin-associated congenital stromal corneal dystrophy ## Prevalence CSCD is probably very rare. Seven families with a similar phenotype have been described. In four of these, molecular analyses have revealed ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with pathogenic variants in ## Differential Diagnosis Bilateral congenital opacifications of the cornea can be caused by several disorders/conditions (see Various corneal dystrophies [ Congenital glaucoma Systemic storage disease Malformations of the anterior segment Inflammation Disorders with Bilateral Congenital Opacifications of the Cornea to Consider in the Differential Diagnosis of Congenital Stromal Corneal Dystrophy (CSCD) Corneal clouding Nystagmus Thick cornea Corneal edema Diffuse opacity Changes at Descemets membrane & endothelium w/vesicular lesions Peripheral anterior synechiae Hyperopia Flattening of cornea Thin cornea Sheet-like opacifications Involvement of Descemets membrane & endothelium Corneal clouding Photophobia Tearing & blepharospasm ↑ intraocular pressure ↑ corneal diameter Breaks in Descemets membrane Large, central opacities Iridocorneal adhesions Iris anomalies AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Autosomal recessive inheritance only accounts for a proportion of congenital glaucoma cases. • Various corneal dystrophies [ • Congenital glaucoma • Systemic storage disease • Malformations of the anterior segment • Inflammation • Corneal clouding • Nystagmus • Thick cornea • Corneal edema • Diffuse opacity • Changes at Descemets membrane & endothelium w/vesicular lesions • Peripheral anterior synechiae • Hyperopia • Flattening of cornea • Thin cornea • Sheet-like opacifications • Involvement of Descemets membrane & endothelium • Corneal clouding • Photophobia • Tearing & blepharospasm • ↑ intraocular pressure • ↑ corneal diameter • Breaks in Descemets membrane • Large, central opacities • Iridocorneal adhesions • Iris anomalies ## Management To establish the extent of disease and needs in an individual diagnosed with congenital stromal corneal dystrophy (CSCD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Ophthalmologic evaluation that includes the following: Assessment of visual acuity Assessment of refractive error Assessment of motility and strabismus (orthoptic evaluation) Slit lamp examination Measurement of corneal thickness using pachymetry Measurement of intraocular pressure Consultation with a clinical geneticist and/or genetic counselor The following are appropriate: Spectacles or contact lenses for correction of refractive errors Patching and/or surgical correction of strabismus Keratoplasty. To reduce the risk of amblyopia, penetrating keratoplasty should be considered in children younger than age seven years. Most grafts remain clear after penetrating keratoplasty even in this age group. There is a single report of a successful deep anterior lamellar keratoplasty in a child age four years [ Visual acuity and routine ophthalmologic examination should be performed at least every year in children. Regular surveillance in adults is not necessary unless they have undergone keratoplasty. Affected individuals should be informed about penetrating keratoplasty and advised to contact their eye doctor in case of reduced visual acuity or increased glare. Individuals who have undergone keratoplasty should avoid activities that could cause direct trauma to the eye. No other agents or circumstances need to be avoided. In families with known CSCD, at-risk children should be seen by an ophthalmologist within a few months after birth to determine if they have the condition. Alternatively, if the It is appropriate to clarify the status of at-risk relatives of an affected individual within a few months after birth in order to identify as early as possible those who would benefit from prompt ophthalmologic examination. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Ophthalmologic evaluation if the pathogenic variant in the family is not known. See Search • Ophthalmologic evaluation that includes the following: • Assessment of visual acuity • Assessment of refractive error • Assessment of motility and strabismus (orthoptic evaluation) • Slit lamp examination • Measurement of corneal thickness using pachymetry • Measurement of intraocular pressure • Assessment of visual acuity • Assessment of refractive error • Assessment of motility and strabismus (orthoptic evaluation) • Slit lamp examination • Measurement of corneal thickness using pachymetry • Measurement of intraocular pressure • Consultation with a clinical geneticist and/or genetic counselor • Assessment of visual acuity • Assessment of refractive error • Assessment of motility and strabismus (orthoptic evaluation) • Slit lamp examination • Measurement of corneal thickness using pachymetry • Measurement of intraocular pressure • Spectacles or contact lenses for correction of refractive errors • Patching and/or surgical correction of strabismus • Keratoplasty. To reduce the risk of amblyopia, penetrating keratoplasty should be considered in children younger than age seven years. Most grafts remain clear after penetrating keratoplasty even in this age group. There is a single report of a successful deep anterior lamellar keratoplasty in a child age four years [ • Molecular genetic testing if the pathogenic variant in the family is known; • Ophthalmologic evaluation 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 congenital stromal corneal dystrophy (CSCD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Ophthalmologic evaluation that includes the following: Assessment of visual acuity Assessment of refractive error Assessment of motility and strabismus (orthoptic evaluation) Slit lamp examination Measurement of corneal thickness using pachymetry Measurement of intraocular pressure Consultation with a clinical geneticist and/or genetic counselor • Ophthalmologic evaluation that includes the following: • Assessment of visual acuity • Assessment of refractive error • Assessment of motility and strabismus (orthoptic evaluation) • Slit lamp examination • Measurement of corneal thickness using pachymetry • Measurement of intraocular pressure • Assessment of visual acuity • Assessment of refractive error • Assessment of motility and strabismus (orthoptic evaluation) • Slit lamp examination • Measurement of corneal thickness using pachymetry • Measurement of intraocular pressure • Consultation with a clinical geneticist and/or genetic counselor • Assessment of visual acuity • Assessment of refractive error • Assessment of motility and strabismus (orthoptic evaluation) • Slit lamp examination • Measurement of corneal thickness using pachymetry • Measurement of intraocular pressure ## Treatment of Manifestations The following are appropriate: Spectacles or contact lenses for correction of refractive errors Patching and/or surgical correction of strabismus Keratoplasty. To reduce the risk of amblyopia, penetrating keratoplasty should be considered in children younger than age seven years. Most grafts remain clear after penetrating keratoplasty even in this age group. There is a single report of a successful deep anterior lamellar keratoplasty in a child age four years [ • Spectacles or contact lenses for correction of refractive errors • Patching and/or surgical correction of strabismus • Keratoplasty. To reduce the risk of amblyopia, penetrating keratoplasty should be considered in children younger than age seven years. Most grafts remain clear after penetrating keratoplasty even in this age group. There is a single report of a successful deep anterior lamellar keratoplasty in a child age four years [ ## Surveillance Visual acuity and routine ophthalmologic examination should be performed at least every year in children. Regular surveillance in adults is not necessary unless they have undergone keratoplasty. Affected individuals should be informed about penetrating keratoplasty and advised to contact their eye doctor in case of reduced visual acuity or increased glare. ## Agents/Circumstances to Avoid Individuals who have undergone keratoplasty should avoid activities that could cause direct trauma to the eye. No other agents or circumstances need to be avoided. ## Evaluation of Relatives at Risk In families with known CSCD, at-risk children should be seen by an ophthalmologist within a few months after birth to determine if they have the condition. Alternatively, if the It is appropriate to clarify the status of at-risk relatives of an affected individual within a few months after birth in order to identify as early as possible those who would benefit from prompt ophthalmologic examination. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; Ophthalmologic evaluation if the pathogenic variant in the family is not known. See • Molecular genetic testing if the pathogenic variant in the family is known; • Ophthalmologic evaluation if the pathogenic variant in the family is not known. ## Therapies Under Investigation Search ## Genetic Counseling Congenital stromal corneal dystrophy (CSCD) is inherited in an autosomal dominant manner. Most individuals diagnosed with CSCD have an affected parent. A proband with CSCD may have the disorder as the result of a new pathogenic variant. The proportion of cases caused by Recommendations for the evaluation of parents of a proband with an apparent If a The family history of some individuals diagnosed with CSCD 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 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 If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be the choice of the parents, discussion of these issues may be helpful. • Most individuals diagnosed with CSCD have an affected parent. • A proband with CSCD may have the disorder as the result of a new pathogenic variant. The proportion of cases caused by • Recommendations for the evaluation of parents of a proband with an apparent • If a • The family history of some individuals diagnosed with CSCD 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 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 • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Congenital stromal corneal dystrophy (CSCD) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with CSCD have an affected parent. A proband with CSCD may have the disorder as the result of a new pathogenic variant. The proportion of cases caused by Recommendations for the evaluation of parents of a proband with an apparent If a The family history of some individuals diagnosed with CSCD 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 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 If the parents have not been tested for the • Most individuals diagnosed with CSCD have an affected parent. • A proband with CSCD may have the disorder as the result of a new pathogenic variant. The proportion of cases caused by • Recommendations for the evaluation of parents of a proband with an apparent • If a • The family history of some individuals diagnosed with CSCD 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 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 • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be the choice of the parents, 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 • • • ## Molecular Genetics Congenital Stromal Corneal Dystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Congenital Stromal Corneal Dystrophy ( Corneal transparency requires that collagen fibrils be properly organized with a uniform diameter and a regular interfibrillar space. Congenital stromal corneal dystrophy (CSCD) is characterized by stromal opacities throughout the cornea. By transmission electron microscopy these opacities are seen as layers of amorphous material with thin filaments. The reported Variants listed in the table have been provided by the authors. Decorin is expressed in a wide range of connective tissues and can bind to several biologically important molecules including collagen I, collagen VI, fibronectin, thrombospondin, epidermal growth factor receptor, insulin-like growth factor 1 receptor, and transforming growth factor beta. It has been implicated in a number of biologic processes, primarily in the regulation of collagen fibril morphology, where there is evidence suggesting that decorin is the main inhibitor of lateral growth of collagen fibrils [ Note: Decorin has attracted particular attention in malignancies where the decorin protein has been shown to be a strong inhibitor of cell growth and to act as a pro-apoptotic agent. None of these studies concerns germline variants in humans. ## Molecular Pathogenesis Corneal transparency requires that collagen fibrils be properly organized with a uniform diameter and a regular interfibrillar space. Congenital stromal corneal dystrophy (CSCD) is characterized by stromal opacities throughout the cornea. By transmission electron microscopy these opacities are seen as layers of amorphous material with thin filaments. The reported Variants listed in the table have been provided by the authors. Decorin is expressed in a wide range of connective tissues and can bind to several biologically important molecules including collagen I, collagen VI, fibronectin, thrombospondin, epidermal growth factor receptor, insulin-like growth factor 1 receptor, and transforming growth factor beta. It has been implicated in a number of biologic processes, primarily in the regulation of collagen fibril morphology, where there is evidence suggesting that decorin is the main inhibitor of lateral growth of collagen fibrils [ Note: Decorin has attracted particular attention in malignancies where the decorin protein has been shown to be a strong inhibitor of cell growth and to act as a pro-apoptotic agent. None of these studies concerns germline variants in humans. ## References ## Literature Cited ## Chapter Notes 29 November 2018 (sw) Comprehensive update posted live 2 February 2012 (me) Comprehensive update posted live 25 November 2008 (me) Review posted live 10 September 2008 (er) Original submission • 29 November 2018 (sw) Comprehensive update posted live • 2 February 2012 (me) Comprehensive update posted live • 25 November 2008 (me) Review posted live • 10 September 2008 (er) Original submission ## Revision History 29 November 2018 (sw) Comprehensive update posted live 2 February 2012 (me) Comprehensive update posted live 25 November 2008 (me) Review posted live 10 September 2008 (er) Original submission • 29 November 2018 (sw) Comprehensive update posted live • 2 February 2012 (me) Comprehensive update posted live • 25 November 2008 (me) Review posted live • 10 September 2008 (er) Original submission Slit lamp photograph of the cornea showing slightly irregular surface and small flakes and spots throughout the corneal stroma Transmission electron micrograph showing lamellae of normal collagen fibrils separated by abnormal layers of thin filaments in an electron lucent ground substance
[ "BT Acar, KT Bozkurt, E Duman, S Acar. Bilateral cloudy cornea: is the usual suspect congenital hereditary endothelial dystrophy or stromal dystrophy?. BMJ Case Rep 2016:2016", "C Bredrup, PM Knappskog, J Majewski, E Rødahl, H Boman. Congenital stromal dystrophy of the cornea caused by a mutation in the decorin gene.. Invest Ophthalmol Vis Sci 2005;46:420-6", "C Bredrup, E Stang, O Bruland, BP Palka, RD Young, J Haavik, PM Knappskog, E Rødahl. Decorin accumulation contributes to the stromal opacities found in congenital stromal corneal dystrophy.. Invest Ophthalmol Vis Sci 2010;51:5578-82", "S De Cosmo, V Tassi, S Thomas, GP Piras, R Trevisan, P Cavallo Perin, S Bacci, L Zucaro, C Cisternino, V Trischitta, GC Viberti. The decorin gene 179 allelic variant is associated with a slower progression of renal disease in patients with type 1 diabetes.. Nephron 2002;92:72-6", "MA Gubbiotti, E Seifert, U Rodeck, JB Hoek, RV Iozzo. Metabolic reprogramming of murine cardiomyocytes during autophagy requires the extracellular nutrient sensor decorin.. J Biol Chem. 2018;293:16940-50", "Y Jing, PR Kumar, L Zhu, DP Edward, S Tao, L Wang, R Chuck, C Zhang. Novel decorin mutation in a Chinese family with congenital stromal corneal dystrophy.. Cornea 2014;33:288-93", "JH Kim, JM Ko, I Lee, JY Kim, MJ Kim, H Tchah. A novel mutation of the decorin gene identified in a Korean family with congenital hereditary stromal dystrophy.. Cornea 2011;30:1473-7", "JH Lee, CS Ki, ES Chung, TY Chung. A novel decorin gene mutation in congenital hereditary stromal dystrophy: a Korean family.. Korean J Ophthalmol. 2012;26:301-5", "AE Mellgren, O Bruland, A Vedeler, J Saraste, J Schönheit, C Bredrup, PM Knappskog, E Rødahl. Development of congenital stromal corneal dystrophy is dependent on export and extracellular deposition of truncated decorin.. Invest Ophthalmol Vis Sci. 2015;56:2909-15", "M Odland. Dystrophia corneae parenchymatosa congenita. A clinical, morphological and histochemical examination.. Acta Ophthalmol (Copenh) 1968;46:477-85", "Y Pouliquen, E Lacombe, C Schreinzer, JP Giraud, M Savoldelli. Familial congenital dystrophy of the corneal stroma: Turpin's syndrome (author's transl). J Fr Ophtalmol. 1979;2:115-25", "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", "E Rødahl, R Van Ginderdeuren, PM Knappskog, C Bredrup, H Boman. A second decorin frame shift mutation in a family with congenital stromal corneal dystrophy.. Am J Ophthalmol 2006;142:520-1", "L Schaefer, RV Iozzo. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction.. J Biol Chem 2008;283:21305-9", "R Turpin, M Tisserand, J Sérane. Opacités cornéennes héréditaires et congénitales réparties sur trois générations et atteignant deux jumelles monozygotes. Article in French.. Arch Ophthalmol (Paris) 1939;3:109-11", "R Van Ginderdeuren, R De Vos, I Casteels, B Foets. Report of a new family with dominant congenital heredity stromal dystrophy of the cornea.. Cornea 2002;21:118-20", "H Witschel, BS Fine, P Grützner, JW McTigue. Congenital hereditary stromal dystrophy of the cornea.. Arch Ophthalmol 1978;96:1043-51", "G Zhang, S Chen, S Goldoni, BW Calder, HC Simpson, RT Owens, DJ McQuillan, MF Young, RV Iozzo, DE Birk. Genetic evidence for the coordinated regulation of collagen fibrillogenesis in the cornea by decorin and biglycan.. J Biol Chem. 2009;284:8888-97" ]
25/11/2008
29/11/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
csnb
csnb
[ "X-Linked CSNB", "X-Linked CSNB", "Nyctalopin", "Voltage-dependent L-type calcium channel subunit alpha-1F", "CACNA1F", "NYX", "X-Linked Congenital Stationary Night Blindness" ]
X-Linked Congenital Stationary Night Blindness
Ian M MacDonald, Stephanie Hoang, Sari Tuupanen
Summary X-linked congenital stationary night blindness (CSNB) is characterized by non-progressive retinal findings of reduced visual acuity ranging from 20/30 to 20/200; defective dark adaptation; refractive error, most typically myopia ranging from low (-0.25 diopters [D] to -4.75 D) to high (≥-10.00 D) but occasionally hyperopia; nystagmus; strabismus; normal color vision; and normal fundus examination. Characteristic ERG findings can help distinguish between complete X-linked CSNB and incomplete X-linked CSNB. The diagnosis of X-linked CSNB is established in a male proband with characteristic clinical and electroretinogram (ERG) findings and a family history consistent with X-linked inheritance. Identification of a hemizygous pathogenic variant in By definition, X-linked CSNB is inherited in an X-linked manner. The father of an affected male will not have X-linked CSNB nor will he be hemizygous for the pathogenic variant. If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Males with X-linked CSNB will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for families in which the pathogenic variant has been identified.
## Diagnosis Characteristic clinical findings: Reduced visual acuity Night blindness Myopia Nystagmus (not universal) and strabismus (50%-70%) Normal color vision Normal fundus examination Family history consistent with X-linked inheritance Characteristic findings on ERG examination: ERG is used to assess the changes in electrical activity of the retina in response to light. The b-wave is caused by the depolarization of ON bipolar cells in response to light stimuli and is strictly dependent on synaptic transmission from photoreceptors to ON bipolar cells. Individuals with X-linked CSNB have reduced scotopic b-wave amplitudes in response to bright flashes after dark adaptation ( The ERG can define specific retinal dysfunctions and, in general, differentiate the forms of X-linked CSNB ( Electroretinogram Findings in Complete and Incomplete X-Linked Congenital Stationary Night Blindness OP = oscillatory potential Note: Pupillary responses have been described in the literature and in textbooks as "paradoxic" (i.e., miosis of pupils when lights are turned off, as opposed to dilation). This description predates genotyping. In 17 individuals with incomplete X-linked CSNB ages five to 51 years examined by one of the authors, none clearly demonstrated a paradoxic pupillary response. Further clarification of the presence or absence of this phenomenon in individuals with X-linked CSNB may require measurement with pupillometry. Reduced oscillatory potentials (OPs) associated with rod activity [ Reduced b-wave amplitudes (with unaffected OPs) in one heterozygous female [ Approaches can include Sequence analysis of Sequence analysis of Note: For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Congenital Stationary Night Blindness 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Reduced visual acuity • Night blindness • Myopia • Nystagmus (not universal) and strabismus (50%-70%) • Normal color vision • Normal fundus examination • Family history consistent with X-linked inheritance • ERG is used to assess the changes in electrical activity of the retina in response to light. The b-wave is caused by the depolarization of ON bipolar cells in response to light stimuli and is strictly dependent on synaptic transmission from photoreceptors to ON bipolar cells. • Individuals with X-linked CSNB have reduced scotopic b-wave amplitudes in response to bright flashes after dark adaptation ( • The ERG can define specific retinal dysfunctions and, in general, differentiate the forms of X-linked CSNB ( • Reduced oscillatory potentials (OPs) associated with rod activity [ • Reduced b-wave amplitudes (with unaffected OPs) in one heterozygous female [ • Sequence analysis of • Sequence analysis of ## Suggestive Findings Characteristic clinical findings: Reduced visual acuity Night blindness Myopia Nystagmus (not universal) and strabismus (50%-70%) Normal color vision Normal fundus examination Family history consistent with X-linked inheritance Characteristic findings on ERG examination: ERG is used to assess the changes in electrical activity of the retina in response to light. The b-wave is caused by the depolarization of ON bipolar cells in response to light stimuli and is strictly dependent on synaptic transmission from photoreceptors to ON bipolar cells. Individuals with X-linked CSNB have reduced scotopic b-wave amplitudes in response to bright flashes after dark adaptation ( The ERG can define specific retinal dysfunctions and, in general, differentiate the forms of X-linked CSNB ( Electroretinogram Findings in Complete and Incomplete X-Linked Congenital Stationary Night Blindness OP = oscillatory potential Note: Pupillary responses have been described in the literature and in textbooks as "paradoxic" (i.e., miosis of pupils when lights are turned off, as opposed to dilation). This description predates genotyping. In 17 individuals with incomplete X-linked CSNB ages five to 51 years examined by one of the authors, none clearly demonstrated a paradoxic pupillary response. Further clarification of the presence or absence of this phenomenon in individuals with X-linked CSNB may require measurement with pupillometry. Reduced oscillatory potentials (OPs) associated with rod activity [ Reduced b-wave amplitudes (with unaffected OPs) in one heterozygous female [ • Reduced visual acuity • Night blindness • Myopia • Nystagmus (not universal) and strabismus (50%-70%) • Normal color vision • Normal fundus examination • Family history consistent with X-linked inheritance • ERG is used to assess the changes in electrical activity of the retina in response to light. The b-wave is caused by the depolarization of ON bipolar cells in response to light stimuli and is strictly dependent on synaptic transmission from photoreceptors to ON bipolar cells. • Individuals with X-linked CSNB have reduced scotopic b-wave amplitudes in response to bright flashes after dark adaptation ( • The ERG can define specific retinal dysfunctions and, in general, differentiate the forms of X-linked CSNB ( • Reduced oscillatory potentials (OPs) associated with rod activity [ • Reduced b-wave amplitudes (with unaffected OPs) in one heterozygous female [ ## Establishing the Diagnosis Approaches can include Sequence analysis of Sequence analysis of Note: For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Congenital Stationary Night Blindness 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 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 • Sequence analysis of ## Molecular Genetic Testing Approaches can include Sequence analysis of Sequence analysis of Note: For an introduction to multigene panels click Molecular Genetic Testing Used in X-Linked Congenital Stationary Night Blindness 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 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 • Sequence analysis of ## Clinical Characteristics X-linked congenital stationary night blindness (CSNB) is a congenital non-progressive retinal disorder characterized by defective night vision, reduced visual acuity, myopia, nystagmus, and strabismus that primarily affects males. In a large Mennonite cohort with incomplete (i.e., In general, heterozygous females do not exhibit clinical signs of X-linked CSNB. Females who are homozygous for pathogenic variants in No genotype-phenotype correlations are known. Penetrance of X-linked CSNB is probably 100%, but expressivity is variable [ X-linked CSNB has in the past been referred to as Schubert-Bornschein CSNB, which is a reference to the characteristic "negative" waveform (a-wave larger than the b-wave in response to a bright flash in the scotopic state) of the ERG seen in both X-linked forms of CSNB [ The terms "CSNB1" and "CSNB2" are sometimes used as abbreviations for complete and incomplete CSNB irrespective of the mode of inheritance; originally the terms referred to the two X-linked entities of CSNB. The prevalence of X-linked CSNB is not known. A A common pathogenic variant in A common founder variant in • In general, heterozygous females do not exhibit clinical signs of X-linked CSNB. • Females who are homozygous for pathogenic variants in ## Clinical Description X-linked congenital stationary night blindness (CSNB) is a congenital non-progressive retinal disorder characterized by defective night vision, reduced visual acuity, myopia, nystagmus, and strabismus that primarily affects males. In a large Mennonite cohort with incomplete (i.e., In general, heterozygous females do not exhibit clinical signs of X-linked CSNB. Females who are homozygous for pathogenic variants in • In general, heterozygous females do not exhibit clinical signs of X-linked CSNB. • Females who are homozygous for pathogenic variants in ## Males In a large Mennonite cohort with incomplete (i.e., In general, heterozygous females do not exhibit clinical signs of X-linked CSNB. Females who are homozygous for pathogenic variants in • In general, heterozygous females do not exhibit clinical signs of X-linked CSNB. • Females who are homozygous for pathogenic variants in ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known. ## Penetrance Penetrance of X-linked CSNB is probably 100%, but expressivity is variable [ ## Nomenclature X-linked CSNB has in the past been referred to as Schubert-Bornschein CSNB, which is a reference to the characteristic "negative" waveform (a-wave larger than the b-wave in response to a bright flash in the scotopic state) of the ERG seen in both X-linked forms of CSNB [ The terms "CSNB1" and "CSNB2" are sometimes used as abbreviations for complete and incomplete CSNB irrespective of the mode of inheritance; originally the terms referred to the two X-linked entities of CSNB. ## Prevalence The prevalence of X-linked CSNB is not known. A A common pathogenic variant in A common founder variant in ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Other (OMIM Significant phenotypic overlap between AIED & CSNB2A Retinal disorder ↓ visual acuity Nystagmus Astigmatism Defective dark adaptation ERG reveals abnormalities in both photopic & scotopic functions. Fundus hypopigmentation Myopia is progressive. Protan color vision defect (OMIM Several features of CSNB2A Modest progressive dysfunction of photoreceptors Constricted visual fields Central scotomas General ↓ of sensitivity in central field Red/green or red color defects Intellectual disability Manifestations in heterozygous female (attributed to unique gain-of-function missense variant in CSNB = congenital stationary night blindness; CSNB2A = CSNB caused by a pathogenic variant in A novel pathogenic variant in A pathogenic variant in Described in a large Maori family [ • Significant phenotypic overlap between AIED & CSNB2A • Retinal disorder • ↓ visual acuity • Nystagmus • Astigmatism • Defective dark adaptation • ERG reveals abnormalities in both photopic & scotopic functions. • Fundus hypopigmentation • Myopia is progressive. • Protan color vision defect • Several features of CSNB2A • Modest progressive dysfunction of photoreceptors • Constricted visual fields • Central scotomas • General ↓ of sensitivity in central field • Red/green or red color defects • Intellectual disability • Manifestations in heterozygous female (attributed to unique gain-of-function missense variant in ## Differential Diagnosis Only a few conditions may initially be confused with the X-linked form of congenital stationary night blindness (CSNB). Disorders to Consider in the Differential Diagnosis of X-Linked Congenital Stationary Night Blindness Family history consistent w/XL inheritance may differentiate XL forms of CSNB from AD & AR forms. In AD CSNB, Nougaret type (OMIM Poor vision Nystagmus Abnormal color vision Almost completely abolished photopic ERG contrasting w/normal or minimally affected scotopic ERG Fundus exam in young males is normal; some males develop macular atrophy in late adulthood. Poor vision Nystagmus Normal ERG Normal VEP Normal foveal contour Poor vision Nystagmus Iris transillumination Foveal hypoplasia Heterozygous females have fundus signs (hypopigmentation of retinal pigment epithelium). Absence of selective ↓ in amplitude of b-wave on ERG VEP responses show propensity for more crossing fibers than expected at level of chiasm. Visual acuity ↓ to same range as in XL CSNB Selective ↓ in amplitude of b-wave on ERG Fundus shows discretely scattered white retinal dots. ERG, when recorded under standard conditions, shows selective ↓ in b-wave that normalizes w/prolonged dark adaptation. AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ERG = electroretinogram; MOI = mode of inheritance; VEP = visual evoked potential; XL = X-linked X-linked CSNB is characterized by a normal fundus. See Oguchi disease is a form of CSNB reported in the Japanese. Fundus albipunctatus is a form of CSNB. • Family history consistent w/XL inheritance may differentiate XL forms of CSNB from AD & AR forms. • In AD CSNB, Nougaret type (OMIM • Poor vision • Nystagmus • Abnormal color vision • Almost completely abolished photopic ERG contrasting w/normal or minimally affected scotopic ERG • Fundus exam in young males is normal; some males develop macular atrophy in late adulthood. • Poor vision • Nystagmus • Normal ERG • Normal VEP • Normal foveal contour • Poor vision • Nystagmus • Iris transillumination • Foveal hypoplasia • Heterozygous females have fundus signs (hypopigmentation of retinal pigment epithelium). • Absence of selective ↓ in amplitude of b-wave on ERG • VEP responses show propensity for more crossing fibers than expected at level of chiasm. • Visual acuity ↓ to same range as in XL CSNB • Selective ↓ in amplitude of b-wave on ERG • Fundus shows discretely scattered white retinal dots. • ERG, when recorded under standard conditions, shows selective ↓ in b-wave that normalizes w/prolonged dark adaptation. ## Management To establish the extent of disease in an individual diagnosed with X-linked congenital stationary night blindness (CSNB), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Ophthalmologic examination Electroretinography Dark adaptation (optional) Consultation with a clinical geneticist and/or genetic counselor Coincident high myopia or hyperopia can be managed with glasses or contact lenses. Occasionally, a boy with X-linked CSNB may adopt a cosmetically unacceptable or functionally awkward head posture to dampen the degree of nystagmus in a particular position of gaze (the so-called "null point"). In some instances the position of gaze for the null point may be shifted to a better functional range by carefully planned strabismus surgery. Regular (yearly) eye examinations are recommended with refraction at a young age to monitor for the development of myopia. Reduced visual acuity and difficulties seeing at night may preclude driving a car or restrict the class of driving license. For infants identified with high myopia, unusual head posture, or nystagmus and a family history of CSNB, ophthalmic examination and molecular genetic testing may confirm the diagnosis of CSNB, obviating the need for neuroimaging or clinical electrophysiologic testing under sedation or general anesthesia. See Search • Ophthalmologic examination • Electroretinography • Dark adaptation (optional) • Consultation with a clinical geneticist and/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with X-linked congenital stationary night blindness (CSNB), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Ophthalmologic examination Electroretinography Dark adaptation (optional) Consultation with a clinical geneticist and/or genetic counselor • Ophthalmologic examination • Electroretinography • Dark adaptation (optional) • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Coincident high myopia or hyperopia can be managed with glasses or contact lenses. Occasionally, a boy with X-linked CSNB may adopt a cosmetically unacceptable or functionally awkward head posture to dampen the degree of nystagmus in a particular position of gaze (the so-called "null point"). In some instances the position of gaze for the null point may be shifted to a better functional range by carefully planned strabismus surgery. ## Surveillance Regular (yearly) eye examinations are recommended with refraction at a young age to monitor for the development of myopia. ## Agents/Circumstances to Avoid Reduced visual acuity and difficulties seeing at night may preclude driving a car or restrict the class of driving license. ## Evaluation of Relatives at Risk For infants identified with high myopia, unusual head posture, or nystagmus and a family history of CSNB, ophthalmic examination and molecular genetic testing may confirm the diagnosis of CSNB, obviating the need for neuroimaging or clinical electrophysiologic testing under sedation or general anesthesia. See ## Therapies Under Investigation Search ## Genetic Counseling By definition, X-linked congenital stationary night blindness (CSNB) is inherited in an X-linked manner. The father of an affected male will not have X-linked CSNB nor will he be hemizygous for the In a family with more than one affected male, 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 proband is female and has biallelic pathogenic variants (rare), both the mother and the father may have X-linked CSNB-causing pathogenic variants (i.e., the mother may be a carrier and the father may be affected) [ 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 All of their daughters, who will be heterozygous and will usually not be affected; None of their sons. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband. Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. (2) Identification of female heterozygotes requires either (a) 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 increased 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 X-linked CSNB nor will he be hemizygous for the • In a family with more than one affected male, 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 proband is female and has biallelic pathogenic variants (rare), both the mother and the father may have X-linked CSNB-causing pathogenic variants (i.e., the mother may be a carrier and the father may be affected) [ • 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 • All of their daughters, who will be heterozygous 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 carriers, or are at increased risk of being carriers. ## Mode of Inheritance By definition, X-linked congenital stationary night blindness (CSNB) is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have X-linked CSNB nor will he be hemizygous for the In a family with more than one affected male, 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 proband is female and has biallelic pathogenic variants (rare), both the mother and the father may have X-linked CSNB-causing pathogenic variants (i.e., the mother may be a carrier and the father may be affected) [ 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 All of their daughters, who will be heterozygous and will usually not be affected; None of their sons. • The father of an affected male will not have X-linked CSNB nor will he be hemizygous for the • In a family with more than one affected male, 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 proband is female and has biallelic pathogenic variants (rare), both the mother and the father may have X-linked CSNB-causing pathogenic variants (i.e., the mother may be a carrier and the father may be affected) [ • 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 • All of their daughters, who will be heterozygous and will usually not be affected; • None of their sons. ## Carrier (Heterozygote) Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband. Note: (1) Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected. (2) Identification of female heterozygotes requires either (a) 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 increased 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 increased 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 890 Yonge Street 12th Floor Toronto Ontario M4W 3P4 Canada • • 890 Yonge Street • 12th Floor • Toronto Ontario M4W 3P4 • Canada • • • • • ## Molecular Genetics X-Linked Congenital Stationary Night Blindness: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Congenital Stationary Night Blindness ( Genes associated with X-linked congenital stationary night blindness (X-linked CSNB) encode proteins that are specifically expressed in the retina: nyctalopin and voltage-dependent L-type calcium channel subunit alpha-1F (Ca Pathogenic variants in Expression studies have shown that some (not all) X-Linked Congenital Stationary Night Blindness: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Genes associated with X-linked congenital stationary night blindness (X-linked CSNB) encode proteins that are specifically expressed in the retina: nyctalopin and voltage-dependent L-type calcium channel subunit alpha-1F (Ca Pathogenic variants in Expression studies have shown that some (not all) X-Linked Congenital Stationary Night Blindness: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## References ## Literature Cited ## Chapter Notes The authors would like to thank Linda MacLaren and Karen McElligott for years of service to the Mennonite community affected with CSNB2A. N Torben Bech-Hansen, PhD; University of Calgary (2007-2012)Kym M Boycott, PhD, MD; University of Ottawa, Canada (2007-2019)Stephanie Hoang, MSc (2019-present)Ian M MacDonald, MD, CM (2007-present)Yves Sauvé, PhD; University of Alberta (2007-2019)Sari Tuupanen, PhD (2019-present) 3 July 2019 (sw) Comprehensive update posted live 26 April 2012 (me) Comprehensive update posted live 16 January 2008 (me) Review posted live 9 August 2007 (im) Original submission • 3 July 2019 (sw) Comprehensive update posted live • 26 April 2012 (me) Comprehensive update posted live • 16 January 2008 (me) Review posted live • 9 August 2007 (im) Original submission ## Acknowledgments The authors would like to thank Linda MacLaren and Karen McElligott for years of service to the Mennonite community affected with CSNB2A. ## Author History N Torben Bech-Hansen, PhD; University of Calgary (2007-2012)Kym M Boycott, PhD, MD; University of Ottawa, Canada (2007-2019)Stephanie Hoang, MSc (2019-present)Ian M MacDonald, MD, CM (2007-present)Yves Sauvé, PhD; University of Alberta (2007-2019)Sari Tuupanen, PhD (2019-present) ## Revision History 3 July 2019 (sw) Comprehensive update posted live 26 April 2012 (me) Comprehensive update posted live 16 January 2008 (me) Review posted live 9 August 2007 (im) Original submission • 3 July 2019 (sw) Comprehensive update posted live • 26 April 2012 (me) Comprehensive update posted live • 16 January 2008 (me) Review posted live • 9 August 2007 (im) Original submission Representative full-field ERGs recorded from three males: A. Age 35 years, unaffected B. Age 66 years, with CSNB1A (pathogenic variant in C. Age 35 years, with CSNB2A (pathogenic variant in Arrows indicate the b-wave, which has lower amplitude than the a-wave (so-called "negative ERG"). Traces in panel C adapted with the author's permission from
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Congenital stationary night blindness with negative electroretinogram. A new classification.. Arch Ophthalmol 1986;104:1013-20", "M Nakamura, S Ito, CH Piao, H Terasaki, Y Miyake. Retinal and optic disc atrophy associated with a CACNA1F mutation in a Japanese family.. Arch Ophthalmol 2003;121:1028-33", "CM Pusch, C Zeitz, O Brandau, K Pesch, H Achatz, S Feil, C Scharfe, J Maurer, FK Jacobi, A Pinckers, S Andreasson, A Hardcastle, B Wissinger, W Berger, A Meindl. The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.. Nat Genet 2000;26:324-7", "F Rigaudière, C Roux, P Lachapelle, SG Rosolen, P Bitoun, A Gay-Duval, JF Le Gargasson. ERGs in female carriers of incomplete congenital stationary night blindness (I-CSNB). A family report.. Doc Ophthalmol 2003;107:203-12", "LA Riggs. Electroretinography in cases of night blindness.. Am J Ophthalmol 1954;38:70-8", "G Schubert, H Bornschein. Analysis of the human electroretinogram.. Ophthalmologica 1952;123:396-413", "HJ Simonsz, RJ Florijn, HM van Minderhout, AA Bergen, M Kamermans. Nightblindness-associated transient tonic downgaze (NATTD) in infant boys with chin-up head posture.. Strabismus 2009;17:158-64", "TM Strom, G Nyakatura, E Apfelstedt-Sylla, H Hellebrand, B Lorenz, BH Weber, K Wutz, N Gutwillinger, K Ruther, B Drescher, C Sauer, E Zrenner, T Meitinger, A Rosenthal, A Meindl. An L-type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness.. Nat Genet 1998;19:260-3", "C Zeitz. Molecular genetics and protein function involved in nocturnal vision.. Exp Rev Ophthalmol 2007;2:467-85", "C Zeitz, AG Robson, I Audo. Congenital stationary night blindness: an analysis and update of genotype-phenotype correlations and pathogenic mechanisms.. Prog Retin Eye Res. 2015;45:58-110", "Q Zhang, X Xiao, S Li, X Jia, Z Yang, S Huang, RC Caruso, T Guan, Y Sergeev, X Guo, JF Hejtmancik. Mutations in NYX of individuals with high myopia, but without night blindness.. Mol Vis 2007;13:330-6" ]
16/1/2008
3/7/2019
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
csnk2b-ndd
csnk2b-ndd
[ "Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS)", "Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS)", "Casein kinase II subunit beta", "CSNK2B", "CSNK2B-Related Neurodevelopmental Disorder" ]
Natalie Lippa, Maureen Mulhern, Michelle Ernst Florido, Chelsea Earley, Tristan T Sands
Summary The diagnosis of
## Diagnosis No consensus clinical diagnostic criteria for Mild-to-profound developmental delay (DD), intellectual disability (ID), or learning disability Epilepsy ranging from mild pharmaco-responsive epilepsy to severe intractable epilepsy with recurrent status epilepticus. Seizure types include the following: Generalized tonic or tonic-clonic seizures Absence seizures Myoclonic seizures Atonic or myoclonic-atonic seizures Myoclonic-absence seizures Focal-onset seizures Less common and variable findings include the following: Ataxia or impaired coordination Generalized hypotonia of infancy Neurobehavioral/psychiatric manifestations Facial features Digital abnormalities Short stature 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 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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-profound developmental delay (DD), intellectual disability (ID), or learning disability • Epilepsy ranging from mild pharmaco-responsive epilepsy to severe intractable epilepsy with recurrent status epilepticus. Seizure types include the following: • Generalized tonic or tonic-clonic seizures • Absence seizures • Myoclonic seizures • Atonic or myoclonic-atonic seizures • Myoclonic-absence seizures • Focal-onset seizures • Generalized tonic or tonic-clonic seizures • Absence seizures • Myoclonic seizures • Atonic or myoclonic-atonic seizures • Myoclonic-absence seizures • Focal-onset seizures • Generalized tonic or tonic-clonic seizures • Absence seizures • Myoclonic seizures • Atonic or myoclonic-atonic seizures • Myoclonic-absence seizures • Focal-onset seizures • Ataxia or impaired coordination • Generalized hypotonia of infancy • Neurobehavioral/psychiatric manifestations • Facial features • Digital abnormalities • Short stature • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Mild-to-profound developmental delay (DD), intellectual disability (ID), or learning disability Epilepsy ranging from mild pharmaco-responsive epilepsy to severe intractable epilepsy with recurrent status epilepticus. Seizure types include the following: Generalized tonic or tonic-clonic seizures Absence seizures Myoclonic seizures Atonic or myoclonic-atonic seizures Myoclonic-absence seizures Focal-onset seizures Less common and variable findings include the following: Ataxia or impaired coordination Generalized hypotonia of infancy Neurobehavioral/psychiatric manifestations Facial features Digital abnormalities Short stature • Mild-to-profound developmental delay (DD), intellectual disability (ID), or learning disability • Epilepsy ranging from mild pharmaco-responsive epilepsy to severe intractable epilepsy with recurrent status epilepticus. Seizure types include the following: • Generalized tonic or tonic-clonic seizures • Absence seizures • Myoclonic seizures • Atonic or myoclonic-atonic seizures • Myoclonic-absence seizures • Focal-onset seizures • Generalized tonic or tonic-clonic seizures • Absence seizures • Myoclonic seizures • Atonic or myoclonic-atonic seizures • Myoclonic-absence seizures • Focal-onset seizures • Generalized tonic or tonic-clonic seizures • Absence seizures • Myoclonic seizures • Atonic or myoclonic-atonic seizures • Myoclonic-absence seizures • Focal-onset seizures • Ataxia or impaired coordination • Generalized hypotonia of infancy • Neurobehavioral/psychiatric manifestations • Facial features • Digital abnormalities • Short stature ## 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 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, more than 80 individuals have been identified with a The following discussion is based on information reported on 48 individuals in publications with at least two individuals with Of these individuals, the majority (45/48) had developmental delays in at least one domain. Most (39/45) had both speech and motor delays. Of the three individuals reported not to have developmental delay, two were younger than age five years and one (age nine years at the time of evaluation) had a learning disability [ Two males older than age five years were unable to ambulate independently by the time of evaluation; both had severe epilepsy with recurrent refractory status epilepticus associated with regression. The 12-year-old male lost the ability to walk independently at age nine years; the 26-year-old male had started to walk independently at age seven years but was unable to walk without assistance by the time of evaluation [ Of those older than age five years at the time of evaluation, 23 of 29 had ID. Twelve had borderline or mild ID; five had moderate ID; five had severe or profound ID; and one individual's level of ID was not reported. Of the six who did not have intellectual disability, four had a learning disability. One study noted a possible difference in neurodevelopment outcomes between males and females, with males having a more severe intellectual disability (see Epilepsy types included generalized epilepsy, focal epilepsy, and combined generalized and focal epilepsy [ The severity of epilepsy was highly variable [ Although the course of epilepsy tended to improve with age, several individuals experienced increased seizure frequency between ages 7 and 12 years [ Multifocal epileptiform abnormalities were also described [ Less commonly, some individuals with epilepsy had EEG studies that did not report epileptiform abnormalities (e.g., Patient 5 in Slowing of the EEG background was observed in about 50% of individuals [ Delayed myelination (3 individual) [ Enlargement of subarachnoid spaces (2 individuals) [ Ventriculomegaly that resolved on later imaging (1 individual) [ Cortical gyral simplification [ Periventricular gliosis (1 individual) [ Pineal gland abnormalities [ Scattered signal abnormalities identified in gray and white matter [ Hindbrain abnormalities reported in one or more individuals include T Microcephaly, seen in one individual, was associated with severe intellectual disability [ All five individuals reported by One individual reported by One individual was noted to have growth delay [ No clear genotype-phenotype correlations have been established across all variant classes, given high phenotypic variability and the small total number of individuals reported to date, the small number of individuals with recurrent variants, and the inconsistent reporting of certain phenotypic features. Nonetheless, genotype-phenotype correlations have been proposed for missense variants affecting certain residues [ The term "intellectual disability-craniodigital syndrome (IDCS)" was proposed to refer to the phenotype observed in individuals with substitutions in To date, more than 80 individuals have been identified with a • Two males older than age five years were unable to ambulate independently by the time of evaluation; both had severe epilepsy with recurrent refractory status epilepticus associated with regression. The 12-year-old male lost the ability to walk independently at age nine years; the 26-year-old male had started to walk independently at age seven years but was unable to walk without assistance by the time of evaluation [ • Delayed myelination (3 individual) [ • Enlargement of subarachnoid spaces (2 individuals) [ • Ventriculomegaly that resolved on later imaging (1 individual) [ • Cortical gyral simplification [ • Periventricular gliosis (1 individual) [ • Pineal gland abnormalities [ • Scattered signal abnormalities identified in gray and white matter [ • • All five individuals reported by • One individual reported by • One individual was noted to have growth delay [ • All five individuals reported by • One individual reported by • One individual was noted to have growth delay [ • All five individuals reported by • One individual reported by • One individual was noted to have growth delay [ ## Clinical Description To date, more than 80 individuals have been identified with a The following discussion is based on information reported on 48 individuals in publications with at least two individuals with Of these individuals, the majority (45/48) had developmental delays in at least one domain. Most (39/45) had both speech and motor delays. Of the three individuals reported not to have developmental delay, two were younger than age five years and one (age nine years at the time of evaluation) had a learning disability [ Two males older than age five years were unable to ambulate independently by the time of evaluation; both had severe epilepsy with recurrent refractory status epilepticus associated with regression. The 12-year-old male lost the ability to walk independently at age nine years; the 26-year-old male had started to walk independently at age seven years but was unable to walk without assistance by the time of evaluation [ Of those older than age five years at the time of evaluation, 23 of 29 had ID. Twelve had borderline or mild ID; five had moderate ID; five had severe or profound ID; and one individual's level of ID was not reported. Of the six who did not have intellectual disability, four had a learning disability. One study noted a possible difference in neurodevelopment outcomes between males and females, with males having a more severe intellectual disability (see Epilepsy types included generalized epilepsy, focal epilepsy, and combined generalized and focal epilepsy [ The severity of epilepsy was highly variable [ Although the course of epilepsy tended to improve with age, several individuals experienced increased seizure frequency between ages 7 and 12 years [ Multifocal epileptiform abnormalities were also described [ Less commonly, some individuals with epilepsy had EEG studies that did not report epileptiform abnormalities (e.g., Patient 5 in Slowing of the EEG background was observed in about 50% of individuals [ Delayed myelination (3 individual) [ Enlargement of subarachnoid spaces (2 individuals) [ Ventriculomegaly that resolved on later imaging (1 individual) [ Cortical gyral simplification [ Periventricular gliosis (1 individual) [ Pineal gland abnormalities [ Scattered signal abnormalities identified in gray and white matter [ Hindbrain abnormalities reported in one or more individuals include T Microcephaly, seen in one individual, was associated with severe intellectual disability [ All five individuals reported by One individual reported by One individual was noted to have growth delay [ • Two males older than age five years were unable to ambulate independently by the time of evaluation; both had severe epilepsy with recurrent refractory status epilepticus associated with regression. The 12-year-old male lost the ability to walk independently at age nine years; the 26-year-old male had started to walk independently at age seven years but was unable to walk without assistance by the time of evaluation [ • Delayed myelination (3 individual) [ • Enlargement of subarachnoid spaces (2 individuals) [ • Ventriculomegaly that resolved on later imaging (1 individual) [ • Cortical gyral simplification [ • Periventricular gliosis (1 individual) [ • Pineal gland abnormalities [ • Scattered signal abnormalities identified in gray and white matter [ • • All five individuals reported by • One individual reported by • One individual was noted to have growth delay [ • All five individuals reported by • One individual reported by • One individual was noted to have growth delay [ • All five individuals reported by • One individual reported by • One individual was noted to have growth delay [ ## Genotype-Phenotype Correlations No clear genotype-phenotype correlations have been established across all variant classes, given high phenotypic variability and the small total number of individuals reported to date, the small number of individuals with recurrent variants, and the inconsistent reporting of certain phenotypic features. Nonetheless, genotype-phenotype correlations have been proposed for missense variants affecting certain residues [ ## Nomenclature The term "intellectual disability-craniodigital syndrome (IDCS)" was proposed to refer to the phenotype observed in individuals with substitutions in ## Prevalence To date, more than 80 individuals have been identified with a ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this A contiguous gene deletion in the 6p21.33 region involving A A • A contiguous gene deletion in the 6p21.33 region involving • A • A ## Differential Diagnosis The phenotypic features associated with • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl brain MRI EEG incl sleep study to characterize any recurrent abnormal episodes & evaluate for subtle or subclinical 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 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; Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for No ASM has been demonstrated to have specific efficacy in Different ASMs have been reported to be effective in different persons. 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). 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, behavioral pediatric neurologist, or developmental pediatrician. 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. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Measure growth parameters. Evaluate nutritional status & safety of oral intake. OT = occupational therapy; PT = physical therapy See Search • To incl brain MRI • EEG incl sleep study to characterize any recurrent abnormal episodes & evaluate for subtle or subclinical 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 • Community or • Social work involvement for parental support • Home nursing referral • No ASM has been demonstrated to have specific efficacy in • Different ASMs have been reported to be effective in different persons. • 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). • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl brain MRI EEG incl sleep study to characterize any recurrent abnormal episodes & evaluate for subtle or subclinical 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 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; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI • EEG incl sleep study to characterize any recurrent abnormal episodes & evaluate for subtle or subclinical 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 • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for No ASM has been demonstrated to have specific efficacy in Different ASMs have been reported to be effective in different persons. 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). 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, behavioral pediatric neurologist, or developmental pediatrician. • No ASM has been demonstrated to have specific efficacy in • Different ASMs have been reported to be effective in different persons. • 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). ## 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). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Neurobehavioral/Psychiatric Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, 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, behavioral pediatric neurologist, or developmental pediatrician. ## 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. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Measure growth parameters. Evaluate 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, & movement disorders. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Almost all probands reported to date with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a 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 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 reported to date with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a • The proband has a • The proband inherited a • The proband has a • The proband inherited 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 young adults who are affected and parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members Almost all probands reported to date with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a If a parent of the proband is known to have the If the • Almost all probands reported to date with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a • The proband has a • The proband inherited a • The proband has a • The proband inherited 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 young adults who are affected and 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 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 Canada United Kingdom • • • • • • • Canada • • • • • • • United Kingdom • • • • ## Molecular Genetics CSNK2B-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for CSNK2B-Related Neurodevelopmental Disorder ( It is unclear whether some ID = intellectual disability Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis It is unclear whether some ID = intellectual disability Variants listed in the table have been provided by the authors. ## Chapter Notes Natalie Lippa, MS, CGC, is Assistant Professor of Genetic Counseling in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons. Maureen Mulhern, MS, MAT, CGC, is a genetic counselor in the Inter-Departmental Genetic Counseling Program, Department of Neurology, and in the Precision Genomics Laboratory at the Columbia University Vagelos College of Physicians and Surgeons. Michelle Ernst Florido, MS, CGC, is Assistant Program Director for the Genetic Counseling Graduate Program at the Columbia University Vagelos College of Physicians and Surgeons. Chelsea Earley, MD, is a pediatric clinical epilepsy fellow at Columbia University Irving Medical Center. Tristan T Sands, MD, PhD, is Assistant Professor of Neurology at the Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children's Hospital. Dr Sands sees patients with genetic causes of epilepsy and neurodevelopmental disability, and his laboratory conducts translational research as part of the Center for Translational Research in Neurodevelopmental Disease (CTRND). The CTRND at Columbia University is actively involved in ongoing clinical and translational research on We would like to thank the 5 September 2024 (bp) Review posted live 7 August 2023 (ts) Original submission • 5 September 2024 (bp) Review posted live • 7 August 2023 (ts) Original submission ## Author Notes Natalie Lippa, MS, CGC, is Assistant Professor of Genetic Counseling in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons. Maureen Mulhern, MS, MAT, CGC, is a genetic counselor in the Inter-Departmental Genetic Counseling Program, Department of Neurology, and in the Precision Genomics Laboratory at the Columbia University Vagelos College of Physicians and Surgeons. Michelle Ernst Florido, MS, CGC, is Assistant Program Director for the Genetic Counseling Graduate Program at the Columbia University Vagelos College of Physicians and Surgeons. Chelsea Earley, MD, is a pediatric clinical epilepsy fellow at Columbia University Irving Medical Center. Tristan T Sands, MD, PhD, is Assistant Professor of Neurology at the Columbia University Vagelos College of Physicians and Surgeons and New York-Presbyterian Morgan Stanley Children's Hospital. Dr Sands sees patients with genetic causes of epilepsy and neurodevelopmental disability, and his laboratory conducts translational research as part of the Center for Translational Research in Neurodevelopmental Disease (CTRND). The CTRND at Columbia University is actively involved in ongoing clinical and translational research on ## Acknowledgments We would like to thank the ## Revision History 5 September 2024 (bp) Review posted live 7 August 2023 (ts) Original submission • 5 September 2024 (bp) Review posted live • 7 August 2023 (ts) Original submission ## References ## Literature Cited
[]
5/9/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ctcf-dis
ctcf-dis
[ "Autosomal Dominant Intellectual Disability 21", "CTCF-Related Neurodevelopmental Disorder", "Autosomal Dominant Intellectual Disability 21", "CTCF-Related Neurodevelopmental Disorder", "Transcriptional repressor CTCF", "CTCF", "CTCF-Related Disorder" ]
Hannah Gabriela Valverde de Morales, Hsiao-Lin Wang, Kathryn Garber, Victor Corces, Hong Li
Summary The diagnosis of
## Diagnosis No consensus clinical diagnostic criteria for Mild-to-profound developmental delay (DD) or intellectual disability (ID) AND Any of the following features presenting in infancy or childhood: Hypotonia Feeding difficulties Slow growth Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia Sensorineural or conductive hearing loss Nonspecific dysmorphic features (See Cleft palate Congenital heart defects Tooth anomalies, such as crowded teeth and abnormal decay Genitourinary anomalies Sleep disturbance Recurrent infections Seizures 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 Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q22.1 region. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Theoretically, gene-targeted deletion/duplication analysis should detect all deletions/duplications that can be detected by CMA. However, CMA may not detect all instances of single- or several-exon deletions or duplications depending on the probe coverage through various parts of a gene. • Mild-to-profound developmental delay (DD) or intellectual disability (ID) • Any of the following features presenting in infancy or childhood: • Hypotonia • Feeding difficulties • Slow growth • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia • Sensorineural or conductive hearing loss • Nonspecific dysmorphic features (See • Cleft palate • Congenital heart defects • Tooth anomalies, such as crowded teeth and abnormal decay • Genitourinary anomalies • Sleep disturbance • Recurrent infections • Seizures • Hypotonia • Feeding difficulties • Slow growth • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia • Sensorineural or conductive hearing loss • Nonspecific dysmorphic features (See • Cleft palate • Congenital heart defects • Tooth anomalies, such as crowded teeth and abnormal decay • Genitourinary anomalies • Sleep disturbance • Recurrent infections • Seizures • Hypotonia • Feeding difficulties • Slow growth • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia • Sensorineural or conductive hearing loss • Nonspecific dysmorphic features (See • Cleft palate • Congenital heart defects • Tooth anomalies, such as crowded teeth and abnormal decay • Genitourinary anomalies • Sleep disturbance • Recurrent infections • Seizures • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Mild-to-profound developmental delay (DD) or intellectual disability (ID) AND Any of the following features presenting in infancy or childhood: Hypotonia Feeding difficulties Slow growth Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia Sensorineural or conductive hearing loss Nonspecific dysmorphic features (See Cleft palate Congenital heart defects Tooth anomalies, such as crowded teeth and abnormal decay Genitourinary anomalies Sleep disturbance Recurrent infections Seizures • Mild-to-profound developmental delay (DD) or intellectual disability (ID) • Any of the following features presenting in infancy or childhood: • Hypotonia • Feeding difficulties • Slow growth • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia • Sensorineural or conductive hearing loss • Nonspecific dysmorphic features (See • Cleft palate • Congenital heart defects • Tooth anomalies, such as crowded teeth and abnormal decay • Genitourinary anomalies • Sleep disturbance • Recurrent infections • Seizures • Hypotonia • Feeding difficulties • Slow growth • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia • Sensorineural or conductive hearing loss • Nonspecific dysmorphic features (See • Cleft palate • Congenital heart defects • Tooth anomalies, such as crowded teeth and abnormal decay • Genitourinary anomalies • Sleep disturbance • Recurrent infections • Seizures • Hypotonia • Feeding difficulties • Slow growth • Neurobehavioral/psychiatric manifestations, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, and/or destructive behaviors • Ophthalmologic involvement, including strabismus, hypermetropia, astigmatism, amblyopia, and/or myopia • Sensorineural or conductive hearing loss • Nonspecific dysmorphic features (See • Cleft palate • Congenital heart defects • Tooth anomalies, such as crowded teeth and abnormal decay • Genitourinary anomalies • Sleep disturbance • Recurrent infections • Seizures ## 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 Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q22.1 region. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Theoretically, gene-targeted deletion/duplication analysis should detect all deletions/duplications that can be detected by CMA. However, CMA may not detect all instances of single- or several-exon deletions or duplications depending on the probe coverage through various parts of a gene. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, more than 100 individuals have been identified with a pathogenic variant in Select Features of Adapted from ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; IgA = immunoglobulin A H Li, personal observation About 65% of affected individuals have been reported to have speech delay, ranging from mild delay to individuals who are nonverbal. The mean age of saying the first word is 20 months, with a range of 10 months to 5 years. About 53% of affected individuals have been reported as having motor delay, with 10/42 (24%) of reported individuals having coordination or balance issues. Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. Mean age of walking independently is 18 months, with a range from 12 months to 42 months. At least one affected individual was nonambulatory at age 17 years. Aggression Anxiety Difficulty regulating emotions Destructive behaviors Oppositional behaviors Self-injurious behaviors Feeding problems are most commonly reported in early infancy, with some individuals experiencing resolution of feeding problems at older ages, most with the removal of their feeding tube. About 17% of affected individuals experience constipation. Other reported functional gastrointestinal complications include gastroesophageal reflux disease, dysphagia, and irritable bowel syndrome. Gastrointestinal malformations may include intestinal malrotation and rectal duplication. Hypermetropia Astigmatism Amblyopia Myopia Ptosis Impacted teeth Increased incidence of dental decay Ectopic teeth Absent secondary teeth Abnormal shape of teeth Discoloration of teeth Midline misalignment Kyphosis Vertebral compression fractures, most typically in older individuals Hip dysplasia Pes valgus Bilateral clubfeet Genu valgum Calcaneus valgus Tight tendons requiring tenotomies Finger abnormalities, such as camptodactyly Renal findings include: Dysplastic kidney Solitary kidney Polycystic kidney Renal ectasia Vesicoureteral reflux disease Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor Anomalies of the genitalia in males can include: Cryptorchidism Spermatocele Penile chordee Phimosis Hypospadias In females, hypoplastic labia majora has been noted. Atrial septal defects Tetralogy of Fallot Pulmonary valve stenosis Patent ductus arteriosus Mild aortic coarctation Aortic ectasia (Aortic rupture has not been reported to date in individuals with this condition, although data on progression of this finding is limited.) Bicuspid aortic valve Febrile seizures Generalized tonic-clonic seizures Tonic seizures Petit mal seizures No consistent genotype-phenotype correlations have been identified [ • About 65% of affected individuals have been reported to have speech delay, ranging from mild delay to individuals who are nonverbal. The mean age of saying the first word is 20 months, with a range of 10 months to 5 years. • About 53% of affected individuals have been reported as having motor delay, with 10/42 (24%) of reported individuals having coordination or balance issues. • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. • Mean age of walking independently is 18 months, with a range from 12 months to 42 months. • At least one affected individual was nonambulatory at age 17 years. • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. • Mean age of walking independently is 18 months, with a range from 12 months to 42 months. • At least one affected individual was nonambulatory at age 17 years. • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. • Mean age of walking independently is 18 months, with a range from 12 months to 42 months. • At least one affected individual was nonambulatory at age 17 years. • Aggression • Anxiety • Difficulty regulating emotions • Destructive behaviors • Oppositional behaviors • Self-injurious behaviors • Feeding problems are most commonly reported in early infancy, with some individuals experiencing resolution of feeding problems at older ages, most with the removal of their feeding tube. • About 17% of affected individuals experience constipation. • Other reported functional gastrointestinal complications include gastroesophageal reflux disease, dysphagia, and irritable bowel syndrome. • Gastrointestinal malformations may include intestinal malrotation and rectal duplication. • Hypermetropia • Astigmatism • Amblyopia • Myopia • Ptosis • Impacted teeth • Increased incidence of dental decay • Ectopic teeth • Absent secondary teeth • Abnormal shape of teeth • Discoloration of teeth • Midline misalignment • Kyphosis • Vertebral compression fractures, most typically in older individuals • Hip dysplasia • Pes valgus • Bilateral clubfeet • Genu valgum • Calcaneus valgus • Tight tendons requiring tenotomies • Finger abnormalities, such as camptodactyly • Renal findings include: • Dysplastic kidney • Solitary kidney • Polycystic kidney • Renal ectasia • Vesicoureteral reflux disease • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor • Dysplastic kidney • Solitary kidney • Polycystic kidney • Renal ectasia • Vesicoureteral reflux disease • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor • Anomalies of the genitalia in males can include: • Cryptorchidism • Spermatocele • Penile chordee • Phimosis • Hypospadias • Cryptorchidism • Spermatocele • Penile chordee • Phimosis • Hypospadias • In females, hypoplastic labia majora has been noted. • Dysplastic kidney • Solitary kidney • Polycystic kidney • Renal ectasia • Vesicoureteral reflux disease • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor • Cryptorchidism • Spermatocele • Penile chordee • Phimosis • Hypospadias • Atrial septal defects • Tetralogy of Fallot • Pulmonary valve stenosis • Patent ductus arteriosus • Mild aortic coarctation • Aortic ectasia (Aortic rupture has not been reported to date in individuals with this condition, although data on progression of this finding is limited.) • Bicuspid aortic valve • Febrile seizures • Generalized tonic-clonic seizures • Tonic seizures • Petit mal seizures ## Clinical Description To date, more than 100 individuals have been identified with a pathogenic variant in Select Features of Adapted from ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; IgA = immunoglobulin A H Li, personal observation About 65% of affected individuals have been reported to have speech delay, ranging from mild delay to individuals who are nonverbal. The mean age of saying the first word is 20 months, with a range of 10 months to 5 years. About 53% of affected individuals have been reported as having motor delay, with 10/42 (24%) of reported individuals having coordination or balance issues. Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. Mean age of walking independently is 18 months, with a range from 12 months to 42 months. At least one affected individual was nonambulatory at age 17 years. Aggression Anxiety Difficulty regulating emotions Destructive behaviors Oppositional behaviors Self-injurious behaviors Feeding problems are most commonly reported in early infancy, with some individuals experiencing resolution of feeding problems at older ages, most with the removal of their feeding tube. About 17% of affected individuals experience constipation. Other reported functional gastrointestinal complications include gastroesophageal reflux disease, dysphagia, and irritable bowel syndrome. Gastrointestinal malformations may include intestinal malrotation and rectal duplication. Hypermetropia Astigmatism Amblyopia Myopia Ptosis Impacted teeth Increased incidence of dental decay Ectopic teeth Absent secondary teeth Abnormal shape of teeth Discoloration of teeth Midline misalignment Kyphosis Vertebral compression fractures, most typically in older individuals Hip dysplasia Pes valgus Bilateral clubfeet Genu valgum Calcaneus valgus Tight tendons requiring tenotomies Finger abnormalities, such as camptodactyly Renal findings include: Dysplastic kidney Solitary kidney Polycystic kidney Renal ectasia Vesicoureteral reflux disease Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor Anomalies of the genitalia in males can include: Cryptorchidism Spermatocele Penile chordee Phimosis Hypospadias In females, hypoplastic labia majora has been noted. Atrial septal defects Tetralogy of Fallot Pulmonary valve stenosis Patent ductus arteriosus Mild aortic coarctation Aortic ectasia (Aortic rupture has not been reported to date in individuals with this condition, although data on progression of this finding is limited.) Bicuspid aortic valve Febrile seizures Generalized tonic-clonic seizures Tonic seizures Petit mal seizures • About 65% of affected individuals have been reported to have speech delay, ranging from mild delay to individuals who are nonverbal. The mean age of saying the first word is 20 months, with a range of 10 months to 5 years. • About 53% of affected individuals have been reported as having motor delay, with 10/42 (24%) of reported individuals having coordination or balance issues. • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. • Mean age of walking independently is 18 months, with a range from 12 months to 42 months. • At least one affected individual was nonambulatory at age 17 years. • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. • Mean age of walking independently is 18 months, with a range from 12 months to 42 months. • At least one affected individual was nonambulatory at age 17 years. • Mean age of sitting without support is 12 months, with a range from 6 months to 24 months. • Mean age of walking independently is 18 months, with a range from 12 months to 42 months. • At least one affected individual was nonambulatory at age 17 years. • Aggression • Anxiety • Difficulty regulating emotions • Destructive behaviors • Oppositional behaviors • Self-injurious behaviors • Feeding problems are most commonly reported in early infancy, with some individuals experiencing resolution of feeding problems at older ages, most with the removal of their feeding tube. • About 17% of affected individuals experience constipation. • Other reported functional gastrointestinal complications include gastroesophageal reflux disease, dysphagia, and irritable bowel syndrome. • Gastrointestinal malformations may include intestinal malrotation and rectal duplication. • Hypermetropia • Astigmatism • Amblyopia • Myopia • Ptosis • Impacted teeth • Increased incidence of dental decay • Ectopic teeth • Absent secondary teeth • Abnormal shape of teeth • Discoloration of teeth • Midline misalignment • Kyphosis • Vertebral compression fractures, most typically in older individuals • Hip dysplasia • Pes valgus • Bilateral clubfeet • Genu valgum • Calcaneus valgus • Tight tendons requiring tenotomies • Finger abnormalities, such as camptodactyly • Renal findings include: • Dysplastic kidney • Solitary kidney • Polycystic kidney • Renal ectasia • Vesicoureteral reflux disease • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor • Dysplastic kidney • Solitary kidney • Polycystic kidney • Renal ectasia • Vesicoureteral reflux disease • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor • Anomalies of the genitalia in males can include: • Cryptorchidism • Spermatocele • Penile chordee • Phimosis • Hypospadias • Cryptorchidism • Spermatocele • Penile chordee • Phimosis • Hypospadias • In females, hypoplastic labia majora has been noted. • Dysplastic kidney • Solitary kidney • Polycystic kidney • Renal ectasia • Vesicoureteral reflux disease • Renal insufficiency, typically not as a primary finding but secondary to renal anomalies or history of Wilms tumor • Cryptorchidism • Spermatocele • Penile chordee • Phimosis • Hypospadias • Atrial septal defects • Tetralogy of Fallot • Pulmonary valve stenosis • Patent ductus arteriosus • Mild aortic coarctation • Aortic ectasia (Aortic rupture has not been reported to date in individuals with this condition, although data on progression of this finding is limited.) • Bicuspid aortic valve • Febrile seizures • Generalized tonic-clonic seizures • Tonic seizures • Petit mal seizures ## Genotype-Phenotype Correlations No consistent genotype-phenotype correlations have been identified [ ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The phenotypic features associated with See OMIM Phenotypic Series for genes associated with: • • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl eval of aspiration risk, nutritional status, GERD, & constipation Consider eval for feeding therapy or gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. Assess for intestinal malrotation & GI anomalies prior to gastrostomy tube placement. To incl brain MRI as clinically indicated Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Consider referral to appropriate specialist (pulmonologist if respiratory concerns, ENT if recurrent otitis media, dermatologist if impetigo is present, or nephrologist if there are multiple urinary tract infections). Consider referral to immunologist if recurrent, severe infections are present. 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; ENT = ear, nose, and throat specialist (otolaryngologist); GERD = gastroesophageal reflux disease; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Conductive hearing loss may respond to placement of PET. Hearing aids may be helpful per otolaryngologist. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. 1 affected person responded well to a sodium channel blocker. 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 home nursing Consider involvement in adaptive sports or Adapted from ASM = anti-seizure medication; ENT = ears, nose, and throat specialist (otolaryngologist); OT = occupational therapy; PET = pressure-equalizing tubes; PT = physical therapy H Li, 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; 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 Measure growth parameters. Evaluate nutrition status & safety of oral intake. Adapted from ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; NA = not applicable; OT = occupational therapy; PT = physical therapy Two individuals have been reported with mild aortic dilatation, both of whom were age ten years or younger at the time and both of whom had other cardiovascular findings (bicuspid aortic valve or pulmonary valve stenosis). It is unclear if individuals with It is unclear if individuals with See Limited data is available on pregnancies for women with In general, women with epilepsy or a seizure disorder of 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 or during pregnancy may be possible [ See Search • To incl eval of aspiration risk, nutritional status, GERD, & constipation • Consider eval for feeding therapy or gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. • Assess for intestinal malrotation & GI anomalies prior to gastrostomy tube placement. • To incl brain MRI as clinically indicated • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Consider referral to appropriate specialist (pulmonologist if respiratory concerns, ENT if recurrent otitis media, dermatologist if impetigo is present, or nephrologist if there are multiple urinary tract infections). • Consider referral to immunologist if recurrent, severe infections are present. • Community or • Social work involvement for parental support • Home nursing referral • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Conductive hearing loss may respond to placement of PET. • Hearing aids may be helpful per otolaryngologist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • 1 affected person responded well to a sodium channel blocker. • 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 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 • Measure growth parameters. • Evaluate nutrition status & safety of oral intake. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl eval of aspiration risk, nutritional status, GERD, & constipation Consider eval for feeding therapy or gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. Assess for intestinal malrotation & GI anomalies prior to gastrostomy tube placement. To incl brain MRI as clinically indicated Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Consider referral to appropriate specialist (pulmonologist if respiratory concerns, ENT if recurrent otitis media, dermatologist if impetigo is present, or nephrologist if there are multiple urinary tract infections). Consider referral to immunologist if recurrent, severe infections are present. 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; ENT = ear, nose, and throat specialist (otolaryngologist); GERD = gastroesophageal reflux disease; GI = gastrointestinal; 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, GERD, & constipation • Consider eval for feeding therapy or gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. • Assess for intestinal malrotation & GI anomalies prior to gastrostomy tube placement. • To incl brain MRI as clinically indicated • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Consider referral to appropriate specialist (pulmonologist if respiratory concerns, ENT if recurrent otitis media, dermatologist if impetigo is present, or nephrologist if there are multiple urinary tract infections). • Consider referral to immunologist if recurrent, severe infections are present. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Conductive hearing loss may respond to placement of PET. Hearing aids may be helpful per otolaryngologist. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. 1 affected person responded well to a sodium channel blocker. 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 home nursing Consider involvement in adaptive sports or Adapted from ASM = anti-seizure medication; ENT = ears, nose, and throat specialist (otolaryngologist); OT = occupational therapy; PET = pressure-equalizing tubes; PT = physical therapy H Li, 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; 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. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Conductive hearing loss may respond to placement of PET. • Hearing aids may be helpful per otolaryngologist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • 1 affected person responded well to a sodium channel blocker. • 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 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 Measure growth parameters. Evaluate nutrition status & safety of oral intake. Adapted from ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; NA = not applicable; OT = occupational therapy; PT = physical therapy Two individuals have been reported with mild aortic dilatation, both of whom were age ten years or younger at the time and both of whom had other cardiovascular findings (bicuspid aortic valve or pulmonary valve stenosis). It is unclear if individuals with It is unclear if individuals with • Measure growth parameters. • Evaluate nutrition status & safety of oral intake. ## Evaluation of Relatives at Risk See ## Pregnancy Management Limited data is available on pregnancies for women with In general, women with epilepsy or a seizure disorder of 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 or during pregnancy may be possible [ See ## Therapies Under Investigation Search ## Genetic Counseling Approximately 80% of individuals with To date, nine individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with 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 If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the If the parents have not been tested for the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to 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. • Approximately 80% of individuals with • To date, nine individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with 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 • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members Approximately 80% of individuals with To date, nine individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with 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 If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the If the parents have not been tested for the • Approximately 80% of individuals with • To date, nine individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with 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 • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics CTCF-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for CTCF-Related Disorder ( Transcriptional repressor CTCF (CTCF; also called CCCTC-binding factor) is a DNA-binding transcription factor that plays a critical role in regulating gene expression and chromatin organization [ Missense pathogenic variants account for more than half of reported pathogenic variants. The majority of pathogenic missense variants are located in ZFs, particularly in the DNA-binding region and less commonly in other functional domains, such as the RBD and Tyr-Asp-Phe (YDF) domains [ ## Molecular Pathogenesis Transcriptional repressor CTCF (CTCF; also called CCCTC-binding factor) is a DNA-binding transcription factor that plays a critical role in regulating gene expression and chromatin organization [ Missense pathogenic variants account for more than half of reported pathogenic variants. The majority of pathogenic missense variants are located in ZFs, particularly in the DNA-binding region and less commonly in other functional domains, such as the RBD and Tyr-Asp-Phe (YDF) domains [ ## Chapter Notes The Emory We would like to thank all the families and their clinicians who have contributed to ongoing Emory 25 April 2024 (ma) Review posted live 7 June 2023 (hl) Original submission • 25 April 2024 (ma) Review posted live • 7 June 2023 (hl) Original submission ## Author Notes The Emory ## Acknowledgments We would like to thank all the families and their clinicians who have contributed to ongoing Emory ## Revision History 25 April 2024 (ma) Review posted live 7 June 2023 (hl) Original submission • 25 April 2024 (ma) Review posted live • 7 June 2023 (hl) Original submission ## References ## Literature Cited
[]
25/4/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ctlm
ctlm
[ "Argininosuccinate Synthetase Deficiency", "Argininosuccinic Acid Synthetase Deficiency", "ASS Deficiency", "Classic Citrullinemia", "CTLN1", "ASS Deficiency", "Classic Citrullinemia", "CTLN1", "Argininosuccinic Acid Synthetase Deficiency", "Argininosuccinate Synthetase Deficiency", "Argininosuccinate synthase", "ASS1", "Citrullinemia Type I" ]
Citrullinemia Type I
Shane C Quinonez, Kristen N Lee
Summary Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. Distinction between the forms is based primarily on clinical findings, although emerging evidence suggests that measurement of residual argininosuccinate synthase enzyme activity may help to predict those who are likely to have a severe phenotype and those who are likely to have an attenuated phenotype. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. Even with chronic protein restriction and scavenger therapy, long-term complications such as liver failure and other (rarely reported) organ system manifestations are possible. The late-onset form may be milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals. Women with onset of severe symptoms including acute hepatic decompensation during pregnancy or in the postpartum period have been reported. Furthermore, previously asymptomatic and non-pregnant individuals have been described who remained asymptomatic up to at least age ten years, with the possibility that they could remain asymptomatic lifelong. The diagnosis of CTLN1 is established in a proband with elevated plasma ammonia concentration (>150 µmol/L; may range to ≥2000-3000 µmol/L), elevated plasma citrulline concentration (usually >500 µmol/L), and absent argininosuccinate and/or by identification of biallelic pathogenic variants in Daily routine treatment in those who have not undergone a liver transplantation includes lifelong protein restriction in conjunction with a metabolic nutritionist; nitrogen scavenger medications; arginine supplementation; consideration of carnitine supplementation in those with secondary carnitine deficiency; addressing increased energy/caloric demands through tube feedings (as needed); and routine treatment of developmental delay / intellectual disability. Acute inpatient treatment of a metabolic crisis includes addressing hyperammonemia through withholding of all protein intake for a maximum of 24 to 28 hours; pharmacologic nitrogen scavenger therapy; and consideration of dialysis (the most effective means of reducing plasma ammonia concentration rapidly). To address increased catabolism, administration of high-energy fluids (and insulin, as needed) and intravenous intralipids is typically required. However, care must be taken to avoid electrolyte imbalance and fluid overload, which can contribute to the development of increased intracranial pressure. The patient should be maintained on the dry side of fluid balance (approximately 85 mL/kg of body weight per day in infants and appropriate corresponding fluid restriction in children and adults). CTLN1 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 the pathogenic variants in the family are known.
## Diagnosis Citrullinemia type I (CTLN1) results from deficiency of the enzyme argininosuccinate synthase, the third step in the urea cycle, in which citrulline is condensed with aspartate to form arginosuccinic acid (see Urea Cycle Disorders Overview NBS for CTLN1 is primarily based on quantification of the analyte citrulline on dried blood spots. Citrulline values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following: The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish a definitive diagnosis of CTLN: Inform the family of the NBS result. Evaluate the neonate for evidence of gastrointestinal involvement (poor feeding, vomiting, signs of liver disease), respiratory distress, and neurologic involvement (hypotonia, lethargy, seizures). Initiate confirmatory testing. In consultation with a metabolic specialist, initiate management, including protein restriction, nitrogen scavengers, and arginine supplementation. A symptomatic individual may have either atypical findings associated with later-onset CTLN1 or untreated infantile-onset CTLN1 resulting from any of the following: NBS not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result. Supportive – but nonspecific – clinical, preliminary laboratory, and family history findings can include the following. Increasing lethargy Somnolence Refusal to feed Vomiting Tachypnea Hypotonia Stroke Seizures Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus Recurrent lethargy and somnolence Intense headache Scotomas Migraine-like episodes Ataxia and slurred speech Intellectual disability Supportive laboratory findings include the following: Hyperammonemia Plasma amino acids analysis demonstrating elevated citrulline, absent argininosuccinate, with low-to-normal arginine and ornithine levels Possibly normal urine organic analysis, although orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry, especially during metabolic crises. Note: Though individuals with this presentation are most likely to have CTLN1, other conditions including pyruvate carboxylase deficiency and dihydrolipoamide dehydrogenase deficiency (see 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 CTLN1 Note: (1) Measurement of argininosuccinate synthase (ASS) enzyme activity is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis. (2) Historically, determining the prognosis prospectively was difficult in some individuals who fit the biochemical phenotype but may or may not have had serious clinical illness. Newer data suggest that individuals with ≥8% residual ASS enzymatic activity have less frequent and less severe hyperammonemic events, and better cognition. A cutoff value of 8% residual enzymatic activity has been proposed as a threshold for discrimination between severe (≤8% activity) and mild-to-moderate (>8% activity) disease [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Citrullinemia 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 Of 80 individuals evaluated, both abnormal alleles were identified in 75 (94%), one abnormal allele in four (5%), and no abnormal alleles in one (1%). Sequencing of genomic DNA from a variety of cells or cDNA from cultured fibroblasts detected 154 of 160 (96%) abnormal alleles [Häberle, personal communication]. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods may include a range of techniques such as 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 have been reported [ As ASS protein is predominantly expressed in the liver (and to a lesser extent the kidney), it is difficult to test reduction in protein expression unless using liver tissue. Incorporation of radiolabeled citrulline into argininosuccinic acid has been measured in cultured fibroblasts (see also The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory. Enzyme assay is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis; however, a newly established mammalian biallelic expression system has been successful in determining residual enzymatic activity of ASS. This assay has proposed specific residual enzymatic activity as correlating with severe (≤8% activity) vs mild-to-moderate (>8% activity) disease [ • Inform the family of the NBS result. • Evaluate the neonate for evidence of gastrointestinal involvement (poor feeding, vomiting, signs of liver disease), respiratory distress, and neurologic involvement (hypotonia, lethargy, seizures). • Initiate confirmatory testing. • In consultation with a metabolic specialist, initiate management, including protein restriction, nitrogen scavengers, and arginine supplementation. • Increasing lethargy • Somnolence • Refusal to feed • Vomiting • Tachypnea • Hypotonia • Stroke • Seizures • Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus • Recurrent lethargy and somnolence • Intense headache • Scotomas • Migraine-like episodes • Ataxia and slurred speech • Intellectual disability • Hyperammonemia • Plasma amino acids analysis demonstrating elevated citrulline, absent argininosuccinate, with low-to-normal arginine and ornithine levels • Possibly normal urine organic analysis, although orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry, especially during metabolic crises. • For an introduction to multigene panels click • The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory. • Enzyme assay is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis; however, a newly established mammalian biallelic expression system has been successful in determining residual enzymatic activity of ASS. This assay has proposed specific residual enzymatic activity as correlating with severe (≤8% activity) vs mild-to-moderate (>8% activity) disease [ ## Suggestive Findings NBS for CTLN1 is primarily based on quantification of the analyte citrulline on dried blood spots. Citrulline values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following: The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish a definitive diagnosis of CTLN: Inform the family of the NBS result. Evaluate the neonate for evidence of gastrointestinal involvement (poor feeding, vomiting, signs of liver disease), respiratory distress, and neurologic involvement (hypotonia, lethargy, seizures). Initiate confirmatory testing. In consultation with a metabolic specialist, initiate management, including protein restriction, nitrogen scavengers, and arginine supplementation. A symptomatic individual may have either atypical findings associated with later-onset CTLN1 or untreated infantile-onset CTLN1 resulting from any of the following: NBS not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result. Supportive – but nonspecific – clinical, preliminary laboratory, and family history findings can include the following. Increasing lethargy Somnolence Refusal to feed Vomiting Tachypnea Hypotonia Stroke Seizures Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus Recurrent lethargy and somnolence Intense headache Scotomas Migraine-like episodes Ataxia and slurred speech Intellectual disability Supportive laboratory findings include the following: Hyperammonemia Plasma amino acids analysis demonstrating elevated citrulline, absent argininosuccinate, with low-to-normal arginine and ornithine levels Possibly normal urine organic analysis, although orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry, especially during metabolic crises. Note: Though individuals with this presentation are most likely to have CTLN1, other conditions including pyruvate carboxylase deficiency and dihydrolipoamide dehydrogenase deficiency (see 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. • Inform the family of the NBS result. • Evaluate the neonate for evidence of gastrointestinal involvement (poor feeding, vomiting, signs of liver disease), respiratory distress, and neurologic involvement (hypotonia, lethargy, seizures). • Initiate confirmatory testing. • In consultation with a metabolic specialist, initiate management, including protein restriction, nitrogen scavengers, and arginine supplementation. • Increasing lethargy • Somnolence • Refusal to feed • Vomiting • Tachypnea • Hypotonia • Stroke • Seizures • Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus • Recurrent lethargy and somnolence • Intense headache • Scotomas • Migraine-like episodes • Ataxia and slurred speech • Intellectual disability • Hyperammonemia • Plasma amino acids analysis demonstrating elevated citrulline, absent argininosuccinate, with low-to-normal arginine and ornithine levels • Possibly normal urine organic analysis, although orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry, especially during metabolic crises. ## Scenario 1: Abnormal Newborn Screening (NBS) Result NBS for CTLN1 is primarily based on quantification of the analyte citrulline on dried blood spots. Citrulline values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, which usually demonstrates the following: The following medical interventions need to begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine whether this a true positive NBS result and to establish a definitive diagnosis of CTLN: Inform the family of the NBS result. Evaluate the neonate for evidence of gastrointestinal involvement (poor feeding, vomiting, signs of liver disease), respiratory distress, and neurologic involvement (hypotonia, lethargy, seizures). Initiate confirmatory testing. In consultation with a metabolic specialist, initiate management, including protein restriction, nitrogen scavengers, and arginine supplementation. • Inform the family of the NBS result. • Evaluate the neonate for evidence of gastrointestinal involvement (poor feeding, vomiting, signs of liver disease), respiratory distress, and neurologic involvement (hypotonia, lethargy, seizures). • Initiate confirmatory testing. • In consultation with a metabolic specialist, initiate management, including protein restriction, nitrogen scavengers, and arginine supplementation. ## Scenario 2: Symptomatic Individual A symptomatic individual may have either atypical findings associated with later-onset CTLN1 or untreated infantile-onset CTLN1 resulting from any of the following: NBS not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result. Supportive – but nonspecific – clinical, preliminary laboratory, and family history findings can include the following. Increasing lethargy Somnolence Refusal to feed Vomiting Tachypnea Hypotonia Stroke Seizures Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus Recurrent lethargy and somnolence Intense headache Scotomas Migraine-like episodes Ataxia and slurred speech Intellectual disability Supportive laboratory findings include the following: Hyperammonemia Plasma amino acids analysis demonstrating elevated citrulline, absent argininosuccinate, with low-to-normal arginine and ornithine levels Possibly normal urine organic analysis, although orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry, especially during metabolic crises. Note: Though individuals with this presentation are most likely to have CTLN1, other conditions including pyruvate carboxylase deficiency and dihydrolipoamide dehydrogenase deficiency (see 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. • Increasing lethargy • Somnolence • Refusal to feed • Vomiting • Tachypnea • Hypotonia • Stroke • Seizures • Increased intracranial pressure (secondary to hyperammonemia) resulting in increased neuromuscular tone, spasticity, and ankle clonus • Recurrent lethargy and somnolence • Intense headache • Scotomas • Migraine-like episodes • Ataxia and slurred speech • Intellectual disability • Hyperammonemia • Plasma amino acids analysis demonstrating elevated citrulline, absent argininosuccinate, with low-to-normal arginine and ornithine levels • Possibly normal urine organic analysis, although orotic acid may be detected as part of urinary organic acid analysis by gas chromatography/mass spectrometry, especially during metabolic crises. ## Establishing the Diagnosis The diagnosis of CTLN1 Note: (1) Measurement of argininosuccinate synthase (ASS) enzyme activity is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis. (2) Historically, determining the prognosis prospectively was difficult in some individuals who fit the biochemical phenotype but may or may not have had serious clinical illness. Newer data suggest that individuals with ≥8% residual ASS enzymatic activity have less frequent and less severe hyperammonemic events, and better cognition. A cutoff value of 8% residual enzymatic activity has been proposed as a threshold for discrimination between severe (≤8% activity) and mild-to-moderate (>8% activity) disease [ For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Citrullinemia 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 Of 80 individuals evaluated, both abnormal alleles were identified in 75 (94%), one abnormal allele in four (5%), and no abnormal alleles in one (1%). Sequencing of genomic DNA from a variety of cells or cDNA from cultured fibroblasts detected 154 of 160 (96%) abnormal alleles [Häberle, personal communication]. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods may include a range of techniques such as 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 have been reported [ As ASS protein is predominantly expressed in the liver (and to a lesser extent the kidney), it is difficult to test reduction in protein expression unless using liver tissue. Incorporation of radiolabeled citrulline into argininosuccinic acid has been measured in cultured fibroblasts (see also The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory. Enzyme assay is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis; however, a newly established mammalian biallelic expression system has been successful in determining residual enzymatic activity of ASS. This assay has proposed specific residual enzymatic activity as correlating with severe (≤8% activity) vs mild-to-moderate (>8% activity) disease [ • For an introduction to multigene panels click • The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory. • Enzyme assay is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis; however, a newly established mammalian biallelic expression system has been successful in determining residual enzymatic activity of ASS. This assay has proposed specific residual enzymatic activity as correlating with severe (≤8% activity) vs mild-to-moderate (>8% activity) disease [ ## Molecular Genetic Testing Approaches For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Citrullinemia 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 Of 80 individuals evaluated, both abnormal alleles were identified in 75 (94%), one abnormal allele in four (5%), and no abnormal alleles in one (1%). Sequencing of genomic DNA from a variety of cells or cDNA from cultured fibroblasts detected 154 of 160 (96%) abnormal alleles [Häberle, personal communication]. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods may include a range of techniques such as 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 have been reported [ • For an introduction to multigene panels click ## ASS Enzyme Activity As ASS protein is predominantly expressed in the liver (and to a lesser extent the kidney), it is difficult to test reduction in protein expression unless using liver tissue. Incorporation of radiolabeled citrulline into argininosuccinic acid has been measured in cultured fibroblasts (see also The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory. Enzyme assay is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis; however, a newly established mammalian biallelic expression system has been successful in determining residual enzymatic activity of ASS. This assay has proposed specific residual enzymatic activity as correlating with severe (≤8% activity) vs mild-to-moderate (>8% activity) disease [ • The normal enzyme activity in fibroblasts is 0.8-3.8 nmol/min/mg protein, but this is specific to tissue, method, and laboratory. • Enzyme assay is not currently widely used because the clinical presentation and relatively specific pattern of metabolites found in affected individuals are sufficient to establish the diagnosis; however, a newly established mammalian biallelic expression system has been successful in determining residual enzymatic activity of ASS. This assay has proposed specific residual enzymatic activity as correlating with severe (≤8% activity) vs mild-to-moderate (>8% activity) disease [ ## Clinical Characteristics Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. It has been proposed that measurement of residual enzyme activity can be used to classify individuals as "predicted severe" (≤8% activity) and "predicted attenuated" (>8% activity) [ Severity-adjusted analysis determined that individuals identified by NBS had a lower peak ammonia level than those diagnosed by symptoms. This effect was greater in individuals with residual enzyme activity >8% (initial mean ammonia within normal range) versus those with residual enzyme activity ≤8% (initial mean ammonia 318 µmol/L). Early diagnosis by NBS (vs diagnosis after symptom onset) for individuals with CTLN1 and ASA was associated with improved cognitive outcomes [ However, early diagnosis via NBS was not associated with lower frequency of hyperammonemic events, despite appropriate early treatment [ The infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively more lethargic, feeds poorly, may vomit, and may develop signs of liver failure as well as cerebral edema as hyperammonemia progresses [ Neonates and children diagnosed and referred for appropriate treatment (see In those individuals with neuropsychologic deficits: Gross motor skills tend to be less well developed than expressive language skills, with individuals exhibiting strengths in reasoning abilities and weaknesses in visual-spatial comprehension and fine motor skills. Thirty percent were described as hyperactive with attention deficits. Cognitive impairment scores were variable by age, with 17% of school-aged children, and 50% of adults, reported to have IQ scores in the cognitive impairment range [ In a study of children undergoing liver transplantation for urea cycle disorders (of which CTLN1 was the second-highest encountered diagnosis), nearly 40% of children had definitive cognitive delay post transplant, related to hyperammonemic events prior to transplant. Transplant ultimately prevented further hyperammonemic episodes [ More rare neuroimaging findings include bilateral insular cortex and basifrontal involvement, suggesting herpes encephalitis [ The clinical course may be similar to or milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. However, specific Intense headache Scotomas Migraine-like episodes Ataxia Slurred speech Lethargy Somnolence Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [ Liver failure is now recognized as a primary presentation of CTLN1, contradicting the established dogma of central nervous system symptoms as the primary finding [ Late-onset urea cycle disorder can be associated with high mortality: neonatal plus late-onset mortality has been reported in 7% of individuals with CTLN1 [ Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [ Another previously undiagnosed woman presented at 14-18 weeks' gestation with hyperemesis gravidarum progressing to acute hepatic failure; once appropriate treatment was implemented she went on to deliver a healthy neonate [ CTLN1 has been implicated in postpartum psychosis [ In contrast, a healthy woman with untreated CTLN1 underwent two successful pregnancies [ While certain Severe, classic (neonatal-onset) CTLN1 typically results from 22 defined pathogenic variants [ Mild (i.e., late-onset) CTLN1 is associated with 12 pathogenic variants, including The preferred terms for argininosuccinic acid synthetase deficiency are "citrullinemia type I" and "classic citrullinemia," which are used to avoid confusion with the genetically distinct disease citrullinemia type II, also known as CTLN1 is the second-most frequent urea cycle disorder, and has been estimated to occur in 1:220,000 births [ Newborn screening programs found CTLN1 in the following: In Korea: two in 44,300 newborns [ In New England: one in 200,000 newborns [ In Taiwan: five (2 severe and 3 mild) in a pilot program of 592,717 newborns; overall incidence one in 118,543 [ In Austria: one in 77,811 among 622,489 newborns [ In Texas, New York, Michigan, California, Massachusetts, North Carolina, and Wisconsin, estimated combined prevalence of CTLN1 and argininosuccinate lyase deficiency: one in 117,000 [ • Severity-adjusted analysis determined that individuals identified by NBS had a lower peak ammonia level than those diagnosed by symptoms. This effect was greater in individuals with residual enzyme activity >8% (initial mean ammonia within normal range) versus those with residual enzyme activity ≤8% (initial mean ammonia 318 µmol/L). • Early diagnosis by NBS (vs diagnosis after symptom onset) for individuals with CTLN1 and ASA was associated with improved cognitive outcomes [ • However, early diagnosis via NBS was not associated with lower frequency of hyperammonemic events, despite appropriate early treatment [ • Gross motor skills tend to be less well developed than expressive language skills, with individuals exhibiting strengths in reasoning abilities and weaknesses in visual-spatial comprehension and fine motor skills. • Thirty percent were described as hyperactive with attention deficits. • Cognitive impairment scores were variable by age, with 17% of school-aged children, and 50% of adults, reported to have IQ scores in the cognitive impairment range [ • In a study of children undergoing liver transplantation for urea cycle disorders (of which CTLN1 was the second-highest encountered diagnosis), nearly 40% of children had definitive cognitive delay post transplant, related to hyperammonemic events prior to transplant. Transplant ultimately prevented further hyperammonemic episodes [ • More rare neuroimaging findings include bilateral insular cortex and basifrontal involvement, suggesting herpes encephalitis [ • Intense headache • Scotomas • Migraine-like episodes • Ataxia • Slurred speech • Lethargy • Somnolence • Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [ • Another previously undiagnosed woman presented at 14-18 weeks' gestation with hyperemesis gravidarum progressing to acute hepatic failure; once appropriate treatment was implemented she went on to deliver a healthy neonate [ • CTLN1 has been implicated in postpartum psychosis [ • In contrast, a healthy woman with untreated CTLN1 underwent two successful pregnancies [ • Severe, classic (neonatal-onset) CTLN1 typically results from 22 defined pathogenic variants [ • Mild (i.e., late-onset) CTLN1 is associated with 12 pathogenic variants, including • In Korea: two in 44,300 newborns [ • In New England: one in 200,000 newborns [ • In Taiwan: five (2 severe and 3 mild) in a pilot program of 592,717 newborns; overall incidence one in 118,543 [ • In Austria: one in 77,811 among 622,489 newborns [ • In Texas, New York, Michigan, California, Massachusetts, North Carolina, and Wisconsin, estimated combined prevalence of CTLN1 and argininosuccinate lyase deficiency: one in 117,000 [ ## Clinical Description Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. It has been proposed that measurement of residual enzyme activity can be used to classify individuals as "predicted severe" (≤8% activity) and "predicted attenuated" (>8% activity) [ Severity-adjusted analysis determined that individuals identified by NBS had a lower peak ammonia level than those diagnosed by symptoms. This effect was greater in individuals with residual enzyme activity >8% (initial mean ammonia within normal range) versus those with residual enzyme activity ≤8% (initial mean ammonia 318 µmol/L). Early diagnosis by NBS (vs diagnosis after symptom onset) for individuals with CTLN1 and ASA was associated with improved cognitive outcomes [ However, early diagnosis via NBS was not associated with lower frequency of hyperammonemic events, despite appropriate early treatment [ The infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively more lethargic, feeds poorly, may vomit, and may develop signs of liver failure as well as cerebral edema as hyperammonemia progresses [ Neonates and children diagnosed and referred for appropriate treatment (see In those individuals with neuropsychologic deficits: Gross motor skills tend to be less well developed than expressive language skills, with individuals exhibiting strengths in reasoning abilities and weaknesses in visual-spatial comprehension and fine motor skills. Thirty percent were described as hyperactive with attention deficits. Cognitive impairment scores were variable by age, with 17% of school-aged children, and 50% of adults, reported to have IQ scores in the cognitive impairment range [ In a study of children undergoing liver transplantation for urea cycle disorders (of which CTLN1 was the second-highest encountered diagnosis), nearly 40% of children had definitive cognitive delay post transplant, related to hyperammonemic events prior to transplant. Transplant ultimately prevented further hyperammonemic episodes [ More rare neuroimaging findings include bilateral insular cortex and basifrontal involvement, suggesting herpes encephalitis [ The clinical course may be similar to or milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. However, specific Intense headache Scotomas Migraine-like episodes Ataxia Slurred speech Lethargy Somnolence Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [ Liver failure is now recognized as a primary presentation of CTLN1, contradicting the established dogma of central nervous system symptoms as the primary finding [ Late-onset urea cycle disorder can be associated with high mortality: neonatal plus late-onset mortality has been reported in 7% of individuals with CTLN1 [ Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [ Another previously undiagnosed woman presented at 14-18 weeks' gestation with hyperemesis gravidarum progressing to acute hepatic failure; once appropriate treatment was implemented she went on to deliver a healthy neonate [ CTLN1 has been implicated in postpartum psychosis [ In contrast, a healthy woman with untreated CTLN1 underwent two successful pregnancies [ • Severity-adjusted analysis determined that individuals identified by NBS had a lower peak ammonia level than those diagnosed by symptoms. This effect was greater in individuals with residual enzyme activity >8% (initial mean ammonia within normal range) versus those with residual enzyme activity ≤8% (initial mean ammonia 318 µmol/L). • Early diagnosis by NBS (vs diagnosis after symptom onset) for individuals with CTLN1 and ASA was associated with improved cognitive outcomes [ • However, early diagnosis via NBS was not associated with lower frequency of hyperammonemic events, despite appropriate early treatment [ • Gross motor skills tend to be less well developed than expressive language skills, with individuals exhibiting strengths in reasoning abilities and weaknesses in visual-spatial comprehension and fine motor skills. • Thirty percent were described as hyperactive with attention deficits. • Cognitive impairment scores were variable by age, with 17% of school-aged children, and 50% of adults, reported to have IQ scores in the cognitive impairment range [ • In a study of children undergoing liver transplantation for urea cycle disorders (of which CTLN1 was the second-highest encountered diagnosis), nearly 40% of children had definitive cognitive delay post transplant, related to hyperammonemic events prior to transplant. Transplant ultimately prevented further hyperammonemic episodes [ • More rare neuroimaging findings include bilateral insular cortex and basifrontal involvement, suggesting herpes encephalitis [ • Intense headache • Scotomas • Migraine-like episodes • Ataxia • Slurred speech • Lethargy • Somnolence • Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [ • Another previously undiagnosed woman presented at 14-18 weeks' gestation with hyperemesis gravidarum progressing to acute hepatic failure; once appropriate treatment was implemented she went on to deliver a healthy neonate [ • CTLN1 has been implicated in postpartum psychosis [ • In contrast, a healthy woman with untreated CTLN1 underwent two successful pregnancies [ ## Neonatal ("Classic") Form The infant appears normal at birth. After an interval of one to a few days, the infant becomes progressively more lethargic, feeds poorly, may vomit, and may develop signs of liver failure as well as cerebral edema as hyperammonemia progresses [ Neonates and children diagnosed and referred for appropriate treatment (see In those individuals with neuropsychologic deficits: Gross motor skills tend to be less well developed than expressive language skills, with individuals exhibiting strengths in reasoning abilities and weaknesses in visual-spatial comprehension and fine motor skills. Thirty percent were described as hyperactive with attention deficits. Cognitive impairment scores were variable by age, with 17% of school-aged children, and 50% of adults, reported to have IQ scores in the cognitive impairment range [ In a study of children undergoing liver transplantation for urea cycle disorders (of which CTLN1 was the second-highest encountered diagnosis), nearly 40% of children had definitive cognitive delay post transplant, related to hyperammonemic events prior to transplant. Transplant ultimately prevented further hyperammonemic episodes [ More rare neuroimaging findings include bilateral insular cortex and basifrontal involvement, suggesting herpes encephalitis [ • Gross motor skills tend to be less well developed than expressive language skills, with individuals exhibiting strengths in reasoning abilities and weaknesses in visual-spatial comprehension and fine motor skills. • Thirty percent were described as hyperactive with attention deficits. • Cognitive impairment scores were variable by age, with 17% of school-aged children, and 50% of adults, reported to have IQ scores in the cognitive impairment range [ • In a study of children undergoing liver transplantation for urea cycle disorders (of which CTLN1 was the second-highest encountered diagnosis), nearly 40% of children had definitive cognitive delay post transplant, related to hyperammonemic events prior to transplant. Transplant ultimately prevented further hyperammonemic episodes [ • More rare neuroimaging findings include bilateral insular cortex and basifrontal involvement, suggesting herpes encephalitis [ ## Non-Classic Form The clinical course may be similar to or milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. However, specific Intense headache Scotomas Migraine-like episodes Ataxia Slurred speech Lethargy Somnolence Individuals with hyperammonemia also display respiratory alkalosis and tachypnea [ Liver failure is now recognized as a primary presentation of CTLN1, contradicting the established dogma of central nervous system symptoms as the primary finding [ Late-onset urea cycle disorder can be associated with high mortality: neonatal plus late-onset mortality has been reported in 7% of individuals with CTLN1 [ Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [ Another previously undiagnosed woman presented at 14-18 weeks' gestation with hyperemesis gravidarum progressing to acute hepatic failure; once appropriate treatment was implemented she went on to deliver a healthy neonate [ CTLN1 has been implicated in postpartum psychosis [ In contrast, a healthy woman with untreated CTLN1 underwent two successful pregnancies [ • Intense headache • Scotomas • Migraine-like episodes • Ataxia • Slurred speech • Lethargy • Somnolence • Three women not known to have citrullinemia presented in hyperammonemic coma shortly after delivery; one died and two survived without neurologic sequelae [ • Another previously undiagnosed woman presented at 14-18 weeks' gestation with hyperemesis gravidarum progressing to acute hepatic failure; once appropriate treatment was implemented she went on to deliver a healthy neonate [ • CTLN1 has been implicated in postpartum psychosis [ • In contrast, a healthy woman with untreated CTLN1 underwent two successful pregnancies [ ## Genotype-Phenotype Correlations While certain Severe, classic (neonatal-onset) CTLN1 typically results from 22 defined pathogenic variants [ Mild (i.e., late-onset) CTLN1 is associated with 12 pathogenic variants, including • Severe, classic (neonatal-onset) CTLN1 typically results from 22 defined pathogenic variants [ • Mild (i.e., late-onset) CTLN1 is associated with 12 pathogenic variants, including ## Nomenclature The preferred terms for argininosuccinic acid synthetase deficiency are "citrullinemia type I" and "classic citrullinemia," which are used to avoid confusion with the genetically distinct disease citrullinemia type II, also known as ## Prevalence CTLN1 is the second-most frequent urea cycle disorder, and has been estimated to occur in 1:220,000 births [ Newborn screening programs found CTLN1 in the following: In Korea: two in 44,300 newborns [ In New England: one in 200,000 newborns [ In Taiwan: five (2 severe and 3 mild) in a pilot program of 592,717 newborns; overall incidence one in 118,543 [ In Austria: one in 77,811 among 622,489 newborns [ In Texas, New York, Michigan, California, Massachusetts, North Carolina, and Wisconsin, estimated combined prevalence of CTLN1 and argininosuccinate lyase deficiency: one in 117,000 [ • In Korea: two in 44,300 newborns [ • In New England: one in 200,000 newborns [ • In Taiwan: five (2 severe and 3 mild) in a pilot program of 592,717 newborns; overall incidence one in 118,543 [ • In Austria: one in 77,811 among 622,489 newborns [ • In Texas, New York, Michigan, California, Massachusetts, North Carolina, and Wisconsin, estimated combined prevalence of CTLN1 and argininosuccinate lyase deficiency: one in 117,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Classic citrullinemia type I (a defect in step 3 of the urea cycle) shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway: carbamoylphosphate synthetase I deficiency (step 1), Selected Disorders in the Differential Diagnosis of Acute Neonatal ("Classic") Citrullinemia Type I AR = autosomal recessive; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked The milder late-onset citrullinemia type I phenotype shares a later onset with other disorders such as late-onset ## Neonatal ("Classic") Presentation Classic citrullinemia type I (a defect in step 3 of the urea cycle) shares the phenotype of the typical acute neonatal hyperammonemia displayed by other defects in the first four steps in the urea cycle pathway: carbamoylphosphate synthetase I deficiency (step 1), Selected Disorders in the Differential Diagnosis of Acute Neonatal ("Classic") Citrullinemia Type I AR = autosomal recessive; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked ## Milder Late-Onset Presentation The milder late-onset citrullinemia type I phenotype shares a later onset with other disorders such as late-onset ## Management Clinical practice guidelines for citrullinemia type I (CTLN1) have been published. See When CTLN1 is suspected during the diagnostic evaluation due to elevated citrulline on newborn screening, metabolic treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center. To establish the extent of disease and needs in an individual diagnosed with CTLN1, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of Citrullinemia Type I Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (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 acute encephalopathic crises). Plasma ammonia level Blood gases Electrolytes Plasma amino acids For eval of overall neurologic status Assessment of intracranial pressure in those who are acutely ill Consider brain MRI in those w/neurologic features &/or seizures. MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist After a new diagnosis of CTLN1 in a child, the closest hospital and local pediatrician should also be informed. Medical geneticist, certified genetic counselor, certified advanced genetic nurse See also Definitive Treatment in Individuals with Citrullinemia Type I Liver transplantation should ideally be performed in affected persons before age 1 yr (prior to development of any neurocognitive impairment) but after age 3 mos &/or when body weight is >5 kg to ↓ complications & ↑ survival rates. Although liver transplantation cures ASS enzyme deficiency, arginine is extrahepatically synthesized & remains low post transplant, requiring ongoing supplementation. Liver transplantation of nine individuals with CTLN1 between ages four and 86 months showed better developmental outcomes when the transplant was performed at earlier ages [ A living related-donor liver transplantation from mother to son resulted in continued elevation in plasma concentration of citrulline (200-400 µmol/L). The mother, a heterozygote, had 28% residual ASS1 enzyme activity [ Survival rates in those who underwent liver transplantation prior to age two years was between 90% and 95% five years post transplant [ Routine Daily Treatment in Individuals with Citrullinemia Type I Adequate protein intake can be based on FAO/WHO/UNU 2007 "safe levels of protein intake." If EAA supplements are needed, it is reasonable to provide 20%-30% total protein intake in this form. The protein source for infants should be breastmilk or standard infant formula. Dietary therapy should be done in conjunction w/metabolic nutritionist. Exclusive on-demand breastfeeding is possible but requires close analytic monitoring & may require supplementation w/protein-free infant formula. In bottle-fed infants, total daily protein amounts are divided evenly between daily feeds, & can be supplemented w/protein-free formula to round out caloric intake, &/or to appetite, w/goal for total amount to supply all required nutrients. In persons weighing <20 kg: up to 250 mg/kg In persons weighing >20 kg: 5 g/m Initial dose for phenylbutyrate-naïve persons: 4.5-11.2 mL/m Dose for those transitioning from sodium phenylbutyrate: daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate (g) x 0.86 In persons weighing <20 kg: 100-300 mg/kg/d or 0.5-1.5 mmol/kg/d In persons weighing >20 kg: 2.5-6 g/m /d = per day; EAA = essential amino acid; FAO = Food and Agriculture Organization of the United States; WHO = World Health Organization; UNU = United Nations University Success of therapy is defined by a plasma ammonia concentration lower than100 µmol/L and near-normal plasma glutamine concentration. This nitrogen scavenging medication may be more palatable. Plasma arginine concentration may be up to 250% above upper normal limit for age. Emergency Outpatient Treatment in Individuals with Citrullinemia Type I Carbohydrate supplementation orally or via tube feed ↓ natural protein intake ↑ carnitine supplementation Fever <38.5°C (101°F); enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia) Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment. Some centers advocate additional steps such as reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (<24 hours) in the outpatient setting during intercurrent illness. Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/d in infants) may be considered [ Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases 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 hospital. Acute Inpatient Treatment in Individuals with Citrullinemia Type I Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Failure to control ammonia w/scavenger therapy requires emergency use of dialysis. Hemodialysis is preferred method of dialysis & exceeds both peritoneal dialysis & hemofiltration in rate of ammonia clearance. Continue scavenger therapy while dialysis is being performed. Administer high-energy fluids & (if needed) insulin. IV interlipids Consider L-carnitine supplementation, esp if deficient. Address electrolytes & pH imbalances w/IV fluid mgmt. Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt. Ongoing assessment of hemodynamic status & for new neurologic signs is critical. Inadequate or delayed start of emergency treatment → high risk of neurologic injury w/consequent long-term neurodisability. To provide 0.25 g/kg/d of protein & 50 kcal/kg/d, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/d of protein & 100-120 kcal/kg/d Standard TPN solutions of dextrose, aminosol, & intralipid are used. It is critical to monitor fluid balance, intake & output, & body weight. ↑ intracranial pressure is manifested by tension in fontanelle, acute enlargement of liver, edema, & worsening neurologic signs incl fisting, scissoring, ankle clonus, & coma. Cerebral edema & ischemia may be documented by brain MRI. /d = per day; EAA = essential amino acid; IV = intravenous; TPN = total parenteral nutrition 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. Repeat boluses are not recommended unless the individual is receiving dialysis. Exchange transfusions have no place in hyperammonemic treatment. IV glucose solutions should provide 12-15 g/kg/d glucose for infants and 10-12 g/kg/d for children age 12 months to 6 years. In small infants, 40 kcal/100 mL given as D10W can be significant in averting catabolism. Use of insulin if hyperglycemia emerges; IV insulin given at a starting dose of 0.025 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria) L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability. Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CTLN1 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 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 Prevention of hyperammonemia is achieved through lifelong protein restriction, nitrogen scavenger therapy, and possible liver transplantation based on metabolic control (see 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 and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see Prevention of Secondary Manifestations in Individuals with Citrullinemia Type I Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home MedicAlert Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources) Medication required for maintenance & emergency treatment (antipyretics) should always be maintained at home. Provide written protocols for maintenance & emergency treatment to parents & primary care providers / pediatricians & to teachers & school staff. Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for CTLN1 & containing contact info for primary treating metabolic center. For any planned travel or vacations, consider contacting 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). The night before surgery, & esp once patient is made NPO, drug treatment should be switched to IV & nutrition w/10% glucose w/age-appropriate electrolytes should be administered via IV to promote anabolism. IV = intravenous; NPO = nil per os ("nothing by mouth") Essential information including written treatment protocols should be in place in anticipation of possible future need for inpatient emergency treatment. Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for persons deemed to be at high risk for perioperative complications. Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required (see Recommended Surveillance for Individuals with Citrullinemia Type I Measurement of growth parameters Eval of nutritional status & safety of oral intake During 1st yr of life: at least every 3 mos In teen/adult yrs: every 6-12 mos, depending on clinical stability EEA = essential amino acids; OT = occupational therapy; PT = physical therapy This should prompt assessment of (at a minimum) plasma ammonia level, plasma amino acid analysis, and other metabolic labs (electrolytes, glucose level, liver function tests, and complete blood count). Plasma glutamate concentration may rise 48 hours in advance of plasma ammonia concentration. Avoid the following: Excess protein intake Prolonged fasting Obvious exposure to communicable diseases Molecular genetic testing if the pathogenic variants in the family are known, In utero diagnosis (which permits appropriate oral therapy beginning with first feeds), if possible, is preferred. Measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment. Newborn full sibs of individuals who had early-onset presentation and in whom prenatal genetic testing has not been performed should be started on a protein-restricted diet with consideration of immediately starting an IV with provision of (1) age-appropriate glucose infusion rates and appropriate electrolytes and (2) protein-free infant formula, pending completion of the diagnostic evaluation. See Because women with onset of severe symptoms during pregnancy or in the postpartum period have been reported, scrupulous attention needs to be paid to diet and medication during these periods. See Gene therapy has been suggested; success has not been achieved to date. Phase I and Phase II clinical trials to assess the safety and efficacy of human hepatocyte transplantation as either an alternative to liver transplantation or a temporizing measure for individuals with CTLN1 awaiting transplantation have completed. Search Ketoacids of essential amino acids were an early form of auxiliary waste nitrogen disposal enhancement, now replaced by the agents described in • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (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 acute encephalopathic crises). • Plasma ammonia level • Blood gases • Electrolytes • Plasma amino acids • For eval of overall neurologic status • Assessment of intracranial pressure in those who are acutely ill • Consider brain MRI in those w/neurologic features &/or seizures. • Liver transplantation should ideally be performed in affected persons before age 1 yr (prior to development of any neurocognitive impairment) but after age 3 mos &/or when body weight is >5 kg to ↓ complications & ↑ survival rates. • Although liver transplantation cures ASS enzyme deficiency, arginine is extrahepatically synthesized & remains low post transplant, requiring ongoing supplementation. • Adequate protein intake can be based on FAO/WHO/UNU 2007 "safe levels of protein intake." • If EAA supplements are needed, it is reasonable to provide 20%-30% total protein intake in this form. • The protein source for infants should be breastmilk or standard infant formula. • Dietary therapy should be done in conjunction w/metabolic nutritionist. • Exclusive on-demand breastfeeding is possible but requires close analytic monitoring & may require supplementation w/protein-free infant formula. • In bottle-fed infants, total daily protein amounts are divided evenly between daily feeds, & can be supplemented w/protein-free formula to round out caloric intake, &/or to appetite, w/goal for total amount to supply all required nutrients. • In persons weighing <20 kg: up to 250 mg/kg • In persons weighing >20 kg: 5 g/m • Initial dose for phenylbutyrate-naïve persons: 4.5-11.2 mL/m • Dose for those transitioning from sodium phenylbutyrate: daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate (g) x 0.86 • In persons weighing <20 kg: 100-300 mg/kg/d or 0.5-1.5 mmol/kg/d • In persons weighing >20 kg: 2.5-6 g/m • Carbohydrate supplementation orally or via tube feed • ↓ natural protein intake • ↑ carnitine supplementation • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Failure to control ammonia w/scavenger therapy requires emergency use of dialysis. • Hemodialysis is preferred method of dialysis & exceeds both peritoneal dialysis & hemofiltration in rate of ammonia clearance. • Continue scavenger therapy while dialysis is being performed. • Administer high-energy fluids & (if needed) insulin. • IV interlipids • Consider L-carnitine supplementation, esp if deficient. • Address electrolytes & pH imbalances w/IV fluid mgmt. • Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt. • Ongoing assessment of hemodynamic status & for new neurologic signs is critical. • Inadequate or delayed start of emergency treatment → high risk of neurologic injury w/consequent long-term neurodisability. • To provide 0.25 g/kg/d of protein & 50 kcal/kg/d, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/d of protein & 100-120 kcal/kg/d • Standard TPN solutions of dextrose, aminosol, & intralipid are used. • It is critical to monitor fluid balance, intake & output, & body weight. • ↑ intracranial pressure is manifested by tension in fontanelle, acute enlargement of liver, edema, & worsening neurologic signs incl fisting, scissoring, ankle clonus, & coma. • Cerebral edema & ischemia may be documented by brain MRI. • Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CTLN1 together with pediatric metabolic experts, dietitians, psychologists, and social workers. • As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 • Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises • Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home • MedicAlert • Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources) • Medication required for maintenance & emergency treatment (antipyretics) should always be maintained at home. • Provide written protocols for maintenance & emergency treatment to parents & primary care providers / pediatricians & to teachers & school staff. • Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for CTLN1 & containing contact info for primary treating metabolic center. • For any planned travel or vacations, consider contacting 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). • The night before surgery, & esp once patient is made NPO, drug treatment should be switched to IV & nutrition w/10% glucose w/age-appropriate electrolytes should be administered via IV to promote anabolism. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • During 1st yr of life: at least every 3 mos • In teen/adult yrs: every 6-12 mos, depending on clinical stability • Excess protein intake • Prolonged fasting • Obvious exposure to communicable diseases • Molecular genetic testing if the pathogenic variants in the family are known, In utero diagnosis (which permits appropriate oral therapy beginning with first feeds), if possible, is preferred. • Measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment. • Newborn full sibs of individuals who had early-onset presentation and in whom prenatal genetic testing has not been performed should be started on a protein-restricted diet with consideration of immediately starting an IV with provision of (1) age-appropriate glucose infusion rates and appropriate electrolytes and (2) protein-free infant formula, pending completion of the diagnostic evaluation. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CTLN1, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis of Citrullinemia Type I Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (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 acute encephalopathic crises). Plasma ammonia level Blood gases Electrolytes Plasma amino acids For eval of overall neurologic status Assessment of intracranial pressure in those who are acutely ill Consider brain MRI in those w/neurologic features &/or seizures. MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist After a new diagnosis of CTLN1 in a child, the closest hospital and local pediatrician should also be informed. Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). • Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). • Plasma ammonia level • Blood gases • Electrolytes • Plasma amino acids • For eval of overall neurologic status • Assessment of intracranial pressure in those who are acutely ill • Consider brain MRI in those w/neurologic features &/or seizures. ## Treatment of Manifestations See also Definitive Treatment in Individuals with Citrullinemia Type I Liver transplantation should ideally be performed in affected persons before age 1 yr (prior to development of any neurocognitive impairment) but after age 3 mos &/or when body weight is >5 kg to ↓ complications & ↑ survival rates. Although liver transplantation cures ASS enzyme deficiency, arginine is extrahepatically synthesized & remains low post transplant, requiring ongoing supplementation. Liver transplantation of nine individuals with CTLN1 between ages four and 86 months showed better developmental outcomes when the transplant was performed at earlier ages [ A living related-donor liver transplantation from mother to son resulted in continued elevation in plasma concentration of citrulline (200-400 µmol/L). The mother, a heterozygote, had 28% residual ASS1 enzyme activity [ Survival rates in those who underwent liver transplantation prior to age two years was between 90% and 95% five years post transplant [ Routine Daily Treatment in Individuals with Citrullinemia Type I Adequate protein intake can be based on FAO/WHO/UNU 2007 "safe levels of protein intake." If EAA supplements are needed, it is reasonable to provide 20%-30% total protein intake in this form. The protein source for infants should be breastmilk or standard infant formula. Dietary therapy should be done in conjunction w/metabolic nutritionist. Exclusive on-demand breastfeeding is possible but requires close analytic monitoring & may require supplementation w/protein-free infant formula. In bottle-fed infants, total daily protein amounts are divided evenly between daily feeds, & can be supplemented w/protein-free formula to round out caloric intake, &/or to appetite, w/goal for total amount to supply all required nutrients. In persons weighing <20 kg: up to 250 mg/kg In persons weighing >20 kg: 5 g/m Initial dose for phenylbutyrate-naïve persons: 4.5-11.2 mL/m Dose for those transitioning from sodium phenylbutyrate: daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate (g) x 0.86 In persons weighing <20 kg: 100-300 mg/kg/d or 0.5-1.5 mmol/kg/d In persons weighing >20 kg: 2.5-6 g/m /d = per day; EAA = essential amino acid; FAO = Food and Agriculture Organization of the United States; WHO = World Health Organization; UNU = United Nations University Success of therapy is defined by a plasma ammonia concentration lower than100 µmol/L and near-normal plasma glutamine concentration. This nitrogen scavenging medication may be more palatable. Plasma arginine concentration may be up to 250% above upper normal limit for age. Emergency Outpatient Treatment in Individuals with Citrullinemia Type I Carbohydrate supplementation orally or via tube feed ↓ natural protein intake ↑ carnitine supplementation Fever <38.5°C (101°F); enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea; absence of neurologic symptoms (altered consciousness, irritability, hypotonia, dystonia) Stringent guidelines to quantify carbohydrate/caloric requirements are available to guide nutritional arrangements in the outpatient setting, with some centers recommending frequent provision of carbohydrate-rich, protein-free beverages every two hours, with frequent reassessment. Some centers advocate additional steps such as reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (<24 hours) in the outpatient setting during intercurrent illness. Temporarily increasing L-carnitine doses (e.g., to 200 mg/kg/d in infants) may be considered [ Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases 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 hospital. Acute Inpatient Treatment in Individuals with Citrullinemia Type I Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Failure to control ammonia w/scavenger therapy requires emergency use of dialysis. Hemodialysis is preferred method of dialysis & exceeds both peritoneal dialysis & hemofiltration in rate of ammonia clearance. Continue scavenger therapy while dialysis is being performed. Administer high-energy fluids & (if needed) insulin. IV interlipids Consider L-carnitine supplementation, esp if deficient. Address electrolytes & pH imbalances w/IV fluid mgmt. Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt. Ongoing assessment of hemodynamic status & for new neurologic signs is critical. Inadequate or delayed start of emergency treatment → high risk of neurologic injury w/consequent long-term neurodisability. To provide 0.25 g/kg/d of protein & 50 kcal/kg/d, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/d of protein & 100-120 kcal/kg/d Standard TPN solutions of dextrose, aminosol, & intralipid are used. It is critical to monitor fluid balance, intake & output, & body weight. ↑ intracranial pressure is manifested by tension in fontanelle, acute enlargement of liver, edema, & worsening neurologic signs incl fisting, scissoring, ankle clonus, & coma. Cerebral edema & ischemia may be documented by brain MRI. /d = per day; EAA = essential amino acid; IV = intravenous; TPN = total parenteral nutrition 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. Repeat boluses are not recommended unless the individual is receiving dialysis. Exchange transfusions have no place in hyperammonemic treatment. IV glucose solutions should provide 12-15 g/kg/d glucose for infants and 10-12 g/kg/d for children age 12 months to 6 years. In small infants, 40 kcal/100 mL given as D10W can be significant in averting catabolism. Use of insulin if hyperglycemia emerges; IV insulin given at a starting dose of 0.025 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma, or glucosuria) L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability. Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CTLN1 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 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 • Liver transplantation should ideally be performed in affected persons before age 1 yr (prior to development of any neurocognitive impairment) but after age 3 mos &/or when body weight is >5 kg to ↓ complications & ↑ survival rates. • Although liver transplantation cures ASS enzyme deficiency, arginine is extrahepatically synthesized & remains low post transplant, requiring ongoing supplementation. • Adequate protein intake can be based on FAO/WHO/UNU 2007 "safe levels of protein intake." • If EAA supplements are needed, it is reasonable to provide 20%-30% total protein intake in this form. • The protein source for infants should be breastmilk or standard infant formula. • Dietary therapy should be done in conjunction w/metabolic nutritionist. • Exclusive on-demand breastfeeding is possible but requires close analytic monitoring & may require supplementation w/protein-free infant formula. • In bottle-fed infants, total daily protein amounts are divided evenly between daily feeds, & can be supplemented w/protein-free formula to round out caloric intake, &/or to appetite, w/goal for total amount to supply all required nutrients. • In persons weighing <20 kg: up to 250 mg/kg • In persons weighing >20 kg: 5 g/m • Initial dose for phenylbutyrate-naïve persons: 4.5-11.2 mL/m • Dose for those transitioning from sodium phenylbutyrate: daily dose of glycerol phenylbutyrate (mL) = daily dose of sodium phenylbutyrate (g) x 0.86 • In persons weighing <20 kg: 100-300 mg/kg/d or 0.5-1.5 mmol/kg/d • In persons weighing >20 kg: 2.5-6 g/m • Carbohydrate supplementation orally or via tube feed • ↓ natural protein intake • ↑ carnitine supplementation • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Failure to control ammonia w/scavenger therapy requires emergency use of dialysis. • Hemodialysis is preferred method of dialysis & exceeds both peritoneal dialysis & hemofiltration in rate of ammonia clearance. • Continue scavenger therapy while dialysis is being performed. • Administer high-energy fluids & (if needed) insulin. • IV interlipids • Consider L-carnitine supplementation, esp if deficient. • Address electrolytes & pH imbalances w/IV fluid mgmt. • Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine profiling, & urine pH/ketone screening may all be useful in guiding mgmt. • Ongoing assessment of hemodynamic status & for new neurologic signs is critical. • Inadequate or delayed start of emergency treatment → high risk of neurologic injury w/consequent long-term neurodisability. • To provide 0.25 g/kg/d of protein & 50 kcal/kg/d, advancing (as plasma ammonia concentration allows) to 1.0-1.5 g/kg/d of protein & 100-120 kcal/kg/d • Standard TPN solutions of dextrose, aminosol, & intralipid are used. • It is critical to monitor fluid balance, intake & output, & body weight. • ↑ intracranial pressure is manifested by tension in fontanelle, acute enlargement of liver, edema, & worsening neurologic signs incl fisting, scissoring, ankle clonus, & coma. • Cerebral edema & ischemia may be documented by brain MRI. • Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with CTLN1 together with pediatric metabolic experts, dietitians, psychologists, and social workers. • As the long-term course of pediatric metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise with metabolic diseases with sufficient resources is essential. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 ## Prevention of Primary Manifestations Prevention of hyperammonemia is achieved through lifelong protein restriction, nitrogen scavenger therapy, and possible liver transplantation based on metabolic control (see ## 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 and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors (see Prevention of Secondary Manifestations in Individuals with Citrullinemia Type I Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home MedicAlert Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources) Medication required for maintenance & emergency treatment (antipyretics) should always be maintained at home. Provide written protocols for maintenance & emergency treatment to parents & primary care providers / pediatricians & to teachers & school staff. Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for CTLN1 & containing contact info for primary treating metabolic center. For any planned travel or vacations, consider contacting 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). The night before surgery, & esp once patient is made NPO, drug treatment should be switched to IV & nutrition w/10% glucose w/age-appropriate electrolytes should be administered via IV to promote anabolism. IV = intravenous; NPO = nil per os ("nothing by mouth") Essential information including written treatment protocols should be in place in anticipation of possible future need for inpatient emergency treatment. Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature rises >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for persons deemed to be at high risk for perioperative complications. • Intense & ongoing education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute encephalopathic crises • Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while away from home • MedicAlert • Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources) • Medication required for maintenance & emergency treatment (antipyretics) should always be maintained at home. • Provide written protocols for maintenance & emergency treatment to parents & primary care providers / pediatricians & to teachers & school staff. • Emergency letters/cards should be provided summarizing key info & principles of emergency treatment for CTLN1 & containing contact info for primary treating metabolic center. • For any planned travel or vacations, consider contacting 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). • The night before surgery, & esp once patient is made NPO, drug treatment should be switched to IV & nutrition w/10% glucose w/age-appropriate electrolytes should be administered via IV to promote anabolism. ## Surveillance Follow up in a metabolic clinic with a qualified metabolic nutritionist and clinical biochemical geneticist is required (see Recommended Surveillance for Individuals with Citrullinemia Type I Measurement of growth parameters Eval of nutritional status & safety of oral intake During 1st yr of life: at least every 3 mos In teen/adult yrs: every 6-12 mos, depending on clinical stability EEA = essential amino acids; OT = occupational therapy; PT = physical therapy This should prompt assessment of (at a minimum) plasma ammonia level, plasma amino acid analysis, and other metabolic labs (electrolytes, glucose level, liver function tests, and complete blood count). Plasma glutamate concentration may rise 48 hours in advance of plasma ammonia concentration. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • During 1st yr of life: at least every 3 mos • In teen/adult yrs: every 6-12 mos, depending on clinical stability ## Agents/Circumstances to Avoid Avoid the following: Excess protein intake Prolonged fasting Obvious exposure to communicable diseases • Excess protein intake • Prolonged fasting • Obvious exposure to communicable diseases ## Evaluation of Relatives at Risk Molecular genetic testing if the pathogenic variants in the family are known, In utero diagnosis (which permits appropriate oral therapy beginning with first feeds), if possible, is preferred. Measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment. Newborn full sibs of individuals who had early-onset presentation and in whom prenatal genetic testing has not been performed should be started on a protein-restricted diet with consideration of immediately starting an IV with provision of (1) age-appropriate glucose infusion rates and appropriate electrolytes and (2) protein-free infant formula, pending completion of the diagnostic evaluation. See • Molecular genetic testing if the pathogenic variants in the family are known, In utero diagnosis (which permits appropriate oral therapy beginning with first feeds), if possible, is preferred. • Measurement of plasma concentrations of ammonia and citrulline on day one of life. Elevation of either above acceptable levels (ammonia >100 µmol/L or plasma citrulline >~100 µmol/L) is sufficient evidence to initiate treatment. • Newborn full sibs of individuals who had early-onset presentation and in whom prenatal genetic testing has not been performed should be started on a protein-restricted diet with consideration of immediately starting an IV with provision of (1) age-appropriate glucose infusion rates and appropriate electrolytes and (2) protein-free infant formula, pending completion of the diagnostic evaluation. ## Pregnancy Management Because women with onset of severe symptoms during pregnancy or in the postpartum period have been reported, scrupulous attention needs to be paid to diet and medication during these periods. See ## Therapies Under Investigation Gene therapy has been suggested; success has not been achieved to date. Phase I and Phase II clinical trials to assess the safety and efficacy of human hepatocyte transplantation as either an alternative to liver transplantation or a temporizing measure for individuals with CTLN1 awaiting transplantation have completed. Search ## Other Ketoacids of essential amino acids were an early form of auxiliary waste nitrogen disposal enhancement, now replaced by the agents described in ## Genetic Counseling Citrullinemia type I (CTLN1) 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 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) have no symptoms of the urea cycle defect phenotype. If both parents are known to be heterozygous for an Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management, Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype. 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. Note: Improvement in diagnostic accuracy using the ratio of citrulline-to-ornithine concentrations in amniotic fluid has been reported, with proposed approach of combining 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 • 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 • 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) have no symptoms of the urea cycle defect phenotype. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management, • Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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 Citrullinemia type I (CTLN1) 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 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) have no symptoms of the urea cycle defect phenotype. If both parents are known to be heterozygous for an Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management, Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype. • 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 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) have no symptoms of the urea cycle defect phenotype. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • Sibs should be evaluated immediately after birth and placed on a protein-restricted diet until the diagnostic evaluation is complete (see Management, • Heterozygotes (carriers) have no symptoms of the urea cycle defect phenotype. ## 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 Note: Improvement in diagnostic accuracy using the ratio of citrulline-to-ornithine concentrations in amniotic fluid has been reported, with proposed approach of combining 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 TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom United Kingdom Health Resources & Services Administration Children's National Medical Center • • • • • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • United Kingdom • • • Health Resources & Services Administration • • • • • • • • • Children's National Medical Center • ## Molecular Genetics Citrullinemia Type I: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Citrullinemia Type I ( The translational product argininosuccinate synthase is a homotetramer of 186 kilodaltons. Each monomer consists of a nucleotide-binding domain, a synthetase domain, and a C-terminal helix. It catalyzes an essential reaction in the biosynthesis of urea, causing the condensation of citrulline and aspartate to argininosuccinic acid in the cytosol, and requiring 1 mol of ATP. Failure of the urea cycle at this step leads to accumulation of citrulline, glutamine, and ammonia in plasma, and increased orotic acid production and excretion in the urine. Subsequently there are low plasma levels of argininosuccinate and arginine. High citrulline levels differentiate cytosolic from mitochondrial urea cycle disorders. Citrulline includes in its molecular structure one molecule of ornithine and one atom of waste nitrogen, as opposed to argininosuccinate, which carries two atoms of waste nitrogen, making citrulline a poorer waste nitrogen carrier. Urinary excretion of citrulline helps to remove waste nitrogen, though at the expense of two molecules of ornithine per urea equivalent. Hyperammonemic episodes are more frequent in individuals with citrullinemia type I compared to argininosuccinate lyase deficiency, as secondary impairment of ornithine transcarbamylas occurs in part due to poor bioavailability of ornithine [ Notable CTLN1 = citrullinemia type I Variants listed in the table have been provided by the authors. Fifty percent of individuals with non-classic presentations were found to be homozygous for one of the following three missense variants: p.Trp179Arg, p.Val263Met, or p.Gly362Val [ ## Molecular Pathogenesis The translational product argininosuccinate synthase is a homotetramer of 186 kilodaltons. Each monomer consists of a nucleotide-binding domain, a synthetase domain, and a C-terminal helix. It catalyzes an essential reaction in the biosynthesis of urea, causing the condensation of citrulline and aspartate to argininosuccinic acid in the cytosol, and requiring 1 mol of ATP. Failure of the urea cycle at this step leads to accumulation of citrulline, glutamine, and ammonia in plasma, and increased orotic acid production and excretion in the urine. Subsequently there are low plasma levels of argininosuccinate and arginine. High citrulline levels differentiate cytosolic from mitochondrial urea cycle disorders. Citrulline includes in its molecular structure one molecule of ornithine and one atom of waste nitrogen, as opposed to argininosuccinate, which carries two atoms of waste nitrogen, making citrulline a poorer waste nitrogen carrier. Urinary excretion of citrulline helps to remove waste nitrogen, though at the expense of two molecules of ornithine per urea equivalent. Hyperammonemic episodes are more frequent in individuals with citrullinemia type I compared to argininosuccinate lyase deficiency, as secondary impairment of ornithine transcarbamylas occurs in part due to poor bioavailability of ornithine [ Notable CTLN1 = citrullinemia type I Variants listed in the table have been provided by the authors. Fifty percent of individuals with non-classic presentations were found to be homozygous for one of the following three missense variants: p.Trp179Arg, p.Val263Met, or p.Gly362Val [ ## Chapter Notes Dr Lee is a clinical and medical biochemical geneticist in the Pediatric, Adult Medical, and Cancer Genetics Clinics at Michigan Medicine. Her research interests include newborn screening, treatment of genetic disease including clinical trials for metabolic disorders, outcomes in adults with metabolic disorders, medical education for genetics trainees, and delineation of newly recognized genetic syndromes. Dr Quinonez is a clinical and clinical biochemical geneticist in the Pediatric, Adult Medical, and Cancer Genetics Clinics at Michigan Medicine. His research interests include the expansion of genetic services in low- and middle-income countries, treatment of genetic disease including clinical trials for metabolic disorders, increasing diversity, equity, and inclusion in the field of genetics, and medical education for genetics trainees. Kristen N Lee, MD (2022-present)Shane C Quinonez, MD (2014-present)Jess G Thoene, MD; University of Michigan (2004-2022) 18 August 2022 (ma) Comprehensive update posted live 1 September 2016 (ma) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 11 August 2011 (me) Comprehensive update posted live 2 June 2009 (me) Comprehensive update posted live 22 December 2006 (me) Comprehensive update posted live 7 July 2004 (me) Review posted live 9 February 2004 (jt) Original submission • 18 August 2022 (ma) Comprehensive update posted live • 1 September 2016 (ma) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 11 August 2011 (me) Comprehensive update posted live • 2 June 2009 (me) Comprehensive update posted live • 22 December 2006 (me) Comprehensive update posted live • 7 July 2004 (me) Review posted live • 9 February 2004 (jt) Original submission ## Author Notes Dr Lee is a clinical and medical biochemical geneticist in the Pediatric, Adult Medical, and Cancer Genetics Clinics at Michigan Medicine. Her research interests include newborn screening, treatment of genetic disease including clinical trials for metabolic disorders, outcomes in adults with metabolic disorders, medical education for genetics trainees, and delineation of newly recognized genetic syndromes. Dr Quinonez is a clinical and clinical biochemical geneticist in the Pediatric, Adult Medical, and Cancer Genetics Clinics at Michigan Medicine. His research interests include the expansion of genetic services in low- and middle-income countries, treatment of genetic disease including clinical trials for metabolic disorders, increasing diversity, equity, and inclusion in the field of genetics, and medical education for genetics trainees. ## Author History Kristen N Lee, MD (2022-present)Shane C Quinonez, MD (2014-present)Jess G Thoene, MD; University of Michigan (2004-2022) ## Revision History 18 August 2022 (ma) Comprehensive update posted live 1 September 2016 (ma) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 11 August 2011 (me) Comprehensive update posted live 2 June 2009 (me) Comprehensive update posted live 22 December 2006 (me) Comprehensive update posted live 7 July 2004 (me) Review posted live 9 February 2004 (jt) Original submission • 18 August 2022 (ma) Comprehensive update posted live • 1 September 2016 (ma) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 11 August 2011 (me) Comprehensive update posted live • 2 June 2009 (me) Comprehensive update posted live • 22 December 2006 (me) Comprehensive update posted live • 7 July 2004 (me) Review posted live • 9 February 2004 (jt) Original submission ## References Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. [ 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. [ The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available • Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. [ • 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. [ • The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available ## Published Guidelines / Consensus Statements Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. [ 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. [ The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available • Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, Karall D, Martinelli D, Crespo PS, Santer R, Servais A, Valayannopoulos V, Lindner M, Rubio V, Dionisi-Vici C. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. [ • 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. [ • The Urea Cycle Disorders Conference Group. Consensus statement from a conference for the management of patients with urea cycle disorders. Available ## Literature Cited
[]
7/7/2004
18/8/2022
22/4/2008
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ctnnb1-ndd
ctnnb1-ndd
[ "Catenin beta-1", "CTNNB1", "CTNNB1 Neurodevelopmental Disorder" ]
Stephanie KL Ho, Mandy HY Tsang, Mianne Lee, Shirley SW Cheng, Ho-ming Luk, Ivan FM Lo, Brian HY Chung
Summary The diagnosis of
## Diagnosis No consensus clinical diagnostic criteria for Mild-to-profound developmental delay or intellectual disability Exudative vitreoretinopathy with a range of findings observed in familial exudative vitreoretinopathy (FEVR) that include: asymptomatic peripheral retina avascularity, neovascularization, and fibrosis; a varying degree of visual impairment associated with macula and vessel dragging; and total blindness resulting from tractional and/or exudative retinal detachments [ Any of the following common features presenting in infancy or childhood: Truncal hypotonia Peripheral spasticity Dystonia Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness Microcephaly (≤2 SD below age- and sex-adjusted mean) Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus Other less common features presenting in infancy or childhood: Intrauterine growth restriction Short stature Feeding difficulties Scoliosis Suggestive facial features (See 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 Information on individuals with genotypes involving a contiguous gene deletion of Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Mild-to-profound developmental delay or intellectual disability • Exudative vitreoretinopathy with a range of findings observed in familial exudative vitreoretinopathy (FEVR) that include: asymptomatic peripheral retina avascularity, neovascularization, and fibrosis; a varying degree of visual impairment associated with macula and vessel dragging; and total blindness resulting from tractional and/or exudative retinal detachments [ • Any of the following common features presenting in infancy or childhood: • Truncal hypotonia • Peripheral spasticity • Dystonia • Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness • Microcephaly (≤2 SD below age- and sex-adjusted mean) • Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus • Truncal hypotonia • Peripheral spasticity • Dystonia • Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness • Microcephaly (≤2 SD below age- and sex-adjusted mean) • Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus • Truncal hypotonia • Peripheral spasticity • Dystonia • Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness • Microcephaly (≤2 SD below age- and sex-adjusted mean) • Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus • Intrauterine growth restriction • Short stature • Feeding difficulties • Scoliosis • Suggestive facial features (See • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Mild-to-profound developmental delay or intellectual disability Exudative vitreoretinopathy with a range of findings observed in familial exudative vitreoretinopathy (FEVR) that include: asymptomatic peripheral retina avascularity, neovascularization, and fibrosis; a varying degree of visual impairment associated with macula and vessel dragging; and total blindness resulting from tractional and/or exudative retinal detachments [ Any of the following common features presenting in infancy or childhood: Truncal hypotonia Peripheral spasticity Dystonia Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness Microcephaly (≤2 SD below age- and sex-adjusted mean) Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus Other less common features presenting in infancy or childhood: Intrauterine growth restriction Short stature Feeding difficulties Scoliosis Suggestive facial features (See • Mild-to-profound developmental delay or intellectual disability • Exudative vitreoretinopathy with a range of findings observed in familial exudative vitreoretinopathy (FEVR) that include: asymptomatic peripheral retina avascularity, neovascularization, and fibrosis; a varying degree of visual impairment associated with macula and vessel dragging; and total blindness resulting from tractional and/or exudative retinal detachments [ • Any of the following common features presenting in infancy or childhood: • Truncal hypotonia • Peripheral spasticity • Dystonia • Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness • Microcephaly (≤2 SD below age- and sex-adjusted mean) • Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus • Truncal hypotonia • Peripheral spasticity • Dystonia • Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness • Microcephaly (≤2 SD below age- and sex-adjusted mean) • Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus • Truncal hypotonia • Peripheral spasticity • Dystonia • Behavior problems including autism spectrum disorder, inattention, hyperactivity, aggression, self-mutilation, temper tantrums, anxiety, sleep disturbances, and restlessness • Microcephaly (≤2 SD below age- and sex-adjusted mean) • Other ophthalmologic findings including refractive errors (myopia, hypermetropia, astigmatism) and strabismus • Intrauterine growth restriction • Short stature • Feeding difficulties • Scoliosis • Suggestive facial features (See ## 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 Information on individuals with genotypes involving a contiguous gene deletion of Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, at least 57 individuals have been identified with a pathogenic variant in Select Features of ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction Based on Myopia was detected in three of 56 reported individuals (5.4%) and hypermetropia in 14 of 56 reported individuals (25%). Regression in ability to ambulate and cognitive function was reported in some affected individuals, which may be explained by progressive peripheral spasticity and/or visual impairment [ Age of walking with assistance ranged from 21 months to 12 years. Some affected individuals continued to require assistance for walking as adults and some regressed to become wheelchair bound [ Age of first words in individuals with developmental delay ranged from 12 months to 14 years. Age of ability to speak in sentences was between six and 14 years in those who were able. The lower limbs are often affected, whereas the upper limbs have milder involvement. Spinal MRI is often unremarkable, although tethered cord, syringomyelia, and lipomyelomeningocele have been reported [ Manifestations of FEVR can range from an incidental finding of localized peripheral retinal avascularity that does not affect vision, to total blindness resulting from tractional and exudative retinal detachments. Although the majority of individuals reported with Significant visual impairment was reported in 17.5% (10/57) of affected individuals; 7% (4/57) of affected individuals were legally blind [ To date, no genotype-phenotype correlations have been identified [ As of October 2021, 57 individuals with • Age of walking with assistance ranged from 21 months to 12 years. • Some affected individuals continued to require assistance for walking as adults and some regressed to become wheelchair bound [ • Age of first words in individuals with developmental delay ranged from 12 months to 14 years. • Age of ability to speak in sentences was between six and 14 years in those who were able. ## Clinical Description To date, at least 57 individuals have been identified with a pathogenic variant in Select Features of ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction Based on Myopia was detected in three of 56 reported individuals (5.4%) and hypermetropia in 14 of 56 reported individuals (25%). Regression in ability to ambulate and cognitive function was reported in some affected individuals, which may be explained by progressive peripheral spasticity and/or visual impairment [ Age of walking with assistance ranged from 21 months to 12 years. Some affected individuals continued to require assistance for walking as adults and some regressed to become wheelchair bound [ Age of first words in individuals with developmental delay ranged from 12 months to 14 years. Age of ability to speak in sentences was between six and 14 years in those who were able. The lower limbs are often affected, whereas the upper limbs have milder involvement. Spinal MRI is often unremarkable, although tethered cord, syringomyelia, and lipomyelomeningocele have been reported [ Manifestations of FEVR can range from an incidental finding of localized peripheral retinal avascularity that does not affect vision, to total blindness resulting from tractional and exudative retinal detachments. Although the majority of individuals reported with Significant visual impairment was reported in 17.5% (10/57) of affected individuals; 7% (4/57) of affected individuals were legally blind [ • Age of walking with assistance ranged from 21 months to 12 years. • Some affected individuals continued to require assistance for walking as adults and some regressed to become wheelchair bound [ • Age of first words in individuals with developmental delay ranged from 12 months to 14 years. • Age of ability to speak in sentences was between six and 14 years in those who were able. ## Neurodevelopmental Features Regression in ability to ambulate and cognitive function was reported in some affected individuals, which may be explained by progressive peripheral spasticity and/or visual impairment [ Age of walking with assistance ranged from 21 months to 12 years. Some affected individuals continued to require assistance for walking as adults and some regressed to become wheelchair bound [ Age of first words in individuals with developmental delay ranged from 12 months to 14 years. Age of ability to speak in sentences was between six and 14 years in those who were able. The lower limbs are often affected, whereas the upper limbs have milder involvement. Spinal MRI is often unremarkable, although tethered cord, syringomyelia, and lipomyelomeningocele have been reported [ • Age of walking with assistance ranged from 21 months to 12 years. • Some affected individuals continued to require assistance for walking as adults and some regressed to become wheelchair bound [ • Age of first words in individuals with developmental delay ranged from 12 months to 14 years. • Age of ability to speak in sentences was between six and 14 years in those who were able. ## Ophthalmologic Features Manifestations of FEVR can range from an incidental finding of localized peripheral retinal avascularity that does not affect vision, to total blindness resulting from tractional and exudative retinal detachments. Although the majority of individuals reported with Significant visual impairment was reported in 17.5% (10/57) of affected individuals; 7% (4/57) of affected individuals were legally blind [ ## Other Features ## Genotype-Phenotype Correlations To date, no genotype-phenotype correlations have been identified [ ## Prevalence As of October 2021, 57 individuals with ## Genetically Related (Allelic) Disorders ## Differential Diagnosis The cognitive and motor features of The ophthalmologic features of Pediatric Retinal Diseases in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; XL = X-linked ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Assess for spasticity & dystonia. Consider MRI of spine if evidence of lower limb spasticity to assess for possibility of underlying tethered cord. 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 motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl eval of aspiration risk, swallowing difficulties, reflux & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. To assess for the range of retinal manifestations of exudative vitreoretinopathy at time of 1st diagnosis (incl early infancy) May require fluorescein angiography 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; Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care by a multidisciplinary team often includes a neurologist, speech-language pathologist, physiatrist, occupational therapist, physical therapist, feeding team, ophthalmologist, audiologist, and developmental pediatrician. Treatment of Manifestations in Individuals with Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Regular PT w/stretching Botulinum toxin & intrathecal baclofen injection may be considered. Consider need for positioning & mobility devices, disability parking placard. For retinal findings only evident on wide-field FA: discuss w/treating retina specialist for consideration of prophylactic laser due to ↑ risk of retinal detachment. For significant retinal findings: argon laser photocoagulation, scleral buckling &/or pars plana vitrectomy to attempt to halt progressive changes & ↓ complications 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 FA = fluorescein angiogram; 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 consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 Levodopa, 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 Measurement of growth parameters Eval of nutritional status & safety of oral intake OT = occupational therapy; PT = physical therapy See Search • Assess for spasticity & dystonia. • Consider MRI of spine if evidence of lower limb spasticity to assess for possibility of underlying tethered cord. • 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 motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl eval of aspiration risk, swallowing difficulties, reflux & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • To assess for the range of retinal manifestations of exudative vitreoretinopathy at time of 1st diagnosis (incl early infancy) • May require fluorescein angiography • Community or • Social work involvement for parental support; • Home nursing referral. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Regular PT w/stretching • Botulinum toxin & intrathecal baclofen injection may be considered. • Consider need for positioning & mobility devices, disability parking placard. • For retinal findings only evident on wide-field FA: discuss w/treating retina specialist for consideration of prophylactic laser due to ↑ risk of retinal detachment. • For significant retinal findings: argon laser photocoagulation, scleral buckling &/or pars plana vitrectomy to attempt to halt progressive changes & ↓ complications • 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 Levodopa, baclofen, tizanidine, Botox • 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 Assess for spasticity & dystonia. Consider MRI of spine if evidence of lower limb spasticity to assess for possibility of underlying tethered cord. 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 motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl eval of aspiration risk, swallowing difficulties, reflux & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. To assess for the range of retinal manifestations of exudative vitreoretinopathy at time of 1st diagnosis (incl early infancy) May require fluorescein angiography 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; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assess for spasticity & dystonia. • Consider MRI of spine if evidence of lower limb spasticity to assess for possibility of underlying tethered cord. • 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 motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl eval of aspiration risk, swallowing difficulties, reflux & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • To assess for the range of retinal manifestations of exudative vitreoretinopathy at time of 1st diagnosis (incl early infancy) • May require fluorescein angiography • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Supportive care by a multidisciplinary team often includes a neurologist, speech-language pathologist, physiatrist, occupational therapist, physical therapist, feeding team, ophthalmologist, audiologist, and developmental pediatrician. Treatment of Manifestations in Individuals with Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Regular PT w/stretching Botulinum toxin & intrathecal baclofen injection may be considered. Consider need for positioning & mobility devices, disability parking placard. For retinal findings only evident on wide-field FA: discuss w/treating retina specialist for consideration of prophylactic laser due to ↑ risk of retinal detachment. For significant retinal findings: argon laser photocoagulation, scleral buckling &/or pars plana vitrectomy to attempt to halt progressive changes & ↓ complications 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 FA = fluorescein angiogram; 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 consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 Levodopa, 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. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Regular PT w/stretching • Botulinum toxin & intrathecal baclofen injection may be considered. • Consider need for positioning & mobility devices, disability parking placard. • For retinal findings only evident on wide-field FA: discuss w/treating retina specialist for consideration of prophylactic laser due to ↑ risk of retinal detachment. • For significant retinal findings: argon laser photocoagulation, scleral buckling &/or pars plana vitrectomy to attempt to halt progressive changes & ↓ complications • 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 Levodopa, 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 Levodopa, 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 Levodopa, 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 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 Search ## Genetic Counseling Most probands reported to date with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ If a parent of the proband is known to have the If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ • 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 probands reported to date with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ If a parent of the proband is known to have the If the • Most probands reported to date with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Germline mosaicism was reported in one family with two affected offspring and normal parental studies [ • If a parent of the proband is known to have the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • • • • • United Kingdom • • • ## Molecular Genetics CTNNB1 Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for CTNNB1 Neurodevelopmental Disorder ( To date there is no evidence that individuals with the loss-of-function ## Molecular Pathogenesis ## Cancer and Benign Tumors To date there is no evidence that individuals with the loss-of-function ## Chapter Notes We would like to thank the families of individuals with 19 May 2022 (bp) Review posted live 17 November 2021 (sh) Original submission • 19 May 2022 (bp) Review posted live • 17 November 2021 (sh) Original submission ## Acknowledgments We would like to thank the families of individuals with ## Revision History 19 May 2022 (bp) Review posted live 17 November 2021 (sh) Original submission • 19 May 2022 (bp) Review posted live • 17 November 2021 (sh) Original submission ## References ## Literature Cited Facial features in individuals with Common findings are a bulbous nasal tip, thin upper lip, small alae nasi, and long and smooth philtrum. Less common findings are upslanting palpebral fissures and hypotelorism. Note thin, fair, or sparse hair, abnormal hair pattern, and fair skin complexion. Patient 1. Chinese male. A: age 8 months; B: age 24 months; C: age 18 years, 3 months; D: age 20 years, 11 months Patient 2. Chinese female. A: age 1 year, 1 month with her affected mother (age 32 years); B: age 5 years, 1 month Patient 3. Chinese female. A: 1 year, 4 months; B: 4 years Patient 4. White American female. 2 years, 11 months Patient 5. Chinese male. 3 years, 7 months Patient 6. Male. 4 years Patient 7. Chinese female. A: 4 years, 4 months, B: 6 years, 10 months Patient 8. German and Irish male. 5 years Patient 9. White Western European female. 5 years, 2 months Patient 10. Chinese male. 5 years, 3 months Patient 11. White female. A: 9 years; B: 10 years; C: 11 years; D: 12 years; E: 13 years Patient 12. Male. 9 years Patient 13. Female. 14 years Patient 14. European male. 16 years Patient 15. White European male. 18 years Patient 16. Thai female. 19 years Reprinted with permission from
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Eur J Med Genet. 2017;60:130-5", "A Kuechler, MH Willemsen, B Albrecht, CA Bacino, DW Bartholomew, H van Bokhoven, MJ van den Boogaard, N Bramswig, C Buttner, K Cremer, JC Czeschik, H Engels, K van Gassen, E Graf, M van Haelst, W He, JS Hogue, M Kempers, D Koolen, G Monroe, S de Munnik, M Pastore, A Reis, MS Reuter, DH Tegay, J Veltman, G Visser, P van Hasselt, EE Smeets, L Vissers, T Wieland, W Wissink, H Yntema, AM Zink, TM Strom, HJ Ludecke, T Kleefstra, D Wieczorek. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum.. Hum Genet. 2015;134:97-109", "N Li, Y Xu, G Li, T Yu, RE Yao, X Wang, J Wang. Exome sequencing identifies a de novo mutation of CTNNB1 gene in a patient mainly presented with retinal detachment, lens and vitreous opacities, microcephaly, and developmental delay: case report and literature review.. 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Mov Disord. 2018;33:656-7", "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", "LZ Rossetti, MR Bekheirnia, AM Lewis, HC Mefford, K Golden-Grant, K Tarczy-Hornoch, LC Briere, DA Sweetser, MA Walker, E Kravets, DA Stevenson, G Bruenner, J Sebastian, J Knapo, JA Rosenfeld, PC Marcogliese, MF Wangler. Missense variants in CTNNB1 can be associated with vitreoretinopathy-seven new cases of CTNNB1-associated neurodevelopmental disorder including a previously unreported retinal phenotype.. Mol Genet Genomic Med. 2021;9", "W Sun, X Xiao, S Li, X Jia, P Wang, Q. Zhang. Germline Mutations in CTNNB1 associated with syndromic FEVR or Norrie disease.. Invest Ophthalmol Vis Sci. 2019;60:93-7", "V Tucci, T Kleefstra, A Hardy, I Heise, S Maggi, MH Willemsen, H Hilton, C Esapa, M Simon, MT Buenavista, LJ McGuffin, L Vizor, L Dodero, S Tsaftaris, R Romero, WN Nillesen, LE Vissers, MJ Kempers, AT Vulto-van Silfhout, Z Iqbal, M Orlando, A Maccione, G Lassi, P Farisello, A Contestabile, F Tinarelli, T Nieus, A Raimondi, B Greco, D Cantatore, L Gasparini, L Berdondini, A Bifone, A Gozzi, S Wells, PM Nolan. Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features.. J Clin Invest. 2014;124:1468-82", "H Wang, Y Zhao, L Yang, S Han, M Qi. Identification of a novel splice mutation in CTNNB1 gene in a Chinese family with both severe intellectual disability and serious visual defects.. Neurol Sci. 2019;40:1701-4", "A Winczewska-Wiktor, M Badura-Stronka, A Monies-Nowicka, MM Nowicki, B Steinborn, A Latos-Bielenska, D Monies. 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19/5/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ctns
ctns
[ "Non-Nephropathic (Ocular) Cystinosis", "Later-Onset (Juvenile) Cystinosis", "Nephropathic Cystinosis", "Cystinosin", "CTNS", "Cystinosis" ]
Cystinosis
William A Gahl
Summary Cystinosis comprises three allelic clinical phenotypes caused by pathogenic variants in The diagnosis of cystinosis is established in a proband with cystine crystals in the cornea identified on slit lamp examination, elevated cystine concentration in polymorphonuclear leukocytes, and/or demonstration of increased cystine content in cultured fibroblasts or in the placenta at the time of birth, and biallelic pathogenic variants in Cystinosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
Nephropathic cystinosis Later-onset (juvenile) cystinosis Non-nephropathic (ocular) cystinosis For synonyms and outdated names see • Nephropathic cystinosis • Later-onset (juvenile) cystinosis • Non-nephropathic (ocular) cystinosis ## Diagnosis Typically, birth weight and initial growth are normal. Poor weight gain and growth deficiency occurs by age six to 12 months. Vomiting and feeding difficulties Severe polyuria, polydipsia, and dehydration Progressive rachitic skeletal changes; failure to walk at a normal age Tetany Corneal crystals, typically observed by slit lamp examination in most individuals by age 12 months and in virtually all individuals by age 18 months [ Hypochloremic metabolic acidosis Renal Fanconi syndrome: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, and tubular protein including β2-microglobulin Elevated serum alkaline phosphatase Hypocalcemia, hypophosphatemia, and hypokalemia Elevated cystine concentration in polymorphonuclear leukocytes, cultured fibroblasts, or placenta (See Establishing the Diagnosis, Radiographic features of rickets including bowing of the long bones in the lower extremities, widened metaphyses, frayed epiphyses, and generalized osteopenia Renal ultrasound features including medullary nephrocalcinosis and/or increased echogenicity The diagnosis of cystinosis 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: The most common pathogenic variant in individuals from northern Europe and North America is a large 57-kb deletion including the promoter region, the first ten exons of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Cystinosis 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. Various methods for quantification of intracellular cystine in leucocytes are used for both diagnosis and monitoring of cystinosis therapy. These include ion exchange chromatography, high pressure liquid chromatography, and tandem mass spectrometry (MS/MS); MS/MS is the most sensitive method [ Individuals with nephropathic cystinosis generally have a concentration of 3.0-23.0 nmol half-cystine/mg protein. Individuals with non-nephropathic cystinosis have concentrations of 1.0-3.0 nmol half-cystine/mg protein. Heterozygous individuals have concentrations of ≤1.0 nmol half-cystine/mg protein. Normal intracellular concentration is ≤0.2 nmol half-cystine/mg protein. Note: (1) In preparing leukocytes for assay, care must be taken to avoid: (a) a significant number of lymphocytes, which store only fivefold normal amounts of cystine compared with 50-fold normal amounts in polymorphonuclear leukocytes; and (b) contamination with red blood cells, which contribute protein but not cystine to the calculated cystine value. Both interfering substances produce artifactually low leukocyte cystine levels. (2) Measurement by amino acid analysis (i.e., anion exchange chromatography) is less sensitive and can give spurious results if small amounts of leukocyte protein are present. • Typically, birth weight and initial growth are normal. Poor weight gain and growth deficiency occurs by age six to 12 months. • Vomiting and feeding difficulties • Severe polyuria, polydipsia, and dehydration • Progressive rachitic skeletal changes; failure to walk at a normal age • Tetany • Corneal crystals, typically observed by slit lamp examination in most individuals by age 12 months and in virtually all individuals by age 18 months [ • Hypochloremic metabolic acidosis • Renal Fanconi syndrome: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, and tubular protein including β2-microglobulin • Elevated serum alkaline phosphatase • Hypocalcemia, hypophosphatemia, and hypokalemia • Elevated cystine concentration in polymorphonuclear leukocytes, cultured fibroblasts, or placenta (See Establishing the Diagnosis, • Radiographic features of rickets including bowing of the long bones in the lower extremities, widened metaphyses, frayed epiphyses, and generalized osteopenia • Renal ultrasound features including medullary nephrocalcinosis and/or increased echogenicity • Individuals with nephropathic cystinosis generally have a concentration of 3.0-23.0 nmol half-cystine/mg protein. • Individuals with non-nephropathic cystinosis have concentrations of 1.0-3.0 nmol half-cystine/mg protein. • Heterozygous individuals have concentrations of ≤1.0 nmol half-cystine/mg protein. • Normal intracellular concentration is ≤0.2 nmol half-cystine/mg protein. ## Suggestive Findings Typically, birth weight and initial growth are normal. Poor weight gain and growth deficiency occurs by age six to 12 months. Vomiting and feeding difficulties Severe polyuria, polydipsia, and dehydration Progressive rachitic skeletal changes; failure to walk at a normal age Tetany Corneal crystals, typically observed by slit lamp examination in most individuals by age 12 months and in virtually all individuals by age 18 months [ Hypochloremic metabolic acidosis Renal Fanconi syndrome: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, and tubular protein including β2-microglobulin Elevated serum alkaline phosphatase Hypocalcemia, hypophosphatemia, and hypokalemia Elevated cystine concentration in polymorphonuclear leukocytes, cultured fibroblasts, or placenta (See Establishing the Diagnosis, Radiographic features of rickets including bowing of the long bones in the lower extremities, widened metaphyses, frayed epiphyses, and generalized osteopenia Renal ultrasound features including medullary nephrocalcinosis and/or increased echogenicity • Typically, birth weight and initial growth are normal. Poor weight gain and growth deficiency occurs by age six to 12 months. • Vomiting and feeding difficulties • Severe polyuria, polydipsia, and dehydration • Progressive rachitic skeletal changes; failure to walk at a normal age • Tetany • Corneal crystals, typically observed by slit lamp examination in most individuals by age 12 months and in virtually all individuals by age 18 months [ • Hypochloremic metabolic acidosis • Renal Fanconi syndrome: increased urinary excretion of electrolytes (sodium, potassium, bicarbonate), minerals (calcium, phosphate, magnesium), glucose, amino acids, and tubular protein including β2-microglobulin • Elevated serum alkaline phosphatase • Hypocalcemia, hypophosphatemia, and hypokalemia • Elevated cystine concentration in polymorphonuclear leukocytes, cultured fibroblasts, or placenta (See Establishing the Diagnosis, • Radiographic features of rickets including bowing of the long bones in the lower extremities, widened metaphyses, frayed epiphyses, and generalized osteopenia • Renal ultrasound features including medullary nephrocalcinosis and/or increased echogenicity ## Establishing the Diagnosis The diagnosis of cystinosis 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: The most common pathogenic variant in individuals from northern Europe and North America is a large 57-kb deletion including the promoter region, the first ten exons of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Cystinosis 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. Various methods for quantification of intracellular cystine in leucocytes are used for both diagnosis and monitoring of cystinosis therapy. These include ion exchange chromatography, high pressure liquid chromatography, and tandem mass spectrometry (MS/MS); MS/MS is the most sensitive method [ Individuals with nephropathic cystinosis generally have a concentration of 3.0-23.0 nmol half-cystine/mg protein. Individuals with non-nephropathic cystinosis have concentrations of 1.0-3.0 nmol half-cystine/mg protein. Heterozygous individuals have concentrations of ≤1.0 nmol half-cystine/mg protein. Normal intracellular concentration is ≤0.2 nmol half-cystine/mg protein. Note: (1) In preparing leukocytes for assay, care must be taken to avoid: (a) a significant number of lymphocytes, which store only fivefold normal amounts of cystine compared with 50-fold normal amounts in polymorphonuclear leukocytes; and (b) contamination with red blood cells, which contribute protein but not cystine to the calculated cystine value. Both interfering substances produce artifactually low leukocyte cystine levels. (2) Measurement by amino acid analysis (i.e., anion exchange chromatography) is less sensitive and can give spurious results if small amounts of leukocyte protein are present. • Individuals with nephropathic cystinosis generally have a concentration of 3.0-23.0 nmol half-cystine/mg protein. • Individuals with non-nephropathic cystinosis have concentrations of 1.0-3.0 nmol half-cystine/mg protein. • Heterozygous individuals have concentrations of ≤1.0 nmol half-cystine/mg protein. • Normal intracellular concentration is ≤0.2 nmol half-cystine/mg protein. ## Option 1 Note: The most common pathogenic variant in individuals from northern Europe and North America is a large 57-kb deletion including the promoter region, the first ten exons of For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Cystinosis 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. ## Other Testing Various methods for quantification of intracellular cystine in leucocytes are used for both diagnosis and monitoring of cystinosis therapy. These include ion exchange chromatography, high pressure liquid chromatography, and tandem mass spectrometry (MS/MS); MS/MS is the most sensitive method [ Individuals with nephropathic cystinosis generally have a concentration of 3.0-23.0 nmol half-cystine/mg protein. Individuals with non-nephropathic cystinosis have concentrations of 1.0-3.0 nmol half-cystine/mg protein. Heterozygous individuals have concentrations of ≤1.0 nmol half-cystine/mg protein. Normal intracellular concentration is ≤0.2 nmol half-cystine/mg protein. Note: (1) In preparing leukocytes for assay, care must be taken to avoid: (a) a significant number of lymphocytes, which store only fivefold normal amounts of cystine compared with 50-fold normal amounts in polymorphonuclear leukocytes; and (b) contamination with red blood cells, which contribute protein but not cystine to the calculated cystine value. Both interfering substances produce artifactually low leukocyte cystine levels. (2) Measurement by amino acid analysis (i.e., anion exchange chromatography) is less sensitive and can give spurious results if small amounts of leukocyte protein are present. • Individuals with nephropathic cystinosis generally have a concentration of 3.0-23.0 nmol half-cystine/mg protein. • Individuals with non-nephropathic cystinosis have concentrations of 1.0-3.0 nmol half-cystine/mg protein. • Heterozygous individuals have concentrations of ≤1.0 nmol half-cystine/mg protein. • Normal intracellular concentration is ≤0.2 nmol half-cystine/mg protein. ## Clinical Characteristics Although phenotypes may overlap, three clinical phenotypes of cystinosis are recognized: nephropathic (the most severe form that presents in infancy), later-onset (juvenile), and non-nephropathic (ocular) cystinosis [ The clinical characteristics of untreated nephropathic cystinosis include poor weight gain, growth deficiency, renal tubular Fanconi syndrome, renal glomerular failure, and non-renal involvement of a variety of tissues and organ systems. Treatment with cysteamine allows depletion of lysosomal cystine in most tissues. Although cysteamine does not cure the disease, it dramatically improves the overall prognosis and life span [ A high frequency of vomiting (usually in the morning), poor appetite, and feeding difficulties, combined with renal losses of nutrients, causes poor nutrition and severe failure to gain weight. With the development of chronic kidney disease (CKD), there are marked alterations in linear growth and poor weight gain for height. Overall, linear growth was significantly more impaired in individuals with nephrogenic cystinosis compared to individuals with CKD due to other causes, suggesting there are additional factors that contribute to growth deficiency in nephrogenic cystinosis [ Early and optimal cystine-depleting therapy allows for a normal growth rate but does not provide catch-up growth. Treated infants and toddlers with nephropathic cystinosis have height in the 10th-25th centile for age and fall in the range of mid-parental constitutional growth. Growth hormone administration improves growth velocity in prepubertal children. Hypophosphatemic/calcipenic rickets, characterized by high excretion of phosphate and calcium, elevated serum alkaline phosphatase, and bone deformities, make walking painful enough to delay ambulation. Nutritional deficiencies of vitamin D and calcium may accompany rickets, leading to seizures and tetany. Severe hypokalemia can cause cardiac conduction abnormalities. Occasionally, hyponatremia and hypomagnesemia also occur. Diligent treatment with replacement of renal losses is required for resolution of rickets, tetany, acidosis, and laboratory abnormalities. Cystine-depleting therapy begun just after birth when tubular damage is not complete can attenuate renal tubular Fanconi syndrome [ Early treatment with cystine-depleting therapy (i.e., oral cysteamine) slows or stops the progression of glomerular damage and can delay or eliminate the need for kidney transplantation [ Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [ Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life. Affected individuals typically develop hypothyroidism at the end of the first decade of life. Sweating is impaired and affected individuals can suffer heat prostration [ Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [ Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [ Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [ Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [ Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication. Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia ( Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [ Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [ Central nervous system (CNS) calcifications ( Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [ All the early manifestations of untreated nephropathic cystinosis, including renal tubular Fanconi syndrome, growth delay, photophobia, and glomerular failure, occur in individuals with untreated intermediate cystinosis but at a later age, mostly beginning in adolescence. Individuals with untreated ocular cystinosis experience photophobia. The kidneys may still be affected later in life in some individuals diagnosed with ocular cystinosis, but then the diagnosis should revert to later-onset cystinosis [ Some genotype-phenotype correlations have been reported (see Individuals with apparent residual activity (and lower levels of cystine accumulation in leukocytes) often have The pathogenic variant c.416C>T (p.Ser139Phe) may cause later-onset (juvenile) phenotype [ Nephropathic cystinosis is also referred to as infantile nephropathic cystinosis. Later-onset (juvenile) cystinosis is also referred to as intermediate cystinosis or adolescent (or juvenile) nephropathic cystinosis. The terms "adult cystinosis" and "benign cystinosis" should be replaced by "ocular cystinosis," "non-nephropathic cystinosis," or "ocular non-nephropathic cystinosis." Cystinosis occurs with a frequency of approximately one in 150,000 to 200,000 and has been found worldwide in all ethnic groups [ Cystinosis accounts for 5% of childhood kidney failure [ The 57-kb deletion represents more than 50% of • Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [ • Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life. • Affected individuals typically develop hypothyroidism at the end of the first decade of life. • Sweating is impaired and affected individuals can suffer heat prostration [ • Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [ • Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [ • Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [ • Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV • Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [ • Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication. • Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia ( • Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [ • Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [ • Central nervous system (CNS) calcifications ( • Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [ • Individuals with apparent residual activity (and lower levels of cystine accumulation in leukocytes) often have • The pathogenic variant c.416C>T (p.Ser139Phe) may cause later-onset (juvenile) phenotype [ ## Clinical Description Although phenotypes may overlap, three clinical phenotypes of cystinosis are recognized: nephropathic (the most severe form that presents in infancy), later-onset (juvenile), and non-nephropathic (ocular) cystinosis [ The clinical characteristics of untreated nephropathic cystinosis include poor weight gain, growth deficiency, renal tubular Fanconi syndrome, renal glomerular failure, and non-renal involvement of a variety of tissues and organ systems. Treatment with cysteamine allows depletion of lysosomal cystine in most tissues. Although cysteamine does not cure the disease, it dramatically improves the overall prognosis and life span [ A high frequency of vomiting (usually in the morning), poor appetite, and feeding difficulties, combined with renal losses of nutrients, causes poor nutrition and severe failure to gain weight. With the development of chronic kidney disease (CKD), there are marked alterations in linear growth and poor weight gain for height. Overall, linear growth was significantly more impaired in individuals with nephrogenic cystinosis compared to individuals with CKD due to other causes, suggesting there are additional factors that contribute to growth deficiency in nephrogenic cystinosis [ Early and optimal cystine-depleting therapy allows for a normal growth rate but does not provide catch-up growth. Treated infants and toddlers with nephropathic cystinosis have height in the 10th-25th centile for age and fall in the range of mid-parental constitutional growth. Growth hormone administration improves growth velocity in prepubertal children. Hypophosphatemic/calcipenic rickets, characterized by high excretion of phosphate and calcium, elevated serum alkaline phosphatase, and bone deformities, make walking painful enough to delay ambulation. Nutritional deficiencies of vitamin D and calcium may accompany rickets, leading to seizures and tetany. Severe hypokalemia can cause cardiac conduction abnormalities. Occasionally, hyponatremia and hypomagnesemia also occur. Diligent treatment with replacement of renal losses is required for resolution of rickets, tetany, acidosis, and laboratory abnormalities. Cystine-depleting therapy begun just after birth when tubular damage is not complete can attenuate renal tubular Fanconi syndrome [ Early treatment with cystine-depleting therapy (i.e., oral cysteamine) slows or stops the progression of glomerular damage and can delay or eliminate the need for kidney transplantation [ Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [ Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life. Affected individuals typically develop hypothyroidism at the end of the first decade of life. Sweating is impaired and affected individuals can suffer heat prostration [ Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [ Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [ Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [ Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [ Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication. Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia ( Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [ Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [ Central nervous system (CNS) calcifications ( Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [ All the early manifestations of untreated nephropathic cystinosis, including renal tubular Fanconi syndrome, growth delay, photophobia, and glomerular failure, occur in individuals with untreated intermediate cystinosis but at a later age, mostly beginning in adolescence. Individuals with untreated ocular cystinosis experience photophobia. The kidneys may still be affected later in life in some individuals diagnosed with ocular cystinosis, but then the diagnosis should revert to later-onset cystinosis [ • Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [ • Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life. • Affected individuals typically develop hypothyroidism at the end of the first decade of life. • Sweating is impaired and affected individuals can suffer heat prostration [ • Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [ • Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [ • Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [ • Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV • Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [ • Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication. • Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia ( • Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [ • Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [ • Central nervous system (CNS) calcifications ( • Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [ ## Nephropathic Cystinosis The clinical characteristics of untreated nephropathic cystinosis include poor weight gain, growth deficiency, renal tubular Fanconi syndrome, renal glomerular failure, and non-renal involvement of a variety of tissues and organ systems. Treatment with cysteamine allows depletion of lysosomal cystine in most tissues. Although cysteamine does not cure the disease, it dramatically improves the overall prognosis and life span [ A high frequency of vomiting (usually in the morning), poor appetite, and feeding difficulties, combined with renal losses of nutrients, causes poor nutrition and severe failure to gain weight. With the development of chronic kidney disease (CKD), there are marked alterations in linear growth and poor weight gain for height. Overall, linear growth was significantly more impaired in individuals with nephrogenic cystinosis compared to individuals with CKD due to other causes, suggesting there are additional factors that contribute to growth deficiency in nephrogenic cystinosis [ Early and optimal cystine-depleting therapy allows for a normal growth rate but does not provide catch-up growth. Treated infants and toddlers with nephropathic cystinosis have height in the 10th-25th centile for age and fall in the range of mid-parental constitutional growth. Growth hormone administration improves growth velocity in prepubertal children. Hypophosphatemic/calcipenic rickets, characterized by high excretion of phosphate and calcium, elevated serum alkaline phosphatase, and bone deformities, make walking painful enough to delay ambulation. Nutritional deficiencies of vitamin D and calcium may accompany rickets, leading to seizures and tetany. Severe hypokalemia can cause cardiac conduction abnormalities. Occasionally, hyponatremia and hypomagnesemia also occur. Diligent treatment with replacement of renal losses is required for resolution of rickets, tetany, acidosis, and laboratory abnormalities. Cystine-depleting therapy begun just after birth when tubular damage is not complete can attenuate renal tubular Fanconi syndrome [ Early treatment with cystine-depleting therapy (i.e., oral cysteamine) slows or stops the progression of glomerular damage and can delay or eliminate the need for kidney transplantation [ Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [ Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life. Affected individuals typically develop hypothyroidism at the end of the first decade of life. Sweating is impaired and affected individuals can suffer heat prostration [ Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [ Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [ Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [ Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [ Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication. Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia ( Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [ Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [ Central nervous system (CNS) calcifications ( Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [ • Children with cystinosis have mildly altered craniofacial morphology, reduced airway dimensions, and delayed dental development with delayed eruption of permanent teeth [ • Photophobia develops as the cornea becomes packed with cystine crystals, generally at the end of the first decade of life. • Affected individuals typically develop hypothyroidism at the end of the first decade of life. • Sweating is impaired and affected individuals can suffer heat prostration [ • Intracranial hypertension occasionally develops as the deposition of cystine in the meninges and arachnoid villi may reduce cerebrospinal fluid absorption [ • Puberty is generally delayed one to two years. Females with cystinosis appear to have normal fertility, although complications secondary to the disease and kidney transplantation frequently occur during pregnancy [ • Increased cystine content in the muscles causes vacuolar myopathy in 60% of individuals [ • Extrinsic chest muscle impairment causes extraparenchymal restriction of ventilation leading to pulmonary insufficiency with decreased values of forced vital capacity (FVC) and forced expiratory volume in one second (FEV • Gastrointestinal findings can include reflux, dysmotility, esophagitis, gastric/duodenal ulcers, hepatomegaly with nodular regenerating hyperplasia of the liver and portal hypertension, exocrine pancreatic insufficiency, inflammatory bowel disease, bowel perforation, and peritonitis [ • Pancreatic endocrine insufficiency can result in diabetes mellitus, exacerbated by post-transplant steroid use as an anti-rejection medication. • Cardiovascular manifestations can include arteriopathy caused by the combination of vascular calcifications, obstructive atherosclerosis with hypercholesterolemia ( • Metabolic bone disease develops because of direct deposition of cystine crystals in bone, mineral imbalance, and renal osteodystrophy prior to kidney transplantation [ • Hypercoagulopathy or hypocoagulopathy can occur because of kidney failure and platelet aggregation dysfunction [ • Central nervous system (CNS) calcifications ( • Late ocular complications can include crystal deposition in the anterior chamber, iris, ciliary body, choroid, fundus, and optic nerve that manifests as anterior and posterior segment problems [ ## Later-Onset (Juvenile) Cystinosis All the early manifestations of untreated nephropathic cystinosis, including renal tubular Fanconi syndrome, growth delay, photophobia, and glomerular failure, occur in individuals with untreated intermediate cystinosis but at a later age, mostly beginning in adolescence. ## Non-Nephropathic (Ocular) Cystinosis Individuals with untreated ocular cystinosis experience photophobia. The kidneys may still be affected later in life in some individuals diagnosed with ocular cystinosis, but then the diagnosis should revert to later-onset cystinosis [ ## Genotype-Phenotype Correlations Some genotype-phenotype correlations have been reported (see Individuals with apparent residual activity (and lower levels of cystine accumulation in leukocytes) often have The pathogenic variant c.416C>T (p.Ser139Phe) may cause later-onset (juvenile) phenotype [ • Individuals with apparent residual activity (and lower levels of cystine accumulation in leukocytes) often have • The pathogenic variant c.416C>T (p.Ser139Phe) may cause later-onset (juvenile) phenotype [ ## Nomenclature Nephropathic cystinosis is also referred to as infantile nephropathic cystinosis. Later-onset (juvenile) cystinosis is also referred to as intermediate cystinosis or adolescent (or juvenile) nephropathic cystinosis. The terms "adult cystinosis" and "benign cystinosis" should be replaced by "ocular cystinosis," "non-nephropathic cystinosis," or "ocular non-nephropathic cystinosis." ## Prevalence Cystinosis occurs with a frequency of approximately one in 150,000 to 200,000 and has been found worldwide in all ethnic groups [ Cystinosis accounts for 5% of childhood kidney failure [ The 57-kb deletion represents more than 50% of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genetic Disorders Associated with Renal Tubular Fanconi Syndrome in the Differential Diagnosis of Cystinosis AR = autosomal recessive; CKD = chronic kidney disease; CNS = central nervous system; ID = intellectual disability; LMW = low-molecular-weight; MOI = mode of inheritance; XL = X-linked Other considerations: Glucosuria associated with renal tubular Fanconi syndrome can result in misdiagnosis such as diabetes mellitus. Polyuria often leads to a misdiagnosis of diabetes insipidus (see Electrolyte abnormalities can suggest Bartter syndrome. The rickets of cystinosis can falsely suggest vitamin D-deficient rickets. • Glucosuria associated with renal tubular Fanconi syndrome can result in misdiagnosis such as diabetes mellitus. • Polyuria often leads to a misdiagnosis of diabetes insipidus (see • Electrolyte abnormalities can suggest Bartter syndrome. • The rickets of cystinosis can falsely suggest vitamin D-deficient rickets. ## Management Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients is available, including clinical recommendations [ Cystinosis: Recommended Evaluations Following Initial Diagnosis Height & weight, plotted on age-appropriate growth charts Assessment of feeding & nutrition Lipid panel to assess nutritional status in those w/feeding difficulties requiring formula feeding by gastrostomy tube Serum concentrations of creatinine, phosphate, bicarbonate, & potassium Urine concentrations of creatinine, phosphate, bicarbonate, sodium, potassium, magnesium, glucose, & protein Quantitative measurement of urine amino acids & GFR or creatinine clearance test Slit lamp exam of cornea for cystine crystals ERG to assess retinal involvement Fundoscopic exam to assess for intracranial hypertension Community or Social work involvement for parental support Home nursing referral DXA = dual-energy x-ray absorptiometry; ERG = electroretinogram; FSH = follicle-stimulating hormone; GFR = glomerular filtration rate; LH = luteinizing hormone; MOI = mode of inheritance; US = ultrasound Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) It is recommended that a multidisciplinary team that includes specialists in nephrology, metabolic disease, ophthalmology, neurology, gastroenterology, nutrition, and psychology manage individuals with cystinosis. A clinical care coordinator should be identified (e.g., nephrologist or metabolic disease specialist). There is no cure for cystinosis. Cystinosis: Targeted Therapy Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m Adults: 500 mg free base every 6 hrs Titrate dose if possible, to ↓ leukocyte cystine concentration (measured 5-6 hrs after a dose) to below 1.0 nmol half-cystine/mg protein. Approved worldwide for cystinosis regardless of age & transplant status Early, diligent treatment can prolong survival into 20s w/o need for kidney transplant. Initiate therapy immediately to allow for kidney growth & acquisition, rather than loss, of function. Cysteamine prevents or delays ESKD Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m Adults: 500 mg free base every 12 hrs Delayed-release oral capsule (every 12 hrs) is approved for persons age ≥6 yrs. Required to achieve sufficient tissue concentration to dissolve corneal crystals Relieves photophobia w/in weeks ( May be best treatment option for those w/CKD Transplant is indicated when reciprocal serum creatinine value plotted against age reaches ~0.1. Clinical manifestations often determine exact time of transplantation. CKD = chronic kidney disease; ESKD = end-stage kidney disease See Free thiol that can deplete cystinotic cells of more than 90% of their cystine content [ Blood testing showed Procysbi Cystinosis: Treatment of Manifestations Supplemental nutrition/feeding to support growth; feeding via gastrostomy tube for those w/dysphagia, poor nutrition, & risk of aspiration Growth hormone therapy as needed Education re balanced diet, adequate caloric intake, & avoidance of dehydration Early & diligent treatment of renal Fanconi syndrome w/supplements & cystine-depleting agents (see Growth hormone stimulates catch-up growth & can result in normal height for age. Replacement of tubular losses of electrolytes, bicarbonate, minerals, & other small-molecular-weight nutrients For children, free access to water, bathroom privileges, & supplementation w/citrate to alkalinize blood Phosphate replacement to prevent & treat rickets Vitamin D supplementation to assist GI absorption of phosphate & calcium Early treatment of skeletal deformities per orthopedist Treatment of late-onset metabolic bone disease per orthopedist, endocrinologist, &/or metabolic bone disease specialist Cystine-depleting agents (See In those requiring dialysis: continue cysteamine treatment to protect extrarenal organs; hemo- & peritoneal dialysis are suitable; tailor ultrafiltration & adapt potassium & phosphate supplementation for those on hemodialysis. Kidney transplantation may be best treatment option for those w/CKD (see Cystine-depleting agents (See Photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, & lubrication w/over-the-counter eye drops. Consider anti-inflammatory agents or other local treatments for corneal complications. Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations. Retinal involvement is irreversible. Cystine-depleting agents (See Diuretics CSF eval w/drainage as needed Testosterone to induce secondary sexual characteristics & improve linear growth in males Referral to fertility specialists, endocrinologist, &/or urologist for fertility counseling & mgmt as needed Frequent exercise w/PT as needed PT & OT to guide specific exercises for muscle deterioration & swallowing difficulties of older persons w/cystinosis Hand tendon transfer has been partially successful in improving strength. Treatment w/proton pump inhibitors (e.g., omeprazole 20 mg/day for adults; dose according to weight in children Treatment of other GI complications per gastroenterologist Developmental & educational support Speech therapy, PT, & OT Education re disease, medication side effects, & planning for autonomy Psychosocial support Referral for transitional care program from adolescence to adulthood CKD = chronic kidney disease; CSF = cerebrospinal fluid; GI = gastrointestinal; OT = occupational therapy/therapist; PT = physical therapy/therapist; SPF = sun protection factor To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Cystinosis: Recommended Surveillance Assess weight & nutrition. Assess for difficulty w/chewing, aspiration, dysphasia, weight loss, mealtimes of long duration, & respiratory symptoms incl respiratory infection. Test of masticating & swallowing solids Videofluoroscopic swallowing study or fiber optic endoscopic eval of swallowing Assessment for visual acuity, photophobia, & intraocular pressure ERG to assess retinal involvement Fundoscopic exam for retinal crystals, depigmentation, pigment epithelial alterations, affected vasculature, & pseudotumor cerebri OCT Visual field testing as needed Corneal exam for crystals & ulcerations (Findings should be documented by digital imaging; corneal cystine crystal score & photophobia score are useful to monitor treatment efficacy.) Assessment of cognitive function using MMSE or MoCA; incl assessment of visual-motor integration, visual memory, planning, sustained attention, & motor speed Assessment for headaches, pyramidal or cerebellar syndrome, bradykinesia, other focal features suggestive of stroke PT & OT assessment incl rating scale to evaluate & monitor chronic muscle disorders ALT, AST, GGT, ALP, lipase to assess for liver & pancreatic dysfunction Clinical exam for hepatomegaly, splenomegaly Assessment for symptoms of GERD Chest CT to assess for coronary & other vascular calcification EKG Assess well-being & quality of life, adherence to medical care, school difficulties. Assess for depression, anxiety, emotional stress. Assess annually or more frequently as needed. Start transition to adult care at age 12-25 yrs. ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; eGFR = estimated glomerular filtration rate; ERG = electroretinogram; FSH = follicle-stimulating hormone; GERD = gastroesophageal reflux disease; GGT = gamma-glutamyl transferase; GI = gastrointestinal; Hgb = hemoglobin; LH = luteinizing hormone; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; OCT = optical coherence tomography; TSH = thyroid-stimulating hormone; US = ultrasound Avoid the following: Dehydration, which compromises remaining kidney function Sun exposure, which can exacerbate photophobia See Pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely [ One study demonstrated low amounts of cysteamine in breast milk. The authors concluded that these levels were unlikely to be clinically significant. This information may be reassuring for women with cystinosis who desire to breastfeed. However, additional data is needed to confirm the safety of cysteamine use in breastfeeding [ Pregnancy should be managed by an experienced obstetrician and nephrologist due to high incidence of polypharmacy and comorbidities associated with cystinosis, such as chronic kidney disease, hypothyroidism, hypertension, diabetes, and pulmonary and neuromuscular complications. Search Development of a newborn screening test for cystinosis will potentially allow broader therapeutic success [ • Height & weight, plotted on age-appropriate growth charts • Assessment of feeding & nutrition • Lipid panel to assess nutritional status in those w/feeding difficulties requiring formula feeding by gastrostomy tube • Serum concentrations of creatinine, phosphate, bicarbonate, & potassium • Urine concentrations of creatinine, phosphate, bicarbonate, sodium, potassium, magnesium, glucose, & protein • Quantitative measurement of urine amino acids & GFR or creatinine clearance test • Slit lamp exam of cornea for cystine crystals • ERG to assess retinal involvement • Fundoscopic exam to assess for intracranial hypertension • Community or • Social work involvement for parental support • Home nursing referral • Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m • Adults: 500 mg free base every 6 hrs • Titrate dose if possible, to ↓ leukocyte cystine concentration (measured 5-6 hrs after a dose) to below 1.0 nmol half-cystine/mg protein. • Approved worldwide for cystinosis regardless of age & transplant status • Early, diligent treatment can prolong survival into 20s w/o need for kidney transplant. • Initiate therapy immediately to allow for kidney growth & acquisition, rather than loss, of function. • Cysteamine prevents or delays ESKD • Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m • Adults: 500 mg free base every 12 hrs • Delayed-release oral capsule (every 12 hrs) is approved for persons age ≥6 yrs. • Required to achieve sufficient tissue concentration to dissolve corneal crystals • Relieves photophobia w/in weeks ( • May be best treatment option for those w/CKD • Transplant is indicated when reciprocal serum creatinine value plotted against age reaches ~0.1. • Clinical manifestations often determine exact time of transplantation. • Supplemental nutrition/feeding to support growth; feeding via gastrostomy tube for those w/dysphagia, poor nutrition, & risk of aspiration • Growth hormone therapy as needed • Education re balanced diet, adequate caloric intake, & avoidance of dehydration • Early & diligent treatment of renal Fanconi syndrome w/supplements & cystine-depleting agents (see • Growth hormone stimulates catch-up growth & can result in normal height for age. • Replacement of tubular losses of electrolytes, bicarbonate, minerals, & other small-molecular-weight nutrients • For children, free access to water, bathroom privileges, & supplementation w/citrate to alkalinize blood • Phosphate replacement to prevent & treat rickets • Vitamin D supplementation to assist GI absorption of phosphate & calcium • Early treatment of skeletal deformities per orthopedist • Treatment of late-onset metabolic bone disease per orthopedist, endocrinologist, &/or metabolic bone disease specialist • Cystine-depleting agents (See • In those requiring dialysis: continue cysteamine treatment to protect extrarenal organs; hemo- & peritoneal dialysis are suitable; tailor ultrafiltration & adapt potassium & phosphate supplementation for those on hemodialysis. • Kidney transplantation may be best treatment option for those w/CKD (see • Cystine-depleting agents (See • Photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, & lubrication w/over-the-counter eye drops. • Consider anti-inflammatory agents or other local treatments for corneal complications. • Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations. • Retinal involvement is irreversible. • Cystine-depleting agents (See • Diuretics • CSF eval w/drainage as needed • Testosterone to induce secondary sexual characteristics & improve linear growth in males • Referral to fertility specialists, endocrinologist, &/or urologist for fertility counseling & mgmt as needed • Frequent exercise w/PT as needed • PT & OT to guide specific exercises for muscle deterioration & swallowing difficulties of older persons w/cystinosis • Hand tendon transfer has been partially successful in improving strength. • Treatment w/proton pump inhibitors (e.g., omeprazole 20 mg/day for adults; dose according to weight in children • Treatment of other GI complications per gastroenterologist • Developmental & educational support • Speech therapy, PT, & OT • Education re disease, medication side effects, & planning for autonomy • Psychosocial support • Referral for transitional care program from adolescence to adulthood • Assess weight & nutrition. • Assess for difficulty w/chewing, aspiration, dysphasia, weight loss, mealtimes of long duration, & respiratory symptoms incl respiratory infection. • Test of masticating & swallowing solids • Videofluoroscopic swallowing study or fiber optic endoscopic eval of swallowing • Assessment for visual acuity, photophobia, & intraocular pressure • ERG to assess retinal involvement • Fundoscopic exam for retinal crystals, depigmentation, pigment epithelial alterations, affected vasculature, & pseudotumor cerebri • OCT • Visual field testing as needed • Corneal exam for crystals & ulcerations (Findings should be documented by digital imaging; corneal cystine crystal score & photophobia score are useful to monitor treatment efficacy.) • Assessment of cognitive function using MMSE or MoCA; incl assessment of visual-motor integration, visual memory, planning, sustained attention, & motor speed • Assessment for headaches, pyramidal or cerebellar syndrome, bradykinesia, other focal features suggestive of stroke • PT & OT assessment incl rating scale to evaluate & monitor chronic muscle disorders • ALT, AST, GGT, ALP, lipase to assess for liver & pancreatic dysfunction • Clinical exam for hepatomegaly, splenomegaly • Assessment for symptoms of GERD • Chest CT to assess for coronary & other vascular calcification • EKG • Assess well-being & quality of life, adherence to medical care, school difficulties. • Assess for depression, anxiety, emotional stress. • Assess annually or more frequently as needed. • Start transition to adult care at age 12-25 yrs. • Dehydration, which compromises remaining kidney function • Sun exposure, which can exacerbate photophobia ## Evaluations Following Initial Diagnosis Cystinosis: Recommended Evaluations Following Initial Diagnosis Height & weight, plotted on age-appropriate growth charts Assessment of feeding & nutrition Lipid panel to assess nutritional status in those w/feeding difficulties requiring formula feeding by gastrostomy tube Serum concentrations of creatinine, phosphate, bicarbonate, & potassium Urine concentrations of creatinine, phosphate, bicarbonate, sodium, potassium, magnesium, glucose, & protein Quantitative measurement of urine amino acids & GFR or creatinine clearance test Slit lamp exam of cornea for cystine crystals ERG to assess retinal involvement Fundoscopic exam to assess for intracranial hypertension Community or Social work involvement for parental support Home nursing referral DXA = dual-energy x-ray absorptiometry; ERG = electroretinogram; FSH = follicle-stimulating hormone; GFR = glomerular filtration rate; LH = luteinizing hormone; MOI = mode of inheritance; US = ultrasound Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Height & weight, plotted on age-appropriate growth charts • Assessment of feeding & nutrition • Lipid panel to assess nutritional status in those w/feeding difficulties requiring formula feeding by gastrostomy tube • Serum concentrations of creatinine, phosphate, bicarbonate, & potassium • Urine concentrations of creatinine, phosphate, bicarbonate, sodium, potassium, magnesium, glucose, & protein • Quantitative measurement of urine amino acids & GFR or creatinine clearance test • Slit lamp exam of cornea for cystine crystals • ERG to assess retinal involvement • Fundoscopic exam to assess for intracranial hypertension • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations It is recommended that a multidisciplinary team that includes specialists in nephrology, metabolic disease, ophthalmology, neurology, gastroenterology, nutrition, and psychology manage individuals with cystinosis. A clinical care coordinator should be identified (e.g., nephrologist or metabolic disease specialist). There is no cure for cystinosis. Cystinosis: Targeted Therapy Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m Adults: 500 mg free base every 6 hrs Titrate dose if possible, to ↓ leukocyte cystine concentration (measured 5-6 hrs after a dose) to below 1.0 nmol half-cystine/mg protein. Approved worldwide for cystinosis regardless of age & transplant status Early, diligent treatment can prolong survival into 20s w/o need for kidney transplant. Initiate therapy immediately to allow for kidney growth & acquisition, rather than loss, of function. Cysteamine prevents or delays ESKD Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m Adults: 500 mg free base every 12 hrs Delayed-release oral capsule (every 12 hrs) is approved for persons age ≥6 yrs. Required to achieve sufficient tissue concentration to dissolve corneal crystals Relieves photophobia w/in weeks ( May be best treatment option for those w/CKD Transplant is indicated when reciprocal serum creatinine value plotted against age reaches ~0.1. Clinical manifestations often determine exact time of transplantation. CKD = chronic kidney disease; ESKD = end-stage kidney disease See Free thiol that can deplete cystinotic cells of more than 90% of their cystine content [ Blood testing showed Procysbi Cystinosis: Treatment of Manifestations Supplemental nutrition/feeding to support growth; feeding via gastrostomy tube for those w/dysphagia, poor nutrition, & risk of aspiration Growth hormone therapy as needed Education re balanced diet, adequate caloric intake, & avoidance of dehydration Early & diligent treatment of renal Fanconi syndrome w/supplements & cystine-depleting agents (see Growth hormone stimulates catch-up growth & can result in normal height for age. Replacement of tubular losses of electrolytes, bicarbonate, minerals, & other small-molecular-weight nutrients For children, free access to water, bathroom privileges, & supplementation w/citrate to alkalinize blood Phosphate replacement to prevent & treat rickets Vitamin D supplementation to assist GI absorption of phosphate & calcium Early treatment of skeletal deformities per orthopedist Treatment of late-onset metabolic bone disease per orthopedist, endocrinologist, &/or metabolic bone disease specialist Cystine-depleting agents (See In those requiring dialysis: continue cysteamine treatment to protect extrarenal organs; hemo- & peritoneal dialysis are suitable; tailor ultrafiltration & adapt potassium & phosphate supplementation for those on hemodialysis. Kidney transplantation may be best treatment option for those w/CKD (see Cystine-depleting agents (See Photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, & lubrication w/over-the-counter eye drops. Consider anti-inflammatory agents or other local treatments for corneal complications. Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations. Retinal involvement is irreversible. Cystine-depleting agents (See Diuretics CSF eval w/drainage as needed Testosterone to induce secondary sexual characteristics & improve linear growth in males Referral to fertility specialists, endocrinologist, &/or urologist for fertility counseling & mgmt as needed Frequent exercise w/PT as needed PT & OT to guide specific exercises for muscle deterioration & swallowing difficulties of older persons w/cystinosis Hand tendon transfer has been partially successful in improving strength. Treatment w/proton pump inhibitors (e.g., omeprazole 20 mg/day for adults; dose according to weight in children Treatment of other GI complications per gastroenterologist Developmental & educational support Speech therapy, PT, & OT Education re disease, medication side effects, & planning for autonomy Psychosocial support Referral for transitional care program from adolescence to adulthood CKD = chronic kidney disease; CSF = cerebrospinal fluid; GI = gastrointestinal; OT = occupational therapy/therapist; PT = physical therapy/therapist; SPF = sun protection factor • Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m • Adults: 500 mg free base every 6 hrs • Titrate dose if possible, to ↓ leukocyte cystine concentration (measured 5-6 hrs after a dose) to below 1.0 nmol half-cystine/mg protein. • Approved worldwide for cystinosis regardless of age & transplant status • Early, diligent treatment can prolong survival into 20s w/o need for kidney transplant. • Initiate therapy immediately to allow for kidney growth & acquisition, rather than loss, of function. • Cysteamine prevents or delays ESKD • Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m • Adults: 500 mg free base every 12 hrs • Delayed-release oral capsule (every 12 hrs) is approved for persons age ≥6 yrs. • Required to achieve sufficient tissue concentration to dissolve corneal crystals • Relieves photophobia w/in weeks ( • May be best treatment option for those w/CKD • Transplant is indicated when reciprocal serum creatinine value plotted against age reaches ~0.1. • Clinical manifestations often determine exact time of transplantation. • Supplemental nutrition/feeding to support growth; feeding via gastrostomy tube for those w/dysphagia, poor nutrition, & risk of aspiration • Growth hormone therapy as needed • Education re balanced diet, adequate caloric intake, & avoidance of dehydration • Early & diligent treatment of renal Fanconi syndrome w/supplements & cystine-depleting agents (see • Growth hormone stimulates catch-up growth & can result in normal height for age. • Replacement of tubular losses of electrolytes, bicarbonate, minerals, & other small-molecular-weight nutrients • For children, free access to water, bathroom privileges, & supplementation w/citrate to alkalinize blood • Phosphate replacement to prevent & treat rickets • Vitamin D supplementation to assist GI absorption of phosphate & calcium • Early treatment of skeletal deformities per orthopedist • Treatment of late-onset metabolic bone disease per orthopedist, endocrinologist, &/or metabolic bone disease specialist • Cystine-depleting agents (See • In those requiring dialysis: continue cysteamine treatment to protect extrarenal organs; hemo- & peritoneal dialysis are suitable; tailor ultrafiltration & adapt potassium & phosphate supplementation for those on hemodialysis. • Kidney transplantation may be best treatment option for those w/CKD (see • Cystine-depleting agents (See • Photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, & lubrication w/over-the-counter eye drops. • Consider anti-inflammatory agents or other local treatments for corneal complications. • Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations. • Retinal involvement is irreversible. • Cystine-depleting agents (See • Diuretics • CSF eval w/drainage as needed • Testosterone to induce secondary sexual characteristics & improve linear growth in males • Referral to fertility specialists, endocrinologist, &/or urologist for fertility counseling & mgmt as needed • Frequent exercise w/PT as needed • PT & OT to guide specific exercises for muscle deterioration & swallowing difficulties of older persons w/cystinosis • Hand tendon transfer has been partially successful in improving strength. • Treatment w/proton pump inhibitors (e.g., omeprazole 20 mg/day for adults; dose according to weight in children • Treatment of other GI complications per gastroenterologist • Developmental & educational support • Speech therapy, PT, & OT • Education re disease, medication side effects, & planning for autonomy • Psychosocial support • Referral for transitional care program from adolescence to adulthood ## Targeted Therapies Cystinosis: Targeted Therapy Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m Adults: 500 mg free base every 6 hrs Titrate dose if possible, to ↓ leukocyte cystine concentration (measured 5-6 hrs after a dose) to below 1.0 nmol half-cystine/mg protein. Approved worldwide for cystinosis regardless of age & transplant status Early, diligent treatment can prolong survival into 20s w/o need for kidney transplant. Initiate therapy immediately to allow for kidney growth & acquisition, rather than loss, of function. Cysteamine prevents or delays ESKD Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m Adults: 500 mg free base every 12 hrs Delayed-release oral capsule (every 12 hrs) is approved for persons age ≥6 yrs. Required to achieve sufficient tissue concentration to dissolve corneal crystals Relieves photophobia w/in weeks ( May be best treatment option for those w/CKD Transplant is indicated when reciprocal serum creatinine value plotted against age reaches ~0.1. Clinical manifestations often determine exact time of transplantation. CKD = chronic kidney disease; ESKD = end-stage kidney disease See Free thiol that can deplete cystinotic cells of more than 90% of their cystine content [ Blood testing showed Procysbi • Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m • Adults: 500 mg free base every 6 hrs • Titrate dose if possible, to ↓ leukocyte cystine concentration (measured 5-6 hrs after a dose) to below 1.0 nmol half-cystine/mg protein. • Approved worldwide for cystinosis regardless of age & transplant status • Early, diligent treatment can prolong survival into 20s w/o need for kidney transplant. • Initiate therapy immediately to allow for kidney growth & acquisition, rather than loss, of function. • Cysteamine prevents or delays ESKD • Children: 60-90 mg/kg/day of free base (1.3-1.95 g/m • Adults: 500 mg free base every 12 hrs • Delayed-release oral capsule (every 12 hrs) is approved for persons age ≥6 yrs. • Required to achieve sufficient tissue concentration to dissolve corneal crystals • Relieves photophobia w/in weeks ( • May be best treatment option for those w/CKD • Transplant is indicated when reciprocal serum creatinine value plotted against age reaches ~0.1. • Clinical manifestations often determine exact time of transplantation. ## Supportive Care Cystinosis: Treatment of Manifestations Supplemental nutrition/feeding to support growth; feeding via gastrostomy tube for those w/dysphagia, poor nutrition, & risk of aspiration Growth hormone therapy as needed Education re balanced diet, adequate caloric intake, & avoidance of dehydration Early & diligent treatment of renal Fanconi syndrome w/supplements & cystine-depleting agents (see Growth hormone stimulates catch-up growth & can result in normal height for age. Replacement of tubular losses of electrolytes, bicarbonate, minerals, & other small-molecular-weight nutrients For children, free access to water, bathroom privileges, & supplementation w/citrate to alkalinize blood Phosphate replacement to prevent & treat rickets Vitamin D supplementation to assist GI absorption of phosphate & calcium Early treatment of skeletal deformities per orthopedist Treatment of late-onset metabolic bone disease per orthopedist, endocrinologist, &/or metabolic bone disease specialist Cystine-depleting agents (See In those requiring dialysis: continue cysteamine treatment to protect extrarenal organs; hemo- & peritoneal dialysis are suitable; tailor ultrafiltration & adapt potassium & phosphate supplementation for those on hemodialysis. Kidney transplantation may be best treatment option for those w/CKD (see Cystine-depleting agents (See Photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, & lubrication w/over-the-counter eye drops. Consider anti-inflammatory agents or other local treatments for corneal complications. Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations. Retinal involvement is irreversible. Cystine-depleting agents (See Diuretics CSF eval w/drainage as needed Testosterone to induce secondary sexual characteristics & improve linear growth in males Referral to fertility specialists, endocrinologist, &/or urologist for fertility counseling & mgmt as needed Frequent exercise w/PT as needed PT & OT to guide specific exercises for muscle deterioration & swallowing difficulties of older persons w/cystinosis Hand tendon transfer has been partially successful in improving strength. Treatment w/proton pump inhibitors (e.g., omeprazole 20 mg/day for adults; dose according to weight in children Treatment of other GI complications per gastroenterologist Developmental & educational support Speech therapy, PT, & OT Education re disease, medication side effects, & planning for autonomy Psychosocial support Referral for transitional care program from adolescence to adulthood CKD = chronic kidney disease; CSF = cerebrospinal fluid; GI = gastrointestinal; OT = occupational therapy/therapist; PT = physical therapy/therapist; SPF = sun protection factor • Supplemental nutrition/feeding to support growth; feeding via gastrostomy tube for those w/dysphagia, poor nutrition, & risk of aspiration • Growth hormone therapy as needed • Education re balanced diet, adequate caloric intake, & avoidance of dehydration • Early & diligent treatment of renal Fanconi syndrome w/supplements & cystine-depleting agents (see • Growth hormone stimulates catch-up growth & can result in normal height for age. • Replacement of tubular losses of electrolytes, bicarbonate, minerals, & other small-molecular-weight nutrients • For children, free access to water, bathroom privileges, & supplementation w/citrate to alkalinize blood • Phosphate replacement to prevent & treat rickets • Vitamin D supplementation to assist GI absorption of phosphate & calcium • Early treatment of skeletal deformities per orthopedist • Treatment of late-onset metabolic bone disease per orthopedist, endocrinologist, &/or metabolic bone disease specialist • Cystine-depleting agents (See • In those requiring dialysis: continue cysteamine treatment to protect extrarenal organs; hemo- & peritoneal dialysis are suitable; tailor ultrafiltration & adapt potassium & phosphate supplementation for those on hemodialysis. • Kidney transplantation may be best treatment option for those w/CKD (see • Cystine-depleting agents (See • Photophobia, resulting from corneal crystal accumulation, can be ameliorated by sun avoidance, dark glasses, & lubrication w/over-the-counter eye drops. • Consider anti-inflammatory agents or other local treatments for corneal complications. • Corneal transplantation is very rarely required for intractable pain resulting from recurrent corneal ulcerations. • Retinal involvement is irreversible. • Cystine-depleting agents (See • Diuretics • CSF eval w/drainage as needed • Testosterone to induce secondary sexual characteristics & improve linear growth in males • Referral to fertility specialists, endocrinologist, &/or urologist for fertility counseling & mgmt as needed • Frequent exercise w/PT as needed • PT & OT to guide specific exercises for muscle deterioration & swallowing difficulties of older persons w/cystinosis • Hand tendon transfer has been partially successful in improving strength. • Treatment w/proton pump inhibitors (e.g., omeprazole 20 mg/day for adults; dose according to weight in children • Treatment of other GI complications per gastroenterologist • Developmental & educational support • Speech therapy, PT, & OT • Education re disease, medication side effects, & planning for autonomy • Psychosocial support • Referral for transitional care program from adolescence to adulthood ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Cystinosis: Recommended Surveillance Assess weight & nutrition. Assess for difficulty w/chewing, aspiration, dysphasia, weight loss, mealtimes of long duration, & respiratory symptoms incl respiratory infection. Test of masticating & swallowing solids Videofluoroscopic swallowing study or fiber optic endoscopic eval of swallowing Assessment for visual acuity, photophobia, & intraocular pressure ERG to assess retinal involvement Fundoscopic exam for retinal crystals, depigmentation, pigment epithelial alterations, affected vasculature, & pseudotumor cerebri OCT Visual field testing as needed Corneal exam for crystals & ulcerations (Findings should be documented by digital imaging; corneal cystine crystal score & photophobia score are useful to monitor treatment efficacy.) Assessment of cognitive function using MMSE or MoCA; incl assessment of visual-motor integration, visual memory, planning, sustained attention, & motor speed Assessment for headaches, pyramidal or cerebellar syndrome, bradykinesia, other focal features suggestive of stroke PT & OT assessment incl rating scale to evaluate & monitor chronic muscle disorders ALT, AST, GGT, ALP, lipase to assess for liver & pancreatic dysfunction Clinical exam for hepatomegaly, splenomegaly Assessment for symptoms of GERD Chest CT to assess for coronary & other vascular calcification EKG Assess well-being & quality of life, adherence to medical care, school difficulties. Assess for depression, anxiety, emotional stress. Assess annually or more frequently as needed. Start transition to adult care at age 12-25 yrs. ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; eGFR = estimated glomerular filtration rate; ERG = electroretinogram; FSH = follicle-stimulating hormone; GERD = gastroesophageal reflux disease; GGT = gamma-glutamyl transferase; GI = gastrointestinal; Hgb = hemoglobin; LH = luteinizing hormone; MMSE = Mini-Mental State Examination; MoCA = Montreal Cognitive Assessment; OCT = optical coherence tomography; TSH = thyroid-stimulating hormone; US = ultrasound • Assess weight & nutrition. • Assess for difficulty w/chewing, aspiration, dysphasia, weight loss, mealtimes of long duration, & respiratory symptoms incl respiratory infection. • Test of masticating & swallowing solids • Videofluoroscopic swallowing study or fiber optic endoscopic eval of swallowing • Assessment for visual acuity, photophobia, & intraocular pressure • ERG to assess retinal involvement • Fundoscopic exam for retinal crystals, depigmentation, pigment epithelial alterations, affected vasculature, & pseudotumor cerebri • OCT • Visual field testing as needed • Corneal exam for crystals & ulcerations (Findings should be documented by digital imaging; corneal cystine crystal score & photophobia score are useful to monitor treatment efficacy.) • Assessment of cognitive function using MMSE or MoCA; incl assessment of visual-motor integration, visual memory, planning, sustained attention, & motor speed • Assessment for headaches, pyramidal or cerebellar syndrome, bradykinesia, other focal features suggestive of stroke • PT & OT assessment incl rating scale to evaluate & monitor chronic muscle disorders • ALT, AST, GGT, ALP, lipase to assess for liver & pancreatic dysfunction • Clinical exam for hepatomegaly, splenomegaly • Assessment for symptoms of GERD • Chest CT to assess for coronary & other vascular calcification • EKG • Assess well-being & quality of life, adherence to medical care, school difficulties. • Assess for depression, anxiety, emotional stress. • Assess annually or more frequently as needed. • Start transition to adult care at age 12-25 yrs. ## Agents/Circumstances to Avoid Avoid the following: Dehydration, which compromises remaining kidney function Sun exposure, which can exacerbate photophobia • Dehydration, which compromises remaining kidney function • Sun exposure, which can exacerbate photophobia ## Evaluation of Relatives at Risk See ## Pregnancy Management Pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely [ One study demonstrated low amounts of cysteamine in breast milk. The authors concluded that these levels were unlikely to be clinically significant. This information may be reassuring for women with cystinosis who desire to breastfeed. However, additional data is needed to confirm the safety of cysteamine use in breastfeeding [ Pregnancy should be managed by an experienced obstetrician and nephrologist due to high incidence of polypharmacy and comorbidities associated with cystinosis, such as chronic kidney disease, hypothyroidism, hypertension, diabetes, and pulmonary and neuromuscular complications. ## Therapies Under Investigation Search ## Other Development of a newborn screening test for cystinosis will potentially allow broader therapeutic success [ ## Genetic Counseling Cystinosis 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 A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has cystinosis or is a carrier, offspring will be obligate heterozygotes (carriers) for a Rarely, families with two-generation involvement (sometimes called "pseudodominance") have been identified; two-generation involvement results from an affected individual having children with a partner who is heterozygous (i.e., a carrier) for a Molecular genetic carrier testing for at-risk family members requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with cystinosis, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Females with cystinosis have had successful pregnancies resulting in healthy newborns. However, pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely (see Most males with nephropathic cystinosis suffer from obstructive azoospermia; thus, when they reach reproductive age they may benefit from fertility counseling and discussion of assistive reproductive technology options [ 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 the 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 • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has cystinosis or is a carrier, offspring will be obligate heterozygotes (carriers) for a • Rarely, families with two-generation involvement (sometimes called "pseudodominance") have been identified; two-generation involvement results from an affected individual having children with a partner who is heterozygous (i.e., a carrier) for a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with cystinosis, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see • Females with cystinosis have had successful pregnancies resulting in healthy newborns. However, pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely (see • Most males with nephropathic cystinosis suffer from obstructive azoospermia; thus, when they reach reproductive age they may benefit from fertility counseling and discussion of assistive reproductive technology options [ ## Mode of Inheritance Cystinosis 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 A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has cystinosis or is a carrier, offspring will be obligate heterozygotes (carriers) for a Rarely, families with two-generation involvement (sometimes called "pseudodominance") have been identified; two-generation involvement results from an affected individual having children with a partner who is heterozygous (i.e., a carrier) for a • 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 • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity. • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has cystinosis or is a carrier, offspring will be obligate heterozygotes (carriers) for a • Rarely, families with two-generation involvement (sometimes called "pseudodominance") have been identified; two-generation involvement results from an affected individual having children with a partner who is heterozygous (i.e., a carrier) for a ## Carrier Detection Molecular genetic carrier testing for at-risk family members requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with cystinosis, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Females with cystinosis have had successful pregnancies resulting in healthy newborns. However, pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely (see Most males with nephropathic cystinosis suffer from obstructive azoospermia; thus, when they reach reproductive age they may benefit from fertility counseling and discussion of assistive reproductive technology options [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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 cystinosis, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see • Females with cystinosis have had successful pregnancies resulting in healthy newborns. However, pregnancies in females with cystinosis are at increased risk for premature delivery and must be monitored closely (see • Most males with nephropathic cystinosis suffer from obstructive azoospermia; thus, when they reach reproductive age they may benefit from fertility counseling and discussion of assistive reproductive technology options [ ## 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 the use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Ireland United Kingdom • • Ireland • • • • • • • United Kingdom • ## Molecular Genetics Cystinosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Cystinosis ( Cystinosin, the protein product of A 57-kb deletion that includes the promotor region, exons 1-9, and interrupts exon 10 is the most common pathogenic variant identified in individuals with cystinosis from northern Europe and North America; Germany is considered the country of origin of this suspected founder variant. This deletion accounts for 50%-70% of pathogenic variants identified in individuals from these regions [ Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Cystinosin, the protein product of A 57-kb deletion that includes the promotor region, exons 1-9, and interrupts exon 10 is the most common pathogenic variant identified in individuals with cystinosis from northern Europe and North America; Germany is considered the country of origin of this suspected founder variant. This deletion accounts for 50%-70% of pathogenic variants identified in individuals from these regions [ Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Gahl is actively involved in clinical research regarding individuals with cystinosis and would be happy to communicate with persons who have any questions regarding diagnosis of cystinosis or other considerations. Cystinosis Research Network (CRN) for providing clinical and scientific information to patients. Dr Francisco Emma (Pediatric Nephrology Division at Bambino Gesù Children's Hospital in Rome), Dr Katharina Hohenfeller (Department of Pediatrics, Pediatric Nephrology, RoMed Kliniken, Pettenkoferstr.10, 83022 Rosenheim, Germany), and Dr Elena Levtchenko (Amsterdam Gastroenterology Endocrinology Metabolism) for recent investigations in cellular pathophysiology of cystinosis, contributions to developing newborn screening, and coordination of guidelines for management. William A Gahl, MD, PhD (2001-present)Robert Kleta, MD, PhD; National Human Genome Research Institute (2001-2009)Galina Nesterova, MD (2009-2025) 14 August 2025 (sw) Comprehensive update posted live 6 October 2016 (sw) Comprehensive update posted live 30 January 2014 (me) Comprehensive update posted live 11 August 2011 (me) Comprehensive update posted live 9 April 2009 (me) Comprehensive update posted live 18 October 2005 (me) Comprehensive update posted live 6 June 2003 (ca) Comprehensive update posted live 22 March 2001 (me) Review posted live January 2001 (wg) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 14 August 2025 (sw) Comprehensive update posted live • 6 October 2016 (sw) Comprehensive update posted live • 30 January 2014 (me) Comprehensive update posted live • 11 August 2011 (me) Comprehensive update posted live • 9 April 2009 (me) Comprehensive update posted live • 18 October 2005 (me) Comprehensive update posted live • 6 June 2003 (ca) Comprehensive update posted live • 22 March 2001 (me) Review posted live • January 2001 (wg) Original submission ## Author Notes Dr Gahl is actively involved in clinical research regarding individuals with cystinosis and would be happy to communicate with persons who have any questions regarding diagnosis of cystinosis or other considerations. ## Acknowledgments Cystinosis Research Network (CRN) for providing clinical and scientific information to patients. Dr Francisco Emma (Pediatric Nephrology Division at Bambino Gesù Children's Hospital in Rome), Dr Katharina Hohenfeller (Department of Pediatrics, Pediatric Nephrology, RoMed Kliniken, Pettenkoferstr.10, 83022 Rosenheim, Germany), and Dr Elena Levtchenko (Amsterdam Gastroenterology Endocrinology Metabolism) for recent investigations in cellular pathophysiology of cystinosis, contributions to developing newborn screening, and coordination of guidelines for management. ## Author History William A Gahl, MD, PhD (2001-present)Robert Kleta, MD, PhD; National Human Genome Research Institute (2001-2009)Galina Nesterova, MD (2009-2025) ## Revision History 14 August 2025 (sw) Comprehensive update posted live 6 October 2016 (sw) Comprehensive update posted live 30 January 2014 (me) Comprehensive update posted live 11 August 2011 (me) Comprehensive update posted live 9 April 2009 (me) Comprehensive update posted live 18 October 2005 (me) Comprehensive update posted live 6 June 2003 (ca) Comprehensive update posted live 22 March 2001 (me) Review posted live January 2001 (wg) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 14 August 2025 (sw) Comprehensive update posted live • 6 October 2016 (sw) Comprehensive update posted live • 30 January 2014 (me) Comprehensive update posted live • 11 August 2011 (me) Comprehensive update posted live • 9 April 2009 (me) Comprehensive update posted live • 18 October 2005 (me) Comprehensive update posted live • 6 June 2003 (ca) Comprehensive update posted live • 22 March 2001 (me) Review posted live • January 2001 (wg) Original submission ## Key Sections in This ## References Ariceta G, Camacho JA, Fernández-Obispo M, Fernández-Polo A, Gamez J, García-Villoria J, Lara Monteczuma E, Leyes P, Martín-Begué N, Oppenheimer F, Perelló M, Morell GP, Torra R, Santandreu AV, Güell A; Grupo T-CiS.bcn. Cystinosis in adult and adolescent patients: recommendations for the comprehensive care of cystinosis. Nefrologia. 2015;35:304-21. [ Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29 Suppl 4:iv87-94. [ Hohenfellner K, Rauch F, Ariceta G, Awan A, Bacchetta J, Bergmann C, Bechtold S, Cassidy N, Deschenes G, Elenberg E, Gahl WA, Greil O, Harms E, Herzig N, Hoppe B, Koeppl C, Lewis MA, Levtchenko E, Nesterova G, Santos F, Schlingmann KP, Servais A, Soliman NA, Steidle G, Sweeney C, Treikauskas U, Topaloglu R, Tsygin A, Veys K, V Vigier R, Zustin J, Haffner D. Management of bone disease in cystinosis: statement from an international conference. J Inherit Metab Dis. 2019;42:1019-29. [ Levtchenko E, Servais A, Hulton SA, Ariceta G, Emma F, Game DS, Lange K, Lapatto R, Liang H, Sberro-Soussan R, Topaloglu R, Das AM, Webb NJA, Wanner C. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clin Kidney J. 2022;15:1675-84. [ Stabouli S, Sommer A, Kraft S, Schweer K, Bethe D, Bertholet-Thomas A, Batte S, Ariceta G, Brengmann S, Bacchetta J, Emma F, Levtchenko E, Topaloglu R, Willem L, Haffner D, Oh J. Addressing the psychosocial aspects of transition to adult care in patients with cystinosis. Pediatr Nephrol. 2024;39:2861-74. [ • Ariceta G, Camacho JA, Fernández-Obispo M, Fernández-Polo A, Gamez J, García-Villoria J, Lara Monteczuma E, Leyes P, Martín-Begué N, Oppenheimer F, Perelló M, Morell GP, Torra R, Santandreu AV, Güell A; Grupo T-CiS.bcn. Cystinosis in adult and adolescent patients: recommendations for the comprehensive care of cystinosis. Nefrologia. 2015;35:304-21. [ • Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29 Suppl 4:iv87-94. [ • Hohenfellner K, Rauch F, Ariceta G, Awan A, Bacchetta J, Bergmann C, Bechtold S, Cassidy N, Deschenes G, Elenberg E, Gahl WA, Greil O, Harms E, Herzig N, Hoppe B, Koeppl C, Lewis MA, Levtchenko E, Nesterova G, Santos F, Schlingmann KP, Servais A, Soliman NA, Steidle G, Sweeney C, Treikauskas U, Topaloglu R, Tsygin A, Veys K, V Vigier R, Zustin J, Haffner D. Management of bone disease in cystinosis: statement from an international conference. J Inherit Metab Dis. 2019;42:1019-29. [ • Levtchenko E, Servais A, Hulton SA, Ariceta G, Emma F, Game DS, Lange K, Lapatto R, Liang H, Sberro-Soussan R, Topaloglu R, Das AM, Webb NJA, Wanner C. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clin Kidney J. 2022;15:1675-84. [ • Stabouli S, Sommer A, Kraft S, Schweer K, Bethe D, Bertholet-Thomas A, Batte S, Ariceta G, Brengmann S, Bacchetta J, Emma F, Levtchenko E, Topaloglu R, Willem L, Haffner D, Oh J. Addressing the psychosocial aspects of transition to adult care in patients with cystinosis. Pediatr Nephrol. 2024;39:2861-74. [ ## Published Guidelines / Consensus Statements Ariceta G, Camacho JA, Fernández-Obispo M, Fernández-Polo A, Gamez J, García-Villoria J, Lara Monteczuma E, Leyes P, Martín-Begué N, Oppenheimer F, Perelló M, Morell GP, Torra R, Santandreu AV, Güell A; Grupo T-CiS.bcn. Cystinosis in adult and adolescent patients: recommendations for the comprehensive care of cystinosis. Nefrologia. 2015;35:304-21. [ Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29 Suppl 4:iv87-94. [ Hohenfellner K, Rauch F, Ariceta G, Awan A, Bacchetta J, Bergmann C, Bechtold S, Cassidy N, Deschenes G, Elenberg E, Gahl WA, Greil O, Harms E, Herzig N, Hoppe B, Koeppl C, Lewis MA, Levtchenko E, Nesterova G, Santos F, Schlingmann KP, Servais A, Soliman NA, Steidle G, Sweeney C, Treikauskas U, Topaloglu R, Tsygin A, Veys K, V Vigier R, Zustin J, Haffner D. Management of bone disease in cystinosis: statement from an international conference. J Inherit Metab Dis. 2019;42:1019-29. [ Levtchenko E, Servais A, Hulton SA, Ariceta G, Emma F, Game DS, Lange K, Lapatto R, Liang H, Sberro-Soussan R, Topaloglu R, Das AM, Webb NJA, Wanner C. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clin Kidney J. 2022;15:1675-84. [ Stabouli S, Sommer A, Kraft S, Schweer K, Bethe D, Bertholet-Thomas A, Batte S, Ariceta G, Brengmann S, Bacchetta J, Emma F, Levtchenko E, Topaloglu R, Willem L, Haffner D, Oh J. Addressing the psychosocial aspects of transition to adult care in patients with cystinosis. Pediatr Nephrol. 2024;39:2861-74. [ • Ariceta G, Camacho JA, Fernández-Obispo M, Fernández-Polo A, Gamez J, García-Villoria J, Lara Monteczuma E, Leyes P, Martín-Begué N, Oppenheimer F, Perelló M, Morell GP, Torra R, Santandreu AV, Güell A; Grupo T-CiS.bcn. Cystinosis in adult and adolescent patients: recommendations for the comprehensive care of cystinosis. Nefrologia. 2015;35:304-21. [ • Emma F, Nesterova G, Langman C, Labbé A, Cherqui S, Goodyer P, Janssen MC, Greco M, Topaloglu R, Elenberg E, Dohil R, Trauner D, Antignac C, Cochat P, Kaskel F, Servais A, Wühl E, Niaudet P, Van't Hoff W, Gahl W, Levtchenko E. Nephropathic cystinosis: an international consensus document. Nephrol Dial Transplant. 2014;29 Suppl 4:iv87-94. [ • Hohenfellner K, Rauch F, Ariceta G, Awan A, Bacchetta J, Bergmann C, Bechtold S, Cassidy N, Deschenes G, Elenberg E, Gahl WA, Greil O, Harms E, Herzig N, Hoppe B, Koeppl C, Lewis MA, Levtchenko E, Nesterova G, Santos F, Schlingmann KP, Servais A, Soliman NA, Steidle G, Sweeney C, Treikauskas U, Topaloglu R, Tsygin A, Veys K, V Vigier R, Zustin J, Haffner D. Management of bone disease in cystinosis: statement from an international conference. J Inherit Metab Dis. 2019;42:1019-29. [ • Levtchenko E, Servais A, Hulton SA, Ariceta G, Emma F, Game DS, Lange K, Lapatto R, Liang H, Sberro-Soussan R, Topaloglu R, Das AM, Webb NJA, Wanner C. Expert guidance on the multidisciplinary management of cystinosis in adolescent and adult patients. Clin Kidney J. 2022;15:1675-84. [ • Stabouli S, Sommer A, Kraft S, Schweer K, Bethe D, Bertholet-Thomas A, Batte S, Ariceta G, Brengmann S, Bacchetta J, Emma F, Levtchenko E, Topaloglu R, Willem L, Haffner D, Oh J. Addressing the psychosocial aspects of transition to adult care in patients with cystinosis. Pediatr Nephrol. 2024;39:2861-74. [ ## Literature Cited Findings on slit lamp examination of the cornea in individuals with cystinosis a. Band keratopathy in an individual age 33 years with cystinosis treated with cysteamine eye drops, which dissolved the cystine crystals, but not the calcified band (arrow) b. Corneal crystals in an untreated individual age 43 months c. The same child in (b) after 12 months of cysteamine eye drop therapy Reproduced with permission from A man age 37 years with nephropathic cystinosis a. Thin habitus b. Gastrostomy tube c. Clawed hand with wasting of thenar and hypothenar eminences and interosseous muscles d. Muscle wasting in upper trunk e. Chest CT showing calcification of the left coronary artery (arrow) f. Brain CT showing atrophy and calcifications of the basal ganglia Reproduced with permission from
[]
22/3/2001
14/8/2025
7/12/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ctx
ctx
[ "Sterol 26-hydroxylase, mitochondrial", "CYP27A1", "Cerebrotendinous Xanthomatosis" ]
Cerebrotendinous Xanthomatosis
Antonio Federico, Gian Nicola Gallus
Summary Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the third decade in more than 50% of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased chenodeoxycholic acid (CDCA), increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid. The diagnosis of CTX is established in a proband with suggestive findings and biallelic pathogenic variants in CTX is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
## Diagnosis A consensus paper on the diagnostic criteria and management of cerebrotendinous xanthomatosis (CTX) has been published [ CTX, a lipid storage disease, Neonatal cholestasis Infantile-onset diarrhea Childhood-onset cataract Adolescent- to young adult-onset tendon xanthomas ( Adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures) High plasma and tissue cholestanol concentration ( Normal-to-low plasma cholesterol concentration Markedly decreased formation of chenodeoxycholic acid as a result of impaired primary bile acid synthesis Increased concentration of bile alcohols and their glyconjugates in bile, urine, and plasma ( Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid Increased plasma lactate concentration Biochemical Abnormalities in Cerebrotendinous Xanthomatosis Bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter ( Increased brain lactate and decreased n-acetylaspartate concentration (by MR spectroscopy) The diagnosis of CTX 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 Cerebrotendinous Xanthomatosis 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 and Ensembl 105: Dec 2021 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Neonatal cholestasis • Infantile-onset diarrhea • Childhood-onset cataract • Adolescent- to young adult-onset tendon xanthomas ( • Adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures) • High plasma and tissue cholestanol concentration ( • Normal-to-low plasma cholesterol concentration • Markedly decreased formation of chenodeoxycholic acid as a result of impaired primary bile acid synthesis • Increased concentration of bile alcohols and their glyconjugates in bile, urine, and plasma ( • Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid • Increased plasma lactate concentration • Bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter ( • Increased brain lactate and decreased n-acetylaspartate concentration (by MR spectroscopy) ## Suggestive Findings CTX, a lipid storage disease, Neonatal cholestasis Infantile-onset diarrhea Childhood-onset cataract Adolescent- to young adult-onset tendon xanthomas ( Adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures) High plasma and tissue cholestanol concentration ( Normal-to-low plasma cholesterol concentration Markedly decreased formation of chenodeoxycholic acid as a result of impaired primary bile acid synthesis Increased concentration of bile alcohols and their glyconjugates in bile, urine, and plasma ( Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid Increased plasma lactate concentration Biochemical Abnormalities in Cerebrotendinous Xanthomatosis Bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter ( Increased brain lactate and decreased n-acetylaspartate concentration (by MR spectroscopy) • Neonatal cholestasis • Infantile-onset diarrhea • Childhood-onset cataract • Adolescent- to young adult-onset tendon xanthomas ( • Adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, and seizures) • High plasma and tissue cholestanol concentration ( • Normal-to-low plasma cholesterol concentration • Markedly decreased formation of chenodeoxycholic acid as a result of impaired primary bile acid synthesis • Increased concentration of bile alcohols and their glyconjugates in bile, urine, and plasma ( • Increased concentration of cholestanol and apolipoprotein B in cerebrospinal fluid • Increased plasma lactate concentration • Bilateral hyperintensity of the dentate nuclei and cerebral and cerebellar white matter ( • Increased brain lactate and decreased n-acetylaspartate concentration (by MR spectroscopy) ## Establishing the Diagnosis The diagnosis of CTX 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 Cerebrotendinous Xanthomatosis 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 and Ensembl 105: Dec 2021 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Cerebrotendinous Xanthomatosis 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 and Ensembl 105: Dec 2021 [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Intrafamilial variability is considerable. A suspicion index for diagnosis has been reported based on clinical and laboratory findings [ Cerebrotendinous Xanthomatosis: Frequency of Select Features Based on Other findings include palpebral xanthelasmas, optic nerve atrophy and proptosis, paleness of the optic disk, premature retinal senescence with retinal vessel sclerosis, cholesterol-like deposits along vascular arcades, and myelinated nerve fibers [ Some individuals present with a spinal form, in which progressive spastic paraparesis is the main clinical concern [ Heterozygotes are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. No genotype-phenotype correlations for Terms used in the past for CTX and no longer in use include the following: Cerebral cholesterinosis Cerebrotendinous cholesterosis Van Bogaert-Scherer-Epstein syndrome More than 400 individuals with CTX have been reported worldwide [ • Cerebral cholesterinosis • Cerebrotendinous cholesterosis • Van Bogaert-Scherer-Epstein syndrome ## Clinical Description Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Intrafamilial variability is considerable. A suspicion index for diagnosis has been reported based on clinical and laboratory findings [ Cerebrotendinous Xanthomatosis: Frequency of Select Features Based on Other findings include palpebral xanthelasmas, optic nerve atrophy and proptosis, paleness of the optic disk, premature retinal senescence with retinal vessel sclerosis, cholesterol-like deposits along vascular arcades, and myelinated nerve fibers [ Some individuals present with a spinal form, in which progressive spastic paraparesis is the main clinical concern [ Heterozygotes are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. ## Neurologic Signs Some individuals present with a spinal form, in which progressive spastic paraparesis is the main clinical concern [ ## Heterozygotes Heterozygotes are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Nomenclature Terms used in the past for CTX and no longer in use include the following: Cerebral cholesterinosis Cerebrotendinous cholesterosis Van Bogaert-Scherer-Epstein syndrome • Cerebral cholesterinosis • Cerebrotendinous cholesterosis • Van Bogaert-Scherer-Epstein syndrome ## Prevalence More than 400 individuals with CTX have been reported worldwide [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Selected monogenic disorders that may present with clinical features similar to those of cerebrotendinous xanthomatosis are summarized in Selected Monogenic Disorders in the Differential Diagnosis of Cerebrotendinous Xanthomatosis AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; XL = X-linked Inheritance is autosomal recessive with the exception of ## Management A clinical practice guideline on the diagnosis, treatment, and management of cerebrotendinous xanthomatosis (CTX) has been published, based on expert opinion collected with the Delphi method [ To establish the extent of disease and needs in an individual diagnosed with CTX, the evaluations summarized in Cerebrotendinous Xanthomatosis: Recommended Evaluations Following Initial Diagnosis Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; NCV = nerve conduction velocity Medical geneticist, certified genetic counselor, certified advanced genetic nurse Early treatment with chenodeoxycholic acid (CDCA) in presymptomatic individuals appears to prevent clinical manifestations (see Cerebrotendinous Xanthomatosis: Targeted Therapy Long-term treatment w/CDCA Should be started early as effect of therapy depends largely on extent of irreversible structural damage to axons Normalizes plasma & CSF concentration of cholestanol by suppressing cholestanol biosynthesis Improves neurophysiologic findings (normalization of NCVs & stabilization; slow & continuous improvement of MEPs & SEPs) Also improves osteoporosis See CDCA = chenodeoxycholic acid; CSF = cerebrospinal fluid; MEP = motor evoked potential; NCV = nerve conduction velocity, SEP = sensory evoked potential Cerebrotendinous Xanthomatosis: Treatment of Manifestations Cholic acid treatment has been used in a few persons Such therapy may be useful in those who experience side effects w/CDCA treatments. CDCA = chenodeoxycholic acid; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A Cerebrotendinous Xanthomatosis: Recommended Surveillance Caution in the use of statins has been suggested [ 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 CDCA treatment and surveillance. Early treatment with CDCA in presymptomatic individuals appears to prevent clinical manifestations (see Molecular genetic testing if the Biochemical testing including cholestanol plasma concentration if the pathogenic variants in the family are not known. See Treatment with CDCA should not be interrupted during pregnancy. Gene therapies are under investigation in a mouse model of CTX [ Search • Community or • Social work involvement for parental support; • Home nursing referral. • Long-term treatment w/CDCA • Should be started early as effect of therapy depends largely on extent of irreversible structural damage to axons • Normalizes plasma & CSF concentration of cholestanol by suppressing cholestanol biosynthesis • Improves neurophysiologic findings (normalization of NCVs & stabilization; slow & continuous improvement of MEPs & SEPs) • Also improves osteoporosis • See • Cholic acid treatment has been used in a few persons • Such therapy may be useful in those who experience side effects w/CDCA treatments. • Molecular genetic testing if the • Biochemical testing including cholestanol plasma concentration 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 CTX, the evaluations summarized in Cerebrotendinous Xanthomatosis: Recommended Evaluations Following Initial Diagnosis Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; NCV = nerve conduction velocity Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Early treatment with chenodeoxycholic acid (CDCA) in presymptomatic individuals appears to prevent clinical manifestations (see Cerebrotendinous Xanthomatosis: Targeted Therapy Long-term treatment w/CDCA Should be started early as effect of therapy depends largely on extent of irreversible structural damage to axons Normalizes plasma & CSF concentration of cholestanol by suppressing cholestanol biosynthesis Improves neurophysiologic findings (normalization of NCVs & stabilization; slow & continuous improvement of MEPs & SEPs) Also improves osteoporosis See CDCA = chenodeoxycholic acid; CSF = cerebrospinal fluid; MEP = motor evoked potential; NCV = nerve conduction velocity, SEP = sensory evoked potential Cerebrotendinous Xanthomatosis: Treatment of Manifestations Cholic acid treatment has been used in a few persons Such therapy may be useful in those who experience side effects w/CDCA treatments. CDCA = chenodeoxycholic acid; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A • Long-term treatment w/CDCA • Should be started early as effect of therapy depends largely on extent of irreversible structural damage to axons • Normalizes plasma & CSF concentration of cholestanol by suppressing cholestanol biosynthesis • Improves neurophysiologic findings (normalization of NCVs & stabilization; slow & continuous improvement of MEPs & SEPs) • Also improves osteoporosis • See • Cholic acid treatment has been used in a few persons • Such therapy may be useful in those who experience side effects w/CDCA treatments. ## Targeted Therapy Early treatment with chenodeoxycholic acid (CDCA) in presymptomatic individuals appears to prevent clinical manifestations (see Cerebrotendinous Xanthomatosis: Targeted Therapy Long-term treatment w/CDCA Should be started early as effect of therapy depends largely on extent of irreversible structural damage to axons Normalizes plasma & CSF concentration of cholestanol by suppressing cholestanol biosynthesis Improves neurophysiologic findings (normalization of NCVs & stabilization; slow & continuous improvement of MEPs & SEPs) Also improves osteoporosis See CDCA = chenodeoxycholic acid; CSF = cerebrospinal fluid; MEP = motor evoked potential; NCV = nerve conduction velocity, SEP = sensory evoked potential • Long-term treatment w/CDCA • Should be started early as effect of therapy depends largely on extent of irreversible structural damage to axons • Normalizes plasma & CSF concentration of cholestanol by suppressing cholestanol biosynthesis • Improves neurophysiologic findings (normalization of NCVs & stabilization; slow & continuous improvement of MEPs & SEPs) • Also improves osteoporosis • See ## Supportive Care Cerebrotendinous Xanthomatosis: Treatment of Manifestations Cholic acid treatment has been used in a few persons Such therapy may be useful in those who experience side effects w/CDCA treatments. CDCA = chenodeoxycholic acid; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A • Cholic acid treatment has been used in a few persons • Such therapy may be useful in those who experience side effects w/CDCA treatments. ## Surveillance Cerebrotendinous Xanthomatosis: Recommended Surveillance ## Agents/Circumstances to Avoid Caution in the use of statins has been suggested [ ## 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 CDCA treatment and surveillance. Early treatment with CDCA in presymptomatic individuals appears to prevent clinical manifestations (see Molecular genetic testing if the Biochemical testing including cholestanol plasma concentration if the pathogenic variants in the family are not known. See • Molecular genetic testing if the • Biochemical testing including cholestanol plasma concentration if the pathogenic variants in the family are not known. ## Pregnancy Management Treatment with CDCA should not be interrupted during pregnancy. ## Therapies Under Investigation Gene therapies are under investigation in a mouse model of CTX [ Search ## Genetic Counseling Cerebrotendinous xanthomatosis (CTX) 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 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 generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. If both parents are known to be heterozygous for a Significant clinical variability may be observed between affected family members: a sib with biallelic pathogenic variants may experience less severe manifestations with later onset of neurologic signs than the proband [ Heterozygotes (carriers) are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. The offspring of an individual with CTX are obligate heterozygotes for a If the reproductive partner of a proband is heterozygous for a Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Significant clinical variability may be observed between affected family members: a sib with biallelic pathogenic variants may experience less severe manifestations with later onset of neurologic signs than the proband [ • Heterozygotes (carriers) are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. • The offspring of an individual with CTX are obligate heterozygotes for a • If the reproductive partner of a proband is heterozygous for a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Cerebrotendinous xanthomatosis (CTX) 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 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 generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. If both parents are known to be heterozygous for a Significant clinical variability may be observed between affected family members: a sib with biallelic pathogenic variants may experience less severe manifestations with later onset of neurologic signs than the proband [ Heterozygotes (carriers) are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. The offspring of an individual with CTX are obligate heterozygotes for a If the reproductive partner of a proband is heterozygous for a • 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 • 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 generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Significant clinical variability may be observed between affected family members: a sib with biallelic pathogenic variants may experience less severe manifestations with later onset of neurologic signs than the proband [ • Heterozygotes (carriers) are generally asymptomatic; however, clinical findings have been reported in heterozygotes ranging from an increased incidence of cardiovascular disorders to gallstones [Author, personal observation]. • The offspring of an individual with CTX are obligate heterozygotes for a • If the reproductive partner of a proband is heterozygous for a ## 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 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 Cerebrotendinous Xanthomatosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Cerebrotendinous Xanthomatosis ( Cerebrotendinous xanthomatosis (CTX) is caused by biallelic pathogenic variants in Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Cerebrotendinous xanthomatosis (CTX) is caused by biallelic pathogenic variants in Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Antonio Federico is Emeritus professor of Clinical Neurology, Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena Italy. Gian Nicola Gallus is a postdoctoral fellow in Molecular Biology, Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy. We acknowledge all our colleagues who in the last 40 years have collaborated with us in the investigation of this condition: Prof GC Guazzi, Prof N De Stefano, Prof A Malandrini, Dr C Battisti, Dr E Cardaioli, Dr P Formichi, Dr S Bianchi, Dr A Rufa, Dr F Sicurelli; particular thanks to Prof MT Dotti and Dr A Mignarri, and all the physicians who referred patients from Italy and abroad. We also acknowledge all our patients. Maria Teresa Dotti, MD; University of Siena (2003-2022)Antonio Federico, MD (2003-present)Gian Nicola Gallus, DSci (2003-present) 14 November 2024 (ma) Revision: 17 March 2022 (ha) Comprehensive update posted live 14 April 2016 (ma) Comprehensive update posted live 1 August 2013 (me) Comprehensive update posted live 16 November 2010 (me) Comprehensive update posted live 7 February 2006 (me) Comprehensive update posted live 16 July 2003 (me) Review posted live 18 December 2002 (af) Original submission • 14 November 2024 (ma) Revision: • 17 March 2022 (ha) Comprehensive update posted live • 14 April 2016 (ma) Comprehensive update posted live • 1 August 2013 (me) Comprehensive update posted live • 16 November 2010 (me) Comprehensive update posted live • 7 February 2006 (me) Comprehensive update posted live • 16 July 2003 (me) Review posted live • 18 December 2002 (af) Original submission ## Author Notes Antonio Federico is Emeritus professor of Clinical Neurology, Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena Italy. Gian Nicola Gallus is a postdoctoral fellow in Molecular Biology, Department of Medicine, Surgery and Neurosciences, Medical School, University of Siena, Siena, Italy. ## Acknowledgments We acknowledge all our colleagues who in the last 40 years have collaborated with us in the investigation of this condition: Prof GC Guazzi, Prof N De Stefano, Prof A Malandrini, Dr C Battisti, Dr E Cardaioli, Dr P Formichi, Dr S Bianchi, Dr A Rufa, Dr F Sicurelli; particular thanks to Prof MT Dotti and Dr A Mignarri, and all the physicians who referred patients from Italy and abroad. We also acknowledge all our patients. ## Author History Maria Teresa Dotti, MD; University of Siena (2003-2022)Antonio Federico, MD (2003-present)Gian Nicola Gallus, DSci (2003-present) ## Revision History 14 November 2024 (ma) Revision: 17 March 2022 (ha) Comprehensive update posted live 14 April 2016 (ma) Comprehensive update posted live 1 August 2013 (me) Comprehensive update posted live 16 November 2010 (me) Comprehensive update posted live 7 February 2006 (me) Comprehensive update posted live 16 July 2003 (me) Review posted live 18 December 2002 (af) Original submission • 14 November 2024 (ma) Revision: • 17 March 2022 (ha) Comprehensive update posted live • 14 April 2016 (ma) Comprehensive update posted live • 1 August 2013 (me) Comprehensive update posted live • 16 November 2010 (me) Comprehensive update posted live • 7 February 2006 (me) Comprehensive update posted live • 16 July 2003 (me) Review posted live • 18 December 2002 (af) Original submission ## Key Sections in This ## References Stelten BML, Dotti MT, Verrips A, Elibol B, Falik-Zaccai TC, Hanman K, Mignarri A, Sithole B, Steiner RD, Verma S, Yahalom G, Zubarioglu T, Mochel F, Federico A. Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study. Available • Stelten BML, Dotti MT, Verrips A, Elibol B, Falik-Zaccai TC, Hanman K, Mignarri A, Sithole B, Steiner RD, Verma S, Yahalom G, Zubarioglu T, Mochel F, Federico A. Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study. Available ## Published Guidelines / Consensus Statements Stelten BML, Dotti MT, Verrips A, Elibol B, Falik-Zaccai TC, Hanman K, Mignarri A, Sithole B, Steiner RD, Verma S, Yahalom G, Zubarioglu T, Mochel F, Federico A. Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study. Available • Stelten BML, Dotti MT, Verrips A, Elibol B, Falik-Zaccai TC, Hanman K, Mignarri A, Sithole B, Steiner RD, Verma S, Yahalom G, Zubarioglu T, Mochel F, Federico A. Expert opinion on diagnosing, treating and managing patients with cerebrotendinous xanthomatosis (CTX): a modified Delphi study. Available ## Literature Cited Different localization and severity of tendon xanthomas in CTX. Besides the classic xanthomas of the Achilles tendon (A), xanthomas of the patellar tendon (B), the extensor tendons of the hand (C), and the extensor tendons of the elbow (D) have been observed. MRI findings in three persons with CTX A. Signal alterations of cerebral peduncle B. Signal abnormalities of corona radiata and subcortical white matter C. Hyperintensities of dentate nuclei and cerebellar white matter
[]
16/7/2003
17/3/2022
14/11/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
cutis-laxa
cutis-laxa
[ "ATP6V0A2-CDG", "Autosomal Recessive Cutis Laxa Type 2A (ARCL2A)", "Autosomal Recessive Cutis Laxa Type 2A (ARCL2A)", "ATP6V0A2-CDG", "Debré-Type Cutis Laxa", "Wrinkly Skin Syndrome", "V-type proton ATPase 116 kDa subunit a 2", "ATP6V0A2", "ATP6V0A2-Related Cutis Laxa" ]
Lionel Van Maldergem, William Dobyns, Uwe Kornak
Summary The diagnosis of
Debré-type cutis laxa Wrinkly skin syndrome • Debré-type cutis laxa • Wrinkly skin syndrome ## Diagnosis Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains its consistency Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features that also include prominent nasal root and downslanted palpebral fissures Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age 1 year) Congenital dislocation of the hips Inguinal hernias High myopia Bruch's membrane rupture, cataracts, corneal clouding (infrequent) Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: Disialotransferrin: 2.5%-9.8% Trisialotransferrin: 3.4%-13.7% Note: (1) These findings are also observed in type 2 congenital disorder of glycosylation (CDG type 2) [ Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues Increased amounts of monosialotransferrin. Normal ranges depend on age; in adults: Monosialotransferrin: 43%-69% Disialotransferrin: 23%-50% Note: Abnormal O-glycosylation is supportive of the diagnosis, but a normal or inconclusive result does not eliminate the possibility of Light microscopy is normal. Electron microscopy (EM) shows rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities [ Note: EM studies require a high level of expertise and are only available in specialized centers. The EM findings strongly support but are not specific for the diagnosis of This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes the disorder from true polymicrogyria. 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 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 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 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. • Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin • Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains its consistency • Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features that also include prominent nasal root and downslanted palpebral fissures • Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age 1 year) • Congenital dislocation of the hips • Inguinal hernias • High myopia • Bruch's membrane rupture, cataracts, corneal clouding (infrequent) • Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues • Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues • Increased amounts of monosialotransferrin. Normal ranges depend on age; in adults: • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Light microscopy is normal. • Electron microscopy (EM) shows rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities [ • Note: EM studies require a high level of expertise and are only available in specialized centers. • The EM findings strongly support but are not specific for the diagnosis of • This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes the disorder from true polymicrogyria. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains its consistency Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features that also include prominent nasal root and downslanted palpebral fissures Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age 1 year) Congenital dislocation of the hips Inguinal hernias High myopia Bruch's membrane rupture, cataracts, corneal clouding (infrequent) Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: Disialotransferrin: 2.5%-9.8% Trisialotransferrin: 3.4%-13.7% Note: (1) These findings are also observed in type 2 congenital disorder of glycosylation (CDG type 2) [ Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues Increased amounts of monosialotransferrin. Normal ranges depend on age; in adults: Monosialotransferrin: 43%-69% Disialotransferrin: 23%-50% Note: Abnormal O-glycosylation is supportive of the diagnosis, but a normal or inconclusive result does not eliminate the possibility of Light microscopy is normal. Electron microscopy (EM) shows rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities [ Note: EM studies require a high level of expertise and are only available in specialized centers. The EM findings strongly support but are not specific for the diagnosis of This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes the disorder from true polymicrogyria. 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. • Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin • Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains its consistency • Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features that also include prominent nasal root and downslanted palpebral fissures • Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age 1 year) • Congenital dislocation of the hips • Inguinal hernias • High myopia • Bruch's membrane rupture, cataracts, corneal clouding (infrequent) • Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues • Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues • Increased amounts of monosialotransferrin. Normal ranges depend on age; in adults: • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Light microscopy is normal. • Electron microscopy (EM) shows rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities [ • Note: EM studies require a high level of expertise and are only available in specialized centers. • The EM findings strongly support but are not specific for the diagnosis of • This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes the disorder from true polymicrogyria. ## Clinical Findings Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains its consistency Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features that also include prominent nasal root and downslanted palpebral fissures Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age 1 year) Congenital dislocation of the hips Inguinal hernias High myopia Bruch's membrane rupture, cataracts, corneal clouding (infrequent) • Furrowing of the skin of the whole body; particularly obvious in neck, axillae, and groin • Skin that when extended does not display marked hyperelasticity (as is observed in the Ehlers-Danlos syndromes) but rather maintains its consistency • Droopy skin on the cheeks of the face and marked nasolabial folds, giving rise to distinctive facial features that also include prominent nasal root and downslanted palpebral fissures • Enlarged fontanelles (i.e., delayed closure of the fontanelles) manifest in newborns (anterior fontanelle >6x6 cm in the newborn; >3x3 cm at age 1 year) • Congenital dislocation of the hips • Inguinal hernias • High myopia • Bruch's membrane rupture, cataracts, corneal clouding (infrequent) ## Laboratory Findings Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: Disialotransferrin: 2.5%-9.8% Trisialotransferrin: 3.4%-13.7% Note: (1) These findings are also observed in type 2 congenital disorder of glycosylation (CDG type 2) [ Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues Increased amounts of monosialotransferrin. Normal ranges depend on age; in adults: Monosialotransferrin: 43%-69% Disialotransferrin: 23%-50% Note: Abnormal O-glycosylation is supportive of the diagnosis, but a normal or inconclusive result does not eliminate the possibility of Light microscopy is normal. Electron microscopy (EM) shows rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities [ Note: EM studies require a high level of expertise and are only available in specialized centers. The EM findings strongly support but are not specific for the diagnosis of • Reduction of the main protein band, which corresponds to transferrin containing four sialic acid residues • Increased amounts of disialo- and trisialo-transferrin that indicate altered N-glycosylation over the normal ranges of: • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Disialotransferrin: 2.5%-9.8% • Trisialotransferrin: 3.4%-13.7% • Reduction of the main protein band, which corresponds to apolipoprotein CIII containing two sialic acid residues • Increased amounts of monosialotransferrin. Normal ranges depend on age; in adults: • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Monosialotransferrin: 43%-69% • Disialotransferrin: 23%-50% • Light microscopy is normal. • Electron microscopy (EM) shows rarefaction and fragmentation of the elastin network in which elastic fibers are small and misshapen. Within these fibers both elastin and elastofibrils can be distinguished based on their different densities [ • Note: EM studies require a high level of expertise and are only available in specialized centers. • The EM findings strongly support but are not specific for the diagnosis of ## Imaging Findings This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes the disorder from true polymicrogyria. • This cortical malformation differs from lissencephaly and polymicrogyria by a consistent and predominant bilateral, symmetric, and frontal distribution that is more severe in the posterior portion of the frontal lobe and the anterior portion of the parietal lobes (including the perisylvian cortex) and less severe in the anterior portion of the frontal lobe and often the superior portion of the temporal lobe. No well-defined microgyri are seen, which also distinguishes the disorder from true polymicrogyria. ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of 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 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 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. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics This disorder spans a phenotypic spectrum that includes the historical diagnoses of Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end; these two phenotypes were thought to be distinct clinical entities until their molecular genetic nature was determined. Children diagnosed in the past with Debré-type cutis laxa had more severe developmental and neurologic abnormalities and a less severe cutaneous phenotype than children diagnosed with wrinkly skin syndrome, in whom the skin showed tighter wrinkles and the changes in facial features were milder [ To date, about 80 individuals have been identified with a pathogenic variant in Facial features Droopy skin on cheeks Prominent nasal bridge Premature aged appearance Downslanting palpebral fissures In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean Findings of a generalized connective tissue disorder including: Enlarged fontanels Congenital dislocation of the hips Inguinal hernia Heart valve dysplasia and/or widening of aortic root Scoliosis Joint laxity One Portuguese individual had an unclassified corneal dysplasia requiring engraftment. A Belgian individual had unilateral rupture of Bruch's membrane. Strabismus has been observed in nearly half of individuals. No genotype-phenotype correlations are known. The prevalence of all types of cutis laxa is 1:4,000,000 according to Rhône-Alpes Eurocat registry [E Robert, personal observation]. It is the second- to third-most common form of autosomal recessive cutis laxa. • Facial features • Droopy skin on cheeks • Prominent nasal bridge • Premature aged appearance • Downslanting palpebral fissures • In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean • Droopy skin on cheeks • Prominent nasal bridge • Premature aged appearance • Downslanting palpebral fissures • In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean • Findings of a generalized connective tissue disorder including: • Enlarged fontanels • Congenital dislocation of the hips • Inguinal hernia • Heart valve dysplasia and/or widening of aortic root • Scoliosis • Joint laxity • Enlarged fontanels • Congenital dislocation of the hips • Inguinal hernia • Heart valve dysplasia and/or widening of aortic root • Scoliosis • Joint laxity • Droopy skin on cheeks • Prominent nasal bridge • Premature aged appearance • Downslanting palpebral fissures • In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean • Enlarged fontanels • Congenital dislocation of the hips • Inguinal hernia • Heart valve dysplasia and/or widening of aortic root • Scoliosis • Joint laxity • One Portuguese individual had an unclassified corneal dysplasia requiring engraftment. • A Belgian individual had unilateral rupture of Bruch's membrane. • Strabismus has been observed in nearly half of individuals. ## Clinical Description This disorder spans a phenotypic spectrum that includes the historical diagnoses of Debré-type cutis laxa at the severe end and wrinkly skin syndrome at the mild end; these two phenotypes were thought to be distinct clinical entities until their molecular genetic nature was determined. Children diagnosed in the past with Debré-type cutis laxa had more severe developmental and neurologic abnormalities and a less severe cutaneous phenotype than children diagnosed with wrinkly skin syndrome, in whom the skin showed tighter wrinkles and the changes in facial features were milder [ To date, about 80 individuals have been identified with a pathogenic variant in Facial features Droopy skin on cheeks Prominent nasal bridge Premature aged appearance Downslanting palpebral fissures In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean Findings of a generalized connective tissue disorder including: Enlarged fontanels Congenital dislocation of the hips Inguinal hernia Heart valve dysplasia and/or widening of aortic root Scoliosis Joint laxity One Portuguese individual had an unclassified corneal dysplasia requiring engraftment. A Belgian individual had unilateral rupture of Bruch's membrane. Strabismus has been observed in nearly half of individuals. • Facial features • Droopy skin on cheeks • Prominent nasal bridge • Premature aged appearance • Downslanting palpebral fissures • In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean • Droopy skin on cheeks • Prominent nasal bridge • Premature aged appearance • Downslanting palpebral fissures • In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean • Findings of a generalized connective tissue disorder including: • Enlarged fontanels • Congenital dislocation of the hips • Inguinal hernia • Heart valve dysplasia and/or widening of aortic root • Scoliosis • Joint laxity • Enlarged fontanels • Congenital dislocation of the hips • Inguinal hernia • Heart valve dysplasia and/or widening of aortic root • Scoliosis • Joint laxity • Droopy skin on cheeks • Prominent nasal bridge • Premature aged appearance • Downslanting palpebral fissures • In most, borderline microcephaly with head circumference 2-3 standard deviations below the mean • Enlarged fontanels • Congenital dislocation of the hips • Inguinal hernia • Heart valve dysplasia and/or widening of aortic root • Scoliosis • Joint laxity • One Portuguese individual had an unclassified corneal dysplasia requiring engraftment. • A Belgian individual had unilateral rupture of Bruch's membrane. • Strabismus has been observed in nearly half of individuals. ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known. ## Prevalence The prevalence of all types of cutis laxa is 1:4,000,000 according to Rhône-Alpes Eurocat registry [E Robert, personal observation]. It is the second- to third-most common form of autosomal recessive cutis laxa. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Other disorders characterized by cutis laxa are summarized in Disorders to Consider in the Differential Diagnosis of ADCL = autosomal dominant cutis laxa; ARCL = autosomal recessive cutis laxa; CDG = congenital disorder of glycosylation; CHD = congenital heart disease; DD = developmental delay; ID = intellectual disability; MACS = ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with For newborns: clinical exam w/hip ultrasound as needed For older child at diagnosis: pelvic x-ray (1x only) to identify hip dysplasia in the event that hip dislocation was not treated properly Baseline neurodevelopmental eval Brain MRI EEG if seizures are suspected Community or Social work involvement for parental support; Home nursing referral. DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and 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 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. Recommended Surveillance for Individuals with It is appropriate to test older and younger sibs for presence of the See Search • For newborns: clinical exam w/hip ultrasound as needed • For older child at diagnosis: pelvic x-ray (1x only) to identify hip dysplasia in the event that hip dislocation was not treated properly • Baseline neurodevelopmental eval • Brain MRI • EEG if seizures are suspected • 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 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 Recommended Evaluations Following Initial Diagnosis in Individuals with For newborns: clinical exam w/hip ultrasound as needed For older child at diagnosis: pelvic x-ray (1x only) to identify hip dysplasia in the event that hip dislocation was not treated properly Baseline neurodevelopmental eval Brain MRI EEG if seizures are suspected Community or Social work involvement for parental support; Home nursing referral. DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • For newborns: clinical exam w/hip ultrasound as needed • For older child at diagnosis: pelvic x-ray (1x only) to identify hip dysplasia in the event that hip dislocation was not treated properly • Baseline neurodevelopmental eval • Brain MRI • EEG if seizures are suspected • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and 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 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. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an 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 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 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 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 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 Recommended Surveillance for Individuals with ## Evaluation of Relatives at Risk It is appropriate to test older and younger sibs for presence of the 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 of the parents is recommended 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 Because cognitive development and possible regression depends on the onset, type, and severity of seizures, considerable intrafamilial variability is observed. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The offspring of an individual with To date, individuals with 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 obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing of the parents is recommended 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 • Because cognitive development and possible regression depends on the onset, type, and severity of seizures, considerable intrafamilial variability is observed. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The offspring of an individual with • To date, individuals with • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to 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 Molecular genetic testing of the parents is recommended 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 Because cognitive development and possible regression depends on the onset, type, and severity of seizures, considerable intrafamilial variability is observed. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. The offspring of an individual with To date, individuals with • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing of the parents is recommended 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 • Because cognitive development and possible regression depends on the onset, type, and severity of seizures, considerable intrafamilial variability is observed. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The offspring of an individual with • To date, individuals with ## 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 New Zealand • • New Zealand • • • ## Molecular Genetics ATP6V0A2-Related Cutis Laxa: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ATP6V0A2-Related Cutis Laxa ( ## Molecular Pathogenesis ## Chapter Notes We thank the families for their continuing participation. 16 March 2023 (aa) Revision: 28 January 2021 (ha) Comprehensive update posted live 12 February 2015 (me) Comprehensive update posted live 23 September 2010 (me) Comprehensive update posted live 19 March 2009 (me) Review posted live 10 September 2008 (lvm) Original submission • 16 March 2023 (aa) Revision: • 28 January 2021 (ha) Comprehensive update posted live • 12 February 2015 (me) Comprehensive update posted live • 23 September 2010 (me) Comprehensive update posted live • 19 March 2009 (me) Review posted live • 10 September 2008 (lvm) Original submission ## Acknowledgments We thank the families for their continuing participation. ## Revision History 16 March 2023 (aa) Revision: 28 January 2021 (ha) Comprehensive update posted live 12 February 2015 (me) Comprehensive update posted live 23 September 2010 (me) Comprehensive update posted live 19 March 2009 (me) Review posted live 10 September 2008 (lvm) Original submission • 16 March 2023 (aa) Revision: • 28 January 2021 (ha) Comprehensive update posted live • 12 February 2015 (me) Comprehensive update posted live • 23 September 2010 (me) Comprehensive update posted live • 19 March 2009 (me) Review posted live • 10 September 2008 (lvm) Original submission ## References ## Literature Cited
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19/3/2009
28/1/2021
16/3/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
cvt
cvt
[ "Catecholamine-Induced Polymorphic Ventricular Tachycardia", "CPVT", "CPVT", "Catecholamine-Induced Polymorphic Ventricular Tachycardia", "Calmodulin", "Calmodulin-3", "Calsequestrin-2", "Inward rectifier potassium channel 2", "Ryanodine receptor 2", "Trans-2,3-enoyl-CoA reductase-like", "Triadin", "CALM1", "CALM2", "CALM3", "CASQ2", "KCNJ2", "RYR2", "TECRL", "TRDN", "Catecholaminergic Polymorphic Ventricular Tachycardia" ]
Catecholaminergic Polymorphic Ventricular Tachycardia
Carlo Napolitano, Andrea Mazzanti, Raffaella Bloise, Silvia G Priori
Summary Catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). Spontaneous recovery may occur when these arrhythmias self-terminate. In other instances, ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. The mean onset of symptoms (usually a syncopal episode) is between age seven and 12 years; onset as late as the fourth decade of life has been reported. If untreated, CPVT is highly lethal, as approximately 30% of affected individuals experience at least one cardiac arrest and up to 80% have one or more syncopal spells. Sudden death may be the first manifestation of the disease. The diagnosis of CPVT is established in the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia OR in individuals who have a heterozygous pathogenic variant in Once the CPVT-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
## Diagnosis Catecholaminergic polymorphic ventricular tachycardia (CPVT) Syncope occurring during physical activity or acute emotion; mean onset is age seven to 12 years. Less frequently, first manifestations may occur later in life; individuals with a first event up to age 40 years have been reported. History of exercise- or emotion-related palpitations and dizziness in some individuals Sudden unexpected cardiac death triggered by acute emotional stress or exercise Family history of juvenile sudden cardiac death triggered by exercise or acute emotion Exercise-induced bidirectional or polymorphic ventricular arrhythmias EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ Ventricular fibrillation occurring in the setting of acute stress * Note: The resting EKG of individuals with CPVT is usually normal. Some authors have reported a lower-than-normal resting heart rate [ According to the most recent version of the International Guidelines on Sudden Cardiac Death [ In the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia; OR In individuals who have a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable 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 Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Exon 3 Approximately 25% of individuals with CPVT have no pathogenic variant identified in any of the known genes listed in this table [ • Syncope occurring during physical activity or acute emotion; mean onset is age seven to 12 years. Less frequently, first manifestations may occur later in life; individuals with a first event up to age 40 years have been reported. • History of exercise- or emotion-related palpitations and dizziness in some individuals • Sudden unexpected cardiac death triggered by acute emotional stress or exercise • Family history of juvenile sudden cardiac death triggered by exercise or acute emotion • Exercise-induced bidirectional or polymorphic ventricular arrhythmias • EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ • Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ • EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ • Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ • Ventricular fibrillation occurring in the setting of acute stress • EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ • Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ • In the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia; • OR • In individuals who have a heterozygous pathogenic (or likely pathogenic) variant in • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Catecholaminergic polymorphic ventricular tachycardia (CPVT) Syncope occurring during physical activity or acute emotion; mean onset is age seven to 12 years. Less frequently, first manifestations may occur later in life; individuals with a first event up to age 40 years have been reported. History of exercise- or emotion-related palpitations and dizziness in some individuals Sudden unexpected cardiac death triggered by acute emotional stress or exercise Family history of juvenile sudden cardiac death triggered by exercise or acute emotion Exercise-induced bidirectional or polymorphic ventricular arrhythmias EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ Ventricular fibrillation occurring in the setting of acute stress * Note: The resting EKG of individuals with CPVT is usually normal. Some authors have reported a lower-than-normal resting heart rate [ • Syncope occurring during physical activity or acute emotion; mean onset is age seven to 12 years. Less frequently, first manifestations may occur later in life; individuals with a first event up to age 40 years have been reported. • History of exercise- or emotion-related palpitations and dizziness in some individuals • Sudden unexpected cardiac death triggered by acute emotional stress or exercise • Family history of juvenile sudden cardiac death triggered by exercise or acute emotion • Exercise-induced bidirectional or polymorphic ventricular arrhythmias • EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ • Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ • EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ • Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ • Ventricular fibrillation occurring in the setting of acute stress • EKG during a graded exercise (exercise stress test) * allows ventricular arrhythmias to be reproducibly elicited in the majority of affected individuals. Typically, the onset of ventricular arrhythmias is 90-120 beats per minute. • With increase in workload, the complexity of arrhythmias progressively increases from isolated premature beats to bigeminy and runs of non-sustained ventricular tachycardia (VT). If the affected individual continues exercising, the duration of the runs of VT progressively increases and VT may become sustained. • An alternating 180°-QRS axis on a beat-to-beat basis, so-called bidirectional VT, is often the distinguishing presentation of CPVT arrhythmias [ • Notably, some individuals with CPVT may also present with irregular polymorphic VT without a "stable" QRS vector alternans [ • Exercise-induced supraventricular arrhythmias (supraventricular tachycardia and atrial fibrillation) are common [ ## Establishing the Diagnosis According to the most recent version of the International Guidelines on Sudden Cardiac Death [ In the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia; OR In individuals who have a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable 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 Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. Exon 3 Approximately 25% of individuals with CPVT have no pathogenic variant identified in any of the known genes listed in this table [ • In the presence of a structurally normal heart, normal resting EKG, and exercise- or emotion-induced bidirectional or polymorphic ventricular tachycardia; • OR • In individuals who have a heterozygous pathogenic (or likely pathogenic) variant in • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system. If untreated the disease is highly lethal, as approximately 30% of those affected experience at least one cardiac arrest and up to 80% have one or more syncopal spells. Few clinical studies [ Spontaneous recovery may occur when these arrhythmias self-terminate; OR VT may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. Sudden death may be the first manifestation of the disorder in previously asymptomatic individuals (no history of syncope or dizziness) who die suddenly during exercise or while experiencing acute emotions [ Instances of sudden infant death syndrome have been associated with pathogenic variants in The typical CPVT phenotype is caused by the presence of pathogenic variants in Atypical CPVT is caused by pathogenic variants in the "rare" genes: Preliminary observations suggest that * Although all Gain-of-function pathogenic variants in No genotype-phenotype correlations for The mean penetrance of CPVT has also been referred to as familial polymorphic ventricular tachycardia (FPVT). The true prevalence of CPVT in the population is not known. An estimate of CPVT prevalence is 1:10,000 or less. The high prevalence of simplex cases (i.e., single occurrences in a family) and lethality at a young age suggest that the overall prevalence of CPVT is significantly lower than that of other inherited arrhythmogenic disorders such as • Spontaneous recovery may occur when these arrhythmias self-terminate; • OR • VT may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. • Preliminary observations suggest that ## Clinical Description Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system. If untreated the disease is highly lethal, as approximately 30% of those affected experience at least one cardiac arrest and up to 80% have one or more syncopal spells. Few clinical studies [ Spontaneous recovery may occur when these arrhythmias self-terminate; OR VT may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. Sudden death may be the first manifestation of the disorder in previously asymptomatic individuals (no history of syncope or dizziness) who die suddenly during exercise or while experiencing acute emotions [ Instances of sudden infant death syndrome have been associated with pathogenic variants in • Spontaneous recovery may occur when these arrhythmias self-terminate; • OR • VT may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available. ## Phenotype Correlations by Gene The typical CPVT phenotype is caused by the presence of pathogenic variants in Atypical CPVT is caused by pathogenic variants in the "rare" genes: Preliminary observations suggest that * Although all • Preliminary observations suggest that ## Genotype-Phenotype Correlations Gain-of-function pathogenic variants in No genotype-phenotype correlations for ## Penetrance The mean penetrance of ## Nomenclature CPVT has also been referred to as familial polymorphic ventricular tachycardia (FPVT). ## Prevalence The true prevalence of CPVT in the population is not known. An estimate of CPVT prevalence is 1:10,000 or less. The high prevalence of simplex cases (i.e., single occurrences in a family) and lethality at a young age suggest that the overall prevalence of CPVT is significantly lower than that of other inherited arrhythmogenic disorders such as ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in catecholaminergic polymorphic ventricular tachycardia-related genes are summarized in Allelic Disorders CPVT = catecholaminergic polymorphic ventricular tachycardia; LVNC = left ventricular non-compaction Genes are listed in alphabetic order. ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Catecholaminergic Polymorphic Ventricular Tachycardia AD = autosomal dominant; AR = autosomal recessive; CPVT = catecholaminergic polymorphic ventricular tachycardia; LQTS = long QT syndrome; MOI = mode of inheritance; VT = ventricular tachycardia ARVC is usually inherited in an autosomal dominant manner. It can also be inherited in a digenic or autosomal recessive manner. ## Management To establish the extent of disease and needs in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia CPVT = catecholaminergic polymorphic ventricular tachycardia; MOI = mode of inheritance Exercise stress test should be performed until maximal tolerated effort, as some individuals have high heart rate threshold for induction of arrhythmias. Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management of CPVT is summarized in a specific consensus document from the Heart Rhythm Association (HRS) and the European Heart Rhythm Association (EHRA) [ Treatment of Manifestations in Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia Nadolol is reported to be more effective than selective beta blockers [ Chronic treatment w/full-dose beta-blocking agents prevents recurrence of syncope in majority of affected persons. Dose needs to be individualized w/exercise stress testing & efficacy periodically retested (see Can be given along w/beta blockers to persons who have syncope recurrence or complex arrhythmias during exercise Beta blockers & flecainide together are also indicated for affected persons who have experienced a previous aborted sudden death, to ↓ probability of ICD shocks. The antiarrhythmic effects of flecainide appear to be independent of specific CPVT genetic subtype. May be considered in those w/several appropriate ICD shocks while on beta blocker & flecainide & in those who are intolerant of or w/contraindication to beta-blocker therapy. Side effects incl palpebral ptosis, ↑ of left hemidiaphragm, & lack of sweating from left arm & face. Recurrence of cardiac events may occur even w/LCSD, so it cannot be considered an alternative to ICD. ICD = implantable cardioverter defibrillator; LCSD = left cardiac sympathetic denervation Beta blockers are indicated for primary prevention in all clinically affected individuals (see Management, Recommended Surveillance for Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia Resting EKG Exercise stress test, performed at maximal age-predicted heart rate. For those on beta-blocker therapy (in whom maximal heart rate cannot be reached), test should be performed at highest tolerated workload. Holter monitoring Echocardiogram & MRI at least every 2 yrs Every 6-12 mos (per severity of clinical manifestations) Follow-up visits are very important esp until puberty, as body weight ↑ rapidly & drug dosages must be continually adjusted. Can be defined on basis of exercise stress test done in hospital setting Use of commercially available heart rate monitoring devices for sports participation can be helpful in keeping heart rate in safe range during physical activity but should not be considered as alternative to medical follow-up visits. Since heart rate threshold for onset of arrhythmias is often reproducible in the same person, the advice for allowed exercise intensity should be individualized based on results of exercise stress test. Competitive sports and other strenuous exercise are always contraindicated for individuals with CPVT. All individuals showing exercise-induced arrhythmias should avoid physical activity, except for light training for those individuals showing good suppression of arrhythmias on exercise stress testing while on therapy. It is important to note that efficacy needs to be periodically retested [ Digitalis favors the onset of cardiac arrhythmias as a result of delayed afterdepolarization and triggered activity; therefore, digitalis should be avoided in all individuals with CPVT. Because treatment and surveillance are available to reduce morbidity and mortality, first-degree relatives should be offered clinical evaluation and molecular genetic testing if the family-specific pathogenic variant(s) are known. The availability of effective preventive therapies can reduce the number of fatal arrhythmic events if individuals with pathogenic variants are diagnosed early. If the family-specific pathogenic variant(s) are not known, all first-degree relatives of an affected individual should be evaluated with resting EKG, Holter monitoring, echocardiography, and – most importantly – exercise stress testing. See Beta blockers (preferentially nadolol or propranolol) should be administered throughout pregnancy in affected women. See Search • Nadolol is reported to be more effective than selective beta blockers [ • Chronic treatment w/full-dose beta-blocking agents prevents recurrence of syncope in majority of affected persons. • Dose needs to be individualized w/exercise stress testing & efficacy periodically retested (see • Can be given along w/beta blockers to persons who have syncope recurrence or complex arrhythmias during exercise • Beta blockers & flecainide together are also indicated for affected persons who have experienced a previous aborted sudden death, to ↓ probability of ICD shocks. • The antiarrhythmic effects of flecainide appear to be independent of specific CPVT genetic subtype. • May be considered in those w/several appropriate ICD shocks while on beta blocker & flecainide & in those who are intolerant of or w/contraindication to beta-blocker therapy. • Side effects incl palpebral ptosis, ↑ of left hemidiaphragm, & lack of sweating from left arm & face. • Recurrence of cardiac events may occur even w/LCSD, so it cannot be considered an alternative to ICD. • Resting EKG • Exercise stress test, performed at maximal age-predicted heart rate. For those on beta-blocker therapy (in whom maximal heart rate cannot be reached), test should be performed at highest tolerated workload. • Holter monitoring • Echocardiogram & MRI at least every 2 yrs • Every 6-12 mos (per severity of clinical manifestations) • Follow-up visits are very important esp until puberty, as body weight ↑ rapidly & drug dosages must be continually adjusted. • Can be defined on basis of exercise stress test done in hospital setting • Use of commercially available heart rate monitoring devices for sports participation can be helpful in keeping heart rate in safe range during physical activity but should not be considered as alternative to medical follow-up visits. • Since heart rate threshold for onset of arrhythmias is often reproducible in the same person, the advice for allowed exercise intensity should be individualized based on results of exercise stress test. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia CPVT = catecholaminergic polymorphic ventricular tachycardia; MOI = mode of inheritance Exercise stress test should be performed until maximal tolerated effort, as some individuals have high heart rate threshold for induction of arrhythmias. Medical geneticist, certified genetic counselor, certified advanced genetic nurse ## Treatment of Manifestations Management of CPVT is summarized in a specific consensus document from the Heart Rhythm Association (HRS) and the European Heart Rhythm Association (EHRA) [ Treatment of Manifestations in Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia Nadolol is reported to be more effective than selective beta blockers [ Chronic treatment w/full-dose beta-blocking agents prevents recurrence of syncope in majority of affected persons. Dose needs to be individualized w/exercise stress testing & efficacy periodically retested (see Can be given along w/beta blockers to persons who have syncope recurrence or complex arrhythmias during exercise Beta blockers & flecainide together are also indicated for affected persons who have experienced a previous aborted sudden death, to ↓ probability of ICD shocks. The antiarrhythmic effects of flecainide appear to be independent of specific CPVT genetic subtype. May be considered in those w/several appropriate ICD shocks while on beta blocker & flecainide & in those who are intolerant of or w/contraindication to beta-blocker therapy. Side effects incl palpebral ptosis, ↑ of left hemidiaphragm, & lack of sweating from left arm & face. Recurrence of cardiac events may occur even w/LCSD, so it cannot be considered an alternative to ICD. ICD = implantable cardioverter defibrillator; LCSD = left cardiac sympathetic denervation • Nadolol is reported to be more effective than selective beta blockers [ • Chronic treatment w/full-dose beta-blocking agents prevents recurrence of syncope in majority of affected persons. • Dose needs to be individualized w/exercise stress testing & efficacy periodically retested (see • Can be given along w/beta blockers to persons who have syncope recurrence or complex arrhythmias during exercise • Beta blockers & flecainide together are also indicated for affected persons who have experienced a previous aborted sudden death, to ↓ probability of ICD shocks. • The antiarrhythmic effects of flecainide appear to be independent of specific CPVT genetic subtype. • May be considered in those w/several appropriate ICD shocks while on beta blocker & flecainide & in those who are intolerant of or w/contraindication to beta-blocker therapy. • Side effects incl palpebral ptosis, ↑ of left hemidiaphragm, & lack of sweating from left arm & face. • Recurrence of cardiac events may occur even w/LCSD, so it cannot be considered an alternative to ICD. ## Prevention of Primary Manifestations Beta blockers are indicated for primary prevention in all clinically affected individuals (see Management, ## Surveillance Recommended Surveillance for Individuals with Catecholaminergic Polymorphic Ventricular Tachycardia Resting EKG Exercise stress test, performed at maximal age-predicted heart rate. For those on beta-blocker therapy (in whom maximal heart rate cannot be reached), test should be performed at highest tolerated workload. Holter monitoring Echocardiogram & MRI at least every 2 yrs Every 6-12 mos (per severity of clinical manifestations) Follow-up visits are very important esp until puberty, as body weight ↑ rapidly & drug dosages must be continually adjusted. Can be defined on basis of exercise stress test done in hospital setting Use of commercially available heart rate monitoring devices for sports participation can be helpful in keeping heart rate in safe range during physical activity but should not be considered as alternative to medical follow-up visits. Since heart rate threshold for onset of arrhythmias is often reproducible in the same person, the advice for allowed exercise intensity should be individualized based on results of exercise stress test. • Resting EKG • Exercise stress test, performed at maximal age-predicted heart rate. For those on beta-blocker therapy (in whom maximal heart rate cannot be reached), test should be performed at highest tolerated workload. • Holter monitoring • Echocardiogram & MRI at least every 2 yrs • Every 6-12 mos (per severity of clinical manifestations) • Follow-up visits are very important esp until puberty, as body weight ↑ rapidly & drug dosages must be continually adjusted. • Can be defined on basis of exercise stress test done in hospital setting • Use of commercially available heart rate monitoring devices for sports participation can be helpful in keeping heart rate in safe range during physical activity but should not be considered as alternative to medical follow-up visits. • Since heart rate threshold for onset of arrhythmias is often reproducible in the same person, the advice for allowed exercise intensity should be individualized based on results of exercise stress test. ## Agents/Circumstances to Avoid Competitive sports and other strenuous exercise are always contraindicated for individuals with CPVT. All individuals showing exercise-induced arrhythmias should avoid physical activity, except for light training for those individuals showing good suppression of arrhythmias on exercise stress testing while on therapy. It is important to note that efficacy needs to be periodically retested [ Digitalis favors the onset of cardiac arrhythmias as a result of delayed afterdepolarization and triggered activity; therefore, digitalis should be avoided in all individuals with CPVT. ## Evaluation of Relatives at Risk Because treatment and surveillance are available to reduce morbidity and mortality, first-degree relatives should be offered clinical evaluation and molecular genetic testing if the family-specific pathogenic variant(s) are known. The availability of effective preventive therapies can reduce the number of fatal arrhythmic events if individuals with pathogenic variants are diagnosed early. If the family-specific pathogenic variant(s) are not known, all first-degree relatives of an affected individual should be evaluated with resting EKG, Holter monitoring, echocardiography, and – most importantly – exercise stress testing. See ## Pregnancy Management Beta blockers (preferentially nadolol or propranolol) should be administered throughout pregnancy in affected women. See ## Therapies Under Investigation Search ## Genetic Counseling Approximately 50% of individuals with autosomal dominant CPVT have an affected parent. A proband with autosomal dominant CPVT may have the disorder as the result of a If the proband is the only family member known to have CPVT, recommendations for the evaluation of the parents of a proband include a maximal exercise stress test and molecular genetic testing if a molecular diagnosis has been established in the proband. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) The family history of some individuals diagnosed with autosomal dominant CPVT 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 reduced penetrance. 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 is 50%. If the proband has a known CPVT-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 are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CPVT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. The parents of an affected child are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CPVT-related pathogenic variant and to allow reliable recurrence risk assessment. A maximal exercise stress test can also be considered for the parents of a proband with autosomal recessive CPVT. 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. Individuals who are heterozygous for a pathogenic variant in If both parents are known to be heterozygous for a Individuals who are heterozygous for a pathogenic variant in Heterozygote testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the CPVT-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CPVT 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. • Approximately 50% of individuals with autosomal dominant CPVT have an affected parent. • A proband with autosomal dominant CPVT may have the disorder as the result of a • If the proband is the only family member known to have CPVT, recommendations for the evaluation of the parents of a proband include a maximal exercise stress test and molecular genetic testing if a molecular diagnosis has been established in the proband. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) • The family history of some individuals diagnosed with autosomal dominant CPVT 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 reduced penetrance. 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. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) • 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 CPVT-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 are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CPVT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CPVT-related pathogenic variant and to allow reliable recurrence risk assessment. A maximal exercise stress test can also be considered for the parents of a proband with autosomal recessive CPVT. • 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. • Individuals who are heterozygous for a pathogenic variant in • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • Individuals who are heterozygous for a pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Autosomal Dominant Inheritance – Risk to Family Members Approximately 50% of individuals with autosomal dominant CPVT have an affected parent. A proband with autosomal dominant CPVT may have the disorder as the result of a If the proband is the only family member known to have CPVT, recommendations for the evaluation of the parents of a proband include a maximal exercise stress test and molecular genetic testing if a molecular diagnosis has been established in the proband. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) The family history of some individuals diagnosed with autosomal dominant CPVT 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 reduced penetrance. 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 is 50%. If the proband has a known CPVT-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 are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CPVT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Approximately 50% of individuals with autosomal dominant CPVT have an affected parent. • A proband with autosomal dominant CPVT may have the disorder as the result of a • If the proband is the only family member known to have CPVT, recommendations for the evaluation of the parents of a proband include a maximal exercise stress test and molecular genetic testing if a molecular diagnosis has been established in the proband. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) • The family history of some individuals diagnosed with autosomal dominant CPVT 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 reduced penetrance. 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. 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. (Note: Parental mosaicism for a CPVT-related pathogenic variant has not been reported to date.) • 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 CPVT-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 are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for CPVT 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 an affected child are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CPVT-related pathogenic variant and to allow reliable recurrence risk assessment. A maximal exercise stress test can also be considered for the parents of a proband with autosomal recessive CPVT. 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. Individuals who are heterozygous for a pathogenic variant in If both parents are known to be heterozygous for a Individuals who are heterozygous for a pathogenic variant in Heterozygote testing for at-risk relatives requires prior identification of the • The parents of an affected child are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a CPVT-related pathogenic variant and to allow reliable recurrence risk assessment. A maximal exercise stress test can also be considered for the parents of a proband with autosomal recessive CPVT. • 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. • Individuals who are heterozygous for a pathogenic variant in • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 • Individuals who are heterozygous for a pathogenic variant in ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are 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 CPVT-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CPVT are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart SADS UK United Kingdom Italian Association of Families with Inherited Arrhythmias Via Salvatore Maugeri 27100 Pavia Italy • • • • • • Canada • • • European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart • • • • • SADS UK • United Kingdom • • • Italian Association of Families with Inherited Arrhythmias • Via Salvatore Maugeri • 27100 Pavia • Italy ## Molecular Genetics Catecholaminergic Polymorphic Ventricular Tachycardia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Catecholaminergic Polymorphic Ventricular Tachycardia ( Few studies have functionally assessed the effect of pathogenic variants in In order to activate the DAD-TA arrhythmogenesis, the RyR2 channel is destabilized during the diastolic phase with a consequent leakage of calcium ions that follow the concentration gradient from the SR (high concentration) to the cytosol (low concentration). This condition is therefore the result of a gain-of-function effect. A leaky RyR2 channel can be caused by While the functional consequence of A subset of ## Molecular Pathogenesis Few studies have functionally assessed the effect of pathogenic variants in In order to activate the DAD-TA arrhythmogenesis, the RyR2 channel is destabilized during the diastolic phase with a consequent leakage of calcium ions that follow the concentration gradient from the SR (high concentration) to the cytosol (low concentration). This condition is therefore the result of a gain-of-function effect. A leaky RyR2 channel can be caused by While the functional consequence of A subset of ## Chapter Notes SG Priori's We acknowledge the contribution of the European Research Council (ERC) and the EU-Rhythmy CPVT research project for the development of gene therapies for CPVT and calcium-related sudden death syndromes. 23 June 2022 (ha/sw) Comprehensive update posted live 13 October 2016 (sw) Comprehensive update posted live 6 March 2014 (me) Comprehensive update posted live 7 February 2013 (cd) Revision: multigene panels now listed in the GeneTests™ Laboratory Directory; mutations in 16 February 2012 (me) Comprehensive update posted live 7 July 2009 (me) Comprehensive update posted live 22 March 2007 (me) Comprehensive update posted live 22 May 2006 (cn) Revision: Prenatal diagnosis available for 14 October 2004 (me) Review posted live 1 June 2004 (cn) Original submission • 23 June 2022 (ha/sw) Comprehensive update posted live • 13 October 2016 (sw) Comprehensive update posted live • 6 March 2014 (me) Comprehensive update posted live • 7 February 2013 (cd) Revision: multigene panels now listed in the GeneTests™ Laboratory Directory; mutations in • 16 February 2012 (me) Comprehensive update posted live • 7 July 2009 (me) Comprehensive update posted live • 22 March 2007 (me) Comprehensive update posted live • 22 May 2006 (cn) Revision: Prenatal diagnosis available for • 14 October 2004 (me) Review posted live • 1 June 2004 (cn) Original submission ## Author Notes SG Priori's ## Acknowledgments We acknowledge the contribution of the European Research Council (ERC) and the EU-Rhythmy CPVT research project for the development of gene therapies for CPVT and calcium-related sudden death syndromes. ## Revision History 23 June 2022 (ha/sw) Comprehensive update posted live 13 October 2016 (sw) Comprehensive update posted live 6 March 2014 (me) Comprehensive update posted live 7 February 2013 (cd) Revision: multigene panels now listed in the GeneTests™ Laboratory Directory; mutations in 16 February 2012 (me) Comprehensive update posted live 7 July 2009 (me) Comprehensive update posted live 22 March 2007 (me) Comprehensive update posted live 22 May 2006 (cn) Revision: Prenatal diagnosis available for 14 October 2004 (me) Review posted live 1 June 2004 (cn) Original submission • 23 June 2022 (ha/sw) Comprehensive update posted live • 13 October 2016 (sw) Comprehensive update posted live • 6 March 2014 (me) Comprehensive update posted live • 7 February 2013 (cd) Revision: multigene panels now listed in the GeneTests™ Laboratory Directory; mutations in • 16 February 2012 (me) Comprehensive update posted live • 7 July 2009 (me) Comprehensive update posted live • 22 March 2007 (me) Comprehensive update posted live • 22 May 2006 (cn) Revision: Prenatal diagnosis available for • 14 October 2004 (me) Review posted live • 1 June 2004 (cn) Original submission ## References Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220. Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Available Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C; Document Reviewers, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Available Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES; ESC Scientific Document Group. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm. 2022;38:491-553. • Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220. • Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Available • Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C; Document Reviewers, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Available • Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES; ESC Scientific Document Group. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm. 2022;38:491-553. ## Published Guidelines / Consensus Statements Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220. Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Available Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C; Document Reviewers, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Available Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES; ESC Scientific Document Group. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm. 2022;38:491-553. • Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2018;72:e91-e220. • Priori SG, Blomström-Lundqvist C, Mazzanti A, Blom N, Borggrefe M, Camm J, Elliott PM, Fitzsimons D, Hatala R, Hindricks G, Kirchhof P, Kjeldsen K, Kuck KH, Hernandez-Madrid A, Nikolaou N, Norekvål TM, Spaulding C, Van Veldhuisen DJ. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC). Available • Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C; Document Reviewers, Ackerman M, Belhassen B, Estes NA 3rd, Fatkin D, Kalman J, Kaufman E, Kirchhof P, Schulze-Bahr E, Wolpert C, Vohra J, Refaat M, Etheridge SP, Campbell RM, Martin ET, Quek SC. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Available • Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES; ESC Scientific Document Group. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. J Arrhythm. 2022;38:491-553. ## Literature Cited
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J Am Coll Cardiol 1999;34:2015-22", "R Fischer, M Koller, M Flura, S Mathews, MA Strehler-Page, J Krebs, JT Penniston, E Carafoli, EE Strehler. Multiple divergent mRNAs code for a single human calmodulin.. J Biol Chem. 1988;263:17055-62", "CH George, GV Higgs, FA Lai. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes.. Circ Res 2003;93:531-40", "JR Giudicessi, MJ Ackerman. Exercise testing oversights underlie missed and delayed diagnosis of catecholaminergic polymorphic ventricular tachycardia in young sudden cardiac arrest survivors.. Heart Rhythm. 2019;16:1232-9", "N Gomez-Hurtado, NJ Boczek, DO Kryshtal, CN Johnson, J Sun, FR Nitu, RL Cornea, WJ Chazin, ML Calvert, DJ Tester, MJ Ackerman, BC Knollmann. Novel CPVT-associated calmodulin mutation in CALM3 (CALM3-A103V) activates arrhythmogenic Ca waves and sparks.. Circ Arrhythm Electrophysiol. 2016:9", "H Heidbüchel, D Corrado, A Biffi, E Hoffmann, N Panhuyzen-Goedkoop, J Hoogsteen, P Delise, PI Hoff, A Pelliccia. Recommendations for participation in leisure-time physical activity and competitive sports of patients with arrhythmias and potentially arrhythmogenic conditions. Part II: ventricular arrhythmias, channelopathies and implantable defibrillators.. Eur J Cardiovasc Prev Rehabil 2006;13:676-86", "C Hou, X Jiang, H Zhang, J Zheng, Q Qiu, Y Zhang, X Sun, M Xu, ACY Chang, L Xie, T Xiao. TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes.. Commun Biol. 2022;5:470", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. J Community Genet. 2022;13:389-97", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "U Kohli, Z Aziz, AD Beaser, HM Nayak. A large deletion in RYR2 exon 3 is associated with nadolol and flecainide refractory catecholaminergic polymorphic ventricular tachycardia.. Pacing Clin Electrophysiol. 2019;42:1146-54", "U Kohli, L Kuntz, HM Nayak. RYR2 p.R169L mutation and left ventricular hypertrophy in a child with emotion-triggered sudden death.. Cardiol Young. 2020;30:1039-42", "AD Krahn, M Gollob, R Yee, LJ Gula, AC Skanes, BD Walker, GJ Klein. Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.. Circulation 2005;112:2228-34", "A Leenhardt, V Lucet, I Denjoy, F Grau, DD Ngoc, P Coumel. Catecholaminergic polymorphic ventricular tachycardia in children. A 7-year follow-up of 21 patients.. Circulation 1995;91:1512-9", "IS Leren, J Saberniak, E Majid, TF Haland, T Edvardsen, KH Haugaa. Nadolol decreases the incidence and severity of ventricular arrhythmias during exercise stress testing compared with β1-selective β-blockers in patients with catecholaminergic polymorphic ventricular tachycardia.. Heart Rhythm. 2016;13:433-40", "A Mazzanti, D Kukavica, A Trancuccio, M Memmi, R Bloise, P Gambelli, M Marino, M Ortíz-Genga, M Morini, N Monteforte, U Giordano, R Keegan, L Tomasi, A Anastasakis, AM Davis, W Shimizu, NA Blom, DJ Santiago, C Napolitano, L Monserrat, SG Priori. Outcomes of patients with catecholaminergic polymorphic ventricular tachycardia treated with β-blockers.. JAMA Cardiol. 2022;7:504-12", "A Moscu-Gregor, C Marschall, C Müntjes, A Schönecker, F Schuessler-Hahn, F Hohendanner, AS Parwani, LH Boldt, CE Ott, A Bennewiz, T Paul, U Krause, I Rost. Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms.. J Cardiovasc Electrophysiol. 2020;31:1527-35", "S Ohno, M Omura, M Kawamura, H Kimura, H Itoh, T Makiyama, H Ushinohama, N Makita, M. Horie. Exon 3 deletion of RYR2 encoding cardiac ryanodine receptor is associated with left ventricular non-compaction.. Europace. 2014;16:1646-54", "PJ Peltenburg, D Kallas, JM Bos, KVV Lieve, S Franciosi, TM Roston, I Denjoy, KB Sorensen, S Ohno, F Roses-Noguer, T Aiba, A Maltret, MJ LaPage, J Atallah, JR Giudicessi, SB Clur, NA Blom, M Tanck, F Extramiana, K Kato, J Barc, M Borggrefe, ER Behr, G Sarquella-Brugada, J Tfelt-Hansen, E Zorio, H Swan, JAE Kammeraad, AD Krahn, A Davis, F Sacher, PJ Schwartz, JD Roberts, JR Skinner, MP van den Berg, PJ Kannankeril, F Drago, T Robyns, K Haugaa, T Tavacova, C Semsarian, J Till, V Probst, R Brugada, W Shimizu, M Horie, A Leenhardt, MJ Ackerman, S Sanatani, C van der Werf, AAM Wilde. An international multicenter cohort study on β-blockers for the treatment of symptomatic children with catecholaminergic polymorphic ventricular tachycardia.. Circulation. 2022;145:333-44", "AV Postma, ZA Bhuiyan, H Bikker. Molecular diagnostics of catecholaminergic polymorphic ventricular tachycardia using denaturing high-performance liquid chromatography and sequencing.. Methods Mol Med 2006;126:171-83", "AV Postma, I Denjoy, J Kamblock, M Alders, JM Lupoglazoff, G Vaksmann, L Dubosq-Bidot, P Sebillon, MM Mannens, P Guicheney, AA Wilde. Catecholaminergic polymorphic ventricular tachycardia: RYR2 mutations, bradycardia, and follow up of the patients.. J Med Genet 2005;42:863-70", "O Prakash, M Held, LF McCormick, N Gupta, LY Lian, S Antonyuk, LP Haynes, NL Thomas, N Helassa. CPVT-associated calmodulin variants N53I and A102V dysregulate Ca2+ signalling via different mechanisms.. J Cell Sci. 2022;135", "SG Priori, C Blomström-Lundqvist, A Mazzanti, N Blom, M Borggrefe, J Camm, PM Elliott, D Fitzsimons, R Hatala, G Hindricks, P Kirchhof, K Kjeldsen, KH Kuck, A Hernandez-Madrid, N Nikolaou, TM Norekvål, C Spaulding, DJ Van Veldhuisen. 2015 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology (ESC). Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC).. Eur Heart J. 2015;36:2793-867", "SG Priori, SR Chen. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis.. Circ Res. 2011;108:871-83", "SG Priori, A Mazzanti, DJ Santiago, D Kukavica, A Trancuccio, JC Kovacic. Precision medicine in catecholaminergic polymorphic ventricular tachycardia: JACC Focus Seminar 5/5.. J Am Coll Cardiol. 2021;77:2592-612", "SG Priori, C Napolitano, M Memmi, B Colombi, F Drago, M Gasparini, L DeSimone, F Coltorti, R Bloise, R Keegan, FE Cruz Filho, G Vignati, A Benatar, A DeLogu. Clinical and molecular characterization of patients with catecholaminergic polymorphic ventricular tachycardia.. Circulation 2002;106:69-74", "SG Priori, AA Wilde, M Horie, Y Cho, ER Behr, C Berul, N Blom, J Brugada, CE Chiang, H Huikuri, P Kannankeril, A Krahn, A Leenhardt, A Moss, PJ Schwartz, W Shimizu, G Tomaselli, C Tracy. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm. 2013a;10:1932-63", "SG Priori, AA Wilde, M Horie, Y Cho, ER Behr, C Berul, N Blom, J Brugada, CE Chiang, H Huikuri, P Kannankeril, A Krahn, A Leenhardt, A Moss, PJ Schwartz, W Shimizu, G Tomaselli, C Tracy. Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes.. Europace. 2013b;15:1389-406", "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", "TM Roston, Z Yuchi, PJ Kannankeril, J Hathaway, JM Vinocur, SP Etheridge, JE Potts, KR Maginot, JC Salerno, MI Cohen, RM Hamilton, A Pflaumer, S Mohammed, L Kimlicka, RJ Kanter, MJ LaPage, KK Collins, RA Gebauer, JD Temple, AS Batra, C Erickson, M Miszczak-Knecht, P Kubuš, Y Bar-Cohen, M Kantoch, VC Thomas, G Hessling, C Anderson, ML Young, SHJ Choi, M Cabrera Ortega, YR Lau, CL Johnsrude, A Fournier, F Van Petegem, S Sanatani. The clinical and genetic spectrum of catecholaminergic polymorphic ventricular tachycardia: findings from an international multicentre registry.. Europace. 2018;20:541-7", "G Santulli, G Pagano, C Sardu, W Xie, S Reiken, SL D'Ascia, M Cannone, N Marziliano, B Trimarco, TA Guise, A Lacampagne, AR Marks. Calcium release channel RyR2 regulates insulin release and glucose homeostasis.. J Clin Invest. 2015;125:1968-78", "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", "H Swan, K Piippo, M Viitasalo, P Heikkila, T Paavonen, K Kainulainen, J Kere, P Keto, K Kontula, L Toivonen. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.. J Am Coll Cardiol 1999;34:2035-42", "DJ Tester, P Arya, M Will, CM Haglund, AL Farley, JC Makielski, MJ Ackerman. Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing.. Heart Rhythm 2006;3:800-5", "DJ Tester, M Dura, E Carturan, S Reiken, A Wronska, AR Marks, MJ Ackerman. A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.. Heart Rhythm. 2007;4:733-9", "H Watanabe, C van der Werf, F Roses-Noguer, A Adler, N Sumitomo, C Veltmann, R Rosso, ZA Bhuiyan, H Bikker, PJ Kannankeril, M Horie, T Minamino, S Viskin, BC Knollmann, J Till, AA Wilde. Effects of flecainide on exercise-induced ventricular arrhythmias and recurrences in genotype-negative patients with catecholaminergic polymorphic ventricular tachycardia.. Heart Rhythm. 2013;10:542-7", "AAM Wilde, C Semsarian, MF Márquez, A Sepehri Shamloo, MJ Ackerman, EA Ashley, EB Sternick, H Barajas-Martinez, ER Behr, CR Bezzina, J Breckpot, P Charron, P Chockalingam, L Crotti, MH Gollob, S Lubitz, N Makita, S Ohno, M Ortiz-Genga, L Sacilotto, E Schulze-Bahr, W Shimizu, N Sotoodehnia, R Tadros, JS Ware, DS Winlaw, ES Kaufman. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.. J Arrhythm. 2022;38:491-553", "X Zhong, W Guo, J Wei, Y Tang, Y Liu, JZ Zhang, VH Tan, L Zhang, R Wang, PP Jones, C Napolitano, SG Priori, SRW Chen. Identification of loss-of-function RyR2 mutations associated with idiopathic ventricular fibrillation and sudden death.. Biosci Rep. 2021;41" ]
14/10/2004
23/6/2022
7/2/2013
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
cyclic-n
cyclic-n
[ "Cyclic Neutropenia", "Congenital Neutropenia", "Neutrophil elastase", "ELANE", "ELANE-Related Neutropenia" ]
David C Dale, Vahagn Makaryan
Summary In congenital neutropenia, omphalitis immediately after birth may be the first sign; in untreated children diarrhea, pneumonia, and deep abscesses in the liver, lungs, and subcutaneous tissues are common in the first year of life. After 15 years with granulocyte colony-stimulating factor treatment, the risk of developing myelodysplasia (MDS) or acute myelogenous leukemia (AML) is approximately 15%-25%. Cyclic neutropenia is usually diagnosed within the first year of life based on approximately three-week intervals of fever and oral ulcerations and regular oscillations of blood cell counts. Cellulitis, especially perianal cellulitis, is common during neutropenic periods. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Cyclic neutropenia is not associated with risk of malignancy or conversion to leukemia. The diagnosis of
Congenital neutropenia Cyclic neutropenia For synonyms and outdated names see For other genetic causes of these phenotypes see • Congenital neutropenia • Cyclic neutropenia ## Diagnosis Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. Note: The ANC is the white blood cell count (WBC) x % neutrophils. ANCs are <0.5x10 In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. Other hematopoietic cells Monocyte counts tend to be increased (i.e., >1.0x10 Platelet counts tend to be increased. Hematocrit tends to be mildly decreased. Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. Cytogenetic analysis of bone marrow is normal. Most affected individuals have an ANC <0.2x10 Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. Note: (1) Cyclic neutropenia is distinguished from congenital neutropenia by the regular oscillations of blood neutrophil counts in cyclic neutropenia. (2) Often, serial blood cell counts are needed to assure that individuals suspected of having congenital neutropenia do not have cyclic neutropenia; however, this approach has limitations because, in some cases of cyclic neutropenia, the amplitude of the oscillations may be very low. A diagnostic algorithm for cyclic neutropenia has been published [ The diagnosis of Note: The distinction between cyclic neutropenia and congenital neutropenia is primarily based on clinical findings and only secondarily on genotype (see Molecular genetic testing approaches can include Note: Since the presumed mechanism of disease is production of abnormal enzyme that is not inhibited or packaged normally resulting in damage to cells of the neutrophil lineage during their development, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. 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. • • • Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals • Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area • Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers • Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals • Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area • Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers • Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals • Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area • Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers • • At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. • Note: The ANC is the white blood cell count (WBC) x % neutrophils. • ANCs are <0.5x10 • In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. • Other hematopoietic cells • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. • Cytogenetic analysis of bone marrow is normal. • At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. • Note: The ANC is the white blood cell count (WBC) x % neutrophils. • ANCs are <0.5x10 • In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. • Other hematopoietic cells • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. • Cytogenetic analysis of bone marrow is normal. • • Most affected individuals have an ANC <0.2x10 • Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. • Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. • Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. • Most affected individuals have an ANC <0.2x10 • Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. • Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. • Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. • At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. • Note: The ANC is the white blood cell count (WBC) x % neutrophils. • ANCs are <0.5x10 • In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. • Other hematopoietic cells • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. • Cytogenetic analysis of bone marrow is normal. • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Most affected individuals have an ANC <0.2x10 • Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. • Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. • Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. • Note: Since the presumed mechanism of disease is production of abnormal enzyme that is not inhibited or packaged normally resulting in damage to cells of the neutrophil lineage during their development, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. • For an introduction to multigene panels click ## Suggestive Findings Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. Note: The ANC is the white blood cell count (WBC) x % neutrophils. ANCs are <0.5x10 In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. Other hematopoietic cells Monocyte counts tend to be increased (i.e., >1.0x10 Platelet counts tend to be increased. Hematocrit tends to be mildly decreased. Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. Cytogenetic analysis of bone marrow is normal. Most affected individuals have an ANC <0.2x10 Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. Note: (1) Cyclic neutropenia is distinguished from congenital neutropenia by the regular oscillations of blood neutrophil counts in cyclic neutropenia. (2) Often, serial blood cell counts are needed to assure that individuals suspected of having congenital neutropenia do not have cyclic neutropenia; however, this approach has limitations because, in some cases of cyclic neutropenia, the amplitude of the oscillations may be very low. • • • Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals • Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area • Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers • Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals • Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area • Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers • Mouth ulcers, pharyngitis, and fever recurring regularly at three-week intervals • Inflammation and infection of the sinuses, upper- and lower-respiratory tract, and skin including the perianal area • Abdominal pain and signs of an acute abdomen, suggesting sepsis and bacteremia from colonic ulcers • • At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. • Note: The ANC is the white blood cell count (WBC) x % neutrophils. • ANCs are <0.5x10 • In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. • Other hematopoietic cells • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. • Cytogenetic analysis of bone marrow is normal. • At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. • Note: The ANC is the white blood cell count (WBC) x % neutrophils. • ANCs are <0.5x10 • In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. • Other hematopoietic cells • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. • Cytogenetic analysis of bone marrow is normal. • • Most affected individuals have an ANC <0.2x10 • Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. • Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. • Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. • Most affected individuals have an ANC <0.2x10 • Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. • Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. • Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. • At least three absolute neutrophil counts (ANCs) <500/µL obtained ≥3 months after birth supports the diagnosis. • Note: The ANC is the white blood cell count (WBC) x % neutrophils. • ANCs are <0.5x10 • In some individuals, periods with regular oscillations in blood neutrophil counts can be interspersed with periods in which no oscillations in blood neutrophil counts are apparent. • Other hematopoietic cells • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Bone marrow aspirate typically shows "maturation arrest" at the promyelocyte or myelocyte stage of neutrophil formation. Increased bone marrow monocytes and eosinophils may be present. • Cytogenetic analysis of bone marrow is normal. • Monocyte counts tend to be increased (i.e., >1.0x10 • Platelet counts tend to be increased. • Hematocrit tends to be mildly decreased. • Most affected individuals have an ANC <0.2x10 • Oscillations of other cells, including lymphocytes, eosinophils, and platelets may be observed. • Usually, a reciprocal increase in blood monocytes and reticulocytes occurs during the neutrophil nadir. • Bone marrow aspirate shows an abnormality similar to that in congenital neutropenia when neutrophil counts are the lowest; at other times, maturation of cells of the neutrophil lineage is near normal. ## Establishing the Diagnosis A diagnostic algorithm for cyclic neutropenia has been published [ The diagnosis of Note: The distinction between cyclic neutropenia and congenital neutropenia is primarily based on clinical findings and only secondarily on genotype (see Molecular genetic testing approaches can include Note: Since the presumed mechanism of disease is production of abnormal enzyme that is not inhibited or packaged normally resulting in damage to cells of the neutrophil lineage during their development, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. 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. • Note: Since the presumed mechanism of disease is production of abnormal enzyme that is not inhibited or packaged normally resulting in damage to cells of the neutrophil lineage during their development, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. • For an introduction to multigene panels click ## Clinical Characteristics Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In both conditions, individuals have fever and recurrent skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, pharyngitis, and cervical adenopathy). In congenital neutropenia, diarrhea, pneumonia, and deep abscesses in the liver, lung, and subcutaneous tissues are common. Omphalitis immediately after birth may be the first sign [ Treatment with granulocyte colony-stimulating factor (G-CSF) raises blood neutrophil levels and reduces all of these complications in more than 90% of affected individuals [ Individuals with In a study conducted by Cyclic neutropenia is usually diagnosed soon after birth or within the first year of life based on a pattern of recurrent fever and oral ulcerations with serial blood cell counts showing regular oscillations. Peak neutrophil counts are usually <0.2x10 Untreated individuals have recurrent oropharyngeal inflammation; they are particularly prone to developing oral ulcers at approximately three-week intervals. Cellulitis, especially perianal cellulitis, is common during the neutropenic periods. Bacteremia is rare; the greatest risk appears to be for death from necrotizing enterocolitis, peritonitis, and Symptoms tend to be more severe in children than in adults. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Skin infections, fever, lymphadenopathy, and pharyngitis occur less frequently. Sinusitis, headache, and bone pain remain the most common symptoms. Oral ulcers, fatigue, and gingivitis also occur frequently. Permanent tooth loss resulting from chronic gingivitis, tooth abscesses, and alveolar bone loss in adolescence or young adulthood is common. There are no associated congenital abnormalities. Cyclic phenomena in other organ systems have not been recognized, probably because Cyclic neutropenia is not associated with an increased risk of malignancy or conversion to leukemia. However, confusion may arise when the series of counts is insufficient to clearly determine if an affected individual has congenital or cyclic neutropenia. Some affected individuals may at times have an obvious cyclic pattern of fluctuations in the neutrophil counts and at other times have counts that do not cycle, so that the diagnosis of congenital neutropenia seems appropriate. In families with multiple affected members in the same generation, one person may appear to have cyclic neutropenia while another has features more consistent with congenital neutropenia [ Genotype-phenotype correlations are only roughly defined for The risk of developing myelodysplasia or acute myelogenous leukemia varies considerably depending on the specific Some Prior to the discovery of the different genetic causes of severe chronic neutropenia, the term "Kostmann syndrome" was used to refer to individuals with severe chronic neutropenia. The original family reported by Kostmann was found to have bialleic pathogenic variants in Congenital neutropenia has an estimated frequency of 2:1,000,000-3:1,000,000 in the general population. Cyclic neutropenia has an estimated frequency of 1:1,000,000 in the general population, including both familial cases and simplex cases (i.e., single occurrences in a family). ## Clinical Description Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In both conditions, individuals have fever and recurrent skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, pharyngitis, and cervical adenopathy). In congenital neutropenia, diarrhea, pneumonia, and deep abscesses in the liver, lung, and subcutaneous tissues are common. Omphalitis immediately after birth may be the first sign [ Treatment with granulocyte colony-stimulating factor (G-CSF) raises blood neutrophil levels and reduces all of these complications in more than 90% of affected individuals [ Individuals with In a study conducted by Cyclic neutropenia is usually diagnosed soon after birth or within the first year of life based on a pattern of recurrent fever and oral ulcerations with serial blood cell counts showing regular oscillations. Peak neutrophil counts are usually <0.2x10 Untreated individuals have recurrent oropharyngeal inflammation; they are particularly prone to developing oral ulcers at approximately three-week intervals. Cellulitis, especially perianal cellulitis, is common during the neutropenic periods. Bacteremia is rare; the greatest risk appears to be for death from necrotizing enterocolitis, peritonitis, and Symptoms tend to be more severe in children than in adults. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Skin infections, fever, lymphadenopathy, and pharyngitis occur less frequently. Sinusitis, headache, and bone pain remain the most common symptoms. Oral ulcers, fatigue, and gingivitis also occur frequently. Permanent tooth loss resulting from chronic gingivitis, tooth abscesses, and alveolar bone loss in adolescence or young adulthood is common. There are no associated congenital abnormalities. Cyclic phenomena in other organ systems have not been recognized, probably because Cyclic neutropenia is not associated with an increased risk of malignancy or conversion to leukemia. However, confusion may arise when the series of counts is insufficient to clearly determine if an affected individual has congenital or cyclic neutropenia. Some affected individuals may at times have an obvious cyclic pattern of fluctuations in the neutrophil counts and at other times have counts that do not cycle, so that the diagnosis of congenital neutropenia seems appropriate. In families with multiple affected members in the same generation, one person may appear to have cyclic neutropenia while another has features more consistent with congenital neutropenia [ ## Congenital Neutropenia Infectious complications are generally more severe in congenital neutropenia than in cyclic neutropenia. In both conditions, individuals have fever and recurrent skin and oropharyngeal inflammation (i.e., mouth ulcers, gingivitis, sinusitis, pharyngitis, and cervical adenopathy). In congenital neutropenia, diarrhea, pneumonia, and deep abscesses in the liver, lung, and subcutaneous tissues are common. Omphalitis immediately after birth may be the first sign [ Treatment with granulocyte colony-stimulating factor (G-CSF) raises blood neutrophil levels and reduces all of these complications in more than 90% of affected individuals [ Individuals with In a study conducted by ## Cyclic Neutropenia Cyclic neutropenia is usually diagnosed soon after birth or within the first year of life based on a pattern of recurrent fever and oral ulcerations with serial blood cell counts showing regular oscillations. Peak neutrophil counts are usually <0.2x10 Untreated individuals have recurrent oropharyngeal inflammation; they are particularly prone to developing oral ulcers at approximately three-week intervals. Cellulitis, especially perianal cellulitis, is common during the neutropenic periods. Bacteremia is rare; the greatest risk appears to be for death from necrotizing enterocolitis, peritonitis, and Symptoms tend to be more severe in children than in adults. Between neutropenic periods, affected individuals are generally healthy. Symptoms improve in adulthood. Skin infections, fever, lymphadenopathy, and pharyngitis occur less frequently. Sinusitis, headache, and bone pain remain the most common symptoms. Oral ulcers, fatigue, and gingivitis also occur frequently. Permanent tooth loss resulting from chronic gingivitis, tooth abscesses, and alveolar bone loss in adolescence or young adulthood is common. There are no associated congenital abnormalities. Cyclic phenomena in other organ systems have not been recognized, probably because Cyclic neutropenia is not associated with an increased risk of malignancy or conversion to leukemia. However, confusion may arise when the series of counts is insufficient to clearly determine if an affected individual has congenital or cyclic neutropenia. ## Intermediate Phenotypes Some affected individuals may at times have an obvious cyclic pattern of fluctuations in the neutrophil counts and at other times have counts that do not cycle, so that the diagnosis of congenital neutropenia seems appropriate. In families with multiple affected members in the same generation, one person may appear to have cyclic neutropenia while another has features more consistent with congenital neutropenia [ ## Genotype-Phenotype Correlations Genotype-phenotype correlations are only roughly defined for The risk of developing myelodysplasia or acute myelogenous leukemia varies considerably depending on the specific Some ## Nomenclature Prior to the discovery of the different genetic causes of severe chronic neutropenia, the term "Kostmann syndrome" was used to refer to individuals with severe chronic neutropenia. The original family reported by Kostmann was found to have bialleic pathogenic variants in ## Prevalence Congenital neutropenia has an estimated frequency of 2:1,000,000-3:1,000,000 in the general population. Cyclic neutropenia has an estimated frequency of 1:1,000,000 in the general population, including both familial cases and simplex cases (i.e., single occurrences in a family). ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of congenital neutropenia includes the following disorders. Kostmann disease (OMIM Note: Nonsyndromic severe congenital neutropenia as a result of G6PC3 deficiency, an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in Benign familial neutropenia (OMIM Benign ethnic neutropenia associated with the Duffy null genotype (Duffy antigen receptor for chemokines or DARC-null genotype) is a common cause of neutropenia in persons of African heritage [ Autoimmune neutropenia, usually attributed to anti-neutrophil antibodies Idiopathic neutropenia (isolated neutropenia of unknown cause) Cyclic neutropenia Reticular dysgenesis (OMIM Griscelli syndrome (OMIM Wiskott-Aldrich syndrome (See Myelokathexis (WHIM syndrome; OMIM Classic G6PC3 deficiency (severe congenital neutropenia type 4) (See Other diagnoses confused with cyclic neutropenia include congenital neutropenia and idiopathic, autoimmune, and benign neutropenia of childhood. Other disorders with recurrent fevers are • Kostmann disease (OMIM • Note: • Nonsyndromic severe congenital neutropenia as a result of G6PC3 deficiency, an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in • Benign familial neutropenia (OMIM • Benign ethnic neutropenia associated with the Duffy null genotype (Duffy antigen receptor for chemokines or DARC-null genotype) is a common cause of neutropenia in persons of African heritage [ • Autoimmune neutropenia, usually attributed to anti-neutrophil antibodies • Idiopathic neutropenia (isolated neutropenia of unknown cause) • Cyclic neutropenia • • • Reticular dysgenesis (OMIM • • • Griscelli syndrome (OMIM • • Wiskott-Aldrich syndrome (See • • Myelokathexis (WHIM syndrome; OMIM • Classic G6PC3 deficiency (severe congenital neutropenia type 4) (See ## Congenital Neutropenia The differential diagnosis of congenital neutropenia includes the following disorders. Kostmann disease (OMIM Note: Nonsyndromic severe congenital neutropenia as a result of G6PC3 deficiency, an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in Benign familial neutropenia (OMIM Benign ethnic neutropenia associated with the Duffy null genotype (Duffy antigen receptor for chemokines or DARC-null genotype) is a common cause of neutropenia in persons of African heritage [ Autoimmune neutropenia, usually attributed to anti-neutrophil antibodies Idiopathic neutropenia (isolated neutropenia of unknown cause) Cyclic neutropenia Reticular dysgenesis (OMIM Griscelli syndrome (OMIM Wiskott-Aldrich syndrome (See Myelokathexis (WHIM syndrome; OMIM Classic G6PC3 deficiency (severe congenital neutropenia type 4) (See • Kostmann disease (OMIM • Note: • Nonsyndromic severe congenital neutropenia as a result of G6PC3 deficiency, an autosomal recessive form of severe congenital neutropenia caused by biallelic pathogenic variants in • Benign familial neutropenia (OMIM • Benign ethnic neutropenia associated with the Duffy null genotype (Duffy antigen receptor for chemokines or DARC-null genotype) is a common cause of neutropenia in persons of African heritage [ • Autoimmune neutropenia, usually attributed to anti-neutrophil antibodies • Idiopathic neutropenia (isolated neutropenia of unknown cause) • Cyclic neutropenia • • • Reticular dysgenesis (OMIM • • • Griscelli syndrome (OMIM • • Wiskott-Aldrich syndrome (See • • Myelokathexis (WHIM syndrome; OMIM • Classic G6PC3 deficiency (severe congenital neutropenia type 4) (See ## Cyclic Neutropenia Other diagnoses confused with cyclic neutropenia include congenital neutropenia and idiopathic, autoimmune, and benign neutropenia of childhood. ## Fever Other disorders with recurrent fevers are ## Management To establish the extent of disease in an individual diagnosed with Dental examination for gingival and periodontal disease Evaluation (particularly of those with severe congenital neutropenia) by an otolaryngologist and a pulmonologist for chronic sinopulmonary inflammation and deep abscesses Evaluation of individuals with severe congenital neutropenia for evidence of myelodysplasia or leukemia with bone marrow aspirate and biopsy Consultation with a clinical hematologist, geneticist, and/or genetic counselor for specific clinical advice Initiation of broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by either aerobic or anaerobic pathogens. Coverage matching local patterns for infections in immunosuppressed individuals should initially be given for both aerobic and anaerobic organisms. Granulocyte colony-stimulating factor (G-CSF), given subcutaneously, should also be administered daily starting immediately to promote increased neutrophil production and deployment. In cyclic neutropenia, G-CSF shortens the periods of neutropenia as well as the length of the neutropenic cycle. Treatment is known to be effective at least as early as age six months to one year. Studies indicate that treatment is effective with no adverse effects on growth, development, or pregnancy outcome with follow up to age 18 years [ Treatment of cyclic neutropenia requires daily or alternate-day injections of G-CSF, normally in a dose of ~2 µg/kg/day. Individuals with congenital neutropenia often require higher doses (e.g., 5-10 µg/kg/day). Common side effects of G-CSF include bone pain, headache, splenomegaly, and osteoporosis. Vasculitis, rashes, arthralgias, and glomerulonephritis have been infrequently reported [ Note: (1) When affected individuals are given G-CSF and their ANC normalizes, their resistance to infection improves greatly. They should be able to attend school, work, and engage in recreational activities without specific concerns; (2) G-CSF treatment is associated with mild increases in the size of the spleen, but this is very rarely, if ever, a cause for specific concern in those with For affected individuals with a well-matched donor, HSCT may be the preferred treatment option [ HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation. Good dental hygiene with regular hygiene visits (several times per year) and careful brushing and flossing are recommended. Individuals with For those individuals with congenital neutropenia not undergoing HSCT, surveillance for evidence of malignant transformation to MDS/AML is critical to allow early therapeutic intervention. Observation should include the following: General evaluations by parents and medical personnel several times a year Blood counts several times a year Annual bone marrow cytogenetic studies because of the frequent association of monosomy 7 and malignant transformation Note: Although sequencing of the receptor for G-CSF ( Most infections are caused by common organisms on body surfaces including Evaluation of sibs and other at-risk relatives by molecular genetic testing for the Note: Relatives of individuals with typical cycles may have neutropenia but lack obvious cycles. Treatment of these individuals with G-CSF or any other modality should be based on medical history and the severity of symptoms. It is not yet clear if there are specific risks (i.e., osteoporosis, myelodysplasia, or leukemia) associated with administering G-CSF to such individuals, but conservative management is recommended. See Pregnancies in women with severe chronic neutropenia are at substantial risk for miscarriage. A review of the records of 88 women (183 pregnancies) with congenital, cyclic, idiopathic, or autoimmune neutropenia compared outcomes in those on G-CSF therapy during pregnancy with those not on G-CSF therapy during pregnancy [ Reduced risk of fetal loss in the women treated during pregnancy Among 55 women (123 pregnancies) not treated with G-CSF during pregnancy: 11 complications (1 premature rupture of membranes, 2 life-threatening infections, 2 minor infections, and 6 premature labors) Among 41 women (60 pregnancies) treated with G-CSF during pregnancy: no life-threatening infections, no premature labors, five minor infections, and one woman who developed severe thrombocytopenia See Unrelated cord blood transplantation for neutropenia is being investigated; outcome appears to depend on the closeness of the match [ Search • Dental examination for gingival and periodontal disease • Evaluation (particularly of those with severe congenital neutropenia) by an otolaryngologist and a pulmonologist for chronic sinopulmonary inflammation and deep abscesses • Evaluation of individuals with severe congenital neutropenia for evidence of myelodysplasia or leukemia with bone marrow aspirate and biopsy • Consultation with a clinical hematologist, geneticist, and/or genetic counselor for specific clinical advice • Initiation of broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by either aerobic or anaerobic pathogens. Coverage matching local patterns for infections in immunosuppressed individuals should initially be given for both aerobic and anaerobic organisms. • Granulocyte colony-stimulating factor (G-CSF), given subcutaneously, should also be administered daily starting immediately to promote increased neutrophil production and deployment. • For affected individuals with a well-matched donor, HSCT may be the preferred treatment option [ • HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation. • General evaluations by parents and medical personnel several times a year • Blood counts several times a year • Annual bone marrow cytogenetic studies because of the frequent association of monosomy 7 and malignant transformation • Reduced risk of fetal loss in the women treated during pregnancy • Among 55 women (123 pregnancies) not treated with G-CSF during pregnancy: 11 complications (1 premature rupture of membranes, 2 life-threatening infections, 2 minor infections, and 6 premature labors) • Among 41 women (60 pregnancies) treated with G-CSF during pregnancy: no life-threatening infections, no premature labors, five minor infections, and one woman who developed severe thrombocytopenia ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Dental examination for gingival and periodontal disease Evaluation (particularly of those with severe congenital neutropenia) by an otolaryngologist and a pulmonologist for chronic sinopulmonary inflammation and deep abscesses Evaluation of individuals with severe congenital neutropenia for evidence of myelodysplasia or leukemia with bone marrow aspirate and biopsy Consultation with a clinical hematologist, geneticist, and/or genetic counselor for specific clinical advice • Dental examination for gingival and periodontal disease • Evaluation (particularly of those with severe congenital neutropenia) by an otolaryngologist and a pulmonologist for chronic sinopulmonary inflammation and deep abscesses • Evaluation of individuals with severe congenital neutropenia for evidence of myelodysplasia or leukemia with bone marrow aspirate and biopsy • Consultation with a clinical hematologist, geneticist, and/or genetic counselor for specific clinical advice ## Treatment of Manifestations Initiation of broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by either aerobic or anaerobic pathogens. Coverage matching local patterns for infections in immunosuppressed individuals should initially be given for both aerobic and anaerobic organisms. Granulocyte colony-stimulating factor (G-CSF), given subcutaneously, should also be administered daily starting immediately to promote increased neutrophil production and deployment. • Initiation of broad-spectrum antibiotics is important, even lifesaving, when an affected individual has signs of serious infection, which may be caused by either aerobic or anaerobic pathogens. Coverage matching local patterns for infections in immunosuppressed individuals should initially be given for both aerobic and anaerobic organisms. • Granulocyte colony-stimulating factor (G-CSF), given subcutaneously, should also be administered daily starting immediately to promote increased neutrophil production and deployment. ## Prevention of Primary Manifestations In cyclic neutropenia, G-CSF shortens the periods of neutropenia as well as the length of the neutropenic cycle. Treatment is known to be effective at least as early as age six months to one year. Studies indicate that treatment is effective with no adverse effects on growth, development, or pregnancy outcome with follow up to age 18 years [ Treatment of cyclic neutropenia requires daily or alternate-day injections of G-CSF, normally in a dose of ~2 µg/kg/day. Individuals with congenital neutropenia often require higher doses (e.g., 5-10 µg/kg/day). Common side effects of G-CSF include bone pain, headache, splenomegaly, and osteoporosis. Vasculitis, rashes, arthralgias, and glomerulonephritis have been infrequently reported [ Note: (1) When affected individuals are given G-CSF and their ANC normalizes, their resistance to infection improves greatly. They should be able to attend school, work, and engage in recreational activities without specific concerns; (2) G-CSF treatment is associated with mild increases in the size of the spleen, but this is very rarely, if ever, a cause for specific concern in those with For affected individuals with a well-matched donor, HSCT may be the preferred treatment option [ HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation. • For affected individuals with a well-matched donor, HSCT may be the preferred treatment option [ • HSCT is the only alternative therapy for individuals with congenital neutropenia who are refractory to high-dose G-CSF or who undergo malignant transformation. ## Prevention of Secondary Complications Good dental hygiene with regular hygiene visits (several times per year) and careful brushing and flossing are recommended. Individuals with ## Surveillance For those individuals with congenital neutropenia not undergoing HSCT, surveillance for evidence of malignant transformation to MDS/AML is critical to allow early therapeutic intervention. Observation should include the following: General evaluations by parents and medical personnel several times a year Blood counts several times a year Annual bone marrow cytogenetic studies because of the frequent association of monosomy 7 and malignant transformation Note: Although sequencing of the receptor for G-CSF ( • General evaluations by parents and medical personnel several times a year • Blood counts several times a year • Annual bone marrow cytogenetic studies because of the frequent association of monosomy 7 and malignant transformation ## Agents/Circumstances to Avoid Most infections are caused by common organisms on body surfaces including ## Evaluation of Relatives at Risk Evaluation of sibs and other at-risk relatives by molecular genetic testing for the Note: Relatives of individuals with typical cycles may have neutropenia but lack obvious cycles. Treatment of these individuals with G-CSF or any other modality should be based on medical history and the severity of symptoms. It is not yet clear if there are specific risks (i.e., osteoporosis, myelodysplasia, or leukemia) associated with administering G-CSF to such individuals, but conservative management is recommended. See ## Pregnancy Management Pregnancies in women with severe chronic neutropenia are at substantial risk for miscarriage. A review of the records of 88 women (183 pregnancies) with congenital, cyclic, idiopathic, or autoimmune neutropenia compared outcomes in those on G-CSF therapy during pregnancy with those not on G-CSF therapy during pregnancy [ Reduced risk of fetal loss in the women treated during pregnancy Among 55 women (123 pregnancies) not treated with G-CSF during pregnancy: 11 complications (1 premature rupture of membranes, 2 life-threatening infections, 2 minor infections, and 6 premature labors) Among 41 women (60 pregnancies) treated with G-CSF during pregnancy: no life-threatening infections, no premature labors, five minor infections, and one woman who developed severe thrombocytopenia See • Reduced risk of fetal loss in the women treated during pregnancy • Among 55 women (123 pregnancies) not treated with G-CSF during pregnancy: 11 complications (1 premature rupture of membranes, 2 life-threatening infections, 2 minor infections, and 6 premature labors) • Among 41 women (60 pregnancies) treated with G-CSF during pregnancy: no life-threatening infections, no premature labors, five minor infections, and one woman who developed severe thrombocytopenia ## Therapies Under Investigation Unrelated cord blood transplantation for neutropenia is being investigated; outcome appears to depend on the closeness of the match [ Search ## Genetic Counseling Many individuals diagnosed with Some individuals diagnosed with If neither parent is known to be affected, molecular genetic testing of the parents for the If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Note: The family history may appear to be negative because of failure to diagnose the disorder in a mildly affected parent; for example, if the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. The risk to sibs of the proband depends on the genetic status of the parents. If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. If the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. 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. • Many individuals diagnosed with • Some individuals diagnosed with • If neither parent is known to be affected, molecular genetic testing of the parents for the • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Note: The family history may appear to be negative because of failure to diagnose the disorder in a mildly affected parent; for example, if the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The risk to sibs of the proband depends on the genetic status of the parents. • If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. • If the • If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. • If the • If the parents have not been tested for the • If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance ## Risk to Family Members Many individuals diagnosed with Some individuals diagnosed with If neither parent is known to be affected, molecular genetic testing of the parents for the If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Note: The family history may appear to be negative because of failure to diagnose the disorder in a mildly affected parent; for example, if the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. The risk to sibs of the proband depends on the genetic status of the parents. If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. If the If the parents have not been tested for the • Many individuals diagnosed with • Some individuals diagnosed with • If neither parent is known to be affected, molecular genetic testing of the parents for the • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Note: The family history may appear to be negative because of failure to diagnose the disorder in a mildly affected parent; for example, if the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The risk to sibs of the proband depends on the genetic status of the parents. • If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. • If the • If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. • If the • If the parents have not been tested for the • If a parent of the proband is affected or has the pathogenic variant, the risk to sibs is 50%. • 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. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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 • • • • • • • • ## Molecular Genetics ELANE-Related Neutropenia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ELANE-Related Neutropenia ( Neutrophils are an essential part of the innate immune system and, therefore, are required to produce enzymes that are cytotoxic by nature. Selected Variants listed in the table have been provided by the authors. A natural experiment has provided compelling evidence that pathogenic variants in Cellular studies on pathogenesis of cyclic neutropenia have clearly demonstrated that accelerated apoptosis of neutrophil precursors is the proximate cause of the reduced neutrophil production. The oscillation of blood counts in cyclic neutropenia is attributed to the excessive cell turnover in the early neutrophil compartments, coupled to a system of long-range regulation by feedback from peripheral tissues [ ## Molecular Pathogenesis Neutrophils are an essential part of the innate immune system and, therefore, are required to produce enzymes that are cytotoxic by nature. Selected Variants listed in the table have been provided by the authors. A natural experiment has provided compelling evidence that pathogenic variants in Cellular studies on pathogenesis of cyclic neutropenia have clearly demonstrated that accelerated apoptosis of neutrophil precursors is the proximate cause of the reduced neutrophil production. The oscillation of blood counts in cyclic neutropenia is attributed to the excessive cell turnover in the early neutrophil compartments, coupled to a system of long-range regulation by feedback from peripheral tissues [ ## References ## Literature Cited ## Chapter Notes 23 August 2018 (ma) Comprehensive update posted live 14 July 2011 (me) Comprehensive update posted live 7 July 2009 (cd) Revision: gene symbol 9 September 2008 (cg) Comprehensive update posted live 4 January 2007 (cd) Revision: 21 July 2006 (me) Comprehensive update posted live 13 September 2005 (dd) Revision: Genotype-Phenotype Correlations, Surveillance 21 May 2004 (me) Comprehensive update posted live 1 October 2003 (cd) Revision: clinical testing availability 17 June 2002 (me) Review posted live 21 September 2001 (dd) Original submission • 23 August 2018 (ma) Comprehensive update posted live • 14 July 2011 (me) Comprehensive update posted live • 7 July 2009 (cd) Revision: gene symbol • 9 September 2008 (cg) Comprehensive update posted live • 4 January 2007 (cd) Revision: • 21 July 2006 (me) Comprehensive update posted live • 13 September 2005 (dd) Revision: Genotype-Phenotype Correlations, Surveillance • 21 May 2004 (me) Comprehensive update posted live • 1 October 2003 (cd) Revision: clinical testing availability • 17 June 2002 (me) Review posted live • 21 September 2001 (dd) Original submission ## Revision History 23 August 2018 (ma) Comprehensive update posted live 14 July 2011 (me) Comprehensive update posted live 7 July 2009 (cd) Revision: gene symbol 9 September 2008 (cg) Comprehensive update posted live 4 January 2007 (cd) Revision: 21 July 2006 (me) Comprehensive update posted live 13 September 2005 (dd) Revision: Genotype-Phenotype Correlations, Surveillance 21 May 2004 (me) Comprehensive update posted live 1 October 2003 (cd) Revision: clinical testing availability 17 June 2002 (me) Review posted live 21 September 2001 (dd) Original submission • 23 August 2018 (ma) Comprehensive update posted live • 14 July 2011 (me) Comprehensive update posted live • 7 July 2009 (cd) Revision: gene symbol • 9 September 2008 (cg) Comprehensive update posted live • 4 January 2007 (cd) Revision: • 21 July 2006 (me) Comprehensive update posted live • 13 September 2005 (dd) Revision: Genotype-Phenotype Correlations, Surveillance • 21 May 2004 (me) Comprehensive update posted live • 1 October 2003 (cd) Revision: clinical testing availability • 17 June 2002 (me) Review posted live • 21 September 2001 (dd) Original submission
[ "PJ Ancliff, RE Gale, R Liesner, I Hann, DC Linch. Long-term follow-up of granulocyte colony-stimulating factor receptor mutations in patients with severe congenital neutropenia: implications for leukaemogenesis and therapy.. Br J Haematol. 2003a;120:685-90", "PJ Ancliff, RE Gale, DC Linch. Neutrophil elastase mutations in congenital neutropenia.. Hematology. 2003b;8:165-71", "PJ Ancliff, RE Gale, MJ Watts, R Liesner, IM Hann, S Strobel, DC Linch. Paternal mosaicism proves the pathogenic nature of mutations in neutrophil elastase in severe congenital neutropenia.. Blood. 2002;100:707-9", "AG Aprikyan, S Stein, T Kutyavin, E Rodger, AA Bolyard, DC Dale. The causal role of mutations in the neutrophil elastase gene in cyclic and congenital neutropenia.. Soc Exp Hematol. 2002;30:209a", "C Barnes, JT Gerstle, MH Freedman, MD Carcao. Clostridium septicum myonecrosis in congenital neutropenia.. Pediatrics 2004;114:e757-60", "C Bellanné-Chantelot, S Clauin, T Leblanc, B Cassinat, F Rodrigues-Lima, S Beaufils, C Vaury, M Barkaoui, O Fenneteau, M Maier-Redelsperger, C Chomienne, J. Donadieu. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register.. Blood. 2004;103:4119-25", "LA Boxer, AA Bolyard, ML Kelley, TM Marrero, L Phan, JA Bond, BP Alter, MA Bonilla, D Link, PE Newburger, PS Rosenberg, DC Dale. Use of granulocyte colony-stimulating factor during pregnancy in women with chronic neutropenia.. Obstet Gynecol 2015;125:197-203", "LA Boxer, S Stein, D Buckley, AA Bolyard, DC Dale. Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 mutations.. J Pediatr 2006;148:633-6", "G Carlsson, AA Aprikyan, KG Ericson, S Stein, V Makaryan, DC Dale, M Nordenskjold, B Fadeel, J Palmblad, JI Hentera. Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.. Haematologica. 2006;91:589-95", "G Carlsson, AA Aprikyan, R Tehranchi, DC Dale, A Porwit, E Hellstrom-Lindberg, J Palmblad, JI Henter, B Fadeel. Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells.. Blood. 2004;103:3355-61", "SW Choi, J Levine. Indications for hematopoietic cell transplantation for children with severe congenital neutropenia.. Pediatr Transplant 2010;14:937-9", "JA Connelly, SW Choi, JE Levine. Hematopoietic stem cell transplantation for severe congenital neutropenia.. Curr Opin Hematol 2012;19:44-51", "DC Dale. How I manage children with neutropenia.. Br J Haematol 2017;178:351-63", "DC Dale, AA Bolyard, T Marrero, MA Bonilla, DC Link, P Newburger, A Shimamura, LA Boxer, C Spiekerman. Long-term effects of G-CSF therapy in cyclic neutropenia.. N Engl J Med 2017;377:2290-2", "DC Dale, TE Cottle, CJ Fier, AA Bolyard, MA Bonilla, LA Boxer, B Cham, MH Freedman, G Kannourakis, SE Kinsey, R Davis, D Scarlata, B Schwinzer, C Zeidler, K Welte. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry.. Am J Hematol 2003;72:82-93", "J Donadieu, B Beaupain, O Fenneteau, C Bellanné-Chantelot. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history.. Br J Haematol 2017;179:557-74", "F Fioredda, S Iacobelli, A van Biezen, B Gaspar, P Ancliff, J Donadieu, M Aljurf, C Peters, M Calvillo, S Matthes-Martin, G Morreale, N van 't Veer-Tazelaar, L de Wreede, A Al Seraihy, A Yesilipek, A Fischer, M Bierings, G Ozturk, O Smith, P Veys, P Ljungman, R Peffault de Latour, J Sánchez de Toledo Codina, R Or, A Ganser, B Afanasyev, R Wynn, K Kalwak, J Marsh, C Dufour. Stem cell transplantation in severe congenital neutropenia: an analysis from the European Society for Blood and Marrow Transplantation.. Blood 2015;126:1885-92", "D Garwicz, A Lennartsson, SE Jacobsen, U Gullberg, A Lindmark. Biosynthetic profiles of neutrophil serine proteases in a human bone marrow-derived cellular myeloid differentiation model.. Haematologica 2005;90:38-44", "M Germeshausen, C Zeidler, M Stuhrmann, M Lanciotti, M Ballmaier, K Welte. Digenic mutations in severe congenital neutropenia.. Haematologica 2010;95:1207-10", "C Haurie, DC Dale, MC Mackey. Cyclical neutropenia and other periodic hematological disorders: a review of mechanisms and mathematical models.. Blood 1998;92:2629-40", "M Horwitz, KF Benson, RE Person, AG Aprikyan, DC Dale. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.. Nat Genet 1999;23:433-6", "C Klein, M Grudzien, G Appaswamy, M Germeshausen, I Sandrock, AA Schaffer, C Rathinam, K Boztug, B Schwinzer, N Rezaei, G Bohn, M Melin, G Carlsson, B Fadeel, N Dahl, J Palmblad, JI Henter, C Zeidler, B Grimbacher, K Welte. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease).. Nat Genet 2007;39:86-92", "C Klein. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes.. Annu Rev Immunol 2011;29:399-413", "I Köllner, B Sodeik, S Schreek, H Heyn, N von Neuhoff, M Germeshausen, C Zeidler, M Kruger, B Schlegelberger, K Welte, C Beger. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response.. Blood. 2006;108:493-500", "V Makaryan, C Zeidler, AA Bolyard, J Skokowa, E Rodger, ML Kelley, LA Boxer, MA Bonilla, PE Newburger, A Shimamura, B Zhu, PS Rosenberg, DC Link, K Welte, DC Dale. The diversity of mutations and clinical outcomes for. Curr Opin Hematol 2015;22:3-11", "P Massullo, LJ Druhan, BA Bunnell, MG Hunter, JM Robinson, CB Marsh, BR Avalos. Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes.. Blood 2005;105:3397-404", "PE Newburger, TN Pindyck, Z Zhu, AA Bolyard, AA Aprikyan, DC Dale, GD Smith, LA Boxer. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes.. Pediatr Blood Cancer 2010;55:314-17", "K Oshima, R Hanada, R Kobayashi, K Kato, Y Nagatoshi, K Tabuchi, S Kato. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: an analysis of 18 Japanese cases.. Pediatr Transplant 2010;14:657-63", "SE Palmer, K Stephens, DC Dale. Genetics, phenotype, and natural history of autosomal dominant cyclic hematopoiesis.. Am J Med Genet 1996;66:413-22", "HA Papadaki, GD Eliopoulos. The role of apoptosis in the pathophysiology of chronic neutropenias associated with bone marrow failure.. Cell Cycle. 2003;2:447-51", "RE Person, FQ Li, Z Duan, KF Benson, J Wechsler, HA Papadaki, G Eliopoulos, C Kaufman, SJ Bertolone, B Nakamoto, T Papayannopoulou, HL Grimes, M Horwitz. Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2.. Nat Genet 2003;34:308-12", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33", "PS Rosenberg, BP Alter, AA Bolyard, MA Bonilla, LA Boxer, B Cham, C Fier, M Freedman, G Kannourakis, S Kinsey, B Schwinzer, C Zeidler, K Welte, DC Dale. The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy.. Blood 2006;107:4628-35", "PS Rosenberg, BP Alter, DC Link, S Stein, E Rodger, AA Bolyard, AA Aprikyan, MA Bonilla, Y Dror, G Kannourakis, PE Newburger, LA Boxer, DC Dale. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.. Br J Haematol 2008;140:210-3", "PS Rosenberg, C Zeidler, AA Bolyard, BP Alter, MA Bonilla, LA Boxer, Y Dror, S Kinsey, DC Link, PE Newburger, A Shimamura, K Welte, DC Dale. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy.. Br J Haematol 2010;150:196-9", "J Skokowa, DC Dale, IP Touw, C Zeidler, K Welte. Severe congenital neutropenias.. Nat Rev Dis Primers 2017;3:17032", "CF Thobakgale, T Ndung'u. Neutrophil counts in persons of African origin.. Curr Opin Hematol 2014;21:50-7", "IP Touw. Game of clones: the genomic evolution of severe congenital neutropenia.. Hematology Am Soc Hematol Educ Program 2015;2015:1-7", "J Xia, AA Bolyard, E Rodger, S Stein, AA Aprikyan, DC Dale, DC Link. Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia.. Br J Haematol 2009;147:535-42", "C Zeidler, L Boxer, DC Dale, MH Freedman, S Kinsey, K Welte. Management of Kostmann syndrome in the G-CSF era.. Br J Haematol 2000;109:490-5", "C Zeidler, K Welte. Kostmann syndrome and severe congenital neutropenia.. Semin Hematol. 2002;39:82-8" ]
17/6/2002
23/8/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
cyld-cs
cyld-cs
[ "Brooke-Spiegler Syndrome (BSS)", "Familial Cylindromatosis (FC)", "Multiple Familial Trichoepithelioma (MFT)", "Multiple Familial Trichoepithelioma (MFT)", "Familial Cylindromatosis (FC)", "Brooke-Spiegler Syndrome (BSS)", "Ubiquitin carboxyl-terminal hydrolase CYLD", "CYLD", "CYLD Cutaneous Syndrome" ]
Anna Dubois, Neil Rajan
Summary The diagnosis of Germline pathogenic variants in
## Diagnosis Formal diagnostic criteria for The presence of one or more cylindromas or spiradenomas on the face and scalp, perinasal trichoepitheliomas, or a combination of these tumor types in an individual Cylindromas, spiradenomas, and trichoepitheliomas can be diagnosed clinically but may mimic other skin tumors, thus requiring confirmatory skin biopsy. A cylindroma or spiradenoma on the scalp or torso incidentally identified during an imaging study (CT, MRI, and/or PET scan) [ A membranous basal cell adenoma-type salivary gland tumor in an individual with a single cylindroma, spiradenoma, or trichoepithelioma Clinical genetic testing for a germline heterozygous Two or more biopsy-confirmed cylindromas, spiradenomas, or trichoepitheliomas A single biopsy-confirmed cylindroma, spiradenoma, or trichoepithelioma in the setting of a first-degree relative who has any one of these biopsy-confirmed tumors The diagnosis of When the phenotypic and laboratory findings suggest the diagnosis of If no pathogenic variant is found, and there is no known family history of this condition, it is possible that the proband has mosaicism for a If mosaicism is suspected, sequence analysis of Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may also be considered, although intragenic deletions and duplications are rare (see 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 A single test center performing In a smaller study of 25 probands, the presence of cylindromas raised the likelihood of pathogenic variant detection to between 86% and 100% [ In probands with only trichoepitheliomas, the rate of pathogenic variant detection was as low as 40% [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 presence of one or more cylindromas or spiradenomas on the face and scalp, perinasal trichoepitheliomas, or a combination of these tumor types in an individual • Cylindromas, spiradenomas, and trichoepitheliomas can be diagnosed clinically but may mimic other skin tumors, thus requiring confirmatory skin biopsy. • A cylindroma or spiradenoma on the scalp or torso incidentally identified during an imaging study (CT, MRI, and/or PET scan) [ • A membranous basal cell adenoma-type salivary gland tumor in an individual with a single cylindroma, spiradenoma, or trichoepithelioma • Two or more biopsy-confirmed cylindromas, spiradenomas, or trichoepitheliomas • A single biopsy-confirmed cylindroma, spiradenoma, or trichoepithelioma in the setting of a first-degree relative who has any one of these biopsy-confirmed tumors • If no pathogenic variant is found, and there is no known family history of this condition, it is possible that the proband has mosaicism for a • If mosaicism is suspected, sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may also be considered, although intragenic deletions and duplications are rare (see ## Suggestive Findings The presence of one or more cylindromas or spiradenomas on the face and scalp, perinasal trichoepitheliomas, or a combination of these tumor types in an individual Cylindromas, spiradenomas, and trichoepitheliomas can be diagnosed clinically but may mimic other skin tumors, thus requiring confirmatory skin biopsy. A cylindroma or spiradenoma on the scalp or torso incidentally identified during an imaging study (CT, MRI, and/or PET scan) [ A membranous basal cell adenoma-type salivary gland tumor in an individual with a single cylindroma, spiradenoma, or trichoepithelioma Clinical genetic testing for a germline heterozygous Two or more biopsy-confirmed cylindromas, spiradenomas, or trichoepitheliomas A single biopsy-confirmed cylindroma, spiradenoma, or trichoepithelioma in the setting of a first-degree relative who has any one of these biopsy-confirmed tumors • The presence of one or more cylindromas or spiradenomas on the face and scalp, perinasal trichoepitheliomas, or a combination of these tumor types in an individual • Cylindromas, spiradenomas, and trichoepitheliomas can be diagnosed clinically but may mimic other skin tumors, thus requiring confirmatory skin biopsy. • A cylindroma or spiradenoma on the scalp or torso incidentally identified during an imaging study (CT, MRI, and/or PET scan) [ • A membranous basal cell adenoma-type salivary gland tumor in an individual with a single cylindroma, spiradenoma, or trichoepithelioma • Two or more biopsy-confirmed cylindromas, spiradenomas, or trichoepitheliomas • A single biopsy-confirmed cylindroma, spiradenoma, or trichoepithelioma in the setting of a first-degree relative who has any one of these biopsy-confirmed tumors ## Establishing the Diagnosis The diagnosis of When the phenotypic and laboratory findings suggest the diagnosis of If no pathogenic variant is found, and there is no known family history of this condition, it is possible that the proband has mosaicism for a If mosaicism is suspected, sequence analysis of Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may also be considered, although intragenic deletions and duplications are rare (see 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 A single test center performing In a smaller study of 25 probands, the presence of cylindromas raised the likelihood of pathogenic variant detection to between 86% and 100% [ In probands with only trichoepitheliomas, the rate of pathogenic variant detection was as low as 40% [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • If no pathogenic variant is found, and there is no known family history of this condition, it is possible that the proband has mosaicism for a • If mosaicism is suspected, sequence analysis of • Gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may also be considered, although intragenic deletions and duplications are rare (see ## Clinical Characteristics Features of Except where otherwise noted, the table summarizes a single study by While by definition most individuals with To date, more than 100 pedigrees have been identified with a germline pathogenic variant in Natural history studies in Individuals with Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin. Tumors are often painful and may cause sexual dysfunction when they arise on genital skin. Tumors arising within the ear (a favored site for tumor formation) can occlude the external auditory canal and result in conductive hearing loss. Although the tumors are usually benign, malignant transformation is recognized, and affected individuals should be guided to report tumors which are rapidly growing, bleeding, ulcerating, or different in appearance from their usual tumors. Cylindromas are well-circumscribed, smooth, pale pink nodular tumors, often with arborizing vessels visible. The tumors are slow growing and vary in size from a few millimeters to >5 mm (see Early surgical intervention may prevent or delay confluent scalp tumors. One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency. A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy. Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in The true prevalence of pulmonary cylindromas in individuals with Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with Spiradenomas are nodular tumors that are often blue/black in color. They tend to be painful and can grow up to 10 cm in diameter (see Trichoepitheliomas are skin-colored papules or firm nodules, mainly found on the central face (see These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis. MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [ Transcalvarial invasion is uncommon, but has been observed [ Malignant metastases to bone, lung, and liver have been reported [ Death from metastatic disease has been described in affected individuals in the early fifth decade [ Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [ Salivary gland type basal cell adenocarcinoma-like pattern, low-grade Salivary gland type basal cell adenocarcinoma-like pattern, high-grade Invasive adenocarcinoma, not otherwise specified Sarcomatoid (metaplastic) carcinoma Affected individuals may also develop small milia cysts on the skin of the face [ Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [ Squamous cell carcinoma [ Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with No convincing genotype-phenotype correlations have been identified. There is a suggestion that individuals with pathogenic missense variants may have a milder phenotype; however, as missense variants constitute a minority of pathogenic variants in affected individuals (most have pathogenic truncating variants, which can also result in a mild phenotype), further studies are needed to investigate this hypothesis [ Historically, descriptive names including Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT) were assigned on the basis of the predominant tumor type and location. These conditions are now recognized to constitute a clinical spectrum and individuals with the clinical phenotypes of BSS, FC, and MFT can all present in a single family. The lack of prognostication offered by these historical labels favors the use of Outdated terms previously used in the literature to refer to Ancell-Spiegler cylindromas Dermal eccrine cylindroma Turban tumor syndrome (now denoted as confluent scalp tumors) The true prevalence of • Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin. • Tumors are often painful and may cause sexual dysfunction when they arise on genital skin. • Tumors arising within the ear (a favored site for tumor formation) can occlude the external auditory canal and result in conductive hearing loss. • Although the tumors are usually benign, malignant transformation is recognized, and affected individuals should be guided to report tumors which are rapidly growing, bleeding, ulcerating, or different in appearance from their usual tumors. • Early surgical intervention may prevent or delay confluent scalp tumors. • One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic • One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency. • A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy. • Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in • The true prevalence of pulmonary cylindromas in individuals with • Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with • These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis. • MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [ • Transcalvarial invasion is uncommon, but has been observed [ • Malignant metastases to bone, lung, and liver have been reported [ • Death from metastatic disease has been described in affected individuals in the early fifth decade [ • Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [ • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Affected individuals may also develop small milia cysts on the skin of the face [ • Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [ • Squamous cell carcinoma [ • Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with • Ancell-Spiegler cylindromas • Dermal eccrine cylindroma • Turban tumor syndrome (now denoted as confluent scalp tumors) ## Clinical Description Features of Except where otherwise noted, the table summarizes a single study by While by definition most individuals with To date, more than 100 pedigrees have been identified with a germline pathogenic variant in Natural history studies in Individuals with Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin. Tumors are often painful and may cause sexual dysfunction when they arise on genital skin. Tumors arising within the ear (a favored site for tumor formation) can occlude the external auditory canal and result in conductive hearing loss. Although the tumors are usually benign, malignant transformation is recognized, and affected individuals should be guided to report tumors which are rapidly growing, bleeding, ulcerating, or different in appearance from their usual tumors. Cylindromas are well-circumscribed, smooth, pale pink nodular tumors, often with arborizing vessels visible. The tumors are slow growing and vary in size from a few millimeters to >5 mm (see Early surgical intervention may prevent or delay confluent scalp tumors. One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency. A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy. Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in The true prevalence of pulmonary cylindromas in individuals with Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with Spiradenomas are nodular tumors that are often blue/black in color. They tend to be painful and can grow up to 10 cm in diameter (see Trichoepitheliomas are skin-colored papules or firm nodules, mainly found on the central face (see These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis. MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [ Transcalvarial invasion is uncommon, but has been observed [ Malignant metastases to bone, lung, and liver have been reported [ Death from metastatic disease has been described in affected individuals in the early fifth decade [ Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [ Salivary gland type basal cell adenocarcinoma-like pattern, low-grade Salivary gland type basal cell adenocarcinoma-like pattern, high-grade Invasive adenocarcinoma, not otherwise specified Sarcomatoid (metaplastic) carcinoma Affected individuals may also develop small milia cysts on the skin of the face [ Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [ Squamous cell carcinoma [ Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with • Tumors typically arise on the scalp and face but can also arise on the torso and sun-protected sites, such as the genital and axillary skin. • Tumors are often painful and may cause sexual dysfunction when they arise on genital skin. • Tumors arising within the ear (a favored site for tumor formation) can occlude the external auditory canal and result in conductive hearing loss. • Although the tumors are usually benign, malignant transformation is recognized, and affected individuals should be guided to report tumors which are rapidly growing, bleeding, ulcerating, or different in appearance from their usual tumors. • Early surgical intervention may prevent or delay confluent scalp tumors. • One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic • One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency. • A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy. • Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in • The true prevalence of pulmonary cylindromas in individuals with • Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with • These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis. • MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [ • Transcalvarial invasion is uncommon, but has been observed [ • Malignant metastases to bone, lung, and liver have been reported [ • Death from metastatic disease has been described in affected individuals in the early fifth decade [ • Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [ • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Affected individuals may also develop small milia cysts on the skin of the face [ • Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [ • Squamous cell carcinoma [ • Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with ## Cylindromas Cylindromas are well-circumscribed, smooth, pale pink nodular tumors, often with arborizing vessels visible. The tumors are slow growing and vary in size from a few millimeters to >5 mm (see Early surgical intervention may prevent or delay confluent scalp tumors. One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency. A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy. Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in The true prevalence of pulmonary cylindromas in individuals with Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with • Early surgical intervention may prevent or delay confluent scalp tumors. • One study of two families reported that confluent scalp tumors affected up to one in four individuals with a heterozygous germline pathogenic • One individual presented at age 64 with breathlessness on exertion and was found to have multiple pulmonary tumors. This individual required serial monitoring with pulmonary imaging, and received endocopic laser ablation to maintain large airway patency. • A second individual had four asymptomatic pulmonary tumors discovered incidentally on a chest radiograph at age 80 years. The tumors were histologically confirmed on autopsy. • Whole-exome and genome sequencing have shown pulmonary cylindromas to harbor an additional pathogenic variant in • The true prevalence of pulmonary cylindromas in individuals with • Currently, there are no routine surveillance imaging guidelines that can be recommended; however clinicians who care for individuals with ## Spiradenomas Spiradenomas are nodular tumors that are often blue/black in color. They tend to be painful and can grow up to 10 cm in diameter (see ## Trichoepitheliomas Trichoepitheliomas are skin-colored papules or firm nodules, mainly found on the central face (see ## Other Findings These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis. MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [ Transcalvarial invasion is uncommon, but has been observed [ Malignant metastases to bone, lung, and liver have been reported [ Death from metastatic disease has been described in affected individuals in the early fifth decade [ Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [ Salivary gland type basal cell adenocarcinoma-like pattern, low-grade Salivary gland type basal cell adenocarcinoma-like pattern, high-grade Invasive adenocarcinoma, not otherwise specified Sarcomatoid (metaplastic) carcinoma Affected individuals may also develop small milia cysts on the skin of the face [ Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [ Squamous cell carcinoma [ Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with • These tumors typically present as a lump in the parotid gland, may be bilateral, and warrant a biopsy to confirm the diagnosis. • MBCA is a benign entity which may be managed surgically, but recurs in up to 25% of affected individuals [ • Transcalvarial invasion is uncommon, but has been observed [ • Malignant metastases to bone, lung, and liver have been reported [ • Death from metastatic disease has been described in affected individuals in the early fifth decade [ • Malignant histopathology. Four diverse histologic patterns of malignant cylindroma or spiradenoma have been described [ • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Salivary gland type basal cell adenocarcinoma-like pattern, low-grade • Salivary gland type basal cell adenocarcinoma-like pattern, high-grade • Invasive adenocarcinoma, not otherwise specified • Sarcomatoid (metaplastic) carcinoma • Affected individuals may also develop small milia cysts on the skin of the face [ • Vulval cysts consisting histologically of multiple epidermal inclusion cysts and milia were reported in one affected female [ • Squamous cell carcinoma [ • Basal cell carcinoma (BCC) is the most common human cancer, and coexistence in individuals with ## Genotype-Phenotype Correlations No convincing genotype-phenotype correlations have been identified. There is a suggestion that individuals with pathogenic missense variants may have a milder phenotype; however, as missense variants constitute a minority of pathogenic variants in affected individuals (most have pathogenic truncating variants, which can also result in a mild phenotype), further studies are needed to investigate this hypothesis [ ## Nomenclature Historically, descriptive names including Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepithelioma (MFT) were assigned on the basis of the predominant tumor type and location. These conditions are now recognized to constitute a clinical spectrum and individuals with the clinical phenotypes of BSS, FC, and MFT can all present in a single family. The lack of prognostication offered by these historical labels favors the use of Outdated terms previously used in the literature to refer to Ancell-Spiegler cylindromas Dermal eccrine cylindroma Turban tumor syndrome (now denoted as confluent scalp tumors) • Ancell-Spiegler cylindromas • Dermal eccrine cylindroma • Turban tumor syndrome (now denoted as confluent scalp tumors) ## Prevalence The true prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic cylindroma and spiradenoma occurring as single tumors in the absence of any other findings of ## Differential Diagnosis Disorders with multiple facial papules in the differential diagnosis of Disorders with Multiple Facial Papules in the Differential Diagnosis of All of the disorders listed are inherited in an autosomal dominant manner. ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Full skin exam incl skin of the genitalia Painful tumors should be identified & prioritized for excision (see Education about signs & symptoms of malignant transformation Routine imaging not currently recommended If malignant transformation is suspected in a scalp tumor, consider radiologic imaging (preferably MRI), given the possibility of intracranial invasion. Little evidence is available as to when staging imaging should be considered for malignant tumors; consult specialist skin cancer multidisciplinary team. To screen for tumors that occlude the external auditory canal When present, clinical assessment for conductive hearing loss may be considered. Including tumors that are rapidly growing, bleeding, ulcerating or appear different than an affected individual's usual tumors. This team typically includes a dermatologist, plastic surgeon, radiologist, oncologist and pathologist, all of whom can guide a consensus decision making process. Treatment of Manifestations in Individuals with Repeated surgical procedures to ↓ tumor burden typically required "Scalp-sparing" strategies incl early primary excision, tumor enucleation, & excision followed by secondary intention healing techniques recommended; Complete scalp excision to be used only when no feasible alternatives Ablative laser resurfacing of smaller lesions (i.e., perinasal trichoepitheliomas) can yield good cosmetic results. However, the advantage of laser treatment for large cylindromas & spiradenomas over standard excision is not clear. Laser treatment also precludes histologic assessment. Technique allows dermatologic surgeon to track invasive tumor cells & confirm histologic clearance before closing the skin defect. Mohs may be of limited benefit in CCS, as it may be difficult to obtain tumor-negative margins, leading to large defects. At least 8 different types of malignant tumors are seen in affected persons; w/the exception of BCC, these would be considered rare cancers & require appropriate eval following histopathologic assessment (see Each case may need to be assessed & staged; decision should be made by a skin cancer multidisciplinary team w/support from dermatologists, oncologists, pathologists, plastic surgeons, & radiologists. BCC = basal cell carcinoma; CCS = Tumors progressively grow over time such that early treatment may reduce the need for extensive surgical procedures and also allow for the use of local anesthetic. Benign lesions removed for cosmetic reasons should have narrow margins to leave as much normal healthy tissue as possible. Complete scalp excision is not curative. Often tumors develop from follicles within the graft, and individuals can have significant tumors at other sites, such as on the trunk. Histologic assessment of a representative lesion may be useful prior to ablative procedures. If there is a clinical suspicion of basal cell carcinoma, a biopsy should be performed prior to initiating ablative procedures. Repeated treatments are often needed and may not be cost effective. This technique has been used to treat sporadic cylindroma and spiradenoma where recurrence has occurred after primary surgical excision. Mohs may be best reserved for sporadic cases. The role of UV light in the pathogenesis of the tumors seen in It is recommended that individuals with An assessment of tumor burden and rate of new tumor development can be made, and existing tumors can also be monitored for any signs of malignant transformation. Annual monitoring will guide the frequency and interval of surgical procedures. Between appointments, affected individuals should be asked to report growing, ulcerated, or bleeding tumors or tumors that appear different from existing lesions so that they can be assessed to determine if urgent excision is warranted. Radiotherapy should be avoided as it causes DNA damage and may result in further tumor formation or malignant transformation of existing lesions [ 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 Treatment for It is important to recognize that tumors in They are not placebo controlled. No objective measures were used to assess improvement. Only short-term follow-up data are presented. No long-term safety data regarding the repeated use of these agents in treatment of Search • Full skin exam incl skin of the genitalia • Painful tumors should be identified & prioritized for excision (see • Education about signs & symptoms of malignant transformation • Routine imaging not currently recommended • If malignant transformation is suspected in a scalp tumor, consider radiologic imaging (preferably MRI), given the possibility of intracranial invasion. • Little evidence is available as to when staging imaging should be considered for malignant tumors; consult specialist skin cancer multidisciplinary team. • To screen for tumors that occlude the external auditory canal • When present, clinical assessment for conductive hearing loss may be considered. • Repeated surgical procedures to ↓ tumor burden typically required • "Scalp-sparing" strategies incl early primary excision, tumor enucleation, & excision followed by secondary intention healing techniques recommended; • Complete scalp excision to be used only when no feasible alternatives • Ablative laser resurfacing of smaller lesions (i.e., perinasal trichoepitheliomas) can yield good cosmetic results. • However, the advantage of laser treatment for large cylindromas & spiradenomas over standard excision is not clear. Laser treatment also precludes histologic assessment. • Technique allows dermatologic surgeon to track invasive tumor cells & confirm histologic clearance before closing the skin defect. • Mohs may be of limited benefit in CCS, as it may be difficult to obtain tumor-negative margins, leading to large defects. • At least 8 different types of malignant tumors are seen in affected persons; w/the exception of BCC, these would be considered rare cancers & require appropriate eval following histopathologic assessment (see • Each case may need to be assessed & staged; decision should be made by a skin cancer multidisciplinary team w/support from dermatologists, oncologists, pathologists, plastic surgeons, & radiologists. • An assessment of tumor burden and rate of new tumor development can be made, and existing tumors can also be monitored for any signs of malignant transformation. • Annual monitoring will guide the frequency and interval of surgical procedures. • Between appointments, affected individuals should be asked to report growing, ulcerated, or bleeding tumors or tumors that appear different from existing lesions so that they can be assessed to determine if urgent excision is warranted. • They are not placebo controlled. • No objective measures were used to assess improvement. • Only short-term follow-up data are presented. • No long-term safety data regarding the repeated use of these agents in treatment of ## 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 Full skin exam incl skin of the genitalia Painful tumors should be identified & prioritized for excision (see Education about signs & symptoms of malignant transformation Routine imaging not currently recommended If malignant transformation is suspected in a scalp tumor, consider radiologic imaging (preferably MRI), given the possibility of intracranial invasion. Little evidence is available as to when staging imaging should be considered for malignant tumors; consult specialist skin cancer multidisciplinary team. To screen for tumors that occlude the external auditory canal When present, clinical assessment for conductive hearing loss may be considered. Including tumors that are rapidly growing, bleeding, ulcerating or appear different than an affected individual's usual tumors. This team typically includes a dermatologist, plastic surgeon, radiologist, oncologist and pathologist, all of whom can guide a consensus decision making process. • Full skin exam incl skin of the genitalia • Painful tumors should be identified & prioritized for excision (see • Education about signs & symptoms of malignant transformation • Routine imaging not currently recommended • If malignant transformation is suspected in a scalp tumor, consider radiologic imaging (preferably MRI), given the possibility of intracranial invasion. • Little evidence is available as to when staging imaging should be considered for malignant tumors; consult specialist skin cancer multidisciplinary team. • To screen for tumors that occlude the external auditory canal • When present, clinical assessment for conductive hearing loss may be considered. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Repeated surgical procedures to ↓ tumor burden typically required "Scalp-sparing" strategies incl early primary excision, tumor enucleation, & excision followed by secondary intention healing techniques recommended; Complete scalp excision to be used only when no feasible alternatives Ablative laser resurfacing of smaller lesions (i.e., perinasal trichoepitheliomas) can yield good cosmetic results. However, the advantage of laser treatment for large cylindromas & spiradenomas over standard excision is not clear. Laser treatment also precludes histologic assessment. Technique allows dermatologic surgeon to track invasive tumor cells & confirm histologic clearance before closing the skin defect. Mohs may be of limited benefit in CCS, as it may be difficult to obtain tumor-negative margins, leading to large defects. At least 8 different types of malignant tumors are seen in affected persons; w/the exception of BCC, these would be considered rare cancers & require appropriate eval following histopathologic assessment (see Each case may need to be assessed & staged; decision should be made by a skin cancer multidisciplinary team w/support from dermatologists, oncologists, pathologists, plastic surgeons, & radiologists. BCC = basal cell carcinoma; CCS = Tumors progressively grow over time such that early treatment may reduce the need for extensive surgical procedures and also allow for the use of local anesthetic. Benign lesions removed for cosmetic reasons should have narrow margins to leave as much normal healthy tissue as possible. Complete scalp excision is not curative. Often tumors develop from follicles within the graft, and individuals can have significant tumors at other sites, such as on the trunk. Histologic assessment of a representative lesion may be useful prior to ablative procedures. If there is a clinical suspicion of basal cell carcinoma, a biopsy should be performed prior to initiating ablative procedures. Repeated treatments are often needed and may not be cost effective. This technique has been used to treat sporadic cylindroma and spiradenoma where recurrence has occurred after primary surgical excision. Mohs may be best reserved for sporadic cases. • Repeated surgical procedures to ↓ tumor burden typically required • "Scalp-sparing" strategies incl early primary excision, tumor enucleation, & excision followed by secondary intention healing techniques recommended; • Complete scalp excision to be used only when no feasible alternatives • Ablative laser resurfacing of smaller lesions (i.e., perinasal trichoepitheliomas) can yield good cosmetic results. • However, the advantage of laser treatment for large cylindromas & spiradenomas over standard excision is not clear. Laser treatment also precludes histologic assessment. • Technique allows dermatologic surgeon to track invasive tumor cells & confirm histologic clearance before closing the skin defect. • Mohs may be of limited benefit in CCS, as it may be difficult to obtain tumor-negative margins, leading to large defects. • At least 8 different types of malignant tumors are seen in affected persons; w/the exception of BCC, these would be considered rare cancers & require appropriate eval following histopathologic assessment (see • Each case may need to be assessed & staged; decision should be made by a skin cancer multidisciplinary team w/support from dermatologists, oncologists, pathologists, plastic surgeons, & radiologists. ## Prevention of Primary Manifestations The role of UV light in the pathogenesis of the tumors seen in ## Surveillance It is recommended that individuals with An assessment of tumor burden and rate of new tumor development can be made, and existing tumors can also be monitored for any signs of malignant transformation. Annual monitoring will guide the frequency and interval of surgical procedures. Between appointments, affected individuals should be asked to report growing, ulcerated, or bleeding tumors or tumors that appear different from existing lesions so that they can be assessed to determine if urgent excision is warranted. • An assessment of tumor burden and rate of new tumor development can be made, and existing tumors can also be monitored for any signs of malignant transformation. • Annual monitoring will guide the frequency and interval of surgical procedures. • Between appointments, affected individuals should be asked to report growing, ulcerated, or bleeding tumors or tumors that appear different from existing lesions so that they can be assessed to determine if urgent excision is warranted. ## Agents/Circumstances to Avoid Radiotherapy should be avoided as it causes DNA damage and may result in further tumor formation or malignant transformation of existing lesions [ ## 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 ## Therapies Under Investigation Treatment for It is important to recognize that tumors in They are not placebo controlled. No objective measures were used to assess improvement. Only short-term follow-up data are presented. No long-term safety data regarding the repeated use of these agents in treatment of Search • They are not placebo controlled. • No objective measures were used to assess improvement. • Only short-term follow-up data are presented. • No long-term safety data regarding the repeated use of these agents in treatment of ## Genetic Counseling Most individuals diagnosed with Some individuals diagnosed 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 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 minimally affected. Such individuals may present with a unilateral cluster of cylindromas, spiradenomas, or trichoepitheliomas If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Although the penetrance of If the proband has a known If clinical evaluation of a parent suggests a mosaic presentation of See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected 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 • Some individuals diagnosed 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 • 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 minimally affected. Such individuals may present with a unilateral cluster of cylindromas, spiradenomas, or trichoepitheliomas • If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Although the penetrance of • If the proband has a known • If clinical evaluation of a parent suggests a mosaic presentation 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 ## Risk to Family Members Most individuals diagnosed with Some individuals diagnosed 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 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 minimally affected. Such individuals may present with a unilateral cluster of cylindromas, spiradenomas, or trichoepitheliomas If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Although the penetrance of If the proband has a known If clinical evaluation of a parent suggests a mosaic presentation of • Most individuals diagnosed with • Some individuals diagnosed 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 • 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 minimally affected. Such individuals may present with a unilateral cluster of cylindromas, spiradenomas, or trichoepitheliomas • If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Although the penetrance of • If the proband has a known • If clinical evaluation of a parent suggests a mosaic presentation of ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected 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 New Zealand • • New Zealand • • • ## Molecular Genetics CYLD Cutaneous Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for CYLD Cutaneous Syndrome ( CYLD also negatively regulates a range of signaling pathways that are important in inflammation and cancer, including JNK, Wnt, TGFB1, and Notch [ Somatic ## Molecular Pathogenesis CYLD also negatively regulates a range of signaling pathways that are important in inflammation and cancer, including JNK, Wnt, TGFB1, and Notch [ ## Cancer and Benign Tumors Somatic ## References ## Literature Cited ## Chapter Notes Dr Neil Rajan, MD, PhD is a senior lecturer and honorary consultant dermatologist based in Newcastle, UK. He has received fellowships from the Wellcome Trust and the Medical Research Council that have supported his work on the molecular dissection of inherited cutaneous tumor syndromes. His basic science research program is coupled with the delivery of early-phase clinical trials in rare disease, an exemplar of which is the TRAC study in Dr Rajan's We would like to take the opportunity to thank the patients who have generously participated in research. 16 April 2020 (ma) Review posted live 13 September 2019 (nr) Original submission • 16 April 2020 (ma) Review posted live • 13 September 2019 (nr) Original submission ## Author Notes Dr Neil Rajan, MD, PhD is a senior lecturer and honorary consultant dermatologist based in Newcastle, UK. He has received fellowships from the Wellcome Trust and the Medical Research Council that have supported his work on the molecular dissection of inherited cutaneous tumor syndromes. His basic science research program is coupled with the delivery of early-phase clinical trials in rare disease, an exemplar of which is the TRAC study in Dr Rajan's ## Acknowledgments We would like to take the opportunity to thank the patients who have generously participated in research. ## Revision History 16 April 2020 (ma) Review posted live 13 September 2019 (nr) Original submission • 16 April 2020 (ma) Review posted live • 13 September 2019 (nr) Original submission A. Cylindroma demonstrating a well-circumscribed pink nodular lesion with arborizing blood vessels visible on the surface B. Confluent scalp cylindromas in a severely affected individual with A. Histopathology of cylindroma B. Histopathology of spiradenoma Spiradenoma: a well-circumscribed nodular lesion (excision specimen) with characteristic blue/black appearance Trichoepithelioma: small skin-colored papules with a predilection for the central face Mosaic presentations of
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16/4/2020
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
danon
danon
[ "Lysosome-associated membrane glycoprotein 2", "LAMP2", "Danon Disease" ]
Danon Disease
Matthew RG Taylor, Eric D Adler
Summary Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Males are typically more severely affected than females. Males usually present with childhood onset concentric hypertrophic cardiomyopathy that is progressive and often requires heart transplantation. Rarely, hypertrophic cardiomyopathy can evolve to resemble dilated cardiomyopathy. Most affected males also have cardiac conduction abnormalities. Skeletal muscle weakness may lead to delayed acquisition of motor milestones. Learning disability and intellectual disability, most often in the mild range, are common. Additionally, affected males can develop retinopathy with subsequent visual impairment. The clinical features in females are broader and more variable. Females are more likely to have dilated cardiomyopathy, with a smaller proportion requiring heart transplantation compared to affected males. Cardiac conduction abnormalities, skeletal muscle weakness, mild cognitive impairment, and pigmentary retinopathy are variably seen in affected females. The diagnosis of Danon disease is established in a proband (male or female) with suggestive findings and/or a hemizygous (in males) or a heterozygous (in females) pathogenic variant in Danon disease is inherited in an X-linked manner. If the mother of the proband has a
## Diagnosis For the purposes of this Danon disease is a multisystem condition with predominant involvement of the heart, skeletal muscles, and retina, with overlying cognitive dysfunction. Formal clinical diagnostic criteria for Danon disease have not been established. Danon disease Cardiomyopathy that is predominantly hypertrophic and rapidly progressive Mild muscle weakness Retinopathy. The most detailed report of retinal findings to date is from a family with four males with Danon disease, two of whom had a classic cone-rod dystrophy [ Progressive visual impairment Severe color vision disturbances Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses Visual field testing revealing a central scotoma Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE Mild intellectual disability Elevated creatine kinase (~5-fold increase) Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function Muscle biopsy (either skeletal or cardiac) demonstrating a relatively specific vacuolar myopathy on standard histology but best seen by electron microscopy; substantial fibrosis is often present. Note: (1) Muscle biopsy is not required to make the diagnosis; (2) tissue staining demonstrating absence of the LAMP-2 protein can confirm the diagnosis, although this assay is not widely available on a clinical basis. Severe cardiac hypertrophy with or without evidence of outflow obstruction Wolff-Parkinson-White syndrome with pre-excitation on surface electrocardiogram Ventricular arrhythmias and atrial tachyarrhythmias Danon disease Either dilated or hypertrophic cardiomyopathy Retinal changes reminiscent of, but not as severe as, those seen in affected males Normal or mildly increased creatine kinase Normal or mildly increased AST and ALT with preserved hepatic synthetic function 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 Danon disease is broad, individuals with the distinctive features described in When the phenotypic and laboratory findings suggest the diagnosis of Danon disease, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of Danon disease is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Danon Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The vast majority of pathogenic variants reported to date are nonsense, frameshift, splicing, and small insertion-deletion variants. A minority of pathogenic variants are due to large gene deletions, duplications, or rearrangements. • Cardiomyopathy that is predominantly hypertrophic and rapidly progressive • Mild muscle weakness • Retinopathy. The most detailed report of retinal findings to date is from a family with four males with Danon disease, two of whom had a classic cone-rod dystrophy [ • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Mild intellectual disability • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Elevated creatine kinase (~5-fold increase) • Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function • Muscle biopsy (either skeletal or cardiac) demonstrating a relatively specific vacuolar myopathy on standard histology but best seen by electron microscopy; substantial fibrosis is often present. • Severe cardiac hypertrophy with or without evidence of outflow obstruction • Wolff-Parkinson-White syndrome with pre-excitation on surface electrocardiogram • Ventricular arrhythmias and atrial tachyarrhythmias • Either dilated or hypertrophic cardiomyopathy • Retinal changes reminiscent of, but not as severe as, those seen in affected males • Normal or mildly increased creatine kinase • Normal or mildly increased AST and ALT with preserved hepatic synthetic function • For an introduction to multigene panels click ## Suggestive Findings Danon disease Cardiomyopathy that is predominantly hypertrophic and rapidly progressive Mild muscle weakness Retinopathy. The most detailed report of retinal findings to date is from a family with four males with Danon disease, two of whom had a classic cone-rod dystrophy [ Progressive visual impairment Severe color vision disturbances Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses Visual field testing revealing a central scotoma Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE Mild intellectual disability Elevated creatine kinase (~5-fold increase) Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function Muscle biopsy (either skeletal or cardiac) demonstrating a relatively specific vacuolar myopathy on standard histology but best seen by electron microscopy; substantial fibrosis is often present. Note: (1) Muscle biopsy is not required to make the diagnosis; (2) tissue staining demonstrating absence of the LAMP-2 protein can confirm the diagnosis, although this assay is not widely available on a clinical basis. Severe cardiac hypertrophy with or without evidence of outflow obstruction Wolff-Parkinson-White syndrome with pre-excitation on surface electrocardiogram Ventricular arrhythmias and atrial tachyarrhythmias Danon disease Either dilated or hypertrophic cardiomyopathy Retinal changes reminiscent of, but not as severe as, those seen in affected males Normal or mildly increased creatine kinase Normal or mildly increased AST and ALT with preserved hepatic synthetic function • Cardiomyopathy that is predominantly hypertrophic and rapidly progressive • Mild muscle weakness • Retinopathy. The most detailed report of retinal findings to date is from a family with four males with Danon disease, two of whom had a classic cone-rod dystrophy [ • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Mild intellectual disability • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Elevated creatine kinase (~5-fold increase) • Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function • Muscle biopsy (either skeletal or cardiac) demonstrating a relatively specific vacuolar myopathy on standard histology but best seen by electron microscopy; substantial fibrosis is often present. • Severe cardiac hypertrophy with or without evidence of outflow obstruction • Wolff-Parkinson-White syndrome with pre-excitation on surface electrocardiogram • Ventricular arrhythmias and atrial tachyarrhythmias • Either dilated or hypertrophic cardiomyopathy • Retinal changes reminiscent of, but not as severe as, those seen in affected males • Normal or mildly increased creatine kinase • Normal or mildly increased AST and ALT with preserved hepatic synthetic function ## Males Danon disease Cardiomyopathy that is predominantly hypertrophic and rapidly progressive Mild muscle weakness Retinopathy. The most detailed report of retinal findings to date is from a family with four males with Danon disease, two of whom had a classic cone-rod dystrophy [ Progressive visual impairment Severe color vision disturbances Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses Visual field testing revealing a central scotoma Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE Mild intellectual disability Elevated creatine kinase (~5-fold increase) Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function Muscle biopsy (either skeletal or cardiac) demonstrating a relatively specific vacuolar myopathy on standard histology but best seen by electron microscopy; substantial fibrosis is often present. Note: (1) Muscle biopsy is not required to make the diagnosis; (2) tissue staining demonstrating absence of the LAMP-2 protein can confirm the diagnosis, although this assay is not widely available on a clinical basis. Severe cardiac hypertrophy with or without evidence of outflow obstruction Wolff-Parkinson-White syndrome with pre-excitation on surface electrocardiogram Ventricular arrhythmias and atrial tachyarrhythmias • Cardiomyopathy that is predominantly hypertrophic and rapidly progressive • Mild muscle weakness • Retinopathy. The most detailed report of retinal findings to date is from a family with four males with Danon disease, two of whom had a classic cone-rod dystrophy [ • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Mild intellectual disability • Progressive visual impairment • Severe color vision disturbances • Fundus examination revealing a bull's eye maculopathy and diffuse loss of pigment in the retinal pigment epithelium (RPE) • Electroretinogram revealing reduced photopic (cone) and scotopic (rod) responses • Visual field testing revealing a central scotoma • Optical coherence tomography revealing thinning of the retinal outer segments (rods and cones) and RPE • Elevated creatine kinase (~5-fold increase) • Elevated asparate aminotransferase (AST) (~7-fold increase) and alanine aminotransferase (ALT) (~6-fold increase) with preserved hepatic synthetic function • Muscle biopsy (either skeletal or cardiac) demonstrating a relatively specific vacuolar myopathy on standard histology but best seen by electron microscopy; substantial fibrosis is often present. • Severe cardiac hypertrophy with or without evidence of outflow obstruction • Wolff-Parkinson-White syndrome with pre-excitation on surface electrocardiogram • Ventricular arrhythmias and atrial tachyarrhythmias ## Females Danon disease Either dilated or hypertrophic cardiomyopathy Retinal changes reminiscent of, but not as severe as, those seen in affected males Normal or mildly increased creatine kinase Normal or mildly increased AST and ALT with preserved hepatic synthetic function • Either dilated or hypertrophic cardiomyopathy • Retinal changes reminiscent of, but not as severe as, those seen in affected males • Normal or mildly increased creatine kinase • Normal or mildly increased AST and ALT with preserved hepatic synthetic function ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Danon disease is broad, individuals with the distinctive features described in When the phenotypic and laboratory findings suggest the diagnosis of Danon disease, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of Danon disease is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Danon Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The vast majority of pathogenic variants reported to date are nonsense, frameshift, splicing, and small insertion-deletion variants. A minority of pathogenic variants are due to large gene deletions, duplications, or rearrangements. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Danon disease, 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 Danon disease is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Danon Disease See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The vast majority of pathogenic variants reported to date are nonsense, frameshift, splicing, and small insertion-deletion variants. A minority of pathogenic variants are due to large gene deletions, duplications, or rearrangements. ## Clinical Characteristics Danon disease is an X-linked condition in which males are often more severely affected than females. A total of 146 molecularly confirmed affected individuals (90 males and 56 females) with Danon disease have been reported in the literature and the information below summarizes the findings in these individuals [ Features of Danon Disease Males with Danon disease often present with the triad of severe cardiomyopathy, skeletal myopathy, and mild intellectual disability. Penetrance for cardiomyopathy approaches 100% in males, with 80%-90% of affected individuals experiencing some degree of skeletal muscle weakness and more than 70% experiencing some degree of cognitive impairment [ Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ Arrhythmias may cause clinical symptoms of palpitations or syncope. Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. Left-ventricular outflow obstruction is present in some individuals on exercise testing. Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. Although progression may occur, weakness is not typically disabling and most men retain the ability to ambulate. Because of this, the rehabilitation outcomes for men who undergo cardiac transplantation are generally good, although profound muscle weakness after cardiac transplantation has been rarely described [ Creatine kinase (CK) levels are elevated in most males (mean 944 U/L) [ Delayed motor milestones are reported in approximately 20% of affected males [ Dysmetria unrelated to muscle weakness has rarely been reported [ Learn to read Have a job Live independently Take part in a relationship Other neuropsychiatric issues that have been reported primarily in case reports or as part of small case series of affected individuals include [ Attention deficit disorder Behavior problems Psychiatric issues (e.g., severe depression, psychosis) Due to the small number of individuals reported with these particular features, it is unclear whether these issues are directly related to Danon disease. The severity varies even among males in the same family [ While details regarding rate of vision decline in males are not available in the limited number of published reports in Danon disease, Hepatomegaly Elevated liver enzymes without hepatic synthetic dysfunction; however in many instances the elevated transaminases are suspected to be of skeletal muscle origin. Overall, the phenotypic spectrum in females appears to be broader and more variable [ Of the heterozygous females who develop cardiomyopathy, about 18% receive a cardiac transplantation, compared to almost all affected males [ Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ Skeletal muscle weakness is not known to be progressive. Some females with a heterozygous pathogenic variant in Creatine kinase (CK) levels are usually normal in females (mean 106 U/L) [ Near-loss of visible pigment Abnormal electroretinogram Impaired vision To date, no specific genotype-phenotype correlations for pathogenic loss-of-function variants have been confirmed. A small number of pathogenic missense variants and pathogenic variants confined to exon 9B of the LAMP-2B protein isoform have been reported in association with mild or atypical phenotypes [ The penetrance in Danon disease is age dependent and has not been well studied in the literature. Given the severity of the cardiac phenotype, the penetrance is estimated as high or nearly complete in males by the second decade. Females appear to also have a high cardiac penetrance that is later in onset compared to males. Outdated terms for Danon disease represented in the literature: X-linked vacuolar cardiomyopathy and myopathy Glycogen storage disease IIb X-Linked pseudoglycogenosis II Antopol disease Lysosomal glycogen storage disease without acid maltase deficiency Danon disease is rare; measures of the general population prevalence are not known. Among individuals with hypertrophic cardiomyopathy (which has an overall prevalence of ~1:500 persons) the prevalence of those with a pathogenic • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Although progression may occur, weakness is not typically disabling and most men retain the ability to ambulate. Because of this, the rehabilitation outcomes for men who undergo cardiac transplantation are generally good, although profound muscle weakness after cardiac transplantation has been rarely described [ • Creatine kinase (CK) levels are elevated in most males (mean 944 U/L) [ • Delayed motor milestones are reported in approximately 20% of affected males [ • Dysmetria unrelated to muscle weakness has rarely been reported [ • Learn to read • Have a job • Live independently • Take part in a relationship • Attention deficit disorder • Behavior problems • Psychiatric issues (e.g., severe depression, psychosis) • The severity varies even among males in the same family [ • While details regarding rate of vision decline in males are not available in the limited number of published reports in Danon disease, • Hepatomegaly • Elevated liver enzymes without hepatic synthetic dysfunction; however in many instances the elevated transaminases are suspected to be of skeletal muscle origin. • Of the heterozygous females who develop cardiomyopathy, about 18% receive a cardiac transplantation, compared to almost all affected males [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Skeletal muscle weakness is not known to be progressive. • Some females with a heterozygous pathogenic variant in • Creatine kinase (CK) levels are usually normal in females (mean 106 U/L) [ • Near-loss of visible pigment • Abnormal electroretinogram • Impaired vision • X-linked vacuolar cardiomyopathy and myopathy • Glycogen storage disease IIb • X-Linked pseudoglycogenosis II • Antopol disease • Lysosomal glycogen storage disease without acid maltase deficiency ## Clinical Description Danon disease is an X-linked condition in which males are often more severely affected than females. A total of 146 molecularly confirmed affected individuals (90 males and 56 females) with Danon disease have been reported in the literature and the information below summarizes the findings in these individuals [ Features of Danon Disease Males with Danon disease often present with the triad of severe cardiomyopathy, skeletal myopathy, and mild intellectual disability. Penetrance for cardiomyopathy approaches 100% in males, with 80%-90% of affected individuals experiencing some degree of skeletal muscle weakness and more than 70% experiencing some degree of cognitive impairment [ Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ Arrhythmias may cause clinical symptoms of palpitations or syncope. Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. Left-ventricular outflow obstruction is present in some individuals on exercise testing. Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. Although progression may occur, weakness is not typically disabling and most men retain the ability to ambulate. Because of this, the rehabilitation outcomes for men who undergo cardiac transplantation are generally good, although profound muscle weakness after cardiac transplantation has been rarely described [ Creatine kinase (CK) levels are elevated in most males (mean 944 U/L) [ Delayed motor milestones are reported in approximately 20% of affected males [ Dysmetria unrelated to muscle weakness has rarely been reported [ Learn to read Have a job Live independently Take part in a relationship Other neuropsychiatric issues that have been reported primarily in case reports or as part of small case series of affected individuals include [ Attention deficit disorder Behavior problems Psychiatric issues (e.g., severe depression, psychosis) Due to the small number of individuals reported with these particular features, it is unclear whether these issues are directly related to Danon disease. The severity varies even among males in the same family [ While details regarding rate of vision decline in males are not available in the limited number of published reports in Danon disease, Hepatomegaly Elevated liver enzymes without hepatic synthetic dysfunction; however in many instances the elevated transaminases are suspected to be of skeletal muscle origin. Overall, the phenotypic spectrum in females appears to be broader and more variable [ Of the heterozygous females who develop cardiomyopathy, about 18% receive a cardiac transplantation, compared to almost all affected males [ Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ Skeletal muscle weakness is not known to be progressive. Some females with a heterozygous pathogenic variant in Creatine kinase (CK) levels are usually normal in females (mean 106 U/L) [ Near-loss of visible pigment Abnormal electroretinogram Impaired vision • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Although progression may occur, weakness is not typically disabling and most men retain the ability to ambulate. Because of this, the rehabilitation outcomes for men who undergo cardiac transplantation are generally good, although profound muscle weakness after cardiac transplantation has been rarely described [ • Creatine kinase (CK) levels are elevated in most males (mean 944 U/L) [ • Delayed motor milestones are reported in approximately 20% of affected males [ • Dysmetria unrelated to muscle weakness has rarely been reported [ • Learn to read • Have a job • Live independently • Take part in a relationship • Attention deficit disorder • Behavior problems • Psychiatric issues (e.g., severe depression, psychosis) • The severity varies even among males in the same family [ • While details regarding rate of vision decline in males are not available in the limited number of published reports in Danon disease, • Hepatomegaly • Elevated liver enzymes without hepatic synthetic dysfunction; however in many instances the elevated transaminases are suspected to be of skeletal muscle origin. • Of the heterozygous females who develop cardiomyopathy, about 18% receive a cardiac transplantation, compared to almost all affected males [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Skeletal muscle weakness is not known to be progressive. • Some females with a heterozygous pathogenic variant in • Creatine kinase (CK) levels are usually normal in females (mean 106 U/L) [ • Near-loss of visible pigment • Abnormal electroretinogram • Impaired vision ## Males Males with Danon disease often present with the triad of severe cardiomyopathy, skeletal myopathy, and mild intellectual disability. Penetrance for cardiomyopathy approaches 100% in males, with 80%-90% of affected individuals experiencing some degree of skeletal muscle weakness and more than 70% experiencing some degree of cognitive impairment [ Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ Arrhythmias may cause clinical symptoms of palpitations or syncope. Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. Left-ventricular outflow obstruction is present in some individuals on exercise testing. Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. Although progression may occur, weakness is not typically disabling and most men retain the ability to ambulate. Because of this, the rehabilitation outcomes for men who undergo cardiac transplantation are generally good, although profound muscle weakness after cardiac transplantation has been rarely described [ Creatine kinase (CK) levels are elevated in most males (mean 944 U/L) [ Delayed motor milestones are reported in approximately 20% of affected males [ Dysmetria unrelated to muscle weakness has rarely been reported [ Learn to read Have a job Live independently Take part in a relationship Other neuropsychiatric issues that have been reported primarily in case reports or as part of small case series of affected individuals include [ Attention deficit disorder Behavior problems Psychiatric issues (e.g., severe depression, psychosis) Due to the small number of individuals reported with these particular features, it is unclear whether these issues are directly related to Danon disease. The severity varies even among males in the same family [ While details regarding rate of vision decline in males are not available in the limited number of published reports in Danon disease, Hepatomegaly Elevated liver enzymes without hepatic synthetic dysfunction; however in many instances the elevated transaminases are suspected to be of skeletal muscle origin. • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Hypertrophic cardiomyopathy is present in 70%-88% of affected males [ • In contrast to many other forms of hypertrophic cardiomyopathy, progression to severe hypertrophy, heart failure, and an almost certain need for transplantation in the second and third decades of life is typically seen in Danon disease. • Reported ages of cardiac transplantation and death in males are 33.7 and 34.5 years, respectively [ • In a minority of affected males the cardiac features evolve to resemble dilated cardiomyopathy [ • Arrhythmias may cause clinical symptoms of palpitations or syncope. • Pre-excitation, including Wolff-Parkinson-White syndrome, is the most common finding on EKG [ • In some instances a pre-excitation, Wolff-Parkinson-White pattern on electrocardiography may precede overt cardiomyopathy. • Left-ventricular outflow obstruction is present in some individuals on exercise testing. • Increasingly, cardiac MRI is proving to be a useful tool to characterize hypertrophy and quantify the presence of late gadolinium enhancement as a measure of cardiac fibrosis. • Although progression may occur, weakness is not typically disabling and most men retain the ability to ambulate. Because of this, the rehabilitation outcomes for men who undergo cardiac transplantation are generally good, although profound muscle weakness after cardiac transplantation has been rarely described [ • Creatine kinase (CK) levels are elevated in most males (mean 944 U/L) [ • Delayed motor milestones are reported in approximately 20% of affected males [ • Dysmetria unrelated to muscle weakness has rarely been reported [ • Learn to read • Have a job • Live independently • Take part in a relationship • Attention deficit disorder • Behavior problems • Psychiatric issues (e.g., severe depression, psychosis) • The severity varies even among males in the same family [ • While details regarding rate of vision decline in males are not available in the limited number of published reports in Danon disease, • Hepatomegaly • Elevated liver enzymes without hepatic synthetic dysfunction; however in many instances the elevated transaminases are suspected to be of skeletal muscle origin. ## Females Overall, the phenotypic spectrum in females appears to be broader and more variable [ Of the heterozygous females who develop cardiomyopathy, about 18% receive a cardiac transplantation, compared to almost all affected males [ Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ Skeletal muscle weakness is not known to be progressive. Some females with a heterozygous pathogenic variant in Creatine kinase (CK) levels are usually normal in females (mean 106 U/L) [ Near-loss of visible pigment Abnormal electroretinogram Impaired vision • Of the heterozygous females who develop cardiomyopathy, about 18% receive a cardiac transplantation, compared to almost all affected males [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Pre-excitation with Wolff-Parkinson-White is identified in 32% of females at presentation [ • With time, however, the prevalence of cardiac disease in females approaches that of males, with one comprehensive study of published case reports noting a composite outcome (death, heart transplant, or ventricular assist device) occurring in 37% of males and 37% of females [ • Skeletal muscle weakness is not known to be progressive. • Some females with a heterozygous pathogenic variant in • Creatine kinase (CK) levels are usually normal in females (mean 106 U/L) [ • Near-loss of visible pigment • Abnormal electroretinogram • Impaired vision ## Genotype-Phenotype Correlations To date, no specific genotype-phenotype correlations for pathogenic loss-of-function variants have been confirmed. A small number of pathogenic missense variants and pathogenic variants confined to exon 9B of the LAMP-2B protein isoform have been reported in association with mild or atypical phenotypes [ ## Penetrance The penetrance in Danon disease is age dependent and has not been well studied in the literature. Given the severity of the cardiac phenotype, the penetrance is estimated as high or nearly complete in males by the second decade. Females appear to also have a high cardiac penetrance that is later in onset compared to males. ## Nomenclature Outdated terms for Danon disease represented in the literature: X-linked vacuolar cardiomyopathy and myopathy Glycogen storage disease IIb X-Linked pseudoglycogenosis II Antopol disease Lysosomal glycogen storage disease without acid maltase deficiency • X-linked vacuolar cardiomyopathy and myopathy • Glycogen storage disease IIb • X-Linked pseudoglycogenosis II • Antopol disease • Lysosomal glycogen storage disease without acid maltase deficiency ## Prevalence Danon disease is rare; measures of the general population prevalence are not known. Among individuals with hypertrophic cardiomyopathy (which has an overall prevalence of ~1:500 persons) the prevalence of those with a pathogenic ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The disorders listed in Selected Genes of Interest in the Differential Diagnosis of Danon Disease Wolff-Parkinson White syndrome w/or w/o hypertrophic cardiomyopathy Vacuolar cardiomyopathy & ↑ myocardial glycogen (in severe congenital cases; see OMIM Hypotonia & muscle atrophy ↑ creatine kinase Autophagocytic vacuoles on muscle biopsy AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Listed genes represent the most common genes known to be associated with hypertrophic cardiomyopathy. See Mutation of X-linked myopathy w/excessive autophagy is also associated with scoliosis and has extraocular muscle involvement. • Wolff-Parkinson White syndrome w/or w/o hypertrophic cardiomyopathy • Vacuolar cardiomyopathy & ↑ myocardial glycogen (in severe congenital cases; see OMIM • Hypotonia & muscle atrophy • ↑ creatine kinase • Autophagocytic vacuoles on muscle biopsy ## Management Suggested treatment guidelines for Danon disease were reported by To establish the extent of disease and needs in an individual diagnosed with Danon disease, the evaluations summarized in Danon Disease: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention/special education BCVA Refractive error Color vision testing Full-field ERG Spectral-domain optical coherence tomography Adapted from ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCVA = best corrected Snellen visual acuity; ERG = electroretinogram; LDH = lactate dehydrogenase If results are strikingly abnormal, evaluation of liver synthetic function (e.g., total protein, albumin) and evaluation for other causes of abnormal liver function may be considered. Danon Disease: Treatment of Manifestations Institute hypertrophic cardiomyopathy guidelines Timely consideration of implantable cardiac defibrillators Consideration of electrophysiologic studies & ablation therapy Timely consideration of implantable cardiac defibrillators Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. DD = developmental delay; ID = intellectual disability Adapted from See Neurohormonal therapy includes drugs that target the sympathetic nervous system (beta-blockers, alpha-blockers) and the renin-angiotensin system (ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists). Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields. In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living. 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. 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. Danon Disease: Recommended Surveillance Of strength, incl consideration of 6-min walking test For neurologic changes Adapted from Six-minute walking test has not been formally studied as a means of assessing weakness in individuals with Danon disease. Impact on vision and rate of progression of retinal disease is not well understood. Dehydration and over-diuresis should be avoided in those with heart failure. No specific guidelines exist for individuals with non-sarcomeric cardiomyopathy. However, in the presence of significant cardiac hypertrophy with obstruction and/or symptomatic arrhythmia, instituting the guidelines for physical exertion for individuals with sarcomeric hypertrophic cardiomyopathy could be considered [ 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 There are no published guidelines on pregnancy management in women with Danon disease. Management should be guided based on the degree of overt disease in the pregnant woman and as per guidelines for pregnant women with hypertrophic or dilated cardiomyopathy, depending on their condition. See Gene therapy was first offered through a clinical trial in 2019. The ongoing clinical trial ( Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention/special education • BCVA • Refractive error • Color vision testing • Full-field ERG • Spectral-domain optical coherence tomography • Institute hypertrophic cardiomyopathy guidelines • Timely consideration of implantable cardiac defibrillators • Consideration of electrophysiologic studies & ablation therapy • Timely consideration of implantable cardiac defibrillators • 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. • Of strength, incl consideration of 6-min walking test • For neurologic changes ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Danon disease, the evaluations summarized in Danon Disease: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention/special education BCVA Refractive error Color vision testing Full-field ERG Spectral-domain optical coherence tomography Adapted from ALT = alanine aminotransferase; AST = aspartate aminotransferase; BCVA = best corrected Snellen visual acuity; ERG = electroretinogram; LDH = lactate dehydrogenase If results are strikingly abnormal, evaluation of liver synthetic function (e.g., total protein, albumin) and evaluation for other causes of abnormal liver function may be considered. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention/special education • BCVA • Refractive error • Color vision testing • Full-field ERG • Spectral-domain optical coherence tomography ## Treatment of Manifestations Danon Disease: Treatment of Manifestations Institute hypertrophic cardiomyopathy guidelines Timely consideration of implantable cardiac defibrillators Consideration of electrophysiologic studies & ablation therapy Timely consideration of implantable cardiac defibrillators Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. DD = developmental delay; ID = intellectual disability Adapted from See Neurohormonal therapy includes drugs that target the sympathetic nervous system (beta-blockers, alpha-blockers) and the renin-angiotensin system (ACE inhibitors, angiotensin receptor blockers, mineralocorticoid receptor antagonists). Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields. In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living. 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. 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. • Institute hypertrophic cardiomyopathy guidelines • Timely consideration of implantable cardiac defibrillators • Consideration of electrophysiologic studies & ablation therapy • Timely consideration of implantable cardiac defibrillators • 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. ## 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 ## 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. ## Surveillance Danon Disease: Recommended Surveillance Of strength, incl consideration of 6-min walking test For neurologic changes Adapted from Six-minute walking test has not been formally studied as a means of assessing weakness in individuals with Danon disease. Impact on vision and rate of progression of retinal disease is not well understood. • Of strength, incl consideration of 6-min walking test • For neurologic changes ## Agents/Circumstances to Avoid Dehydration and over-diuresis should be avoided in those with heart failure. No specific guidelines exist for individuals with non-sarcomeric cardiomyopathy. However, in the presence of significant cardiac hypertrophy with obstruction and/or symptomatic arrhythmia, instituting the guidelines for physical exertion for individuals with sarcomeric hypertrophic cardiomyopathy could be considered [ ## 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 There are no published guidelines on pregnancy management in women with Danon disease. Management should be guided based on the degree of overt disease in the pregnant woman and as per guidelines for pregnant women with hypertrophic or dilated cardiomyopathy, depending on their condition. See ## Therapies Under Investigation Gene therapy was first offered through a clinical trial in 2019. The ongoing clinical trial ( Search ## Genetic Counseling Danon disease 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 or the affected male may have a A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has a If the proband represents a simplex case (i.e., a single occurrence in a family) and if the If the mother of the proband has a If the father of the proband has a If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Affected males transmit the All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, None of their sons. Women with a Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, Sons who inherit the pathogenic variant will be affected. Note: Molecular genetic testing may be able to identify the family member in whom a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are heterozygotes, or who are at increased risk of being heterozygous and 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. • 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 or the affected male may have a • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has a • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • If the mother of the proband has a • If the father of the proband has a • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Affected males transmit the • All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • None of their sons. • Women with a • Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • Sons who inherit the pathogenic variant will be affected. • Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • Sons who inherit the pathogenic variant will be affected. • All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • None of their sons. • Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • Sons who inherit the pathogenic variant will 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 or are heterozygotes, or who are at increased risk of being heterozygous and affected. ## Mode of Inheritance Danon disease 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 or the affected male may have a A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has a If the proband represents a simplex case (i.e., a single occurrence in a family) and if the If the mother of the proband has a If the father of the proband has a If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Affected males transmit the All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, None of their sons. Women with a Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, Sons who inherit the pathogenic variant will be affected. Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has a • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • If the mother of the proband has a • If the father of the proband has a • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Affected males transmit the • All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • None of their sons. • All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • None of their sons. • Women with a • Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • Sons who inherit the pathogenic variant will be affected. • Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • Sons who inherit the pathogenic variant will be affected. • All of their daughters, who will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • None of their sons. • Daughters who inherit the pathogenic variant will be heterozygotes and have a range of clinical manifestations (see Clinical Description, • Sons who inherit the pathogenic variant will be affected. ## 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 are heterozygotes, or who are at increased risk of being heterozygous and 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 or are heterozygotes, or who are at increased risk of being heterozygous and 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 12700 East 19th Avenue F442, Room 8022 Aurora CO • • 12700 East 19th Avenue • F442, Room 8022 • Aurora CO • ## Molecular Genetics Danon Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Danon Disease ( The specific mechanism of disease remains uncertain, though studies of animal models of Danon as well as pluripotent stem cell derived from affected individuals suggest that the absence of LAMP-2, and more specifically the LAMP-2B isoform, results in impaired macro autophagic and subsequent mitochondrial dysfunction [ Given all of the above, Danon disease is now considered a condition of pathologic autophagy with histologic features of abnormal cytoplasmic trafficking manifest with vacuolar myopathy and elevated glycogen staining. ## Molecular Pathogenesis The specific mechanism of disease remains uncertain, though studies of animal models of Danon as well as pluripotent stem cell derived from affected individuals suggest that the absence of LAMP-2, and more specifically the LAMP-2B isoform, results in impaired macro autophagic and subsequent mitochondrial dysfunction [ Given all of the above, Danon disease is now considered a condition of pathologic autophagy with histologic features of abnormal cytoplasmic trafficking manifest with vacuolar myopathy and elevated glycogen staining. ## Chapter Notes Ongoing Danon Disease research through the Danon Disease Registry is accessible by contacting Matthew Taylor ( 23 May 2024 (ma) Revision: 5 March 2020 (ma) Review posted live 25 July 2019 (mrgt) Original submission • 23 May 2024 (ma) Revision: • 5 March 2020 (ma) Review posted live • 25 July 2019 (mrgt) Original submission ## Author Notes Ongoing Danon Disease research through the Danon Disease Registry is accessible by contacting Matthew Taylor ( ## Revision History 23 May 2024 (ma) Revision: 5 March 2020 (ma) Review posted live 25 July 2019 (mrgt) Original submission • 23 May 2024 (ma) Revision: • 5 March 2020 (ma) Review posted live • 25 July 2019 (mrgt) Original submission ## References ## Literature Cited
[]
5/3/2020
23/5/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dbh
dbh
[ "Dopamine beta-hydroxylase", "DBH", "Dopamine Beta-Hydroxylase Deficiency" ]
Dopamine Beta-Hydroxylase Deficiency
Italo Biaggioni
Summary Dopamine beta-hydroxylase (DBH) deficiency is characterized by lack of sympathetic noradrenergic function resulting in profound deficits in autonomic regulation of cardiovascular function (orthostatic hypotension) and other autonomic dysfunction (ptosis, nasal stuffiness, sleep difficulties, and impaired ejaculation in males). Although DBH deficiency is present from birth, the diagnosis is often not generally recognized until late childhood. In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization, and the diagnosis may be identified fortuitously in the neonatal period with investigation of hypoglycemia. Children may report reduced exercise capacity. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis, and nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain; symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Some individuals have abnormal kidney function, joint laxity, hypotonia, high-arched palate, anemia, and/or hypoglycemia. The diagnosis of DBH deficiency is established in a proband with profound neurogenic orthostatic hypotension, minimal or absent plasma concentrations of norepinephrine and epinephrine, a five- to tenfold elevation of plasma dopamine, and biallelic pathogenic variants in DBH deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
## Diagnosis No consensus clinical diagnostic criteria have been published for dopamine beta-hydroxylase (DBH) deficiency. A clinical assessment including orthostatic vital signs and an ophthalmic exam should be the initial step; if indicated, this should be followed by autonomic function testing and plasma catecholamine analysis. DBH deficiency Presentation: Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. Poor cardiovascular regulation evident from supine, seated, and standing vital signs: A low-to-normal supine blood pressure and low or normal supine heart rate Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function Inability to stand motionless for more than a few minutes Other autonomic dysfunction evident from an ophthalmic examination: Ptosis in some individuals A marked decrease in intraocular pressure with standing [ Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. A comprehensive history and physical examination (including neurologic exam) typically reveal the following: High-arched palate Hyperextensible joints Hypotonia Sluggish deep tendon reflexes Mild facial muscle weakness Intact sweating consistent with intact sympathetic cholinergic function Minimal or absent plasma norepinephrine and epinephrine. Plasma norepinephrine concentration should be below the limits of detection (<25 pg/mL or 0.15 nmol/L). Five- to tenfold elevation of plasma dopamine. Plasma dopamine concentration is frequently higher than 100 pg/mL (0.65 nmol/L). Note: Very low (rather than undetectable) levels of norepinephrine can be reported in some assays due to interference substances. The diagnosis of DBH 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 DBH deficiency, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of DBH deficiency is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dopamine Beta-Hydroxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Presentation: • Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. • Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. • Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. • Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. • Poor cardiovascular regulation evident from supine, seated, and standing vital signs: • A low-to-normal supine blood pressure and low or normal supine heart rate • Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure • An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function • Inability to stand motionless for more than a few minutes • A low-to-normal supine blood pressure and low or normal supine heart rate • Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure • An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function • Inability to stand motionless for more than a few minutes • Other autonomic dysfunction evident from an ophthalmic examination: • Ptosis in some individuals • A marked decrease in intraocular pressure with standing [ • Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. • Ptosis in some individuals • A marked decrease in intraocular pressure with standing [ • Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. • A comprehensive history and physical examination (including neurologic exam) typically reveal the following: • High-arched palate • Hyperextensible joints • Hypotonia • Sluggish deep tendon reflexes • Mild facial muscle weakness • Intact sweating consistent with intact sympathetic cholinergic function • High-arched palate • Hyperextensible joints • Hypotonia • Sluggish deep tendon reflexes • Mild facial muscle weakness • Intact sweating consistent with intact sympathetic cholinergic function • Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. • Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. • A low-to-normal supine blood pressure and low or normal supine heart rate • Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure • An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function • Inability to stand motionless for more than a few minutes • Ptosis in some individuals • A marked decrease in intraocular pressure with standing [ • Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. • High-arched palate • Hyperextensible joints • Hypotonia • Sluggish deep tendon reflexes • Mild facial muscle weakness • Intact sweating consistent with intact sympathetic cholinergic function • Minimal or absent plasma norepinephrine and epinephrine. Plasma norepinephrine concentration should be below the limits of detection (<25 pg/mL or 0.15 nmol/L). • Five- to tenfold elevation of plasma dopamine. Plasma dopamine concentration is frequently higher than 100 pg/mL (0.65 nmol/L). • Note: Very low (rather than undetectable) levels of norepinephrine can be reported in some assays due to interference substances. • For an introduction to multigene panels click ## Suggestive Findings DBH deficiency Presentation: Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. Poor cardiovascular regulation evident from supine, seated, and standing vital signs: A low-to-normal supine blood pressure and low or normal supine heart rate Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function Inability to stand motionless for more than a few minutes Other autonomic dysfunction evident from an ophthalmic examination: Ptosis in some individuals A marked decrease in intraocular pressure with standing [ Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. A comprehensive history and physical examination (including neurologic exam) typically reveal the following: High-arched palate Hyperextensible joints Hypotonia Sluggish deep tendon reflexes Mild facial muscle weakness Intact sweating consistent with intact sympathetic cholinergic function Minimal or absent plasma norepinephrine and epinephrine. Plasma norepinephrine concentration should be below the limits of detection (<25 pg/mL or 0.15 nmol/L). Five- to tenfold elevation of plasma dopamine. Plasma dopamine concentration is frequently higher than 100 pg/mL (0.65 nmol/L). Note: Very low (rather than undetectable) levels of norepinephrine can be reported in some assays due to interference substances. • Presentation: • Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. • Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. • Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. • Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. • Poor cardiovascular regulation evident from supine, seated, and standing vital signs: • A low-to-normal supine blood pressure and low or normal supine heart rate • Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure • An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function • Inability to stand motionless for more than a few minutes • A low-to-normal supine blood pressure and low or normal supine heart rate • Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure • An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function • Inability to stand motionless for more than a few minutes • Other autonomic dysfunction evident from an ophthalmic examination: • Ptosis in some individuals • A marked decrease in intraocular pressure with standing [ • Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. • Ptosis in some individuals • A marked decrease in intraocular pressure with standing [ • Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. • A comprehensive history and physical examination (including neurologic exam) typically reveal the following: • High-arched palate • Hyperextensible joints • Hypotonia • Sluggish deep tendon reflexes • Mild facial muscle weakness • Intact sweating consistent with intact sympathetic cholinergic function • High-arched palate • Hyperextensible joints • Hypotonia • Sluggish deep tendon reflexes • Mild facial muscle weakness • Intact sweating consistent with intact sympathetic cholinergic function • Typical presentation is in adolescence with lifelong difficulties with lightheadedness, fatigue, inability to tolerate standing, reduced exercise capacity, recurrent syncope, and recurrent squatting to compensate for poor cardiovascular regulation. • Infants may present with recurrent vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization. • A low-to-normal supine blood pressure and low or normal supine heart rate • Severely symptomatic orthostatic hypotension with systolic blood pressure falling below 80 mm Hg in the upright position, consistent with sympathetic noradrenergic failure • An intact compensatory rise in heart rate with standing, consistent with preserved parasympathetic function • Inability to stand motionless for more than a few minutes • Ptosis in some individuals • A marked decrease in intraocular pressure with standing [ • Somewhat small pupils that respond to light and accommodation and dilate to noradrenergic agonists (phenylephrine) but not to indirect sympathomimetics (hydroxyamphetamine). Parasympatholytics dilate the pupils appropriately. • High-arched palate • Hyperextensible joints • Hypotonia • Sluggish deep tendon reflexes • Mild facial muscle weakness • Intact sweating consistent with intact sympathetic cholinergic function • Minimal or absent plasma norepinephrine and epinephrine. Plasma norepinephrine concentration should be below the limits of detection (<25 pg/mL or 0.15 nmol/L). • Five- to tenfold elevation of plasma dopamine. Plasma dopamine concentration is frequently higher than 100 pg/mL (0.65 nmol/L). • Note: Very low (rather than undetectable) levels of norepinephrine can be reported in some assays due to interference substances. ## Establishing the Diagnosis The diagnosis of DBH 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 DBH deficiency, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of DBH deficiency is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dopamine Beta-Hydroxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of DBH 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 DBH deficiency is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dopamine Beta-Hydroxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Clinical Characteristics Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function resulting in profound deficits in autonomic regulation of cardiovascular function and other autonomic dysfunction. Most individuals have abnormal kidney function, and some have joint laxity, hypotonia, high-arched palate, anemia, and/or hypoglycemia (in childhood). To date, only about two dozen individuals have been reported with a pathogenic variant in Dopamine Beta-Hydroxylase Deficiency: Frequency of Select Features BUN = blood urea nitrogen Number of individuals with the finding / total number evaluated for the finding Children with DBH deficiency have recurrent syncope and markedly reduced exercise capacity. Symptoms worsen in late adolescence with profound orthostatic hypotension, fatigue, and greatly reduced exercise tolerance. Five affected individuals and ten matched healthy unaffected participants underwent a comprehensive battery of neurocognitive testing in addition to brain MRI, pupillometry, and EEG. Performance of the affected individuals, whether on or off droxidopa treatment, was similar to that of the unaffected individuals in most respects, suggesting that other systems compensate for absent norepinephrine in affected individuals. Brain MRI studies revealed a smaller total brain volume in the affected individuals compared to unaffected individuals, although relative proportions of white and gray matter and cerebrospinal fluid were similar in the two groups. In addition, affected individuals had a temporal attention deficit when they were not on treatment. During an attentional blink task, participants were asked to identify two digits, separated by a variable number of letters. Attentional blink refers to the deficit in processing the second digit when it is presented within 200-400 msec of the first. Accuracy in identifying the second digit was impaired in affected individuals not on treatment, but performance improved with droxidopa treatment [ One individual was not diagnosed with DBH deficiency until age 73 years despite having long-lasting orthostatic hypotension [ There are no known genotype-phenotype correlations. The prevalence of DBH deficiency is unknown. Only 25 affected individuals, all of western European descent, have been reported in the literature, suggesting that it is a rare disorder. It is likely that other individuals have been diagnosed but not reported in the literature. • Five affected individuals and ten matched healthy unaffected participants underwent a comprehensive battery of neurocognitive testing in addition to brain MRI, pupillometry, and EEG. Performance of the affected individuals, whether on or off droxidopa treatment, was similar to that of the unaffected individuals in most respects, suggesting that other systems compensate for absent norepinephrine in affected individuals. • Brain MRI studies revealed a smaller total brain volume in the affected individuals compared to unaffected individuals, although relative proportions of white and gray matter and cerebrospinal fluid were similar in the two groups. • In addition, affected individuals had a temporal attention deficit when they were not on treatment. During an attentional blink task, participants were asked to identify two digits, separated by a variable number of letters. Attentional blink refers to the deficit in processing the second digit when it is presented within 200-400 msec of the first. Accuracy in identifying the second digit was impaired in affected individuals not on treatment, but performance improved with droxidopa treatment [ ## Clinical Description Dopamine beta-hydroxylase (DBH) deficiency is characterized by a lack of sympathetic noradrenergic function resulting in profound deficits in autonomic regulation of cardiovascular function and other autonomic dysfunction. Most individuals have abnormal kidney function, and some have joint laxity, hypotonia, high-arched palate, anemia, and/or hypoglycemia (in childhood). To date, only about two dozen individuals have been reported with a pathogenic variant in Dopamine Beta-Hydroxylase Deficiency: Frequency of Select Features BUN = blood urea nitrogen Number of individuals with the finding / total number evaluated for the finding Children with DBH deficiency have recurrent syncope and markedly reduced exercise capacity. Symptoms worsen in late adolescence with profound orthostatic hypotension, fatigue, and greatly reduced exercise tolerance. Five affected individuals and ten matched healthy unaffected participants underwent a comprehensive battery of neurocognitive testing in addition to brain MRI, pupillometry, and EEG. Performance of the affected individuals, whether on or off droxidopa treatment, was similar to that of the unaffected individuals in most respects, suggesting that other systems compensate for absent norepinephrine in affected individuals. Brain MRI studies revealed a smaller total brain volume in the affected individuals compared to unaffected individuals, although relative proportions of white and gray matter and cerebrospinal fluid were similar in the two groups. In addition, affected individuals had a temporal attention deficit when they were not on treatment. During an attentional blink task, participants were asked to identify two digits, separated by a variable number of letters. Attentional blink refers to the deficit in processing the second digit when it is presented within 200-400 msec of the first. Accuracy in identifying the second digit was impaired in affected individuals not on treatment, but performance improved with droxidopa treatment [ One individual was not diagnosed with DBH deficiency until age 73 years despite having long-lasting orthostatic hypotension [ • Five affected individuals and ten matched healthy unaffected participants underwent a comprehensive battery of neurocognitive testing in addition to brain MRI, pupillometry, and EEG. Performance of the affected individuals, whether on or off droxidopa treatment, was similar to that of the unaffected individuals in most respects, suggesting that other systems compensate for absent norepinephrine in affected individuals. • Brain MRI studies revealed a smaller total brain volume in the affected individuals compared to unaffected individuals, although relative proportions of white and gray matter and cerebrospinal fluid were similar in the two groups. • In addition, affected individuals had a temporal attention deficit when they were not on treatment. During an attentional blink task, participants were asked to identify two digits, separated by a variable number of letters. Attentional blink refers to the deficit in processing the second digit when it is presented within 200-400 msec of the first. Accuracy in identifying the second digit was impaired in affected individuals not on treatment, but performance improved with droxidopa treatment [ ## Genotype-Phenotype Correlations There are no known genotype-phenotype correlations. ## Prevalence The prevalence of DBH deficiency is unknown. Only 25 affected individuals, all of western European descent, have been reported in the literature, suggesting that it is a rare disorder. It is likely that other individuals have been diagnosed but not reported in the literature. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The combination of minimal or absent plasma norepinephrine and epinephrine and a five- to tenfold elevation of plasma dopamine is likely pathognomonic of dopamine beta-hydroxylase (DBH) deficiency and distinguishes DBH deficiency from other disorders. DBH enzymatic function depends on the availability of the cofactor ascorbic acid, which is generated by transmembrane ascorbate-dependent reductase CYB561, encoded by Genetic disorders with orthostatic hypotension to consider in the differential diagnosis of DBH deficiency are summarized in Genetic Disorders with Orthostatic Hypotension in the Differential Diagnosis of Dopamine Beta-Hydroxylase Deficiency DBH activity is depressed in Plasma catechol concentrations are distinctively abnormal at all ages in affected males. In infants w/classic Menkes disease: loss of developmental milestones, hypotonia, seizures, poor growth at age 2-3 mos, & characteristic hair changes (short, sparse, coarse, twisted, often lightly pigmented); death usually by age 3 yrs "Occipital horns," distinctive wedge-shaped calcifications at sites of attachment of trapezius muscle & sternocleidomastoid muscle to occipital bone; lax skin & joints; bladder diverticula; inguinal hernias; vascular tortuosity; low serum copper & serum ceruloplasmin concentrations Sympathetic dysfunction evident by severe symptomatic orthostatic hypotension from infancy or early childhood Undetectable or very low plasma & urinary norepinephrine & epinephrine Impaired renal function, mild anemia, episodic hypoglycemia Can be treated w/droxidopa No ptosis No orthostatic tachycardia in response to drop in blood pressure No skeletal muscle hypotonia Normal plasma dopamine Autonomic dysfunction (GI problems, orthostatic hypotension) & autonomic crises (hypertensive vomiting attacks) Cardiovascular instability Age-related decline in renal function Occurs almost exclusively in persons of Ashkenazi Jewish descent Sensory neuropathy Normal resting plasma norepinephrine, greatly ↑ during autonomic crisis Orthostatic hypotension Attacks of nausea & vomiting Mild-to-severe kidney disease can develop. Amyloidosis (can involve heart, CNS, eyes, & kidneys) Sensorimotor neuropathy; constipation alternating w/diarrhea; anhidrosis; urinary retention or incontinence Onset typically in 3rd-5th decade, but may be later AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DBH = dopamine beta-hydroxylase; GI = gastrointestinal; MOI = mode of inheritance; XL = X-linked • DBH activity is depressed in • Plasma catechol concentrations are distinctively abnormal at all ages in affected males. • In infants w/classic Menkes disease: loss of developmental milestones, hypotonia, seizures, poor growth at age 2-3 mos, & characteristic hair changes (short, sparse, coarse, twisted, often lightly pigmented); death usually by age 3 yrs • "Occipital horns," distinctive wedge-shaped calcifications at sites of attachment of trapezius muscle & sternocleidomastoid muscle to occipital bone; lax skin & joints; bladder diverticula; inguinal hernias; vascular tortuosity; low serum copper & serum ceruloplasmin concentrations • Sympathetic dysfunction evident by severe symptomatic orthostatic hypotension from infancy or early childhood • Undetectable or very low plasma & urinary norepinephrine & epinephrine • Impaired renal function, mild anemia, episodic hypoglycemia • Can be treated w/droxidopa • No ptosis • No orthostatic tachycardia in response to drop in blood pressure • No skeletal muscle hypotonia • Normal plasma dopamine • Autonomic dysfunction (GI problems, orthostatic hypotension) & autonomic crises (hypertensive vomiting attacks) • Cardiovascular instability • Age-related decline in renal function • Occurs almost exclusively in persons of Ashkenazi Jewish descent • Sensory neuropathy • Normal resting plasma norepinephrine, greatly ↑ during autonomic crisis • Orthostatic hypotension • Attacks of nausea & vomiting • Mild-to-severe kidney disease can develop. • Amyloidosis (can involve heart, CNS, eyes, & kidneys) • Sensorimotor neuropathy; constipation alternating w/diarrhea; anhidrosis; urinary retention or incontinence • Onset typically in 3rd-5th decade, but may be later ## Management No clinical practice guidelines for dopamine beta-hydroxylase (DBH) deficiency have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with DBH deficiency, the evaluations summarized in Dopamine Beta-Hydroxylase Deficiency: Recommended Evaluations Following Initial Diagnosis BUN = blood urea nitrogen; DBH = dopamine beta-hydroxylase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Administration of 100-600 mg droxidopa orally two or three times daily increases blood pressure and concomitantly restores plasma norepinephrine to the normal range, although plasma epinephrine concentration still remains below a detectable level. Droxidopa reduces, but does not completely normalize, plasma concentration of dopamine [ This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. Note: An affected female completed a marathon approximately five years after her diagnosis while taking 1,200 mg of droxidopa daily [ Droxidopa improves but does not normalize kidney function, anemia, or hypomagnesemia [ 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 Dopamine Beta-Hydroxylase Deficiency: Treatment of Manifestations Droxidopa (See Fludrocortisone (0.1-0.3 mg daily) provides some benefit, but marked orthostatic hypotension still occurs. Midodrine (2.5-10 mg 3x/day) Standard treatment as needed Avoid nephrotoxic drugs. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Dopamine Beta-Hydroxylase Deficiency: Recommended Surveillance BUN & plasma creatinine to assess kidney function Plasma magnesium & potassium BUN = blood urea nitrogen Untreated individuals with DBH deficiency should avoid hot environments, strenuous exercise, standing motionless, and dehydration. Nephrotoxic drugs should be avoided. See The safety of using droxidopa during pregnancy has not been systematically evaluated, but its use appears justified considering that it is converted to norepinephrine, and that withholding treatment is likely to be riskier. At least three affected women have successfully given birth following uncomplicated deliveries while on droxidopa treatment [ Despite the limited data available, continuing droxidopa treatment during pregnancy has been recommended [ The effects of maternal droxidopa therapy on the developing fetus have not been studied in humans; however, studies on pregnant animals do not suggest an increased risk for malformations in offspring. See Search • Administration of 100-600 mg droxidopa orally two or three times daily increases blood pressure and concomitantly restores plasma norepinephrine to the normal range, although plasma epinephrine concentration still remains below a detectable level. • Droxidopa reduces, but does not completely normalize, plasma concentration of dopamine [ • This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. Note: An affected female completed a marathon approximately five years after her diagnosis while taking 1,200 mg of droxidopa daily [ • Droxidopa improves but does not normalize kidney function, anemia, or hypomagnesemia [ • Droxidopa (See • Fludrocortisone (0.1-0.3 mg daily) provides some benefit, but marked orthostatic hypotension still occurs. • Midodrine (2.5-10 mg 3x/day) • Standard treatment as needed • Avoid nephrotoxic drugs. • BUN & plasma creatinine to assess kidney function • Plasma magnesium & potassium ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DBH deficiency, the evaluations summarized in Dopamine Beta-Hydroxylase Deficiency: Recommended Evaluations Following Initial Diagnosis BUN = blood urea nitrogen; DBH = dopamine beta-hydroxylase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse ## Treatment of Manifestations Administration of 100-600 mg droxidopa orally two or three times daily increases blood pressure and concomitantly restores plasma norepinephrine to the normal range, although plasma epinephrine concentration still remains below a detectable level. Droxidopa reduces, but does not completely normalize, plasma concentration of dopamine [ This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. Note: An affected female completed a marathon approximately five years after her diagnosis while taking 1,200 mg of droxidopa daily [ Droxidopa improves but does not normalize kidney function, anemia, or hypomagnesemia [ 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 Dopamine Beta-Hydroxylase Deficiency: Treatment of Manifestations Droxidopa (See Fludrocortisone (0.1-0.3 mg daily) provides some benefit, but marked orthostatic hypotension still occurs. Midodrine (2.5-10 mg 3x/day) Standard treatment as needed Avoid nephrotoxic drugs. • Administration of 100-600 mg droxidopa orally two or three times daily increases blood pressure and concomitantly restores plasma norepinephrine to the normal range, although plasma epinephrine concentration still remains below a detectable level. • Droxidopa reduces, but does not completely normalize, plasma concentration of dopamine [ • This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. Note: An affected female completed a marathon approximately five years after her diagnosis while taking 1,200 mg of droxidopa daily [ • Droxidopa improves but does not normalize kidney function, anemia, or hypomagnesemia [ • Droxidopa (See • Fludrocortisone (0.1-0.3 mg daily) provides some benefit, but marked orthostatic hypotension still occurs. • Midodrine (2.5-10 mg 3x/day) • Standard treatment as needed • Avoid nephrotoxic drugs. ## Targeted Therapy Administration of 100-600 mg droxidopa orally two or three times daily increases blood pressure and concomitantly restores plasma norepinephrine to the normal range, although plasma epinephrine concentration still remains below a detectable level. Droxidopa reduces, but does not completely normalize, plasma concentration of dopamine [ This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. Note: An affected female completed a marathon approximately five years after her diagnosis while taking 1,200 mg of droxidopa daily [ Droxidopa improves but does not normalize kidney function, anemia, or hypomagnesemia [ • Administration of 100-600 mg droxidopa orally two or three times daily increases blood pressure and concomitantly restores plasma norepinephrine to the normal range, although plasma epinephrine concentration still remains below a detectable level. • Droxidopa reduces, but does not completely normalize, plasma concentration of dopamine [ • This favorable alteration in catecholamines alleviates the orthostatic hypotension and restores function to a near-normal level. Note: An affected female completed a marathon approximately five years after her diagnosis while taking 1,200 mg of droxidopa daily [ • Droxidopa improves but does not normalize kidney function, anemia, or hypomagnesemia [ ## 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 Dopamine Beta-Hydroxylase Deficiency: Treatment of Manifestations Droxidopa (See Fludrocortisone (0.1-0.3 mg daily) provides some benefit, but marked orthostatic hypotension still occurs. Midodrine (2.5-10 mg 3x/day) Standard treatment as needed Avoid nephrotoxic drugs. • Droxidopa (See • Fludrocortisone (0.1-0.3 mg daily) provides some benefit, but marked orthostatic hypotension still occurs. • Midodrine (2.5-10 mg 3x/day) • Standard treatment as needed • Avoid nephrotoxic drugs. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Dopamine Beta-Hydroxylase Deficiency: Recommended Surveillance BUN & plasma creatinine to assess kidney function Plasma magnesium & potassium BUN = blood urea nitrogen • BUN & plasma creatinine to assess kidney function • Plasma magnesium & potassium ## Agents/Circumstances to Avoid Untreated individuals with DBH deficiency should avoid hot environments, strenuous exercise, standing motionless, and dehydration. Nephrotoxic drugs should be avoided. ## Evaluation of Relatives at Risk See ## Pregnancy Management The safety of using droxidopa during pregnancy has not been systematically evaluated, but its use appears justified considering that it is converted to norepinephrine, and that withholding treatment is likely to be riskier. At least three affected women have successfully given birth following uncomplicated deliveries while on droxidopa treatment [ Despite the limited data available, continuing droxidopa treatment during pregnancy has been recommended [ The effects of maternal droxidopa therapy on the developing fetus have not been studied in humans; however, studies on pregnant animals do not suggest an increased risk for malformations in offspring. See ## Therapies Under Investigation Search ## Genetic Counseling Dopamine beta-hydroxylase (DBH) 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) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. If both parents are known to be heterozygous for a Heterozygotes (carriers) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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 Dopamine beta-hydroxylase (DBH) 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) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. If both parents are known to be heterozygous for a Heterozygotes (carriers) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. • 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) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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) appear to be asymptomatic and are not at risk of developing the disorder. However, systematic evaluation of autonomic function in carriers has been insufficient to rule out any impairment. ## Carrier Detection ## 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 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 Dopamine Beta-Hydroxylase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Dopamine Beta-Hydroxylase Deficiency ( DBH = dopamine-beta-hydroxylase Variants listed in the table have been provided by the author. ## Molecular Pathogenesis DBH = dopamine-beta-hydroxylase Variants listed in the table have been provided by the author. ## Chapter Notes Dr Biaggioni has 40 years' experience investigating the interaction between neural (autonomic), metabolic (renin-angiotensin, insulin, incretins), and local (adenosine, nitric oxide) mechanisms involved in cardiovascular regulation. In particular, he is interested in how these interactions participate in the pathophysiology of autonomic disorders. He directs the Italo Biaggioni, MD (2019-present)Emily M Garland, PhD; Vanderbilt University Medical Center (2003-2024)David Robertson, MD; Vanderbilt University (2003-2019) 26 September 2024 (sw) Comprehensive update posted live 25 April 2019 (ha) Comprehensive update posted live 29 October 2015 (me) Comprehensive update posted live 24 January 2013 (me) Comprehensive update posted live 16 September 2010 (me) Comprehensive update posted live 16 December 2005 (me) Comprehensive update posted live 4 September 2003 (me) Review posted live 27 June 2003 (dr) Original submission • 26 September 2024 (sw) Comprehensive update posted live • 25 April 2019 (ha) Comprehensive update posted live • 29 October 2015 (me) Comprehensive update posted live • 24 January 2013 (me) Comprehensive update posted live • 16 September 2010 (me) Comprehensive update posted live • 16 December 2005 (me) Comprehensive update posted live • 4 September 2003 (me) Review posted live • 27 June 2003 (dr) Original submission ## Author Notes Dr Biaggioni has 40 years' experience investigating the interaction between neural (autonomic), metabolic (renin-angiotensin, insulin, incretins), and local (adenosine, nitric oxide) mechanisms involved in cardiovascular regulation. In particular, he is interested in how these interactions participate in the pathophysiology of autonomic disorders. He directs the ## Author History Italo Biaggioni, MD (2019-present)Emily M Garland, PhD; Vanderbilt University Medical Center (2003-2024)David Robertson, MD; Vanderbilt University (2003-2019) ## Revision History 26 September 2024 (sw) Comprehensive update posted live 25 April 2019 (ha) Comprehensive update posted live 29 October 2015 (me) Comprehensive update posted live 24 January 2013 (me) Comprehensive update posted live 16 September 2010 (me) Comprehensive update posted live 16 December 2005 (me) Comprehensive update posted live 4 September 2003 (me) Review posted live 27 June 2003 (dr) Original submission • 26 September 2024 (sw) Comprehensive update posted live • 25 April 2019 (ha) Comprehensive update posted live • 29 October 2015 (me) Comprehensive update posted live • 24 January 2013 (me) Comprehensive update posted live • 16 September 2010 (me) Comprehensive update posted live • 16 December 2005 (me) Comprehensive update posted live • 4 September 2003 (me) Review posted live • 27 June 2003 (dr) Original submission ## Key Sections in This ## References ## Literature Cited Synthesis of norepinephrine from dopamine or droxidopa AADC = aromatic L-amino acid decarboxylase; DBH = dopamine beta-hydroxylase; PNMT = phenylethanolamine N-methyltransferase; TH = tyrosine hydroxylase
[]
4/9/2003
26/9/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dbmd
dbmd
[ "Duchenne Muscular Dystrophy (DMD)", "Becker Muscular Dystrophy (BMD)", "DMD-Associated Dilated Cardiomyopathy", "Dystrophin", "DMD", "Dystrophinopathies" ]
Dystrophinopathies
Basil T Darras, David K Urion, Partha S Ghosh
Summary The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. The diagnosis of a dystrophinopathy is established in a proband with the characteristic clinical findings and elevated CK concentration and/or by identification of a hemizygous pathogenic variant in The dystrophinopathies are inherited in an X-linked manner. The risk to the sibs of a proband depends on the genetic status of the mother. Heterozygous females have a 50% chance of transmitting the
Duchenne muscular dystrophy (DMD) Becker muscular dystrophy (BMD) For synonyms and outdated names see For other genetic causes of these phenotypes see • Duchenne muscular dystrophy (DMD) • Becker muscular dystrophy (BMD) ## Diagnosis The dystrophinopathies cover a spectrum of X-linked muscle disease that ranges from mild to severe and includes Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and A dystrophinopathy Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy Symptoms present before age five years Wheelchair dependency before age 13 years Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign Activity-induced cramping (present in some individuals) Flexion contractures of the elbows (if present, late in the course) Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond Preservation of neck flexor muscle strength (differentiates BMD from DMD) Note: The presence of fasciculations or loss of sensory modalities excludes a suspected diagnosis of a dystrophinopathy. Individuals with an intermediate phenotype (outliers) have symptoms of intermediate severity and become wheelchair dependent between ages 13 and 16 years. DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD Rapid progression to death in several years in males and slower progression over a decade or more in females [ See also Serum Creatine Phosphokinase (CK) Concentration in the Dystrophinopathies Serum CK concentration gradually decreases with advancing age as a result of the progressive elimination of dystrophic muscle fibers that are the source of the elevated serum CK concentration [ Serum CK concentrations are usually increased, but normal concentrations have been reported in Other investigations have confirmed a wide variability in serum CK concentration among DMD/BMD carriers with the mean serum CK concentration significantly higher in carriers age 20 years [ Females may present with a classic dystrophinopathy or may be asymptomatic carriers. A deletion involving Xp21.2 (microarray [CMA] studies) An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) Uniparental disomy (UPD) of the X chromosome (UPD studies) Compound heterozygosity for two Nonrandom X-chromosome inactivation (XCI). See Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Be appropriate if not already performed, to identify multiple gene deletions/duplications (including Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as Detect an unexpected or incidental For an introduction to comprehensive genomic testing click Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic given the frequency of DMD deletions or duplications associated with dystrophinopathy. Molecular Genetic Testing Used in Dystrophinopathies 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. Chromosomal microarray analysis (CMA) may detect Note: If no Findings in the Dystrophin Protein from Skeletal Muscle Biopsy mol wt = molecular weight; XCI = X-chromosome inactivation Normal molecular mass is 427 kb. The quantity of dystrophin is expressed in percent of control values. The reference ranges shown in this table are the ones currently used by clinical laboratories and reflect approximate and reconciled data from the literature. Uses monoclonal antibodies to the C terminus, N terminus, and rod domain of dystrophin [ Asymptomatic to mild disability Quantitative analysis of dystrophin in female carriers is not useful in clinical practice because of the wide range of values and the significant overlap with normal values. Mild, intermediate, severe symptoms. Carriers with mild disease were young (age 5-10 years) [ • Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy • Symptoms present before age five years • Wheelchair dependency before age 13 years • Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign • Activity-induced cramping (present in some individuals) • Flexion contractures of the elbows (if present, late in the course) • Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond • Preservation of neck flexor muscle strength (differentiates BMD from DMD) • DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life • Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD • Rapid progression to death in several years in males and slower progression over a decade or more in females [ • A deletion involving Xp21.2 (microarray [CMA] studies) • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) • Uniparental disomy (UPD) of the X chromosome (UPD studies) • Compound heterozygosity for two • Nonrandom X-chromosome inactivation (XCI). See • A deletion involving Xp21.2 (microarray [CMA] studies) • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) • Uniparental disomy (UPD) of the X chromosome (UPD studies) • Compound heterozygosity for two • Nonrandom X-chromosome inactivation (XCI). See • A deletion involving Xp21.2 (microarray [CMA] studies) • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) • Uniparental disomy (UPD) of the X chromosome (UPD studies) • Compound heterozygosity for two • Nonrandom X-chromosome inactivation (XCI). See • For an introduction to multigene panels click • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as • Detect an unexpected or incidental • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as • Detect an unexpected or incidental • For an introduction to comprehensive genomic testing click • Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic given the frequency of DMD deletions or duplications associated with dystrophinopathy. • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as • Detect an unexpected or incidental ## Suggestive Findings A dystrophinopathy Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy Symptoms present before age five years Wheelchair dependency before age 13 years Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign Activity-induced cramping (present in some individuals) Flexion contractures of the elbows (if present, late in the course) Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond Preservation of neck flexor muscle strength (differentiates BMD from DMD) Note: The presence of fasciculations or loss of sensory modalities excludes a suspected diagnosis of a dystrophinopathy. Individuals with an intermediate phenotype (outliers) have symptoms of intermediate severity and become wheelchair dependent between ages 13 and 16 years. DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD Rapid progression to death in several years in males and slower progression over a decade or more in females [ See also Serum Creatine Phosphokinase (CK) Concentration in the Dystrophinopathies Serum CK concentration gradually decreases with advancing age as a result of the progressive elimination of dystrophic muscle fibers that are the source of the elevated serum CK concentration [ Serum CK concentrations are usually increased, but normal concentrations have been reported in Other investigations have confirmed a wide variability in serum CK concentration among DMD/BMD carriers with the mean serum CK concentration significantly higher in carriers age 20 years [ • Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy • Symptoms present before age five years • Wheelchair dependency before age 13 years • Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign • Activity-induced cramping (present in some individuals) • Flexion contractures of the elbows (if present, late in the course) • Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond • Preservation of neck flexor muscle strength (differentiates BMD from DMD) • DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life • Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD • Rapid progression to death in several years in males and slower progression over a decade or more in females [ ## Clinical Findings Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy Symptoms present before age five years Wheelchair dependency before age 13 years Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign Activity-induced cramping (present in some individuals) Flexion contractures of the elbows (if present, late in the course) Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond Preservation of neck flexor muscle strength (differentiates BMD from DMD) Note: The presence of fasciculations or loss of sensory modalities excludes a suspected diagnosis of a dystrophinopathy. Individuals with an intermediate phenotype (outliers) have symptoms of intermediate severity and become wheelchair dependent between ages 13 and 16 years. DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD Rapid progression to death in several years in males and slower progression over a decade or more in females [ See also • Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy • Symptoms present before age five years • Wheelchair dependency before age 13 years • Progressive symmetric muscle weakness (proximal > distal) often with calf hypertrophy; weakness of quadriceps femoris in some cases the only sign • Activity-induced cramping (present in some individuals) • Flexion contractures of the elbows (if present, late in the course) • Wheelchair dependency (after age 16 years); although some individuals remain ambulatory into their 30s and in rare cases into their 40s and beyond • Preservation of neck flexor muscle strength (differentiates BMD from DMD) • DCM with congestive heart failure, with males typically presenting between ages 20 and 40 years and females presenting later in life • Usually no clinical evidence of skeletal muscle disease; may be classified as "subclinical" BMD • Rapid progression to death in several years in males and slower progression over a decade or more in females [ ## Laboratory Testing Serum Creatine Phosphokinase (CK) Concentration in the Dystrophinopathies Serum CK concentration gradually decreases with advancing age as a result of the progressive elimination of dystrophic muscle fibers that are the source of the elevated serum CK concentration [ Serum CK concentrations are usually increased, but normal concentrations have been reported in Other investigations have confirmed a wide variability in serum CK concentration among DMD/BMD carriers with the mean serum CK concentration significantly higher in carriers age 20 years [ ## Establishing the Diagnosis Females may present with a classic dystrophinopathy or may be asymptomatic carriers. A deletion involving Xp21.2 (microarray [CMA] studies) An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) Uniparental disomy (UPD) of the X chromosome (UPD studies) Compound heterozygosity for two Nonrandom X-chromosome inactivation (XCI). See Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click Be appropriate if not already performed, to identify multiple gene deletions/duplications (including Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as Detect an unexpected or incidental For an introduction to comprehensive genomic testing click Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic given the frequency of DMD deletions or duplications associated with dystrophinopathy. Molecular Genetic Testing Used in Dystrophinopathies 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. Chromosomal microarray analysis (CMA) may detect Note: If no Findings in the Dystrophin Protein from Skeletal Muscle Biopsy mol wt = molecular weight; XCI = X-chromosome inactivation Normal molecular mass is 427 kb. The quantity of dystrophin is expressed in percent of control values. The reference ranges shown in this table are the ones currently used by clinical laboratories and reflect approximate and reconciled data from the literature. Uses monoclonal antibodies to the C terminus, N terminus, and rod domain of dystrophin [ Asymptomatic to mild disability Quantitative analysis of dystrophin in female carriers is not useful in clinical practice because of the wide range of values and the significant overlap with normal values. Mild, intermediate, severe symptoms. Carriers with mild disease were young (age 5-10 years) [ • A deletion involving Xp21.2 (microarray [CMA] studies) • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) • Uniparental disomy (UPD) of the X chromosome (UPD studies) • Compound heterozygosity for two • Nonrandom X-chromosome inactivation (XCI). See • A deletion involving Xp21.2 (microarray [CMA] studies) • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) • Uniparental disomy (UPD) of the X chromosome (UPD studies) • Compound heterozygosity for two • Nonrandom X-chromosome inactivation (XCI). See • A deletion involving Xp21.2 (microarray [CMA] studies) • An X-chromosome rearrangement involving Xp21.2 or complete absence of an X chromosome (i.e., Turner syndrome) (cytogenetic studies) • Uniparental disomy (UPD) of the X chromosome (UPD studies) • Compound heterozygosity for two • Nonrandom X-chromosome inactivation (XCI). See • For an introduction to multigene panels click • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as • Detect an unexpected or incidental • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as • Detect an unexpected or incidental • For an introduction to comprehensive genomic testing click • Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic given the frequency of DMD deletions or duplications associated with dystrophinopathy. • Be appropriate if not already performed, to identify multiple gene deletions/duplications (including • Be considered first in an individual presenting with additional medical concerns associated with known X-linked disorders such as • Detect an unexpected or incidental ## Clinical Characteristics The dystrophinopathies cover a spectrum of muscle disease that ranges from mild to severe. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) when skeletal muscle is primarily affected and as Cardiac involvement is usually asymptomatic in the early stages of the disease, although sinus tachycardia and various EKG abnormalities may be noted. Echocardiography is normal or shows only regional abnormalities. Pericardial effusion with cardiac tamponade and myocardial inflammation precipitating heart failure has been described in people with DMD [ A retrospective study by These retrospective studies thus suggest increased rates of ID, ASD, ADHD, and learning disability in boys with DMD compared to the population at large. This confirms the retrospective work of All of these studies thus suggest that the earlier allegation of poorer verbal function in boys with DMD and without ID was better explained by deficits in executive function, which could also lead to visuospatial difficulties in certain settings. Mildly affected individuals with confirmatory BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle In 1987, a five-generation, 63-member family with DCM but no evidence of skeletal myopathy was reported. Males present in their teens and twenties; the disease course is rapidly progressive and associated ventricular arrhythmias are common. Heterozygous females develop mild dilated cardiomyopathy in the fourth or fifth decade, with slow progression. The only biochemical abnormality is elevation in serum CK concentration. Subsequent study demonstrated that in individuals with the most severe cardiac phenotype the cardiac muscle is usually unable to produce functional dystrophin in the heart, while in skeletal muscle reduced levels of virtually normal dystrophin transcript and protein are present [ In some instances females can have classic DMD (see Signs and symptoms of DMD and BMD were studied among confirmed heterozygous females [ Signs and Symptoms in Females Heterozygous for a From Mild-to-moderate weakness If a pathogenic variant is identified, the diagnosis of a dystrophinopathy is established, but the distinction between DMD and BMD can be difficult in some cases. For example, deletion of exons 3-7, the most extensively investigated deletion associated with both phenotypes, has been found in males with DMD and also with BMD [ Although exceptions to the "reading frame rule" have been documented to occur at a rate below 10% [ Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain with gradual increase from the embryonic stage to adult. Dp71 is very abundant in the hippocampus and some layers of the cerebral cortex with sublocalization in synaptic membranes, microsomes, synaptic vesicles, and mitochondria. The location of the pathogenic variant appears to correlate with full-scale IQ (FSIQ) values (e.g., pathogenic variants affecting the Dp140 isoform 5' UTR affect FSIQ less than those affecting the Dp140 promoter or coding region) [ Exceptions to the reading frame rule occur more commonly in BMD than in DMD. In one large cohort, a BMD phenotype failed to follow the reading frame rule in approximately 15% of cases caused by deletion, and approximately 34% of cases caused by duplication [ In men with BMD, deletions involving the amino-terminal domain correlate with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions affecting part of the rod domain and hinge 3 result in a later-onset DCM (mid-40s) [ Abnormalities in cardiac conduction noted in persons with dystrophinopathies may be related to reduced expression of cardiac sodium channel NA(v)1.5 secondary to dystrophin deficiency [ See also Penetrance of dystrophinopathies is complete in males. Penetrance in heterozygous females varies, and may depend in part on patterns of X-chromosome inactivation (XCI). Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in XCI studies in leukocytes and serum CK concentration, clinical signs, or the proportion of dystrophin-negative fibers observed on muscle biopsy [ In another study of seven symptomatic heterozygous females, the XCI pattern was skewed toward non-random in the four with deletions or duplications but was random in the three with pathogenic nonsense variants [ In contrast, Direct correlation with a skewed XCI pattern was also observed recently in cohorts of symptomatic and asymptomatic DMD/BMD carriers [ The term "pseudohypertrophic muscular dystrophy" was used in the past; however, it is not used currently because pseudohypertrophy is not unique to the DMD or BMD phenotype. Prevalence data are not available. The overall incidence of DMD in Canada (Nova Scotia) is one in 4,700 live male births and has remained stable from 1969 to 2008 [ The incidence of BMD in northern England is 1:18,450 live male births [ During the years 1968 to 1978, the incidence of DMD in southeast Norway was 1:3,917 live male births [ • BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria • "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle • Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain with gradual increase from the embryonic stage to adult. Dp71 is very abundant in the hippocampus and some layers of the cerebral cortex with sublocalization in synaptic membranes, microsomes, synaptic vesicles, and mitochondria. The location of the pathogenic variant appears to correlate with full-scale IQ (FSIQ) values (e.g., pathogenic variants affecting the Dp140 isoform 5' UTR affect FSIQ less than those affecting the Dp140 promoter or coding region) [ • Exceptions to the reading frame rule occur more commonly in BMD than in DMD. In one large cohort, a BMD phenotype failed to follow the reading frame rule in approximately 15% of cases caused by deletion, and approximately 34% of cases caused by duplication [ • In men with BMD, deletions involving the amino-terminal domain correlate with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions affecting part of the rod domain and hinge 3 result in a later-onset DCM (mid-40s) [ • Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in XCI studies in leukocytes and serum CK concentration, clinical signs, or the proportion of dystrophin-negative fibers observed on muscle biopsy [ • In another study of seven symptomatic heterozygous females, the XCI pattern was skewed toward non-random in the four with deletions or duplications but was random in the three with pathogenic nonsense variants [ • In contrast, • Direct correlation with a skewed XCI pattern was also observed recently in cohorts of symptomatic and asymptomatic DMD/BMD carriers [ ## Clinical Description The dystrophinopathies cover a spectrum of muscle disease that ranges from mild to severe. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) when skeletal muscle is primarily affected and as Cardiac involvement is usually asymptomatic in the early stages of the disease, although sinus tachycardia and various EKG abnormalities may be noted. Echocardiography is normal or shows only regional abnormalities. Pericardial effusion with cardiac tamponade and myocardial inflammation precipitating heart failure has been described in people with DMD [ A retrospective study by These retrospective studies thus suggest increased rates of ID, ASD, ADHD, and learning disability in boys with DMD compared to the population at large. This confirms the retrospective work of All of these studies thus suggest that the earlier allegation of poorer verbal function in boys with DMD and without ID was better explained by deficits in executive function, which could also lead to visuospatial difficulties in certain settings. Mildly affected individuals with confirmatory BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle In 1987, a five-generation, 63-member family with DCM but no evidence of skeletal myopathy was reported. Males present in their teens and twenties; the disease course is rapidly progressive and associated ventricular arrhythmias are common. Heterozygous females develop mild dilated cardiomyopathy in the fourth or fifth decade, with slow progression. The only biochemical abnormality is elevation in serum CK concentration. Subsequent study demonstrated that in individuals with the most severe cardiac phenotype the cardiac muscle is usually unable to produce functional dystrophin in the heart, while in skeletal muscle reduced levels of virtually normal dystrophin transcript and protein are present [ In some instances females can have classic DMD (see Signs and symptoms of DMD and BMD were studied among confirmed heterozygous females [ Signs and Symptoms in Females Heterozygous for a From Mild-to-moderate weakness • BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria • "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle ## Males The dystrophinopathies cover a spectrum of muscle disease that ranges from mild to severe. The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) when skeletal muscle is primarily affected and as Cardiac involvement is usually asymptomatic in the early stages of the disease, although sinus tachycardia and various EKG abnormalities may be noted. Echocardiography is normal or shows only regional abnormalities. Pericardial effusion with cardiac tamponade and myocardial inflammation precipitating heart failure has been described in people with DMD [ A retrospective study by These retrospective studies thus suggest increased rates of ID, ASD, ADHD, and learning disability in boys with DMD compared to the population at large. This confirms the retrospective work of All of these studies thus suggest that the earlier allegation of poorer verbal function in boys with DMD and without ID was better explained by deficits in executive function, which could also lead to visuospatial difficulties in certain settings. Mildly affected individuals with confirmatory BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle In 1987, a five-generation, 63-member family with DCM but no evidence of skeletal myopathy was reported. Males present in their teens and twenties; the disease course is rapidly progressive and associated ventricular arrhythmias are common. Heterozygous females develop mild dilated cardiomyopathy in the fourth or fifth decade, with slow progression. The only biochemical abnormality is elevation in serum CK concentration. Subsequent study demonstrated that in individuals with the most severe cardiac phenotype the cardiac muscle is usually unable to produce functional dystrophin in the heart, while in skeletal muscle reduced levels of virtually normal dystrophin transcript and protein are present [ • BMD with "subclinical" skeletal muscle involvement in the presence of elevated serum CK concentration, calf hypertrophy, muscle cramps, myalgia, and exertional myoglobinuria • "Benign" skeletal muscle involvement when "subclinical" findings are accompanied by muscle weakness in the pelvic girdle and/or shoulder girdle ## Females In some instances females can have classic DMD (see Signs and symptoms of DMD and BMD were studied among confirmed heterozygous females [ Signs and Symptoms in Females Heterozygous for a From Mild-to-moderate weakness ## Genotype-Phenotype Correlations If a pathogenic variant is identified, the diagnosis of a dystrophinopathy is established, but the distinction between DMD and BMD can be difficult in some cases. For example, deletion of exons 3-7, the most extensively investigated deletion associated with both phenotypes, has been found in males with DMD and also with BMD [ Although exceptions to the "reading frame rule" have been documented to occur at a rate below 10% [ Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain with gradual increase from the embryonic stage to adult. Dp71 is very abundant in the hippocampus and some layers of the cerebral cortex with sublocalization in synaptic membranes, microsomes, synaptic vesicles, and mitochondria. The location of the pathogenic variant appears to correlate with full-scale IQ (FSIQ) values (e.g., pathogenic variants affecting the Dp140 isoform 5' UTR affect FSIQ less than those affecting the Dp140 promoter or coding region) [ Exceptions to the reading frame rule occur more commonly in BMD than in DMD. In one large cohort, a BMD phenotype failed to follow the reading frame rule in approximately 15% of cases caused by deletion, and approximately 34% of cases caused by duplication [ In men with BMD, deletions involving the amino-terminal domain correlate with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions affecting part of the rod domain and hinge 3 result in a later-onset DCM (mid-40s) [ Abnormalities in cardiac conduction noted in persons with dystrophinopathies may be related to reduced expression of cardiac sodium channel NA(v)1.5 secondary to dystrophin deficiency [ See also • Dp71 and Dp140 are the shorter isoforms of dystrophin and are highly expressed in fetal brain with gradual increase from the embryonic stage to adult. Dp71 is very abundant in the hippocampus and some layers of the cerebral cortex with sublocalization in synaptic membranes, microsomes, synaptic vesicles, and mitochondria. The location of the pathogenic variant appears to correlate with full-scale IQ (FSIQ) values (e.g., pathogenic variants affecting the Dp140 isoform 5' UTR affect FSIQ less than those affecting the Dp140 promoter or coding region) [ • Exceptions to the reading frame rule occur more commonly in BMD than in DMD. In one large cohort, a BMD phenotype failed to follow the reading frame rule in approximately 15% of cases caused by deletion, and approximately 34% of cases caused by duplication [ • In men with BMD, deletions involving the amino-terminal domain correlate with early-onset dilated cardiomyopathy (DCM; mid-20s), whereas deletions affecting part of the rod domain and hinge 3 result in a later-onset DCM (mid-40s) [ ## Penetrance Penetrance of dystrophinopathies is complete in males. Penetrance in heterozygous females varies, and may depend in part on patterns of X-chromosome inactivation (XCI). Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in XCI studies in leukocytes and serum CK concentration, clinical signs, or the proportion of dystrophin-negative fibers observed on muscle biopsy [ In another study of seven symptomatic heterozygous females, the XCI pattern was skewed toward non-random in the four with deletions or duplications but was random in the three with pathogenic nonsense variants [ In contrast, Direct correlation with a skewed XCI pattern was also observed recently in cohorts of symptomatic and asymptomatic DMD/BMD carriers [ • Some studies have shown no clear correlation between the active-to-inactive X-chromosome ratio observed in XCI studies in leukocytes and serum CK concentration, clinical signs, or the proportion of dystrophin-negative fibers observed on muscle biopsy [ • In another study of seven symptomatic heterozygous females, the XCI pattern was skewed toward non-random in the four with deletions or duplications but was random in the three with pathogenic nonsense variants [ • In contrast, • Direct correlation with a skewed XCI pattern was also observed recently in cohorts of symptomatic and asymptomatic DMD/BMD carriers [ ## Nomenclature The term "pseudohypertrophic muscular dystrophy" was used in the past; however, it is not used currently because pseudohypertrophy is not unique to the DMD or BMD phenotype. ## Prevalence Prevalence data are not available. The overall incidence of DMD in Canada (Nova Scotia) is one in 4,700 live male births and has remained stable from 1969 to 2008 [ The incidence of BMD in northern England is 1:18,450 live male births [ During the years 1968 to 1978, the incidence of DMD in southeast Norway was 1:3,917 live male births [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis ## Management To establish the extent of disease and needs in an individual diagnosed with a dystrophinopathy, the following evaluations are recommended if they have not already been completed: Physical therapy assessment Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI [ Consultation with a clinical geneticist and/or genetic counselor Appropriate management of individuals with a dystrophinopathy can prolong survival and improve quality of life. The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [ The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [ Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [ In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. The following published recommendations for corticosteroid therapy are in accordance with the national practice parameters developed by the American Academy of Neurology and the Child Neurology Society [ Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [ The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). If excessive weight gain occurs (>20% above estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. Many clinicians continue treatment with glucocorticoids after loss of ambulation for the purpose of maintaining upper limb strength, delaying the progressive decline of respiratory and cardiac function, and decreasing the risk of scoliosis. Retrospective data suggest that the progression of scoliosis can be reduced by long-term daily corticosteroid treatment; however, an increased risk for vertebral and lower-limb fractures has been documented [ Exon-skipping therapy in DMD restores the reading frame using synthetic antisense oligonucleotides (ASO) targeted to the dystrophin pre-messenger RNA to skip out-of-frame variants [ Dystrophin Restoration Therapies Eteplirsen (exon skip 51 amenable) Golodirsen (exon skip 53 amenable) Viltolarsen (exon skip 53 amenable) Casimersen (exon skip 45 amenable) AAV = adeno-associated virus; ASO = antisense oligonucleotide; FDA = Food and Drug Administration Cardiomyopathy management is similar to the management of DMD- or BMD-associated cardiomyopathy. Evaluation by pulmonary and cardiac specialists before surgeries [ Administration of pneumococcal vaccine and annual influenza vaccination [ Planning to commence steroids [ Dysphagia is present Patient is chronically constipated Major surgery has been planned Patient is malnourished Physical therapy to promote mobility and prevent contractures Exercise All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. Blood Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase 25-hydroxyvitamin D (25-OHD) level in springtime or biannually Consideration of magnesium and parathyroid hormone levels Urine (calcium, sodium, creatinine) Dual-energy x-ray absorptiometry (DXA) scanning At baseline (age ≥3 years) or at start of corticosteroid therapy Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 Spine radiograph If back pain is present To exclude vertebral compression fracture To assess degree of kyphoscoliosis if present on physical examination Bone age if growth failure occurs (height for age <5th percentile or if linear growth is faltering) in persons on or off corticosteroids Interventions: Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures. Supplementation should be carried out in consultation with a dietician. Vitamin D supplementation should be initiated if the vitamin D serum concentration is <20 ng/mL [ Intravenous bisphosphonates; recommended in persons with symptomatic vertebral fracture(s). A bone health expert should be consulted. Note: Use of oral biphosphonates for prophylaxis or treatment remains controversial. The American Academy of Pediatrics (AAP) has published recommendations for optimal cardiac care in persons with dystrophinopathy [ Complete cardiac evaluation at least every two years, beginning at the time of diagnosis Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [ Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years Treatment of cardiac disease similar to that for boys with dystrophinopathy Perform baseline pulmonary function testing before confinement to a wheelchair (usually age ~9-10 years) Twice-yearly evaluation by a pediatric pulmonologist is indicated after ANY of the following [ Confinement to a wheelchair Reduction in vital capacity below 80% predicted Age 12 years The 2010 consensus guidelines [ Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; Manual and mechanically assisted cough techniques; Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. Monitor for orthopedic complications, especially contractures and scoliosis in those with DMD and BMD phenotypes. Evaluate for surgical interventions as needed. Individuals with dystrophinopathy should avoid botulinum toxin injections. Although it is recommended that triggering agents like succinylcholine and inhalational anesthetics be avoided in patients with dystrophinopathy because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions (rhabdomyolysis, cardiac complications, hyperkalemia), it should be noted that an extensive literature search did not find an increased risk for malignant hyperthermia susceptibility in individuals with dystrophinopathy when compared with the general population [ It is appropriate to evaluate at-risk female family members (i.e., the sisters or maternal female relatives of an affected male and first-degree relatives of a known or possible heterozygous female) in order to identify as early as possible heterozygous females who would benefit from cardiac surveillance (see Molecular genetic testing if the Serum creatine phosphokinase (CK) testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative. Molecular genetic testing of the at-risk female if an affected male is not available for testing: By deletion/duplication analysis first If no pathogenic variant is identified, by sequence analysis Linkage analysis to determine carrier status in at-risk females if (1) the Linkage studies are based on accurate clinical diagnosis of DMD/BMD/ Linkage analysis relies on the availability and willingness of family members to be tested. Because the markers used for linkage in DMD/BMD/ Note: (1) The large size of See Symptomatic heterozygous women should undergo an evaluation for dilated cardiomyopathy ideally prior to conceiving a pregnancy or as soon as the pregnancy is recognized. Asymptomatic heterozygous women should consider undergoing a cardiac evaluation prior to conception or when a pregnancy is recognized. Those with evidence of dilated cardiomyopathy should be treated and/or monitored by a cardiologist and a high-risk obstetrician. See also Preclinical efficacy studies showed production of dystrophin in primary muscle cells from humans and A Phase III multicenter 48-week double-blind placebo-controlled trial (ACT DMD) showed no significant benefit of ataluren for the primary endpoint (i.e., change from baseline in the 6-minute walk test), though there was benefit for some secondary endpoints [ Search • Physical therapy assessment • Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary • At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI [ • Consultation with a clinical geneticist and/or genetic counselor • The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. • When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [ • The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [ • Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [ • In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. • Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. • Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. • To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. • To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [ • The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). • If excessive weight gain occurs (>20% above estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. • If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. • Eteplirsen (exon skip 51 amenable) • Golodirsen (exon skip 53 amenable) • Viltolarsen (exon skip 53 amenable) • Casimersen (exon skip 45 amenable) • Evaluation by pulmonary and cardiac specialists before surgeries [ • Administration of pneumococcal vaccine and annual influenza vaccination [ • Planning to commence steroids [ • Dysphagia is present • Patient is chronically constipated • Major surgery has been planned • Patient is malnourished • Physical therapy to promote mobility and prevent contractures • Exercise • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. • Blood • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually • Consideration of magnesium and parathyroid hormone levels • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually • Consideration of magnesium and parathyroid hormone levels • Urine (calcium, sodium, creatinine) • Dual-energy x-ray absorptiometry (DXA) scanning • At baseline (age ≥3 years) or at start of corticosteroid therapy • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 • At baseline (age ≥3 years) or at start of corticosteroid therapy • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 • Spine radiograph • If back pain is present • To exclude vertebral compression fracture • To assess degree of kyphoscoliosis if present on physical examination • If back pain is present • To exclude vertebral compression fracture • To assess degree of kyphoscoliosis if present on physical examination • Bone age if growth failure occurs (height for age <5th percentile or if linear growth is faltering) in persons on or off corticosteroids • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually • Consideration of magnesium and parathyroid hormone levels • At baseline (age ≥3 years) or at start of corticosteroid therapy • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 • If back pain is present • To exclude vertebral compression fracture • To assess degree of kyphoscoliosis if present on physical examination • Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures. Supplementation should be carried out in consultation with a dietician. • Vitamin D supplementation should be initiated if the vitamin D serum concentration is <20 ng/mL [ • Intravenous bisphosphonates; recommended in persons with symptomatic vertebral fracture(s). A bone health expert should be consulted. • Note: Use of oral biphosphonates for prophylaxis or treatment remains controversial. • Complete cardiac evaluation at least every two years, beginning at the time of diagnosis • Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. • At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation • Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. • If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [ • Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure • Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms • Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years • Treatment of cardiac disease similar to that for boys with dystrophinopathy • Confinement to a wheelchair • Reduction in vital capacity below 80% predicted • Age 12 years • Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; • Manual and mechanically assisted cough techniques; • Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. • Molecular genetic testing if the • Serum creatine phosphokinase (CK) testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative. • Molecular genetic testing of the at-risk female if an affected male is not available for testing: • By deletion/duplication analysis first • If no pathogenic variant is identified, by sequence analysis • Linkage analysis to determine carrier status in at-risk females if (1) the • Linkage studies are based on accurate clinical diagnosis of DMD/BMD/ • Linkage analysis relies on the availability and willingness of family members to be tested. • Because the markers used for linkage in DMD/BMD/ • Note: (1) The large size of ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with a dystrophinopathy, the following evaluations are recommended if they have not already been completed: Physical therapy assessment Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI [ Consultation with a clinical geneticist and/or genetic counselor • Physical therapy assessment • Developmental evaluation before entering elementary school for the purpose of designing an individualized educational plan, as necessary • At the time of diagnosis or by age six years, evaluation for cardiomyopathy by electrocardiography, cardiac echocardiography, and/or MRI [ • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Appropriate management of individuals with a dystrophinopathy can prolong survival and improve quality of life. The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [ The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [ Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [ In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. The following published recommendations for corticosteroid therapy are in accordance with the national practice parameters developed by the American Academy of Neurology and the Child Neurology Society [ Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [ The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). If excessive weight gain occurs (>20% above estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. Many clinicians continue treatment with glucocorticoids after loss of ambulation for the purpose of maintaining upper limb strength, delaying the progressive decline of respiratory and cardiac function, and decreasing the risk of scoliosis. Retrospective data suggest that the progression of scoliosis can be reduced by long-term daily corticosteroid treatment; however, an increased risk for vertebral and lower-limb fractures has been documented [ Exon-skipping therapy in DMD restores the reading frame using synthetic antisense oligonucleotides (ASO) targeted to the dystrophin pre-messenger RNA to skip out-of-frame variants [ Dystrophin Restoration Therapies Eteplirsen (exon skip 51 amenable) Golodirsen (exon skip 53 amenable) Viltolarsen (exon skip 53 amenable) Casimersen (exon skip 45 amenable) AAV = adeno-associated virus; ASO = antisense oligonucleotide; FDA = Food and Drug Administration Cardiomyopathy management is similar to the management of DMD- or BMD-associated cardiomyopathy. • The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. • When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [ • The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [ • Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [ • In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. • Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. • Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. • To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. • To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [ • The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). • If excessive weight gain occurs (>20% above estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. • If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. • Eteplirsen (exon skip 51 amenable) • Golodirsen (exon skip 53 amenable) • Viltolarsen (exon skip 53 amenable) • Casimersen (exon skip 45 amenable) ## Duchenne Muscular Dystrophy (DMD) / Becker Muscular Dystrophy (BMD) Phenotypes The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [ The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [ Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [ In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. The following published recommendations for corticosteroid therapy are in accordance with the national practice parameters developed by the American Academy of Neurology and the Child Neurology Society [ Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [ The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). If excessive weight gain occurs (>20% above estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. Many clinicians continue treatment with glucocorticoids after loss of ambulation for the purpose of maintaining upper limb strength, delaying the progressive decline of respiratory and cardiac function, and decreasing the risk of scoliosis. Retrospective data suggest that the progression of scoliosis can be reduced by long-term daily corticosteroid treatment; however, an increased risk for vertebral and lower-limb fractures has been documented [ • The authors' institution commonly treats children with DMD or BMD early with an ACE inhibitor and/or beta blocker. • When used in combination, these appear to lead to initial improvement of left ventricular function; however, ACE inhibitors are also used without beta blockers, with similar results [ • The optimal time to start treatment in DMD is unknown, but most cardiologists will initiate treatment when the left ventricle ejection fraction drops below 55% and fractional shortening is less than 28% [ • Angiotensin II-receptor blockers (ARBs) such as losartan are similarly effective and can be used in cases of poor tolerability of ACE inhibitors [ • In cases of overt heart failure, other heart failure therapies including diuretics and digoxin are used as needed. • Cardiac transplantation is offered to persons with severe dilated cardiomyopathy and BMD with limited or no clinical evidence of skeletal muscle disease. • Boys with DMD should be offered treatment with prednisone (0.75 mg/kg/day, maximum daily dose: 30-40 mg) or deflazacort (0.9 mg/kg/day, maximum daily dose: 36-39 mg) as soon as plateauing or decline in motor skills is noted, which usually occurs at age 4-8 years. Prior to the initiation of therapy, the potential benefits and risks of corticosteroid treatment should be carefully discussed with each individual. • To assess benefits of corticosteroid therapy, the following parameters are useful: timed muscle function tests, pulmonary function tests, and age at loss of independent ambulation. • To assess risks of corticosteroid therapy, maintain awareness of the potential corticosteroid therapy side effects (e.g., weight gain, cushingoid appearance, short stature, decrease in linear growth, acne, excessive hair growth, gastrointestinal symptoms, behavioral changes). There is also an increased frequency of vertebral and long bone fractures with prolonged corticosteroid use [ • The optimal maintenance dose of prednisone (0.75 mg/kg/day) or deflazacort (0.9 mg/kg/day) should be continued if side effects are not severe. Significant but less robust improvement can be seen with gradual tapering of prednisone to as low as 0.3 mg/kg/day (or ~0.4 mg/kg/day of deflazacort). • If excessive weight gain occurs (>20% above estimated normal weight for height over a 12-month period), the prednisone dose should be decreased by 25%-33% and reassessed in a few months. If excessive weight gain continues, the dose should be further decreased by an additional 25% to the minimum effective dose cited above after three to four months. • If significant weight gain or intolerable behavioral side effects occur in patients treated with prednisone, change to deflazacort on a ten-day-on / ten-day-off schedule or a high-dose weekend schedule. In patients on deflazacort, side effects of asymptomatic cataracts and weight gain should be monitored. ## Dystrophin Restoration Therapies in DMD Exon-skipping therapy in DMD restores the reading frame using synthetic antisense oligonucleotides (ASO) targeted to the dystrophin pre-messenger RNA to skip out-of-frame variants [ Dystrophin Restoration Therapies Eteplirsen (exon skip 51 amenable) Golodirsen (exon skip 53 amenable) Viltolarsen (exon skip 53 amenable) Casimersen (exon skip 45 amenable) AAV = adeno-associated virus; ASO = antisense oligonucleotide; FDA = Food and Drug Administration • Eteplirsen (exon skip 51 amenable) • Golodirsen (exon skip 53 amenable) • Viltolarsen (exon skip 53 amenable) • Casimersen (exon skip 45 amenable) Cardiomyopathy management is similar to the management of DMD- or BMD-associated cardiomyopathy. ## Prevention of Secondary Complications Evaluation by pulmonary and cardiac specialists before surgeries [ Administration of pneumococcal vaccine and annual influenza vaccination [ Planning to commence steroids [ Dysphagia is present Patient is chronically constipated Major surgery has been planned Patient is malnourished Physical therapy to promote mobility and prevent contractures Exercise All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. Blood Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase 25-hydroxyvitamin D (25-OHD) level in springtime or biannually Consideration of magnesium and parathyroid hormone levels Urine (calcium, sodium, creatinine) Dual-energy x-ray absorptiometry (DXA) scanning At baseline (age ≥3 years) or at start of corticosteroid therapy Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 Spine radiograph If back pain is present To exclude vertebral compression fracture To assess degree of kyphoscoliosis if present on physical examination Bone age if growth failure occurs (height for age <5th percentile or if linear growth is faltering) in persons on or off corticosteroids Interventions: Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures. Supplementation should be carried out in consultation with a dietician. Vitamin D supplementation should be initiated if the vitamin D serum concentration is <20 ng/mL [ Intravenous bisphosphonates; recommended in persons with symptomatic vertebral fracture(s). A bone health expert should be consulted. Note: Use of oral biphosphonates for prophylaxis or treatment remains controversial. • Evaluation by pulmonary and cardiac specialists before surgeries [ • Administration of pneumococcal vaccine and annual influenza vaccination [ • Planning to commence steroids [ • Dysphagia is present • Patient is chronically constipated • Major surgery has been planned • Patient is malnourished • Physical therapy to promote mobility and prevent contractures • Exercise • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. • All ambulatory boys with DMD or those in early non-ambulatory phase should participate in regular gentle exercise to avoid contractures and disuse atrophy. • Exercise can consist of a combination of swimming pool and recreation-based activities. Swimming can be continued in non-ambulatory patients under close supervision, if medically safe. • If patients complain of muscle pain during or after exercise, the activity should be reduced and monitoring for myoglobinuria should be carried out. Myoglobinuria within 24 hours after exercise indicates overexertion leading to rhabdomyolysis. • Blood • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually • Consideration of magnesium and parathyroid hormone levels • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually • Consideration of magnesium and parathyroid hormone levels • Urine (calcium, sodium, creatinine) • Dual-energy x-ray absorptiometry (DXA) scanning • At baseline (age ≥3 years) or at start of corticosteroid therapy • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 • At baseline (age ≥3 years) or at start of corticosteroid therapy • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 • Spine radiograph • If back pain is present • To exclude vertebral compression fracture • To assess degree of kyphoscoliosis if present on physical examination • If back pain is present • To exclude vertebral compression fracture • To assess degree of kyphoscoliosis if present on physical examination • Bone age if growth failure occurs (height for age <5th percentile or if linear growth is faltering) in persons on or off corticosteroids • Measurement of serum concentrations of calcium and phosphorus, and activity of alkaline phosphatase • 25-hydroxyvitamin D (25-OHD) level in springtime or biannually • Consideration of magnesium and parathyroid hormone levels • At baseline (age ≥3 years) or at start of corticosteroid therapy • Repeated annually in those at risk (history of fractures, chronic corticosteroid therapy) and those with DXA Z score <-2 • If back pain is present • To exclude vertebral compression fracture • To assess degree of kyphoscoliosis if present on physical examination • Exposure to sunshine and a balanced diet rich in vitamin D and calcium to improve bone density and reduce the risk of fractures. Supplementation should be carried out in consultation with a dietician. • Vitamin D supplementation should be initiated if the vitamin D serum concentration is <20 ng/mL [ • Intravenous bisphosphonates; recommended in persons with symptomatic vertebral fracture(s). A bone health expert should be consulted. • Note: Use of oral biphosphonates for prophylaxis or treatment remains controversial. ## Surveillance The American Academy of Pediatrics (AAP) has published recommendations for optimal cardiac care in persons with dystrophinopathy [ Complete cardiac evaluation at least every two years, beginning at the time of diagnosis Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [ Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years Treatment of cardiac disease similar to that for boys with dystrophinopathy Perform baseline pulmonary function testing before confinement to a wheelchair (usually age ~9-10 years) Twice-yearly evaluation by a pediatric pulmonologist is indicated after ANY of the following [ Confinement to a wheelchair Reduction in vital capacity below 80% predicted Age 12 years The 2010 consensus guidelines [ Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; Manual and mechanically assisted cough techniques; Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. Monitor for orthopedic complications, especially contractures and scoliosis in those with DMD and BMD phenotypes. Evaluate for surgical interventions as needed. • Complete cardiac evaluation at least every two years, beginning at the time of diagnosis • Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. • At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation • Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. • If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [ • Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure • Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms • Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years • Treatment of cardiac disease similar to that for boys with dystrophinopathy • Confinement to a wheelchair • Reduction in vital capacity below 80% predicted • Age 12 years • Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; • Manual and mechanically assisted cough techniques; • Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. ## Cardiac The American Academy of Pediatrics (AAP) has published recommendations for optimal cardiac care in persons with dystrophinopathy [ Complete cardiac evaluation at least every two years, beginning at the time of diagnosis Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [ Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years Treatment of cardiac disease similar to that for boys with dystrophinopathy • Complete cardiac evaluation at least every two years, beginning at the time of diagnosis • Note: At minimum, the evaluation should include an electrocardiogram and a noninvasive cardiac imaging study such as echocardiography or cardiac MRI. • At approximately age ten years, or at the onset of cardiac signs and symptoms, annual complete cardiac evaluation • Note: Most individuals with DMD demonstrating cardiac signs and symptoms are relatively late in their course. • If evaluation reveals ventricular dysfunction, initiation of pharmacologic therapy and surveillance at least every six months [ • Education about the risk of developing cardiomyopathy and about the signs and symptoms of heart failure • Complete cardiac evaluation by a cardiac specialist with experience in the treatment of heart failure and/or neuromuscular disorders, with the initial evaluation to take place in late adolescence or early adulthood, or earlier at the appearance of cardiac signs and symptoms • Starting at age 25 to 30 years, screening with a complete cardiac evaluation at least every five years • Treatment of cardiac disease similar to that for boys with dystrophinopathy ## Pulmonary Perform baseline pulmonary function testing before confinement to a wheelchair (usually age ~9-10 years) Twice-yearly evaluation by a pediatric pulmonologist is indicated after ANY of the following [ Confinement to a wheelchair Reduction in vital capacity below 80% predicted Age 12 years The 2010 consensus guidelines [ Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; Manual and mechanically assisted cough techniques; Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. • Confinement to a wheelchair • Reduction in vital capacity below 80% predicted • Age 12 years • Use of self-inflating manual ventilation bag or mechanical insufflation-exsufflation device; • Manual and mechanically assisted cough techniques; • Indications for nocturnal and then daytime noninvasive ventilation as well as for tracheostomy. ## Orthopedic Monitor for orthopedic complications, especially contractures and scoliosis in those with DMD and BMD phenotypes. Evaluate for surgical interventions as needed. ## Agents/Circumstances to Avoid Individuals with dystrophinopathy should avoid botulinum toxin injections. Although it is recommended that triggering agents like succinylcholine and inhalational anesthetics be avoided in patients with dystrophinopathy because of susceptibility to malignant hyperthermia or malignant hyperthermia-like reactions (rhabdomyolysis, cardiac complications, hyperkalemia), it should be noted that an extensive literature search did not find an increased risk for malignant hyperthermia susceptibility in individuals with dystrophinopathy when compared with the general population [ ## Evaluation of Relatives at Risk It is appropriate to evaluate at-risk female family members (i.e., the sisters or maternal female relatives of an affected male and first-degree relatives of a known or possible heterozygous female) in order to identify as early as possible heterozygous females who would benefit from cardiac surveillance (see Molecular genetic testing if the Serum creatine phosphokinase (CK) testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative. Molecular genetic testing of the at-risk female if an affected male is not available for testing: By deletion/duplication analysis first If no pathogenic variant is identified, by sequence analysis Linkage analysis to determine carrier status in at-risk females if (1) the Linkage studies are based on accurate clinical diagnosis of DMD/BMD/ Linkage analysis relies on the availability and willingness of family members to be tested. Because the markers used for linkage in DMD/BMD/ Note: (1) The large size of See • Molecular genetic testing if the • Serum creatine phosphokinase (CK) testing if the pathogenic variant in the family is not known. Although serum CK concentration can be normal in carrier females, if elevated, it will support heterozygosity status in a female relative. • Molecular genetic testing of the at-risk female if an affected male is not available for testing: • By deletion/duplication analysis first • If no pathogenic variant is identified, by sequence analysis • Linkage analysis to determine carrier status in at-risk females if (1) the • Linkage studies are based on accurate clinical diagnosis of DMD/BMD/ • Linkage analysis relies on the availability and willingness of family members to be tested. • Because the markers used for linkage in DMD/BMD/ • Note: (1) The large size of ## Pregnancy Management for Heterozygous Females Symptomatic heterozygous women should undergo an evaluation for dilated cardiomyopathy ideally prior to conceiving a pregnancy or as soon as the pregnancy is recognized. Asymptomatic heterozygous women should consider undergoing a cardiac evaluation prior to conception or when a pregnancy is recognized. Those with evidence of dilated cardiomyopathy should be treated and/or monitored by a cardiologist and a high-risk obstetrician. ## Therapies Under Investigation See also Preclinical efficacy studies showed production of dystrophin in primary muscle cells from humans and A Phase III multicenter 48-week double-blind placebo-controlled trial (ACT DMD) showed no significant benefit of ataluren for the primary endpoint (i.e., change from baseline in the 6-minute walk test), though there was benefit for some secondary endpoints [ Search ## Genetic Counseling The dystrophinopathies are 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. If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a Recommendations for the mother of a proband include molecular genetic testing; heterozygous females need to be identified for the purpose of cardiac surveillance (see Molecular genetic testing can be used to determine the point of origin of a Rarely, a female may be the only affected family member. A female proband may have inherited the The risk to sibs of a male proband depends on the genetic status of the mother; if the proband is female, the risk to sibs depends the genetic status of the mother and the father. If the mother of a proband is heterozygous for a If the If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting the family-specific If the father of an affected female has a Males with DMD usually die before reproductive age or are too debilitated to reproduce. If they were to reproduce, all male offspring would be unaffected and all female offspring would be heterozygotes and could have a range of clinical manifestations (see Males with Becker muscular dystrophy (BMD) and Women with a Carrier testing is possible for at-risk females. See Management, Females who are identified as heterozygous for a See Management, BMD and 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 history of molecular diagnostic testing in DMD and the impact of new techniques including chromosome microarray (CMA) analysis and noninvasive prenatal diagnosis methods are reviewed in various publications [ • 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. • If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • Recommendations for the mother of a proband include molecular genetic testing; heterozygous females need to be identified for the purpose of cardiac surveillance (see • Molecular genetic testing can be used to determine the point of origin of a • Rarely, a female may be the only affected family member. A female proband may have inherited the • The risk to sibs of a male proband depends on the genetic status of the mother; if the proband is female, the risk to sibs depends the genetic status of the mother and the father. • If the mother of a proband is heterozygous for a • If the • If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting the family-specific • If the father of an affected female has a • Males with DMD usually die before reproductive age or are too debilitated to reproduce. If they were to reproduce, all male offspring would be unaffected and all female offspring would be heterozygotes and could have a range of clinical manifestations (see • Males with Becker muscular dystrophy (BMD) and • Women with 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 The dystrophinopathies are 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. If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a Recommendations for the mother of a proband include molecular genetic testing; heterozygous females need to be identified for the purpose of cardiac surveillance (see Molecular genetic testing can be used to determine the point of origin of a Rarely, a female may be the only affected family member. A female proband may have inherited the The risk to sibs of a male proband depends on the genetic status of the mother; if the proband is female, the risk to sibs depends the genetic status of the mother and the father. If the mother of a proband is heterozygous for a If the If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting the family-specific If the father of an affected female has a Males with DMD usually die before reproductive age or are too debilitated to reproduce. If they were to reproduce, all male offspring would be unaffected and all female offspring would be heterozygotes and could have a range of clinical manifestations (see Males with Becker muscular dystrophy (BMD) and Women with a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. • If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • Recommendations for the mother of a proband include molecular genetic testing; heterozygous females need to be identified for the purpose of cardiac surveillance (see • Molecular genetic testing can be used to determine the point of origin of a • Rarely, a female may be the only affected family member. A female proband may have inherited the • The risk to sibs of a male proband depends on the genetic status of the mother; if the proband is female, the risk to sibs depends the genetic status of the mother and the father. • If the mother of a proband is heterozygous for a • If the • If the mother has concomitant somatic and germline mosaicism, the risk to sibs of inheriting the family-specific • If the father of an affected female has a • Males with DMD usually die before reproductive age or are too debilitated to reproduce. If they were to reproduce, all male offspring would be unaffected and all female offspring would be heterozygotes and could have a range of clinical manifestations (see • Males with Becker muscular dystrophy (BMD) and • Women with a ## Heterozygote Detection Carrier testing is possible for at-risk females. See Management, Females who are identified as heterozygous for a ## Related Genetic Counseling Issues See Management, BMD and 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 The history of molecular diagnostic testing in DMD and the impact of new techniques including chromosome microarray (CMA) analysis and noninvasive prenatal diagnosis methods are reviewed in various publications [ ## Resources Canada United Kingdom Parent Project for Muscular Dystrophy Research • • • • • • • • • • • • • • • • • • Canada • • • United Kingdom • • • Parent Project for Muscular Dystrophy Research • ## Molecular Genetics Dystrophinopathies: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Dystrophinopathies ( The frequencies for types of pathogenic variants given in this section are for individuals with DMD or BMD. Data are insufficient to estimate the percentage of individuals with Nonsense variants occur more commonly in DMD – in the range of 20%-25% of cases – as compared to fewer than 5% in BMD [ Splice site variants and small insertions/deletions (indels) are a substantial proportion of sequence changes in both DMD and BMD. Missense variants are not a common cause of either Duchenne or Becker dystrophy. • Nonsense variants occur more commonly in DMD – in the range of 20%-25% of cases – as compared to fewer than 5% in BMD [ • Splice site variants and small insertions/deletions (indels) are a substantial proportion of sequence changes in both DMD and BMD. • Missense variants are not a common cause of either Duchenne or Becker dystrophy. ## Chapter Notes The authors would like to thank Elizabeth DeChene, MS, CGC, and Elicia Estrella, MS, CGC, of the Program in Genomics/Harvard Neuromuscular Disease Project, Children's Hospital Boston, for their assistance in reviewing and editing the Genetic Counseling Section. Basil T Darras, MD (1999-present)Partha S Ghosh, MD (2018-present)Bruce R Korf, MD, PhD, FACMG; University of Alabama-Birmingham (1999-2011)David T Miller, MD, PhD, FACMG; Boston Children’s Hospital (2011-2018)David K Urion, MD (1999-present) 20 January 2022 (aa) Revision: dystrophin restoration therapies (See 26 April 2018 (ha) Comprehensive update posted live 26 November 2014 (me) Comprehensive update posted live 23 November 2011 (me) Comprehensive update posted live 21 March 2008 (me) Comprehensive update posted live 25 August 2005 (me) Comprehensive update posted live 1 October 2004 (cd) Revision 3 August 2004 (cd) Revision: Management 24 March 2004 (cd) Revision: Diagnosis 23 June 2003 (me) Comprehensive update posted live 5 September 2000 (me) Review posted live December 1999 (bk) Original submission • 20 January 2022 (aa) Revision: dystrophin restoration therapies (See • 26 April 2018 (ha) Comprehensive update posted live • 26 November 2014 (me) Comprehensive update posted live • 23 November 2011 (me) Comprehensive update posted live • 21 March 2008 (me) Comprehensive update posted live • 25 August 2005 (me) Comprehensive update posted live • 1 October 2004 (cd) Revision • 3 August 2004 (cd) Revision: Management • 24 March 2004 (cd) Revision: Diagnosis • 23 June 2003 (me) Comprehensive update posted live • 5 September 2000 (me) Review posted live • December 1999 (bk) Original submission ## Acknowledgments The authors would like to thank Elizabeth DeChene, MS, CGC, and Elicia Estrella, MS, CGC, of the Program in Genomics/Harvard Neuromuscular Disease Project, Children's Hospital Boston, for their assistance in reviewing and editing the Genetic Counseling Section. ## Author History Basil T Darras, MD (1999-present)Partha S Ghosh, MD (2018-present)Bruce R Korf, MD, PhD, FACMG; University of Alabama-Birmingham (1999-2011)David T Miller, MD, PhD, FACMG; Boston Children’s Hospital (2011-2018)David K Urion, MD (1999-present) ## Revision History 20 January 2022 (aa) Revision: dystrophin restoration therapies (See 26 April 2018 (ha) Comprehensive update posted live 26 November 2014 (me) Comprehensive update posted live 23 November 2011 (me) Comprehensive update posted live 21 March 2008 (me) Comprehensive update posted live 25 August 2005 (me) Comprehensive update posted live 1 October 2004 (cd) Revision 3 August 2004 (cd) Revision: Management 24 March 2004 (cd) Revision: Diagnosis 23 June 2003 (me) Comprehensive update posted live 5 September 2000 (me) Review posted live December 1999 (bk) Original submission • 20 January 2022 (aa) Revision: dystrophin restoration therapies (See • 26 April 2018 (ha) Comprehensive update posted live • 26 November 2014 (me) Comprehensive update posted live • 23 November 2011 (me) Comprehensive update posted live • 21 March 2008 (me) Comprehensive update posted live • 25 August 2005 (me) Comprehensive update posted live • 1 October 2004 (cd) Revision • 3 August 2004 (cd) Revision: Management • 24 March 2004 (cd) Revision: Diagnosis • 23 June 2003 (me) Comprehensive update posted live • 5 September 2000 (me) Review posted live • December 1999 (bk) Original submission ## References American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Clinical Report: cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Available Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Available Moxley RT III, Ashwal S, Pandya S, Connolly A, Florence J, Mathews K, Baumbach L, McDonald C, Sussman M, Wade C. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Available • American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Clinical Report: cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Available • Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Available • Moxley RT III, Ashwal S, Pandya S, Connolly A, Florence J, Mathews K, Baumbach L, McDonald C, Sussman M, Wade C. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Available ## Published Guidelines / Consensus Statements American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Clinical Report: cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Available Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Available Moxley RT III, Ashwal S, Pandya S, Connolly A, Florence J, Mathews K, Baumbach L, McDonald C, Sussman M, Wade C. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Available • American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Clinical Report: cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Available • Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Available • Moxley RT III, Ashwal S, Pandya S, Connolly A, Florence J, Mathews K, Baumbach L, McDonald C, Sussman M, Wade C. Practice parameter: corticosteroid treatment of Duchenne dystrophy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Available ## Literature Cited
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Improvement of survival in Duchenne muscular dystrophy: retrospective analysis of 835 patients.. Acta Myol 2012;31:121-5", "E Pegoraro, RN Schimke, C Garcia, H Stern, M Cadaldini, C Angelini, E Barbosa, J Carroll, WA Marks, HE Neville, H Marks, S Appleton, H Toriello, HB Wessel, J Donnelly, SM Bernes, JW Taber, L Weiss, EP Hoffman. Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: evidence for failure of dystrophin production in dystrophin-competent myonuclei.. Neurology 1995;45:677-90", "TW Prior, SJ Bridgeman. Experience and strategy for the molecular testing of Duchenne muscular dystrophy.. J Mol Diagn 2005;7:317-26", "R Quinlivan, H Roper, M Davie, NJ Shaw, J McDonagh, K Bushby. Report of a Muscular Dystrophy Campaign funded workshop Birmingham, UK, January 16th 2004. Osteoporosis in Duchenne muscular dystrophy; its prevalence, treatment and prevention.. Neuromuscul Disord 2005;15:72-9", "S Rall, T. Grimm. 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Am Heart J 1996;132:642-7", "SM Schade van Westrum, EM Hoogerwaard, L Dekker, TS Standaar, E Bakker, PF Ippel, JC Oosterwijk, DF Majoor-Krakauer, AJ van Essen, NJ Leschot, AA Wilde, RJ de Haan, M de Visser, AJ van der Kooi. Cardiac abnormalities in a follow-up study on carriers of Duchenne and Becker muscular dystrophy.. Neurology 2011;77:62-6", "M Shimizu, H Ino, T Yasuda, N Fujino, K Uchiyama, T Mabuchi, T Konno, T Kaneda, T Fujita, E Masuta, M Katoh, A Funada, H Mabuchi. Gene mutations in adult Japanese patients with dilated cardiomyopathy.. Circ J 2005;69:150-3", "P Soltanzadeh, MJ Friez, D Dunn, A von Niederhausern, OL Gurvich, KJ Swoboda, JB Sampson, A Pestronk, AM Connolly, JM Florence, RS Finkel, CG Bönnemann, L Medne, JR Mendell, KD Mathews, BL Wong, MD Sussman, J Zonana, K Kovak, SM Gospe, E Gappmaier, LE Taylor, MT Howard, RB Weiss, KM Flanigan. Clinical and genetic characterization of manifesting carriers of DMD mutations.. 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Circulation 1993;87:1854-65", "S Tuffery-Giraud, C Béroud, F Leturcq, RB Yaou, D Hamroun, L Michel-Calemard, MP Moizard, R Bernard, M Cossée, P Boisseau, M Blayau, I Creveaux, A Guiochon-Mantel, B de Martinville, C Philippe, N Monnier, E Bieth, P Khau Van Kien, FO Desmet, V Humbertclaude, JC Kaplan, J Chelly, M Claustres. Genotype-phenotype analysis in 2,405 patients with a dystrophinopathy using the UMD-DMD database: a model of nationwide knowledgebase.. Hum Mutat 2009;30:934-45", "AJ van Essen, HF Busch, GJ te Meerman, LP ten Kate. Birth and population prevalence of Duchenne muscular dystrophy in The Netherlands.. Hum Genet 1992;88:258-66", "AJ van Essen, IM Mulder, P van der Vlies, AH van der Hout, CH Buys, RM Hofstra, JT den Dunnen. Detection of point mutation in dystrophin gene reveals somatic and germline mosaicism in the mother of a patient with Duchenne muscular dystrophy.. Am J Med Genet 2003;118A:296-8", "E Viggiano, M Ergoli, E Picillo, L Politano. Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy.. Hum Genet 2016;135:685-98", "E Viggiano, E Picillo, M Ergoli, A Cirillo, S Del Gaudio, L. Politano. Skewed X-chromosome inactivation plays a crucial role in the onset of symptoms in carriers of Becker muscular dystrophy.. J Gene Med. 2017:19", "L Viollet, PT Thrush, KM Flanigan, JR Mendell, HD Allen. Effects of angiotensin-converting enzyme inhibitors and/or beta blockers on the cardiomyopathy in Duchenne muscular dystrophy.. Am J Cardiol 2012;110:98-102", "KR Wagner, JL Fleckenstein, AA Amato, RJ Barohn, K Bushby, DM Escolar, KM Flanigan, A Pestronk, R Tawil, GI Wolfe, M Eagle, JM Florence, WM King, S Pandya, V Straub, P Juneau, K Meyers, C Csimma, T Araujo, R Allen, SA Parsons, JM Wozney, ER Lavallie, JR Mendell. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy.. Ann Neurol 2008;63:561-71", "KR Wagner, AC McPherron, N Winik, SJ Lee. Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.. Ann Neurol 2002;52:832", "H Wang, Y Xu, X Liu, L Wang, W Jiang, B Xiao, W Wei, Y Chen, W Ye, X Ji. Prenatal diagnosis of Duchenne muscular dystrophy in 131 Chinese families with dystrophinopathy.. Prenat Diagn 2017;37:356-64", "H Watkins, H Ashrafian, C Redwood. Inherited cardiomyopathies.. N Engl J Med 2011;364:1643-56", "EM Welch, ER Barton, J Zhuo, Y Tomizawa, WJ Friesen, P Trifillis, S Paushkin, M Patel, CR Trotta, S Hwang, RG Wilde, G Karp, J Takasugi, G Chen, S Jones, H Ren, YC Moon, D Corson, AA Turpoff, JA Campbell, MM Conn, A Khan, NG Almstead, J Hedrick, A Mollin, N Risher, M Weetall, S Yeh, AA Branstrom, JM Colacino, J Babiak, WD Ju, S Hirawat, VJ Northcutt, LL Miller, P Spatrick, F He, M Kawana, H Feng, A Jacobson, SW Peltz, HL Sweeney. PTC124 targets genetic disorders caused by nonsense mutations.. 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5/9/2000
26/4/2018
20/1/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dcm-lmna
dcm-lmna
[ "Prelamin-A/C", "LMNA", "LMNA-Related Dilated Cardiomyopathy" ]
Ray E Hershberger, Elizabeth Jordan
Summary The diagnosis of
## Diagnosis The diagnosis of Note: Identification of a heterozygous 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 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. At least three reports have identified • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings ## Establishing the Diagnosis The diagnosis of Note: Identification of a heterozygous 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 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. At least three reports have identified • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Symptomatic bradyarrhythmias requiring cardiac pacemakers Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation Large prospective longitudinal studies to define the range of natural history of individuals with No specific genotype-phenotype correlations have been established for A few studies focusing on pathogenic variant type suggest a correlation between splice site variants and increased risk for sudden cardiac death [ Second to • Symptomatic bradyarrhythmias requiring cardiac pacemakers • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) • Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation • Symptomatic bradyarrhythmias requiring cardiac pacemakers • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) • Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation • Symptomatic bradyarrhythmias requiring cardiac pacemakers • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) • Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation ## Clinical Description Symptomatic bradyarrhythmias requiring cardiac pacemakers Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation Large prospective longitudinal studies to define the range of natural history of individuals with • Symptomatic bradyarrhythmias requiring cardiac pacemakers • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) • Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation • Symptomatic bradyarrhythmias requiring cardiac pacemakers • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) • Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation • Symptomatic bradyarrhythmias requiring cardiac pacemakers • Supraventricular arrhythmias including atrial flutter, atrial fibrillation, supraventricular tachycardia, and the sick sinus syndrome (i.e., tachycardia-bradycardia syndrome) • Ventricular arrhythmias including frequent premature ventricular contractions, ventricular tachycardia, and ventricular fibrillation ## Genotype-Phenotype Correlations No specific genotype-phenotype correlations have been established for A few studies focusing on pathogenic variant type suggest a correlation between splice site variants and increased risk for sudden cardiac death [ ## Penetrance ## Prevalence Second to ## Genetically Related (Allelic) Disorders Pathogenic variants in Pathogenic variants have also been identified in several disorders of striated muscle, nerve, adipose, and vascular tissue, collectively referred to as the Selected AD = autosomal dominant; AR = autosomal recessive; DCM = dilated cardiomyopathy; MOI = mode of inheritance ## Differential Diagnosis The genetic differential diagnosis of idiopathic dilated cardiomyopathy (DCM) should include all genes known to be associated with nonsyndromic DCM. Particular attention can be focused on nonsyndromic DCM-related genes that have been associated with arrhythmia and conduction system disease phenotypes (see For individuals with a clinical diagnosis of idiopathic DCM and/or conduction disease/arrhythmias in whom molecular genetic testing fails to identify a pathogenic variant in ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Assessment for skeletal muscle weakness Serum CK level CK = creatine kinase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management guidelines for genetic cardiomyopathies have been published [ Because of the complexity of treatment interventions in Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia). With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this recommendation was included in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an The management of Treatment of Manifestations in Individuals with Anticoagulants Agents for ventricular rate control Pharmacologic agents May be augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations) An implantable electronic pacemaker Strongly consider an ICD (not an electronic pacemaker) due to risk of mortality from sudden cardiac death. Use of an ICD Drug therapy as needed Cardiac transplantation; Durable mechanical circulatory support if cardiac transplantation is contraindicated. ICD = implantable cardioverter defibrillator Recommended Surveillance for Individuals with Drugs (beta blockers, calcium channel blockers, others) that exacerbate heart block, if present, should be avoided in Once a molecular diagnosis of The risk of DCM to family members who do not have the If molecular genetic testing is not possible, the first-degree relatives of a proband with Note: Because the age of onset is variable and penetrance is reduced, a normal baseline echocardiogram and EKG in a first-degree relative who has not undergone molecular genetic testing does not rule out Any abnormal cardiovascular test results in a relative of a proband with a known See Pregnancy is contraindicated in women with DCM because of the significantly increased mortality with pregnancy in DCM. Women with DCM who become pregnant should be followed by a high-risk obstetrician. At-risk women with unknown genetic status should undergo a cardiovascular evaluation and be offered genetic counseling prior to pregnancy. Drugs aimed at reducing mitogen-activated protein (MAP) kinase signaling, a mechanism which has been shown to be increased in Search • Assessment for skeletal muscle weakness • Serum CK level • Because of the complexity of treatment interventions in • Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia). • With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this recommendation was included in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an • Anticoagulants • Agents for ventricular rate control • Pharmacologic agents • May be augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations) • An implantable electronic pacemaker • Strongly consider an ICD (not an electronic pacemaker) due to risk of mortality from sudden cardiac death. • Use of an ICD • Drug therapy as needed • Cardiac transplantation; • Durable mechanical circulatory support if cardiac transplantation is contraindicated. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Assessment for skeletal muscle weakness Serum CK level CK = creatine kinase; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assessment for skeletal muscle weakness • Serum CK level ## Treatment of Manifestations Management guidelines for genetic cardiomyopathies have been published [ Because of the complexity of treatment interventions in Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia). With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this recommendation was included in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an The management of Treatment of Manifestations in Individuals with Anticoagulants Agents for ventricular rate control Pharmacologic agents May be augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations) An implantable electronic pacemaker Strongly consider an ICD (not an electronic pacemaker) due to risk of mortality from sudden cardiac death. Use of an ICD Drug therapy as needed Cardiac transplantation; Durable mechanical circulatory support if cardiac transplantation is contraindicated. ICD = implantable cardioverter defibrillator • Because of the complexity of treatment interventions in • Consider therapy based on cardiac phenotype (i.e., DCM or arrhythmia). • With an established arrhythmia or known risk of arrhythmia, consider ICD implantation before the ejection fraction falls below 35%. Note that this recommendation was included in the Heart Failure Society guidelines in large part because of the risk for lethal arrhythmias in persons with an • Anticoagulants • Agents for ventricular rate control • Pharmacologic agents • May be augmented with electrophysiologic intervention (e.g., atrial or atrioventricular node ablations) • An implantable electronic pacemaker • Strongly consider an ICD (not an electronic pacemaker) due to risk of mortality from sudden cardiac death. • Use of an ICD • Drug therapy as needed • Cardiac transplantation; • Durable mechanical circulatory support if cardiac transplantation is contraindicated. ## Surveillance Recommended Surveillance for Individuals with ## Agents/Circumstances to Avoid Drugs (beta blockers, calcium channel blockers, others) that exacerbate heart block, if present, should be avoided in ## Evaluation of Relatives at Risk Once a molecular diagnosis of The risk of DCM to family members who do not have the If molecular genetic testing is not possible, the first-degree relatives of a proband with Note: Because the age of onset is variable and penetrance is reduced, a normal baseline echocardiogram and EKG in a first-degree relative who has not undergone molecular genetic testing does not rule out Any abnormal cardiovascular test results in a relative of a proband with a known See ## Pregnancy Management Pregnancy is contraindicated in women with DCM because of the significantly increased mortality with pregnancy in DCM. Women with DCM who become pregnant should be followed by a high-risk obstetrician. At-risk women with unknown genetic status should undergo a cardiovascular evaluation and be offered genetic counseling prior to pregnancy. ## Therapies Under Investigation Drugs aimed at reducing mitogen-activated protein (MAP) kinase signaling, a mechanism which has been shown to be increased in Search ## Genetic Counseling Some individuals diagnosed with Note: Both sides of the family should be considered as possibly contributing. Families with DCM in both maternal and paternal lineages have been described [ Some individuals diagnosed with Recommendations for the evaluation of reportedly unaffected parents of a proband include: Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). Molecular genetic testing for the familial If the The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If one parent of the proband has the Due to reduced penetrance, variable expression, and potentially subtle or unknown early cardiovascular phenotypes in the progression of If the Sibs may be offered genetic testing for the familial See Management, Predictive testing for at-risk relatives is possible once the Testing of asymptomatic at-risk individuals is considered predictive testing for predisposition to Predictive testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of DCM onset, severity, or rate of progression. Recent estimates of the likelihood of clinically detectable presentation of In families with early-onset aggressive disease, identification of the familial pathogenic variant may guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease. See the American Academy of Pediatrics and American College of Medical Genetics and Genomics 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once an Differences in perspective exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Some individuals diagnosed with • Note: Both sides of the family should be considered as possibly contributing. Families with DCM in both maternal and paternal lineages have been described [ • Some individuals diagnosed with • Recommendations for the evaluation of reportedly unaffected parents of a proband include: • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). • Molecular genetic testing for the familial • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). • Molecular genetic testing for the familial • If the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • 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. • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). • Molecular genetic testing for the familial • 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 one parent of the proband has the • Due to reduced penetrance, variable expression, and potentially subtle or unknown early cardiovascular phenotypes in the progression of • If the • Sibs may be offered genetic testing for the familial • Predictive testing for at-risk relatives is possible once the • Testing of asymptomatic at-risk individuals is considered predictive testing for predisposition to • Predictive testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of DCM onset, severity, or rate of progression. • Recent estimates of the likelihood of clinically detectable presentation of • In families with early-onset aggressive disease, identification of the familial pathogenic variant may guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease. • See the American Academy of Pediatrics and American College of Medical Genetics and Genomics • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Some individuals diagnosed with Note: Both sides of the family should be considered as possibly contributing. Families with DCM in both maternal and paternal lineages have been described [ Some individuals diagnosed with Recommendations for the evaluation of reportedly unaffected parents of a proband include: Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). Molecular genetic testing for the familial If the The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If one parent of the proband has the Due to reduced penetrance, variable expression, and potentially subtle or unknown early cardiovascular phenotypes in the progression of If the Sibs may be offered genetic testing for the familial • Some individuals diagnosed with • Note: Both sides of the family should be considered as possibly contributing. Families with DCM in both maternal and paternal lineages have been described [ • Some individuals diagnosed with • Recommendations for the evaluation of reportedly unaffected parents of a proband include: • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). • Molecular genetic testing for the familial • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). • Molecular genetic testing for the familial • If the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • 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. • Review of medical history, physical examination, echocardiogram, and EKG to determine if a parent has detectable DCM and/or conduction system disease. Evaluation of parents may determine that one is affected but has previously escaped diagnosis possibly because of a milder phenotypic presentation (e.g., evidence of DCM on echocardiogram without clinical heart failure symptoms). • Molecular genetic testing for the familial • 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 one parent of the proband has the • Due to reduced penetrance, variable expression, and potentially subtle or unknown early cardiovascular phenotypes in the progression of • If the • Sibs may be offered genetic testing for the familial ## Related Genetic Counseling Issues See Management, Predictive testing for at-risk relatives is possible once the Testing of asymptomatic at-risk individuals is considered predictive testing for predisposition to Predictive testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of DCM onset, severity, or rate of progression. Recent estimates of the likelihood of clinically detectable presentation of In families with early-onset aggressive disease, identification of the familial pathogenic variant may guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease. See the American Academy of Pediatrics and American College of Medical Genetics and Genomics 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. 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 • Testing of asymptomatic at-risk individuals is considered predictive testing for predisposition to • Predictive testing should only be performed in the context of formal genetic counseling, and is not useful in predicting age of DCM onset, severity, or rate of progression. • Recent estimates of the likelihood of clinically detectable presentation of • In families with early-onset aggressive disease, identification of the familial pathogenic variant may guide more stringent clinical screening for asymptomatic but clinically detectable cardiovascular disease. • See the American Academy of Pediatrics and American College of Medical Genetics and Genomics • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once an Differences in perspective 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 LMNA-Related Dilated Cardiomyopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for LMNA-Related Dilated Cardiomyopathy ( NOTE: Curation of clinical and experimental evidence through the ClinGen DCM Gene Curation efforts resulted in a definitive classification for the relationship of ## Molecular Pathogenesis NOTE: Curation of clinical and experimental evidence through the ClinGen DCM Gene Curation efforts resulted in a definitive classification for the relationship of ## Chapter Notes Website: The Dilated Cardiomyopathy Research Project, originally launched in 1993 by Dr. Ray Hershberger while at the Oregon Health & Science University, aims to advance our understanding of dilated cardiomyopathy genetics. Multiple studies including data from more than 1500 families affected by DCM across the country have contributed genetic and clinical information to this research program. This multi-institutional effort, still led by Dr Hershberger and now housed at The Ohio State University, leverages the many sites collaborating in the DCM Consortium to identify families eligible for studies within the DCM Research Project, including the recently completed DCM Precision Medicine Study and the ongoing DCM Discovery Study. More information about the DCM Project, affiliated research studies, and other information and resources can be found on the website ( We are deeply grateful for the numerous families who have contributed to the research efforts in the DCM Research Project over the past nearly three decades. Without their gracious participation and engagement, the advances driven by the work of the DCM Research Project to the field would not be possible. Jason Cowan, MS; University of Miami Miller School of Medicine (2008-2011)Ray E Hershberger, MD (2008-present)Ana Morales, MS, CGC; The Ohio State University (2008-2011; 2013-2021)Elizabeth Jordan, MMSc, CGC (2022-present) 17 March 2022 (ha) Comprehensive update posted live 7 July 2016 (ha) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 5 April 2011 (me) Comprehensive update posted live 12 June 2008 (me) Review posted live 7 January 2008 (rh) Original submission • 17 March 2022 (ha) Comprehensive update posted live • 7 July 2016 (ha) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 5 April 2011 (me) Comprehensive update posted live • 12 June 2008 (me) Review posted live • 7 January 2008 (rh) Original submission ## Author Notes Website: The Dilated Cardiomyopathy Research Project, originally launched in 1993 by Dr. Ray Hershberger while at the Oregon Health & Science University, aims to advance our understanding of dilated cardiomyopathy genetics. Multiple studies including data from more than 1500 families affected by DCM across the country have contributed genetic and clinical information to this research program. This multi-institutional effort, still led by Dr Hershberger and now housed at The Ohio State University, leverages the many sites collaborating in the DCM Consortium to identify families eligible for studies within the DCM Research Project, including the recently completed DCM Precision Medicine Study and the ongoing DCM Discovery Study. More information about the DCM Project, affiliated research studies, and other information and resources can be found on the website ( ## Acknowledgments We are deeply grateful for the numerous families who have contributed to the research efforts in the DCM Research Project over the past nearly three decades. Without their gracious participation and engagement, the advances driven by the work of the DCM Research Project to the field would not be possible. ## Author History Jason Cowan, MS; University of Miami Miller School of Medicine (2008-2011)Ray E Hershberger, MD (2008-present)Ana Morales, MS, CGC; The Ohio State University (2008-2011; 2013-2021)Elizabeth Jordan, MMSc, CGC (2022-present) ## Revision History 17 March 2022 (ha) Comprehensive update posted live 7 July 2016 (ha) Comprehensive update posted live 19 September 2013 (me) Comprehensive update posted live 5 April 2011 (me) Comprehensive update posted live 12 June 2008 (me) Review posted live 7 January 2008 (rh) Original submission • 17 March 2022 (ha) Comprehensive update posted live • 7 July 2016 (ha) Comprehensive update posted live • 19 September 2013 (me) Comprehensive update posted live • 5 April 2011 (me) Comprehensive update posted live • 12 June 2008 (me) Review posted live • 7 January 2008 (rh) Original submission ## References ## Published Guidelines/Consensus Statements ## Literature Cited
[]
12/6/2008
17/3/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dcm-ov
dcm-ov
[ "DMD-Related Dilated Cardiomyopathy", "LDB3-Related Dilated Cardiomyopathy", "LMNA-Related Dilated Cardiomyopathy", "MYBPC3-Related Dilated Cardiomyopathy", "MYH7-Related Dilated Cardiomyopathy", "PLN-Related Dilated Cardiomyopathy", "SCN5A-Related Dilated Cardiomyopathy", "SGCD-Related Dilated Cardiomyopathy", "TAZ-Related Dilated Cardiomyopathy", "TNNI3-Related Dilated Cardiomyopathy", "TNNT2-Related Dilated Cardiomyopathy", "TPM1-Related Dilated Cardiomyopathy", "TTN-Related Dilated Cardiomyopathy", "ACTN2-Related Dilated Cardiomyopathy", "VCL-Related Dilated Cardiomyopathy", "TCAP-Related Dilated Cardiomyopathy", "CSRP3-Related Dilated Cardiomyopathy", "ACTC1-Related Dilated Cardiomyopathy", "DES-Related Dilated Cardiomyopathy", "TNNC1-Related Dilated Cardiomyopathy", "ANKRD1-Related Dilated Cardiomyopathy", "PSEN2-Related Dilated Cardiomyopathy", "PSEN1-Related Dilated Cardiomyopathy", "TMPO-Related Dilated Cardiomyopathy", "EYA4-Related Dilated Cardiomyopathy", "BAG3-Related Dilated Cardiomyopathy", "RBM20-Related Dilated Cardiomyopathy", "NEXN-Related Dilated Cardiomyopathy", "MYH6-Related Dilated Cardiomyopathy", "DSG2-Related Dilated Cardiomyopathy", "Actin, alpha cardiac muscle 1", "Alpha-actinin-2", "Ankyrin repeat domain-containing protein 1", "BAG family molecular chaperone regulator 3", "Cysteine and glycine-rich protein 3", "Delta-sarcoglycan", "Desmin", "Desmoglein-2", "Dystrophin", "Lamina-associated polypeptide 2", "LIM domain-binding protein 3", "Myosin-6", "Myosin-7", "Myosin-binding protein C, cardiac-type", "Nexilin", "Phospholamban", "Prelamin-A/C", "Presenilin-1", "Presenilin-2", "Protein phosphatase EYA4", "RNA-binding protein 20", "Sodium channel protein type 5 subunit alpha", "Tafazzin", "Telethonin", "Titin", "Tropomyosin alpha-1 chain", "Troponin C, slow skeletal and cardiac muscles", "Troponin I, cardiac muscle", "Troponin T, cardiac muscle", "Vinculin", "ACTC1", "ACTN2", "ANKRD1", "BAG3", "CSRP3", "DES", "DMD", "DSG2", "EYA4", "LDB3", "LMNA", "MYBPC3", "MYH6", "MYH7", "NEXN", "PLN", "PSEN1", "PSEN2", "RBM20", "SCN5A", "SGCD", "TAFAZZIN", "TCAP", "TMPO", "TNNC1", "TNNI3", "TNNT2", "TPM1", "TTN", "VCL", "Dilated Cardiomyopathy", "Overview" ]
Dilated Cardiomyopathy Overview
Ray E Hershberger, Elizabeth Jordan
Summary The purpose of this overview is to: Identify the Provide the Provide a basic view of
## Dilated Cardiomyopathy (DCM): Definition The diagnosis of DCM is established when both of the following are present: Note: DCM usually initially manifests in adults in the fourth to sixth decade, although it may present at any age (prenatally; in infancy, early or late childhood, or adolescence; or in the elderly). Extensive additional clinical and genetic information on DCM is available [ Persons with DCM may be asymptomatic for a number of years. Manifestations usually occur late in the disease course with one or more of the following findings: ## Dilated Cardiomyopathy (DCM): Categories DCM can be categorized as acquired, syndromic, or nonsyndromic ( The most common cause of acquired DCM is Other less common causes include valvular and congenital heart disease, toxins (most commonly, anthracyclines or other chemotherapeutic agents; various drugs with idiosyncratic reactions), thyroid disease, inflammatory or infectious conditions, severe long-standing hypertension, and radiation. While emerging evidence suggests that DCM arising after chemotherapy exposure may also have a genetic background, the clinical relevance of this information is currently undefined [ Note: Acquired DCM will not be discussed further in this overview. In Note: Syndromic DCM will not be discussed further in this overview. Selected List of Syndromic Dilated Cardiomyopathy Neutropenia Muscle weakness Growth delay Infantile/early-childhood onset Woolly hair Palmoplantar keratoderma Muscle weakness ↑ serum CK levels Loss of ambulation in childhood or later in life Joint contractures ↑ serum creatine kinase (CK) levels Childhood- or adult-onset muscle weakness Cirrhosis Diabetes Hypermelanotic pigmentation ↑ serum iron & ferritin levels Facial weakness Childhood-onset weakness of ankles, great toes, finger extensors, & neck flexors Focal segmental glomerulosclerosis AD = autosomal dominant; AR = autosomal recessive; Mat = maternal inheritance; MOI = mode of inheritance; XL = X-linked Disorders are in alphabetic order. Individuals with DCM who do not have acquired (secondary) DCM or syndromic DCM ( The Note: Left ventricular non-compaction (LVNC) is a feature of the heart muscle that has been observed in the general population, and reported in conjunction with a DCM phenotype as well as numerous other cardiovascular phenotypes; its relationship (if any) to the presence or severity of the DCM phenotype remains unknown [ Nonsyndromic Dilated Cardiomyopathy Genes See AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth hereditary neuropathy; HCM = Genes are organized first by strength of ClinGen classification, then frequency of causation of DCM, and then alphabetically. The percentages provided (based on ≥2 reports screening large numbers of probands with HNDCM) should be interpreted as preliminary estimates. Allelic disorders = other phenotypes caused by pathogenic variants in the same gene. Note: Although 10%-20% of DCM in three cohorts (with or without a family history of DCM) was attributed to The hot spot for pathogenic and likely pathogenic variants associated with DCM is located in exon 9 of • Neutropenia • Muscle weakness • Growth delay • Infantile/early-childhood onset • Woolly hair • Palmoplantar keratoderma • Muscle weakness • ↑ serum CK levels • Loss of ambulation in childhood or later in life • Joint contractures • ↑ serum creatine kinase (CK) levels • Childhood- or adult-onset muscle weakness • Cirrhosis • Diabetes • Hypermelanotic pigmentation • ↑ serum iron & ferritin levels • Facial weakness • Childhood-onset weakness of ankles, great toes, finger extensors, & neck flexors • Focal segmental glomerulosclerosis ## Acquired (Secondary) DCM The most common cause of acquired DCM is Other less common causes include valvular and congenital heart disease, toxins (most commonly, anthracyclines or other chemotherapeutic agents; various drugs with idiosyncratic reactions), thyroid disease, inflammatory or infectious conditions, severe long-standing hypertension, and radiation. While emerging evidence suggests that DCM arising after chemotherapy exposure may also have a genetic background, the clinical relevance of this information is currently undefined [ Note: Acquired DCM will not be discussed further in this overview. ## Syndromic DCM In Note: Syndromic DCM will not be discussed further in this overview. Selected List of Syndromic Dilated Cardiomyopathy Neutropenia Muscle weakness Growth delay Infantile/early-childhood onset Woolly hair Palmoplantar keratoderma Muscle weakness ↑ serum CK levels Loss of ambulation in childhood or later in life Joint contractures ↑ serum creatine kinase (CK) levels Childhood- or adult-onset muscle weakness Cirrhosis Diabetes Hypermelanotic pigmentation ↑ serum iron & ferritin levels Facial weakness Childhood-onset weakness of ankles, great toes, finger extensors, & neck flexors Focal segmental glomerulosclerosis AD = autosomal dominant; AR = autosomal recessive; Mat = maternal inheritance; MOI = mode of inheritance; XL = X-linked Disorders are in alphabetic order. • Neutropenia • Muscle weakness • Growth delay • Infantile/early-childhood onset • Woolly hair • Palmoplantar keratoderma • Muscle weakness • ↑ serum CK levels • Loss of ambulation in childhood or later in life • Joint contractures • ↑ serum creatine kinase (CK) levels • Childhood- or adult-onset muscle weakness • Cirrhosis • Diabetes • Hypermelanotic pigmentation • ↑ serum iron & ferritin levels • Facial weakness • Childhood-onset weakness of ankles, great toes, finger extensors, & neck flexors • Focal segmental glomerulosclerosis ## Nonsyndromic DCM Individuals with DCM who do not have acquired (secondary) DCM or syndromic DCM ( The Note: Left ventricular non-compaction (LVNC) is a feature of the heart muscle that has been observed in the general population, and reported in conjunction with a DCM phenotype as well as numerous other cardiovascular phenotypes; its relationship (if any) to the presence or severity of the DCM phenotype remains unknown [ Nonsyndromic Dilated Cardiomyopathy Genes See AD = autosomal dominant; AR = autosomal recessive; CMT = Charcot-Marie-Tooth hereditary neuropathy; HCM = Genes are organized first by strength of ClinGen classification, then frequency of causation of DCM, and then alphabetically. The percentages provided (based on ≥2 reports screening large numbers of probands with HNDCM) should be interpreted as preliminary estimates. Allelic disorders = other phenotypes caused by pathogenic variants in the same gene. Note: Although 10%-20% of DCM in three cohorts (with or without a family history of DCM) was attributed to The hot spot for pathogenic and likely pathogenic variants associated with DCM is located in exon 9 of ## Establishing (When Possible) the Specific Genetic Cause of DCM Molecular genetic testing should be offered to every individual of any age with nonischemic DCM [ Variants (pathogenic, likely pathogenic, or of unknown significance) in more than 30 genes have been identified in up to 30%-35% of individuals with familial DCM (i.e., in ≥2 first-degree family members) [ A cardiomyopathy multigene panel that includes the genes with a ClinGen classification of definitive, strong, or moderate (as listed in Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click Health care providers ordering genetic testing should be familiar with the genetics of DCM [ ## Genetic Risk Assessment and Cardiac Surveillance of At-Risk Relatives for Detection of Early Treatable Manifestations of DCM Cardiovascular screening of asymptomatic first-degree family members of an individual with DCM can allow early detection of DCM, prompt initiation of treatment, and improvement in long-term outcome [ A basic view of nonsyndromic dilated cardiomyopathy (DCM) genetic risk assessment and cardiac surveillance for at-risk relatives is presented in this section; issues that may be specific to a given family or genetic cause of nonsyndromic DCM are not comprehensively addressed. Note: If a proband has a specific syndrome associated with DCM (e.g., Nonsyndromic dilated cardiomyopathy (DCM) is typically inherited in an autosomal dominant manner. Some individuals diagnosed as having autosomal dominant DCM have an affected parent. Some individuals diagnosed with autosomal dominant DCM have the disorder as the result of a When evaluating for autosomal dominant inheritance, both the maternal and paternal lineages should be considered as possibly contributing to familial DCM. In an unknown proportion of cases, both parents may have evidence of DCM and/or DCM-related pathogenic variants, and thus the proband may have inherited pathogenic variants from one or both parents [ Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. 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 affected and/or has a DCM-related pathogenic or likely pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease. If both parents of a proband have a DCM-related pathogenic or likely pathogenic variant, sibs have a 75% chance of inheriting one or two DCM-related variants and a 25% chance of inheriting neither pathogenic variant. If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DCM because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. The parents of an affected individual are obligate heterozygotes (i.e., presumed to have 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. The heterozygous parents of a child with biallelic pathogenic variants in If both parents are known to be heterozygous for a A sib who is heterozygous for one of the pathogenic variants identified in the proband may be at risk for DCM. It is appropriate to clarify the clinical and genetic status of asymptomatic family members at risk for DCM prior to the onset of manifestations to identify those with asymptomatic DCM and permit initiation of medical therapy aimed at preventing/delaying the morbidity of late-stage symptomatic disease [ The following recommendations for surveillance of asymptomatic at-risk family members reflect the practice guidelines of the Heart Failure Society of America [ See Those identified as having a familial DCM-related pathogenic variant have an increased lifetime risk for DCM and, when asymptomatic, should undergo cardiovascular clinical screening at intervals based on the individual's age [ Note: Asymptomatic at-risk relatives who do not meet criteria for DCM (with other causes ruled out) may represent early DCM when echocardiogram results are ambiguous (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle) and/or echocardiogram results are normal but EKG results are abnormal (e.g., significant conduction system disease and/or arrhythmias). In general, family members without the DCM-related pathogenic variant identified in the proband are no longer considered to be at increased risk for DCM and thus may be discharged from cardiac surveillance. However, because multiple variants in DCM-associated genes have been observed in individuals with nonsyndromic DCM [ See Note: Asymptomatic at-risk relatives who do not meet criteria for DCM (with other causes ruled out) may represent early DCM when echocardiogram results are ambiguous (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle) and/or echocardiogram results are normal but EKG results are abnormal (e.g., significant conduction system disease and/or arrhythmias). If a first-degree at-risk relative shows evidence of dilated cardiomyopathy, a diagnosis of familial DCM is made and the surveillance recommendations should extend to that person's first-degree relatives. Future additional genetic testing for the proband (and other informative family members) may be considered when: Multigene panels are expanded to include more genes and test sensitivity increases (e.g., resulting from better coverage of the genes included and improved detection of deletions/duplications); and Genomic testing (exome sequencing and genome sequencing) becomes more suitable for clinical use. • Some individuals diagnosed as having autosomal dominant DCM have an affected parent. • Some individuals diagnosed with autosomal dominant DCM have the disorder as the result of a • When evaluating for autosomal dominant inheritance, both the maternal and paternal lineages should be considered as possibly contributing to familial DCM. In an unknown proportion of cases, both parents may have evidence of DCM and/or DCM-related pathogenic variants, and thus the proband may have inherited pathogenic variants from one or both parents [ • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. • 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 affected and/or has a DCM-related pathogenic or likely pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease. • If both parents of a proband have a DCM-related pathogenic or likely pathogenic variant, sibs have a 75% chance of inheriting one or two DCM-related variants and a 25% chance of inheriting neither pathogenic variant. • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DCM because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to have 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. • The heterozygous parents of a child with biallelic pathogenic variants in • 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 • A sib who is heterozygous for one of the pathogenic variants identified in the proband may be at risk for DCM. • Multigene panels are expanded to include more genes and test sensitivity increases (e.g., resulting from better coverage of the genes included and improved detection of deletions/duplications); and • Genomic testing (exome sequencing and genome sequencing) becomes more suitable for clinical use. ## Genetic Risk Assessment Nonsyndromic dilated cardiomyopathy (DCM) is typically inherited in an autosomal dominant manner. Some individuals diagnosed as having autosomal dominant DCM have an affected parent. Some individuals diagnosed with autosomal dominant DCM have the disorder as the result of a When evaluating for autosomal dominant inheritance, both the maternal and paternal lineages should be considered as possibly contributing to familial DCM. In an unknown proportion of cases, both parents may have evidence of DCM and/or DCM-related pathogenic variants, and thus the proband may have inherited pathogenic variants from one or both parents [ Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. 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 affected and/or has a DCM-related pathogenic or likely pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease. If both parents of a proband have a DCM-related pathogenic or likely pathogenic variant, sibs have a 75% chance of inheriting one or two DCM-related variants and a 25% chance of inheriting neither pathogenic variant. If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DCM because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. The parents of an affected individual are obligate heterozygotes (i.e., presumed to have 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. The heterozygous parents of a child with biallelic pathogenic variants in If both parents are known to be heterozygous for a A sib who is heterozygous for one of the pathogenic variants identified in the proband may be at risk for DCM. • Some individuals diagnosed as having autosomal dominant DCM have an affected parent. • Some individuals diagnosed with autosomal dominant DCM have the disorder as the result of a • When evaluating for autosomal dominant inheritance, both the maternal and paternal lineages should be considered as possibly contributing to familial DCM. In an unknown proportion of cases, both parents may have evidence of DCM and/or DCM-related pathogenic variants, and thus the proband may have inherited pathogenic variants from one or both parents [ • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. • 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 affected and/or has a DCM-related pathogenic or likely pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease. • If both parents of a proband have a DCM-related pathogenic or likely pathogenic variant, sibs have a 75% chance of inheriting one or two DCM-related variants and a 25% chance of inheriting neither pathogenic variant. • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DCM because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to have 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. • The heterozygous parents of a child with biallelic pathogenic variants in • 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 • A sib who is heterozygous for one of the pathogenic variants identified in the proband may be at risk for DCM. ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed as having autosomal dominant DCM have an affected parent. Some individuals diagnosed with autosomal dominant DCM have the disorder as the result of a When evaluating for autosomal dominant inheritance, both the maternal and paternal lineages should be considered as possibly contributing to familial DCM. In an unknown proportion of cases, both parents may have evidence of DCM and/or DCM-related pathogenic variants, and thus the proband may have inherited pathogenic variants from one or both parents [ Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. 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 affected and/or has a DCM-related pathogenic or likely pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease. If both parents of a proband have a DCM-related pathogenic or likely pathogenic variant, sibs have a 75% chance of inheriting one or two DCM-related variants and a 25% chance of inheriting neither pathogenic variant. If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DCM because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • Some individuals diagnosed as having autosomal dominant DCM have an affected parent. • Some individuals diagnosed with autosomal dominant DCM have the disorder as the result of a • When evaluating for autosomal dominant inheritance, both the maternal and paternal lineages should be considered as possibly contributing to familial DCM. In an unknown proportion of cases, both parents may have evidence of DCM and/or DCM-related pathogenic variants, and thus the proband may have inherited pathogenic variants from one or both parents [ • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status. • 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 affected and/or has a DCM-related pathogenic or likely pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of variable expression and reduced penetrance, no predictions can be made regarding age of onset or severity of disease. • If both parents of a proband have a DCM-related pathogenic or likely pathogenic variant, sibs have a 75% chance of inheriting one or two DCM-related variants and a 25% chance of inheriting neither pathogenic variant. • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DCM because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to have 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. The heterozygous parents of a child with biallelic pathogenic variants in If both parents are known to be heterozygous for a A sib who is heterozygous for one of the pathogenic variants identified in the proband may be at risk for DCM. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to have 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. • The heterozygous parents of a child with biallelic pathogenic variants in • 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 • A sib who is heterozygous for one of the pathogenic variants identified in the proband may be at risk for DCM. ## Cardiac Surveillance It is appropriate to clarify the clinical and genetic status of asymptomatic family members at risk for DCM prior to the onset of manifestations to identify those with asymptomatic DCM and permit initiation of medical therapy aimed at preventing/delaying the morbidity of late-stage symptomatic disease [ The following recommendations for surveillance of asymptomatic at-risk family members reflect the practice guidelines of the Heart Failure Society of America [ See Those identified as having a familial DCM-related pathogenic variant have an increased lifetime risk for DCM and, when asymptomatic, should undergo cardiovascular clinical screening at intervals based on the individual's age [ Note: Asymptomatic at-risk relatives who do not meet criteria for DCM (with other causes ruled out) may represent early DCM when echocardiogram results are ambiguous (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle) and/or echocardiogram results are normal but EKG results are abnormal (e.g., significant conduction system disease and/or arrhythmias). In general, family members without the DCM-related pathogenic variant identified in the proband are no longer considered to be at increased risk for DCM and thus may be discharged from cardiac surveillance. However, because multiple variants in DCM-associated genes have been observed in individuals with nonsyndromic DCM [ See Note: Asymptomatic at-risk relatives who do not meet criteria for DCM (with other causes ruled out) may represent early DCM when echocardiogram results are ambiguous (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle) and/or echocardiogram results are normal but EKG results are abnormal (e.g., significant conduction system disease and/or arrhythmias). If a first-degree at-risk relative shows evidence of dilated cardiomyopathy, a diagnosis of familial DCM is made and the surveillance recommendations should extend to that person's first-degree relatives. Future additional genetic testing for the proband (and other informative family members) may be considered when: Multigene panels are expanded to include more genes and test sensitivity increases (e.g., resulting from better coverage of the genes included and improved detection of deletions/duplications); and Genomic testing (exome sequencing and genome sequencing) becomes more suitable for clinical use. • Multigene panels are expanded to include more genes and test sensitivity increases (e.g., resulting from better coverage of the genes included and improved detection of deletions/duplications); and • Genomic testing (exome sequencing and genome sequencing) becomes more suitable for clinical use. ## If the Proband Has a Known Pathogenic Variant (or Pathogenic Variants) in a DCM-Related Gene See Those identified as having a familial DCM-related pathogenic variant have an increased lifetime risk for DCM and, when asymptomatic, should undergo cardiovascular clinical screening at intervals based on the individual's age [ Note: Asymptomatic at-risk relatives who do not meet criteria for DCM (with other causes ruled out) may represent early DCM when echocardiogram results are ambiguous (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle) and/or echocardiogram results are normal but EKG results are abnormal (e.g., significant conduction system disease and/or arrhythmias). In general, family members without the DCM-related pathogenic variant identified in the proband are no longer considered to be at increased risk for DCM and thus may be discharged from cardiac surveillance. However, because multiple variants in DCM-associated genes have been observed in individuals with nonsyndromic DCM [ ## If the Specific Genetic Cause of DCM in the Proband Has Not Been Identified See Note: Asymptomatic at-risk relatives who do not meet criteria for DCM (with other causes ruled out) may represent early DCM when echocardiogram results are ambiguous (e.g., left ventricular enlargement with normal systolic function, decreased ejection fraction but normal-sized left ventricle) and/or echocardiogram results are normal but EKG results are abnormal (e.g., significant conduction system disease and/or arrhythmias). If a first-degree at-risk relative shows evidence of dilated cardiomyopathy, a diagnosis of familial DCM is made and the surveillance recommendations should extend to that person's first-degree relatives. Future additional genetic testing for the proband (and other informative family members) may be considered when: Multigene panels are expanded to include more genes and test sensitivity increases (e.g., resulting from better coverage of the genes included and improved detection of deletions/duplications); and Genomic testing (exome sequencing and genome sequencing) becomes more suitable for clinical use. • Multigene panels are expanded to include more genes and test sensitivity increases (e.g., resulting from better coverage of the genes included and improved detection of deletions/duplications); and • Genomic testing (exome sequencing and genome sequencing) becomes more suitable for clinical use. ## Resources United Kingdom • • • • United Kingdom • • • • • • • • • ## Chapter Notes Web: The Dilated Cardiomyopathy Research Project, originally launched in 1993 by Dr Ray Hershberger while at the Oregon Health & Science University, aims to advance our understanding of dilated cardiomyopathy genetics. Multiple studies including data from more than 1500 families affected by DCM across the country have contributed genetic and clinical information to this research program. This multi-institutional effort, still led by Dr Hershberger and now housed at The Ohio State University, leverages the many sites collaborating in the DCM Consortium to identify families eligible for studies within the DCM Research Project, including the recently completed DCM Precision Medicine Study and the ongoing DCM Discovery Study. More information about the DCM Project, affiliated research studies, and other information and resources can be found on the website ( We are deeply grateful for the numerous families who have contributed to the research efforts in the DCM Research Project for nearly three decades. Without their gracious participation and engagement, the advances driven by the work of the DCM Research Project to the field would not be possible. Ray E Hershberger, MD (2007-present)Elizabeth Jordan, MS, LGC (2021-present)Jessica D Kushner, MS, CGC; Oregon Health & Science University (2007-2013)Ana Morales, MS, CGC; The Ohio State University (2013-2021)Sharie Parks, PhD; Oregon Health & Science University (2007-2013) 12 December 2024 (sw) Revision: add 7 April 2022 (aa) Revision: cardiac surveillance recommendations ( 29 July 2021 (ha) Comprehensive update posted live 23 August 2018 (bp) Comprehensive update posted live 24 September 2015 (me) Comprehensive update posted live 9 May 2013 (me) Comprehensive update posted live 27 July 2007 (me) Review posted live 6 December 2006 (jdk) Original submission • 12 December 2024 (sw) Revision: add • 7 April 2022 (aa) Revision: cardiac surveillance recommendations ( • 29 July 2021 (ha) Comprehensive update posted live • 23 August 2018 (bp) Comprehensive update posted live • 24 September 2015 (me) Comprehensive update posted live • 9 May 2013 (me) Comprehensive update posted live • 27 July 2007 (me) Review posted live • 6 December 2006 (jdk) Original submission ## Author Notes Web: The Dilated Cardiomyopathy Research Project, originally launched in 1993 by Dr Ray Hershberger while at the Oregon Health & Science University, aims to advance our understanding of dilated cardiomyopathy genetics. Multiple studies including data from more than 1500 families affected by DCM across the country have contributed genetic and clinical information to this research program. This multi-institutional effort, still led by Dr Hershberger and now housed at The Ohio State University, leverages the many sites collaborating in the DCM Consortium to identify families eligible for studies within the DCM Research Project, including the recently completed DCM Precision Medicine Study and the ongoing DCM Discovery Study. More information about the DCM Project, affiliated research studies, and other information and resources can be found on the website ( ## Acknowledgments We are deeply grateful for the numerous families who have contributed to the research efforts in the DCM Research Project for nearly three decades. Without their gracious participation and engagement, the advances driven by the work of the DCM Research Project to the field would not be possible. ## Author History Ray E Hershberger, MD (2007-present)Elizabeth Jordan, MS, LGC (2021-present)Jessica D Kushner, MS, CGC; Oregon Health & Science University (2007-2013)Ana Morales, MS, CGC; The Ohio State University (2013-2021)Sharie Parks, PhD; Oregon Health & Science University (2007-2013) ## Revision History 12 December 2024 (sw) Revision: add 7 April 2022 (aa) Revision: cardiac surveillance recommendations ( 29 July 2021 (ha) Comprehensive update posted live 23 August 2018 (bp) Comprehensive update posted live 24 September 2015 (me) Comprehensive update posted live 9 May 2013 (me) Comprehensive update posted live 27 July 2007 (me) Review posted live 6 December 2006 (jdk) Original submission • 12 December 2024 (sw) Revision: add • 7 April 2022 (aa) Revision: cardiac surveillance recommendations ( • 29 July 2021 (ha) Comprehensive update posted live • 23 August 2018 (bp) Comprehensive update posted live • 24 September 2015 (me) Comprehensive update posted live • 9 May 2013 (me) Comprehensive update posted live • 27 July 2007 (me) Review posted live • 6 December 2006 (jdk) Original submission ## References Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:899-909. [ • Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:899-909. [ ## Published Guidelines / Consensus Statements Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:899-909. [ • Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM, et al. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2018;20:899-909. [ ## Literature Cited Categories of dilated cardiomyopathy
[]
27/7/2007
29/7/2021
12/12/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dcx
dcx
[ "DCX-Related Classic Lissencephaly", "DCX-Related Subcortical Band Heterotopia (SBH)", "Neuronal migration protein doublecortin", "DCX", "DCX-Related Disorders" ]
Tobias Geis, Gökhan Uyanik, Ludwig Aigner, Sebastien Couillard-Despres, Jürgen Winkler, Ute Hehr
Summary The diagnosis of a
Classic lissencephaly Subcortical band heterotopia (SBH) For synonyms and outdated names see For other genetic causes of these phenotypes, see • Classic lissencephaly • Subcortical band heterotopia (SBH) ## Diagnosis For the purposes of this Classic thick lissencephaly, primarily in males Subcortical band heterotopia (SBH), primarily in females Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient) May be accompanied by: Diffuse thick or thin cortex, or partial SBH Prominent perivascular (Virchow-Robin) spaces Delayed or abnormal myelination or mild-to-moderate reduced white matter Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles Normal or diffusely thin corpus callosum No obvious cerebellar or brain stem abnormalities Enlarged caudate head Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration Findings may include: Intellectual disability or developmental delays Speech and language impairment Behavioral issues Epilepsy Microcephaly Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission; affected males related through asymptomatic or less severely affected females). Special attention should be paid to epilepsy, miscarriages, stillbirths, children who died at a young age without a conclusive diagnosis, cognitive impairment, and/or developmental delay. Absence of a known family history does not preclude the diagnosis. Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain MRI findings described in When the phenotypic and neuroimaging findings suggest the diagnosis of a For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click Due to phenotypic overlap with other inherited neuronal migration disorders, For an introduction to comprehensive genomic testing click Note: If no germline pathogenic variant is found in The depth of sequencing and sample type may determine the yield of molecular diagnostic testing using the above approaches. Analysis of DNA from different tissues (e.g., buccal swabs, skin fibroblasts, hair roots), preferably using exome or genome sequencing, can be useful in the detection or confirmation of mosaicism (see Molecular Genetic Testing Used in See See Sequence analysis detects likely pathogenic or pathogenic variants in about 96% of individuals with characteristic neuroimaging findings. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, 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. • Classic thick lissencephaly, primarily in males • Subcortical band heterotopia (SBH), primarily in females • Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see • More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient) • May be accompanied by: • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see • May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration • Intellectual disability or developmental delays • Speech and language impairment • Behavioral issues • Epilepsy • Microcephaly • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Suggestive Findings Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient) May be accompanied by: Diffuse thick or thin cortex, or partial SBH Prominent perivascular (Virchow-Robin) spaces Delayed or abnormal myelination or mild-to-moderate reduced white matter Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles Normal or diffusely thin corpus callosum No obvious cerebellar or brain stem abnormalities Enlarged caudate head Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration Findings may include: Intellectual disability or developmental delays Speech and language impairment Behavioral issues Epilepsy Microcephaly Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission; affected males related through asymptomatic or less severely affected females). Special attention should be paid to epilepsy, miscarriages, stillbirths, children who died at a young age without a conclusive diagnosis, cognitive impairment, and/or developmental delay. Absence of a known family history does not preclude the diagnosis. • Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see • More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient) • May be accompanied by: • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see • May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration • Intellectual disability or developmental delays • Speech and language impairment • Behavioral issues • Epilepsy • Microcephaly ## Neuroimaging Findings Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient) May be accompanied by: Diffuse thick or thin cortex, or partial SBH Prominent perivascular (Virchow-Robin) spaces Delayed or abnormal myelination or mild-to-moderate reduced white matter Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles Normal or diffusely thin corpus callosum No obvious cerebellar or brain stem abnormalities Enlarged caudate head Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration • Typically characterized by agyria (sulci >30 mm apart) or pachygyria (abnormally wide gyri with sulci 15-30 mm apart) with thickened cortex of ~10-20 mm (normal: ~4 mm) (see • More severe anteriorly (referred to as lissencephaly with an anterior-to-posterior (A>P) gradient) • May be accompanied by: • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Diffuse thick or thin cortex, or partial SBH • Prominent perivascular (Virchow-Robin) spaces • Delayed or abnormal myelination or mild-to-moderate reduced white matter • Enlarged ventricles particularly affecting the anterior horns of the lateral ventricles • Normal or diffusely thin corpus callosum • No obvious cerebellar or brain stem abnormalities • Enlarged caudate head • Symmetric, usually bilateral bands of gray matter within the white matter between and parallel to the cortex and the lateral ventricles appearing as an isointense second cortical structure beneath the cortex (double cortex) and separated from the cortex by a thin layer of normal-appearing white matter. The heterotopic band is more often thick than thin (1-7 mm) (~70%) (see • May be accompanied by normal-appearing and/or anteriorly predominant thickened cerebral cortex with or without simplified gyration ## Clinical Findings Findings may include: Intellectual disability or developmental delays Speech and language impairment Behavioral issues Epilepsy Microcephaly • Intellectual disability or developmental delays • Speech and language impairment • Behavioral issues • Epilepsy • Microcephaly ## Family History Family history is consistent with X-linked inheritance (e.g., no male-to-male transmission; affected males related through asymptomatic or less severely affected females). Special attention should be paid to epilepsy, miscarriages, stillbirths, children who died at a young age without a conclusive diagnosis, cognitive impairment, and/or developmental delay. Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain MRI findings described in When the phenotypic and neuroimaging findings suggest the diagnosis of a For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click Due to phenotypic overlap with other inherited neuronal migration disorders, For an introduction to comprehensive genomic testing click Note: If no germline pathogenic variant is found in The depth of sequencing and sample type may determine the yield of molecular diagnostic testing using the above approaches. Analysis of DNA from different tissues (e.g., buccal swabs, skin fibroblasts, hair roots), preferably using exome or genome sequencing, can be useful in the detection or confirmation of mosaicism (see Molecular Genetic Testing Used in See See Sequence analysis detects likely pathogenic or pathogenic variants in about 96% of individuals with characteristic neuroimaging findings. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, 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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and neuroimaging findings suggest the diagnosis of a For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 2 Due to phenotypic overlap with other inherited neuronal migration disorders, For an introduction to comprehensive genomic testing click Note: If no germline pathogenic variant is found in The depth of sequencing and sample type may determine the yield of molecular diagnostic testing using the above approaches. Analysis of DNA from different tissues (e.g., buccal swabs, skin fibroblasts, hair roots), preferably using exome or genome sequencing, can be useful in the detection or confirmation of mosaicism (see Molecular Genetic Testing Used in See See Sequence analysis detects likely pathogenic or pathogenic variants in about 96% of individuals with characteristic neuroimaging findings. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, 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 To date, more than 300 individuals have been identified with a pathogenic variant in Select Features of NA = not applicable; OFC = orbitofrontal cortex; SD = standard deviation Median age at examination was 7.5 years for 33 individuals reported by Leger et al 2008 (range: 1.5-37 years); age range for 43 individuals reported by Heterozygous females may be identified through either molecular genetic testing for a familial pathogenic variant or during a diagnostic workup of clinical features; estimated frequencies of clinical features in both groups are provided here and include asymptomatic heterozygous females. Age range for 78 females with A group of 62 females with Males with a hemizygous Neuropathologically, Motor development is delayed but overall better than in individuals with At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment. All affected individuals had significant cognitive and language impairment. Almost half of the individuals in the study did not develop any speech. Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%. Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis. More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [ Rarely, males may have milder cerebral manifestations of SBH similar to those in females [ Most heterozygous females typically develop some clinical manifestations. The most common cortical malformation is SBH and variable anterior-predominant pachygyria. The phenotype of heterozygous females is usually milder than the classic lissencephaly phenotype in males. It is very variable between and to a lesser extend even within families and roughly correlates with the extent and thickness of the subcortical band as observed on brain imaging. Severe phenotypes associated with thicker SBH typically include the following: Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years). Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen. Truncal hypotonia or spasticity (about 29%) Microcephaly (16%) Hyperkinetic movements (less frequent than other features) Additional findings observed on brain imaging of female Thin or dysmorphic corpus callosum; Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia; Dilatation of the fourth ventricle. Notable clinical variability has also been reported between female relatives of the same family; in one family with a heterozygous Average or mildly impaired cognitive skills [ No additional symptoms Recognition only after prenatal or postnatal diagnosis of a In the cohort reported by About one third of all A slight effect of the type and location of the To date, males with lissencephaly resulting from a constitutional hemizygous Hemizygous Loss-of-function variants are more likely to occur in simplex cases (i.e., a single occurrence in a family); missense variants are more likely to be observed in familial cases [ Hemizygous Truncating variants are more frequently associated with generalized subcortical bands; missense variants are more commonly associated with frontal band heterotopia only [ Hot spot variants, observed multiple times, account for more than one third of identified sequence variants; these include p.Arg39Ter, p.Arg303Ter, p.Arg78Cys, p.Arg78His, p.Arg78Leu, p.Arg192Trp, p.Arg186Cys, p.Arg186His, and p.Arg186Leu [ Asymptomatic heterozygous females more frequently have missense pathogenic variants at the hot spot position p.Arg196. Penetrance was reported to be less than 50% in mothers with a heterozygous or mosaic pathogenic variant in Classic thick lissencephaly has been called lissencephaly type 1 in older publications. In the absence of associated intra- or extracranial malformations it is also termed isolated lissencephaly sequence. Classic thick lissencephaly that occurs in combination with cerebellar hypoplasia is classified as lissencephaly with cerebellar hypoplasia. Classic thick lissencephaly is morphologically and etiologically distinct from lissencephaly type 2, which is also called cobblestone lissencephaly, and from thin lissencephaly. To emphasize X-linked inheritance, X-linked lissencephaly (XLIS) or lissencephaly, X-linked (LISX); Isolated lissencephaly, X-linked (ILSX); Subcortical laminar heterotopia, X-linked (X-SCLH); Subcortical band heterotopia, X-linked (SBHX). The incidence of all forms of lissencephaly has been estimated at 1-4:100,000 births [ Virtually all families with X-linked inheritance of classic lissencephaly and/or SBH; About 10% of all persons with classic thick lissencephaly (38% of all males, but only rarely females); About 53%-85% of all SBH, up to 88% of simplex SBH, and about 29% of SBH in males [ • At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment. • All affected individuals had significant cognitive and language impairment. • Almost half of the individuals in the study did not develop any speech. • Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%. • Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis. • More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. • Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [ • Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years). • Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands • Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands • Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen. • Truncal hypotonia or spasticity (about 29%) • Microcephaly (16%) • Hyperkinetic movements (less frequent than other features) • Thin or dysmorphic corpus callosum; • Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia; • Dilatation of the fourth ventricle. • Average or mildly impaired cognitive skills [ • No additional symptoms • Recognition only after prenatal or postnatal diagnosis of a • To date, males with lissencephaly resulting from a constitutional hemizygous • Hemizygous • Loss-of-function variants are more likely to occur in simplex cases (i.e., a single occurrence in a family); missense variants are more likely to be observed in familial cases [ • Hemizygous • Truncating variants are more frequently associated with generalized subcortical bands; missense variants are more commonly associated with frontal band heterotopia only [ • Hot spot variants, observed multiple times, account for more than one third of identified sequence variants; these include p.Arg39Ter, p.Arg303Ter, p.Arg78Cys, p.Arg78His, p.Arg78Leu, p.Arg192Trp, p.Arg186Cys, p.Arg186His, and p.Arg186Leu [ • Asymptomatic heterozygous females more frequently have missense pathogenic variants at the hot spot position p.Arg196. • X-linked lissencephaly (XLIS) or lissencephaly, X-linked (LISX); • Isolated lissencephaly, X-linked (ILSX); • Subcortical laminar heterotopia, X-linked (X-SCLH); • Subcortical band heterotopia, X-linked (SBHX). • Virtually all families with X-linked inheritance of classic lissencephaly and/or SBH; • About 10% of all persons with classic thick lissencephaly (38% of all males, but only rarely females); • About 53%-85% of all SBH, up to 88% of simplex SBH, and about 29% of SBH in males [ ## Clinical Description To date, more than 300 individuals have been identified with a pathogenic variant in Select Features of NA = not applicable; OFC = orbitofrontal cortex; SD = standard deviation Median age at examination was 7.5 years for 33 individuals reported by Leger et al 2008 (range: 1.5-37 years); age range for 43 individuals reported by Heterozygous females may be identified through either molecular genetic testing for a familial pathogenic variant or during a diagnostic workup of clinical features; estimated frequencies of clinical features in both groups are provided here and include asymptomatic heterozygous females. Age range for 78 females with A group of 62 females with Males with a hemizygous Neuropathologically, Motor development is delayed but overall better than in individuals with At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment. All affected individuals had significant cognitive and language impairment. Almost half of the individuals in the study did not develop any speech. Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%. Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis. More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [ Rarely, males may have milder cerebral manifestations of SBH similar to those in females [ Most heterozygous females typically develop some clinical manifestations. The most common cortical malformation is SBH and variable anterior-predominant pachygyria. The phenotype of heterozygous females is usually milder than the classic lissencephaly phenotype in males. It is very variable between and to a lesser extend even within families and roughly correlates with the extent and thickness of the subcortical band as observed on brain imaging. Severe phenotypes associated with thicker SBH typically include the following: Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years). Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen. Truncal hypotonia or spasticity (about 29%) Microcephaly (16%) Hyperkinetic movements (less frequent than other features) Additional findings observed on brain imaging of female Thin or dysmorphic corpus callosum; Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia; Dilatation of the fourth ventricle. Notable clinical variability has also been reported between female relatives of the same family; in one family with a heterozygous Average or mildly impaired cognitive skills [ No additional symptoms Recognition only after prenatal or postnatal diagnosis of a In the cohort reported by • At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment. • All affected individuals had significant cognitive and language impairment. • Almost half of the individuals in the study did not develop any speech. • Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%. • Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis. • More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. • Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [ • Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years). • Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands • Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands • Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen. • Truncal hypotonia or spasticity (about 29%) • Microcephaly (16%) • Hyperkinetic movements (less frequent than other features) • Thin or dysmorphic corpus callosum; • Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia; • Dilatation of the fourth ventricle. • Average or mildly impaired cognitive skills [ • No additional symptoms • Recognition only after prenatal or postnatal diagnosis of a ## Affected Males Males with a hemizygous Neuropathologically, Motor development is delayed but overall better than in individuals with At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment. All affected individuals had significant cognitive and language impairment. Almost half of the individuals in the study did not develop any speech. Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%. Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis. More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [ Rarely, males may have milder cerebral manifestations of SBH similar to those in females [ • At a median age of 7.5 years (range: 1.5-37 years) almost half were reported to walk independently; the remaining individuals showed moderate-to-severe motor impairment. • All affected individuals had significant cognitive and language impairment. • Almost half of the individuals in the study did not develop any speech. • Moderate behavioral disturbances including autistic features, sleep disorders, or agitation were reported in 30% of individuals, and extreme irritability in 12%. • Abnormal muscle tone with motor delays including limited mobility may result in contractures and scoliosis. • More severe clinical manifestations may also affect feeding and swallowing, thus resulting in insufficient nutrition or aspiration. • Head growth rate may decline postnatally and result in postnatal microcephaly in about 20% of affected individuals [ ## Heterozygous Females Most heterozygous females typically develop some clinical manifestations. The most common cortical malformation is SBH and variable anterior-predominant pachygyria. The phenotype of heterozygous females is usually milder than the classic lissencephaly phenotype in males. It is very variable between and to a lesser extend even within families and roughly correlates with the extent and thickness of the subcortical band as observed on brain imaging. Severe phenotypes associated with thicker SBH typically include the following: Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years). Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen. Truncal hypotonia or spasticity (about 29%) Microcephaly (16%) Hyperkinetic movements (less frequent than other features) Additional findings observed on brain imaging of female Thin or dysmorphic corpus callosum; Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia; Dilatation of the fourth ventricle. Notable clinical variability has also been reported between female relatives of the same family; in one family with a heterozygous Average or mildly impaired cognitive skills [ No additional symptoms Recognition only after prenatal or postnatal diagnosis of a In the cohort reported by • Seizures, which eventually occur in more than 80% of affected individuals during childhood. They may include focal seizures, atypical absences, combined atonic and tonic seizures, and epileptic spasms and frequently are difficult to treat. Lennox-Gastaut syndrome seems to be independent of SBH thickness and has been reported in about 55% of females with thick bands and about 50% of those with thin bands. However, median age at first seizure appears to be earlier in the presence of a thick band (2.2 years) compared to those with thin bands (10 years). • Developmental delay and moderate-to-severe intellectual disability in almost all heterozygous female probands • Severe language impairment and use, poor verbal skills, or absent speech in 84% of females with SBH with thick bands • Moderate-to-severe behavioral problems (about 60% overall and about 78% of females with thick bands); less frequently, autistic features or perseveration, stereotypic behavior, or automutilation are seen. • Truncal hypotonia or spasticity (about 29%) • Microcephaly (16%) • Hyperkinetic movements (less frequent than other features) • Thin or dysmorphic corpus callosum; • Variable cerebellar abnormalities including mild cerebellar vermis hypoplasia; • Dilatation of the fourth ventricle. • Average or mildly impaired cognitive skills [ • No additional symptoms • Recognition only after prenatal or postnatal diagnosis of a ## Genotype-Phenotype Correlations About one third of all A slight effect of the type and location of the To date, males with lissencephaly resulting from a constitutional hemizygous Hemizygous Loss-of-function variants are more likely to occur in simplex cases (i.e., a single occurrence in a family); missense variants are more likely to be observed in familial cases [ Hemizygous Truncating variants are more frequently associated with generalized subcortical bands; missense variants are more commonly associated with frontal band heterotopia only [ Hot spot variants, observed multiple times, account for more than one third of identified sequence variants; these include p.Arg39Ter, p.Arg303Ter, p.Arg78Cys, p.Arg78His, p.Arg78Leu, p.Arg192Trp, p.Arg186Cys, p.Arg186His, and p.Arg186Leu [ Asymptomatic heterozygous females more frequently have missense pathogenic variants at the hot spot position p.Arg196. • To date, males with lissencephaly resulting from a constitutional hemizygous • Hemizygous • Loss-of-function variants are more likely to occur in simplex cases (i.e., a single occurrence in a family); missense variants are more likely to be observed in familial cases [ • Hemizygous • Truncating variants are more frequently associated with generalized subcortical bands; missense variants are more commonly associated with frontal band heterotopia only [ • Hot spot variants, observed multiple times, account for more than one third of identified sequence variants; these include p.Arg39Ter, p.Arg303Ter, p.Arg78Cys, p.Arg78His, p.Arg78Leu, p.Arg192Trp, p.Arg186Cys, p.Arg186His, and p.Arg186Leu [ • Asymptomatic heterozygous females more frequently have missense pathogenic variants at the hot spot position p.Arg196. ## Penetrance Penetrance was reported to be less than 50% in mothers with a heterozygous or mosaic pathogenic variant in ## Nomenclature Classic thick lissencephaly has been called lissencephaly type 1 in older publications. In the absence of associated intra- or extracranial malformations it is also termed isolated lissencephaly sequence. Classic thick lissencephaly that occurs in combination with cerebellar hypoplasia is classified as lissencephaly with cerebellar hypoplasia. Classic thick lissencephaly is morphologically and etiologically distinct from lissencephaly type 2, which is also called cobblestone lissencephaly, and from thin lissencephaly. To emphasize X-linked inheritance, X-linked lissencephaly (XLIS) or lissencephaly, X-linked (LISX); Isolated lissencephaly, X-linked (ILSX); Subcortical laminar heterotopia, X-linked (X-SCLH); Subcortical band heterotopia, X-linked (SBHX). • X-linked lissencephaly (XLIS) or lissencephaly, X-linked (LISX); • Isolated lissencephaly, X-linked (ILSX); • Subcortical laminar heterotopia, X-linked (X-SCLH); • Subcortical band heterotopia, X-linked (SBHX). ## Prevalence The incidence of all forms of lissencephaly has been estimated at 1-4:100,000 births [ Virtually all families with X-linked inheritance of classic lissencephaly and/or SBH; About 10% of all persons with classic thick lissencephaly (38% of all males, but only rarely females); About 53%-85% of all SBH, up to 88% of simplex SBH, and about 29% of SBH in males [ • Virtually all families with X-linked inheritance of classic lissencephaly and/or SBH; • About 10% of all persons with classic thick lissencephaly (38% of all males, but only rarely females); • About 53%-85% of all SBH, up to 88% of simplex SBH, and about 29% of SBH in males [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of interest in the differential diagnosis of Genes of Interest in the Differential Diagnosis of Wasting of shoulder girdle muscles, sensory impairment due to iris or retinal coloboma, &/or sensorineural deafness Agenesis of corpus callosum; brain stem & cerebellum appear normal Perinatal encephalopathy w/intractable seizures Ambiguous or underdeveloped genitalia Chronic diarrhea High lethality in 1st 3 mos of life Agyria, agenesis of corpus callosum, severe cerebellar & pontine hypoplasia, dilated subarachnoid spaces Dysmorphic facial features, lymphedema, arthrogryposis multiplex Early lethality Megalencephaly Thick or thin lissencephaly Normal cerebellum Usually posterior-predominant pachygyria Other brain malformations typically seen include polymicrogyria, nodular heterotopia, thin corpus callosum, & cerebellar & basal ganglia abnormalities Axonal neuropathy seen in some persons Typically assoc w/thick cortex w/pachygyria or agyria Other malformations can include SBH, thin corpus callosum, & dysmorphic basal ganglia Severe IUGR Arthrogryposis Microcephaly Microcephaly Simplified cortical gyral pattern Thin or absent corpus callosum Microhydranencephaly can be seen Most frequent cause of classic or thick lissencephaly Miller-Dieker syndrome, a contiguous gene deletion syndrome involving at least Assoc w/severe cerebellar hypoplasia Other features include lissencephaly &/or simplified cortical gyral pattern & ventriculomegaly Assoc w/several phenotypes incl microcephalic osteodysplastic primordial dwarfism type I/III, Roifman syndrome, & Lowry-Wood syndrome Brain imaging abnormalities include pachygyria, heterotopia, agenesis of corpus callosum, & cerebellar vermis hypoplasia Lissencephaly ranges from thickened cortex & agyria to thickened cortex & pachygyria Characteristic brain malformations include dysmorphic basal ganglia; dysplasia of superior cerebellum, esp vermis (w/"diagonal" folia, i.e., folia crossing midline at oblique angle); & brain stem hypoplasia, usually asymmetric w/midline ventral indentation & asymmetric inferior & middle cerebellar peduncles Hypoplasia of inferior portion of cerebellar vermis & hemispheres, simplified gyration of cerebral hemispheres, & small brain stem, esp pons Non-progressive congenital ataxia, predominantly truncal, results in delayed ambulation, ID, dysarthria, strabismus, & seizures ID = intellectual disability; IUGR = intrauterine growth restriction; SBH = subcortical band heterotopia Including perisylvian lissencephaly Other features include characteristic facial changes, other more variable malformations, and severe neurologic and developmental abnormalities. The facial changes consist of tall and prominent forehead, bitemporal narrowing, short nose with anteverted nares, protuberant vermilion of the upper lip with downturned corners of the mouth, and small jaw (see • Wasting of shoulder girdle muscles, sensory impairment due to iris or retinal coloboma, &/or sensorineural deafness • Agenesis of corpus callosum; brain stem & cerebellum appear normal • Perinatal encephalopathy w/intractable seizures • Ambiguous or underdeveloped genitalia • Chronic diarrhea • High lethality in 1st 3 mos of life • Agyria, agenesis of corpus callosum, severe cerebellar & pontine hypoplasia, dilated subarachnoid spaces • Dysmorphic facial features, lymphedema, arthrogryposis multiplex • Early lethality • Megalencephaly • Thick or thin lissencephaly • Normal cerebellum • Usually posterior-predominant pachygyria • Other brain malformations typically seen include polymicrogyria, nodular heterotopia, thin corpus callosum, & cerebellar & basal ganglia abnormalities • Axonal neuropathy seen in some persons • Typically assoc w/thick cortex w/pachygyria or agyria • Other malformations can include SBH, thin corpus callosum, & dysmorphic basal ganglia • Severe IUGR • Arthrogryposis • Microcephaly • Microcephaly • Simplified cortical gyral pattern • Thin or absent corpus callosum • Microhydranencephaly can be seen • Most frequent cause of classic or thick lissencephaly • Miller-Dieker syndrome, a contiguous gene deletion syndrome involving at least • Assoc w/severe cerebellar hypoplasia • Other features include lissencephaly &/or simplified cortical gyral pattern & ventriculomegaly • Assoc w/several phenotypes incl microcephalic osteodysplastic primordial dwarfism type I/III, Roifman syndrome, & Lowry-Wood syndrome • Brain imaging abnormalities include pachygyria, heterotopia, agenesis of corpus callosum, & cerebellar vermis hypoplasia • Lissencephaly ranges from thickened cortex & agyria to thickened cortex & pachygyria • Characteristic brain malformations include dysmorphic basal ganglia; dysplasia of superior cerebellum, esp vermis (w/"diagonal" folia, i.e., folia crossing midline at oblique angle); & brain stem hypoplasia, usually asymmetric w/midline ventral indentation & asymmetric inferior & middle cerebellar peduncles • Hypoplasia of inferior portion of cerebellar vermis & hemispheres, simplified gyration of cerebral hemispheres, & small brain stem, esp pons • Non-progressive congenital ataxia, predominantly truncal, results in delayed ambulation, ID, dysarthria, strabismus, & seizures ## Management No clinical practice guidelines for Note: The clinical spectrum observed in individuals with To establish the extent of disease and needs in an individual diagnosed with a At initial diagnosis & at least annually thereafter, esp for mgmt of epilepsy that should include an epilepsy specialist Prolonged video EEGs may be required to fully characterize epilepsy burden or spells of unclear clinical etiology To incl early brain imaging to characterize & assess brain malformation To include motor, adaptive, cognitive, & speech-language evals Evals for early intervention / special education Assess visual acuity, abnormal ocular movement, refractive errors, & strabismus. Assess cerebral visual impairment. To include eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (>30 min/meal), &/or aspiration risk. 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) Need for augmentative communication devices & strategies Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; MOI = mode of inheritance; OFC = orbitofrontal cortex; OT = occupational therapy; PT = physical therapy; PV = pathogenic variant; SLP = speech-language pathology Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for Regular lifelong neuropediatric and, later, neurologic evaluations at a center with expertise in the diagnosis and treatment of epilepsy is strongly recommended for any individual with a Education of parents/caregivers An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs Surgical resection of heterotopic brain tissue has been tried in a few persons w/SBH; overall, it was not effective in ↓ seizure activity & thus was not recommended. Deep brain stimulation has been suggested to improve the seizure disorder in persons w/SBH based on results in small cohorts. In a review of non-pharmacologic treatment options for persons w/SBH & drug-resistant epilepsy, an improvement in seizure severity was observed in 16/26. Interventions used included surgical measures such as corpus callosotomy, temporal lobectomy, & (less frequently) vagus nerve stimulation or thalamic deep brain stimulation. Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Vitamin D supplementation if indicated PT & OT incl stretching to support avoidance of contractures & falls Referral for orthopedic surveillance & correction PT helps maintain & promote mobility & prevent contractures. Special adaptive chairs/positioners or other measures may support sitting & mobility. OT may help improve fine motor skills & oral motor control. Orthopedic corrections may be indicated for scoliosis &/or large joint displacements. Consider need for positioning & mobility devices. 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 Referral to community or online family support ASD = autism spectrum disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SBH = subcortical band heterotopia 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 Limited data on ASM use for 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 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 Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features. Measurement of growth parameters Eval of nutritional status & safety of oral intake ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy To date avoidance of any medications or other agents has not been suggested for individuals with See For pregnant women with Counseling should include discussion of the teratogenic risks associated with the currently used anti-seizure medication (ASM). For some ASMS or a combination, a substantially increased risk for fetal malformations may prompt reconsideration of the dosage or drug combination. Pregnant women should, however, be encouraged to continue medical seizure control under close surveillance and be informed about the risks associated with discontinuation of treatment. Counseling should also cover the preferred mode of delivery based on the current neurologic findings as well as any recommended postnatal measures for the newborn related to fetal medication exposure and its postnatal drop. Whenever possible, women should discuss the current ASM or any recommended replacement of medication with higher teratogenic potential prior to any planned pregnancy. See Search • At initial diagnosis & at least annually thereafter, esp for mgmt of epilepsy that should include an epilepsy specialist • Prolonged video EEGs may be required to fully characterize epilepsy burden or spells of unclear clinical etiology • To incl early brain imaging to characterize & assess brain malformation • To include motor, adaptive, cognitive, & speech-language evals • Evals for early intervention / special education • Assess visual acuity, abnormal ocular movement, refractive errors, & strabismus. • Assess cerebral visual impairment. • To include eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (>30 min/meal), &/or aspiration risk. • 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) • Need for augmentative communication devices & strategies • Community or • Social work involvement for parental support • Home nursing referral • Education of parents/caregivers • An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs • Surgical resection of heterotopic brain tissue has been tried in a few persons w/SBH; overall, it was not effective in ↓ seizure activity & thus was not recommended. • Deep brain stimulation has been suggested to improve the seizure disorder in persons w/SBH based on results in small cohorts. • In a review of non-pharmacologic treatment options for persons w/SBH & drug-resistant epilepsy, an improvement in seizure severity was observed in 16/26. Interventions used included surgical measures such as corpus callosotomy, temporal lobectomy, & (less frequently) vagus nerve stimulation or thalamic deep brain stimulation. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Vitamin D supplementation if indicated • PT & OT incl stretching to support avoidance of contractures & falls • Referral for orthopedic surveillance & correction • PT helps maintain & promote mobility & prevent contractures. Special adaptive chairs/positioners or other measures may support sitting & mobility. • OT may help improve fine motor skills & oral motor control. • Orthopedic corrections may be indicated for scoliosis &/or large joint displacements. • Consider need for positioning & mobility devices. • 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 • Referral to community or online family 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. • Special education law requires that children participating in an 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 • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features. • 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 a At initial diagnosis & at least annually thereafter, esp for mgmt of epilepsy that should include an epilepsy specialist Prolonged video EEGs may be required to fully characterize epilepsy burden or spells of unclear clinical etiology To incl early brain imaging to characterize & assess brain malformation To include motor, adaptive, cognitive, & speech-language evals Evals for early intervention / special education Assess visual acuity, abnormal ocular movement, refractive errors, & strabismus. Assess cerebral visual impairment. To include eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (>30 min/meal), &/or aspiration risk. 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) Need for augmentative communication devices & strategies Community or Social work involvement for parental support Home nursing referral ADL = activities of daily living; MOI = mode of inheritance; OFC = orbitofrontal cortex; OT = occupational therapy; PT = physical therapy; PV = pathogenic variant; SLP = speech-language pathology Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • At initial diagnosis & at least annually thereafter, esp for mgmt of epilepsy that should include an epilepsy specialist • Prolonged video EEGs may be required to fully characterize epilepsy burden or spells of unclear clinical etiology • To incl early brain imaging to characterize & assess brain malformation • To include motor, adaptive, cognitive, & speech-language evals • Evals for early intervention / special education • Assess visual acuity, abnormal ocular movement, refractive errors, & strabismus. • Assess cerebral visual impairment. • To include eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia, poor weight gain, excessive feeding times (>30 min/meal), &/or aspiration risk. • 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) • Need for augmentative communication devices & strategies • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Regular lifelong neuropediatric and, later, neurologic evaluations at a center with expertise in the diagnosis and treatment of epilepsy is strongly recommended for any individual with a Education of parents/caregivers An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs Surgical resection of heterotopic brain tissue has been tried in a few persons w/SBH; overall, it was not effective in ↓ seizure activity & thus was not recommended. Deep brain stimulation has been suggested to improve the seizure disorder in persons w/SBH based on results in small cohorts. In a review of non-pharmacologic treatment options for persons w/SBH & drug-resistant epilepsy, an improvement in seizure severity was observed in 16/26. Interventions used included surgical measures such as corpus callosotomy, temporal lobectomy, & (less frequently) vagus nerve stimulation or thalamic deep brain stimulation. Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Vitamin D supplementation if indicated PT & OT incl stretching to support avoidance of contractures & falls Referral for orthopedic surveillance & correction PT helps maintain & promote mobility & prevent contractures. Special adaptive chairs/positioners or other measures may support sitting & mobility. OT may help improve fine motor skills & oral motor control. Orthopedic corrections may be indicated for scoliosis &/or large joint displacements. Consider need for positioning & mobility devices. 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 Referral to community or online family support ASD = autism spectrum disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SBH = subcortical band heterotopia 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 Limited data on ASM use for 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 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. • Education of parents/caregivers • An approach to seizure mgmt that balances seizure control w/side effects & attempts to limit number of ASMs • Surgical resection of heterotopic brain tissue has been tried in a few persons w/SBH; overall, it was not effective in ↓ seizure activity & thus was not recommended. • Deep brain stimulation has been suggested to improve the seizure disorder in persons w/SBH based on results in small cohorts. • In a review of non-pharmacologic treatment options for persons w/SBH & drug-resistant epilepsy, an improvement in seizure severity was observed in 16/26. Interventions used included surgical measures such as corpus callosotomy, temporal lobectomy, & (less frequently) vagus nerve stimulation or thalamic deep brain stimulation. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Vitamin D supplementation if indicated • PT & OT incl stretching to support avoidance of contractures & falls • Referral for orthopedic surveillance & correction • PT helps maintain & promote mobility & prevent contractures. Special adaptive chairs/positioners or other measures may support sitting & mobility. • OT may help improve fine motor skills & oral motor control. • Orthopedic corrections may be indicated for scoliosis &/or large joint displacements. • Consider need for positioning & mobility devices. • 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 • Referral to community or online family 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. • Special education law requires that children participating in an 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 ## 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 Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features. Measurement of growth parameters Eval of nutritional status & safety of oral intake ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures &/or response to ASMs, tone abnormalities, & other neurologic features. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Agents/Circumstances to Avoid To date avoidance of any medications or other agents has not been suggested for individuals with ## Evaluation of Relatives at Risk See ## Pregnancy Management For pregnant women with Counseling should include discussion of the teratogenic risks associated with the currently used anti-seizure medication (ASM). For some ASMS or a combination, a substantially increased risk for fetal malformations may prompt reconsideration of the dosage or drug combination. Pregnant women should, however, be encouraged to continue medical seizure control under close surveillance and be informed about the risks associated with discontinuation of treatment. Counseling should also cover the preferred mode of delivery based on the current neurologic findings as well as any recommended postnatal measures for the newborn related to fetal medication exposure and its postnatal drop. Whenever possible, women should discuss the current ASM or any recommended replacement of medication with higher teratogenic potential prior to any planned pregnancy. See ## Therapies Under Investigation Search ## Genetic Counseling The father of an affected male will not have the disorder nor will he be hemizygous for the A male proband may have the disorder as the result of a The mothers of more than half of males with In a family with more than one affected individual, the mother of an affected male is presumed to have a heterozygous or (depending on family history) mosaic If a mother has more than one affected child and no other affected relatives and if the 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. Molecular genetic testing of the mother for the A female proband may have the disorder as the result of a An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ An asymptomatic or mildly affected father with a The parents of approximately 90% of female probands are clinically unaffected. The Molecular genetic testing of the mother for the If the Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If the mother of the proband is affected and/or heterozygous for a Males who inherit the pathogenic variant will usually be affected with Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, If a male proband is hemizygous for a If a female proband is heterozygous for a If somatic mosaicism for a Males with Females with a Males who inherit the pathogenic variant will usually be affected with Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, For male or female probands with mild phenotypes resulting from mosaicism for If the mother of the proband has a heterozygous The offspring of all heterozygous females have a 50% chance of inheriting a 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 is most informative if the Note: Females who are heterozygous for this X-linked disorder may be clinically unaffected or may present with a wide range of clinical manifestations (see Clinical Description, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having a Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professional 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 • A male proband may have the disorder as the result of a • The mothers of more than half of males with • In a family with more than one affected individual, the mother of an affected male is presumed to have a heterozygous or (depending on family history) mosaic • If a mother has more than one affected child and no other affected relatives and if the • 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 a mother has more than one affected child and no other affected relatives and if the • 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. • Molecular genetic testing of the mother for the • If a mother has more than one affected child and no other affected relatives and if the • Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • A female proband may have the disorder as the result of a • An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ • An asymptomatic or mildly affected father with a • An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ • An asymptomatic or mildly affected father with a • The parents of approximately 90% of female probands are clinically unaffected. The • Molecular genetic testing of the mother for the • If the • Note: Testing of 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. • An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ • An asymptomatic or mildly affected father with a • If the mother of the proband is affected and/or heterozygous for a • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • If a male proband is hemizygous for a • If a female proband is heterozygous for a • If somatic mosaicism for a • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • Males with • Females with a • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • For male or female probands with mild phenotypes resulting from mosaicism for • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • If the mother of the proband has a heterozygous • The offspring of all heterozygous females have a 50% chance 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 are at risk of having a ## Mode of Inheritance ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the A male proband may have the disorder as the result of a The mothers of more than half of males with In a family with more than one affected individual, the mother of an affected male is presumed to have a heterozygous or (depending on family history) mosaic If a mother has more than one affected child and no other affected relatives and if the 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. Molecular genetic testing of the mother for the A female proband may have the disorder as the result of a An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ An asymptomatic or mildly affected father with a The parents of approximately 90% of female probands are clinically unaffected. The Molecular genetic testing of the mother for the If the Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If the mother of the proband is affected and/or heterozygous for a Males who inherit the pathogenic variant will usually be affected with Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, If a male proband is hemizygous for a If a female proband is heterozygous for a If somatic mosaicism for a Males with Females with a Males who inherit the pathogenic variant will usually be affected with Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, For male or female probands with mild phenotypes resulting from mosaicism for If the mother of the proband has a heterozygous The offspring of all heterozygous females have a 50% chance of inheriting a Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • A male proband may have the disorder as the result of a • The mothers of more than half of males with • In a family with more than one affected individual, the mother of an affected male is presumed to have a heterozygous or (depending on family history) mosaic • If a mother has more than one affected child and no other affected relatives and if the • 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 a mother has more than one affected child and no other affected relatives and if the • 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. • Molecular genetic testing of the mother for the • If a mother has more than one affected child and no other affected relatives and if the • Note: Testing of maternal leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • A female proband may have the disorder as the result of a • An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ • An asymptomatic or mildly affected father with a • An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ • An asymptomatic or mildly affected father with a • The parents of approximately 90% of female probands are clinically unaffected. The • Molecular genetic testing of the mother for the • If the • Note: Testing of 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. • An asymptomatic or only mildly affected mother; more than half of identified heterozygous mothers appear clinically unaffected [ • An asymptomatic or mildly affected father with a • If the mother of the proband is affected and/or heterozygous for a • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • If a male proband is hemizygous for a • If a female proband is heterozygous for a • If somatic mosaicism for a • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • Males with • Females with a • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • For male or female probands with mild phenotypes resulting from mosaicism for • Males who inherit the pathogenic variant will usually be affected with • Females who inherit the pathogenic variant will be heterozygous and will be at high risk of developing the variable phenotype associated with SBH (see Clinical Description, • If the mother of the proband has a heterozygous • The offspring of all heterozygous females have a 50% chance of inheriting a ## Heterozygote Detection in Asymptomatic Females Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: Females who are heterozygous for this X-linked disorder may be clinically unaffected or may present with a wide range of clinical manifestations (see Clinical Description, ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are at risk of having 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 are at risk of having a ## Prenatal Testing and Preimplantation Genetic Testing Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professional would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • ## Molecular Genetics DCX-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DCX-Related Disorders ( Abnormal DCX products may affect proper microtubule formation and perturb the mitotic machinery, although not all abnormal products appear to do so to the same extent [ In hemizygous males, all neurons express the pathogenic variant and are disturbed in their migratory properties, leading to the smoothened and disorganized thickened cortex observed in classic lissencephaly. In females heterozygous for a Cells expressing the wild type allele that continue and complete their migratory process to form the normal cortex; Cells expressing the pathogenic variant that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons. Variants listed in the table have been provided by the authors. • Cells expressing the wild type allele that continue and complete their migratory process to form the normal cortex; • Cells expressing the pathogenic variant that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons. ## Molecular Pathogenesis Abnormal DCX products may affect proper microtubule formation and perturb the mitotic machinery, although not all abnormal products appear to do so to the same extent [ In hemizygous males, all neurons express the pathogenic variant and are disturbed in their migratory properties, leading to the smoothened and disorganized thickened cortex observed in classic lissencephaly. In females heterozygous for a Cells expressing the wild type allele that continue and complete their migratory process to form the normal cortex; Cells expressing the pathogenic variant that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons. Variants listed in the table have been provided by the authors. • Cells expressing the wild type allele that continue and complete their migratory process to form the normal cortex; • Cells expressing the pathogenic variant that accumulate in the white matter between the cortex and lateral ventricles as a heterotopic band of neurons. ## Chapter Notes 5 June 2025 (gm) Comprehensive update posted live 7 February 2019 (ha) Comprehensive update posted live 24 March 2011 (me) Comprehensive update posted live 19 October 2007 (me) Review posted live 31 March 2006 (jw) Original submission • 5 June 2025 (gm) Comprehensive update posted live • 7 February 2019 (ha) Comprehensive update posted live • 24 March 2011 (me) Comprehensive update posted live • 19 October 2007 (me) Review posted live • 31 March 2006 (jw) Original submission ## Author Notes ## Revision History 5 June 2025 (gm) Comprehensive update posted live 7 February 2019 (ha) Comprehensive update posted live 24 March 2011 (me) Comprehensive update posted live 19 October 2007 (me) Review posted live 31 March 2006 (jw) Original submission • 5 June 2025 (gm) Comprehensive update posted live • 7 February 2019 (ha) Comprehensive update posted live • 24 March 2011 (me) Comprehensive update posted live • 19 October 2007 (me) Review posted live • 31 March 2006 (jw) Original submission ## References ## Literature Cited Cerebral MRI of three individuals with A. Characteristic bilateral subcortical band heterotopia (*) in a female with heterozygous B-C. Classic thick lissencephaly in two males with hemizygous
[]
19/10/2007
5/6/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ddon
ddon
[ "DDON", "Mohr-Tranebjaerg Syndrome", "Mohr-Tranebjaerg Syndrome", "Mitochondrial import inner membrane translocase subunit Tim8 A", "TIMM8A", "Deafness-Dystonia-Optic Neuronopathy Syndrome" ]
Deafness-Dystonia-Optic Neuronopathy Syndrome
Lisbeth Tranebjærg
Summary Males with deafness-dystonia-optic neuronopathy (DDON) syndrome have prelingual or postlingual sensorineural hearing impairment in early childhood, slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from optic atrophy beginning at approximately age 20 years, and dementia beginning at approximately age 40 years. Psychiatric symptoms such as personality change and paranoia may appear in childhood and progress. The hearing impairment appears to be consistent in age of onset and progression, whereas the neurologic, visual, and neuropsychiatric signs vary in degree of severity and rate of progression. Females may have mild hearing impairment and focal dystonia. The diagnosis of DDON syndrome is established in either a male proband who has a hemizygous DDON syndrome is inherited in an X-linked manner. If the mother of a proband with DDON syndrome has the causative genetic alteration (i.e., a Prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible if the DDON-causing genetic alteration in the family is known.
## Diagnosis Formal diagnostic criteria for deafness-dystonia-optic neuronopathy (DDON) syndrome have not been established. Deafness-dystonia-optic neuronopathy (DDON) syndrome is suspected in males with the following: Progressive sensorineural hearing impairment with prelingual or postlingual onset: Absent stapedius reflex Abnormal findings on auditory brain stem response testing Normal evoked otoacoustic emissions, indicating normal outer hair cells [ Normal findings on CT scan of the inner ear [ Movement disorder (dystonia/ataxia) Gradual onset and slow progression of personality changes, paranoia, dementia Gradual decrease in visual acuity associated with optic atrophy Gradual onset and slow progression of dysphagia A family history consistent with X-linked inheritance The diagnosis of deafness-dystonia-optic neuronopathy (DDON) syndrome A hemizygous A contiguous gene deletion of Xq22.1 involving Note: (1) The clinical features of DDON in individuals with a contiguous gene deletion and in individuals with smaller pathogenic variants are indistinguishable, apart from the additional presence of Options for molecular genetic testing can include a chromosomal microarray analysis (CMA) or use of a multigene panel depending on the phenotype and family history. In a child with hearing loss and evidence of a family history suggestive of XLA, In a young child with hearing impairment and no other phenotypic findings, there should be a strong suspicion of DDON if the auditory phenotype is auditory neuropathy. For an introduction to multigene panels click Molecular Genetic Testing Used in DDON 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 (e.g., those described by Most deletions not detectable by sequence analysis are large deletions that include Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • Progressive sensorineural hearing impairment with prelingual or postlingual onset: • Absent stapedius reflex • Abnormal findings on auditory brain stem response testing • Normal evoked otoacoustic emissions, indicating normal outer hair cells [ • Normal findings on CT scan of the inner ear [ • Absent stapedius reflex • Abnormal findings on auditory brain stem response testing • Normal evoked otoacoustic emissions, indicating normal outer hair cells [ • Normal findings on CT scan of the inner ear [ • Movement disorder (dystonia/ataxia) • Gradual onset and slow progression of personality changes, paranoia, dementia • Gradual decrease in visual acuity associated with optic atrophy • Gradual onset and slow progression of dysphagia • A family history consistent with X-linked inheritance • Absent stapedius reflex • Abnormal findings on auditory brain stem response testing • Normal evoked otoacoustic emissions, indicating normal outer hair cells [ • Normal findings on CT scan of the inner ear [ • A hemizygous • A contiguous gene deletion of Xq22.1 involving ## Suggestive Findings Deafness-dystonia-optic neuronopathy (DDON) syndrome is suspected in males with the following: Progressive sensorineural hearing impairment with prelingual or postlingual onset: Absent stapedius reflex Abnormal findings on auditory brain stem response testing Normal evoked otoacoustic emissions, indicating normal outer hair cells [ Normal findings on CT scan of the inner ear [ Movement disorder (dystonia/ataxia) Gradual onset and slow progression of personality changes, paranoia, dementia Gradual decrease in visual acuity associated with optic atrophy Gradual onset and slow progression of dysphagia A family history consistent with X-linked inheritance • Progressive sensorineural hearing impairment with prelingual or postlingual onset: • Absent stapedius reflex • Abnormal findings on auditory brain stem response testing • Normal evoked otoacoustic emissions, indicating normal outer hair cells [ • Normal findings on CT scan of the inner ear [ • Absent stapedius reflex • Abnormal findings on auditory brain stem response testing • Normal evoked otoacoustic emissions, indicating normal outer hair cells [ • Normal findings on CT scan of the inner ear [ • Movement disorder (dystonia/ataxia) • Gradual onset and slow progression of personality changes, paranoia, dementia • Gradual decrease in visual acuity associated with optic atrophy • Gradual onset and slow progression of dysphagia • A family history consistent with X-linked inheritance • Absent stapedius reflex • Abnormal findings on auditory brain stem response testing • Normal evoked otoacoustic emissions, indicating normal outer hair cells [ • Normal findings on CT scan of the inner ear [ ## Establishing the Diagnosis The diagnosis of deafness-dystonia-optic neuronopathy (DDON) syndrome A hemizygous A contiguous gene deletion of Xq22.1 involving Note: (1) The clinical features of DDON in individuals with a contiguous gene deletion and in individuals with smaller pathogenic variants are indistinguishable, apart from the additional presence of Options for molecular genetic testing can include a chromosomal microarray analysis (CMA) or use of a multigene panel depending on the phenotype and family history. In a child with hearing loss and evidence of a family history suggestive of XLA, In a young child with hearing impairment and no other phenotypic findings, there should be a strong suspicion of DDON if the auditory phenotype is auditory neuropathy. For an introduction to multigene panels click Molecular Genetic Testing Used in DDON 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 (e.g., those described by Most deletions not detectable by sequence analysis are large deletions that include Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • A hemizygous • A contiguous gene deletion of Xq22.1 involving ## Option 1 In a child with hearing loss and evidence of a family history suggestive of XLA, ## Option 2 In a young child with hearing impairment and no other phenotypic findings, there should be a strong suspicion of DDON if the auditory phenotype is auditory neuropathy. For an introduction to multigene panels click Molecular Genetic Testing Used in DDON 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 (e.g., those described by Most deletions not detectable by sequence analysis are large deletions that include Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including ## Clinical Characteristics Deafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive disorder with prelingual or postlingual sensorineural hearing impairment in early childhood. The hearing impairment is always the presenting manifestation. Typically, DDON is associated with slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from approximately age 20 years, and dementia from approximately age 40 years. Psychiatric manifestations such as personality change and paranoia may appear in childhood and progress. The deafness and pronounced visual impairment severely compromise communication in late adulthood. Note: The term "neuronopathy" refers to the destruction of the cell bodies of neurons and is different from "neuropathy," which is defined as a functional disturbance in the peripheral nervous system. The hearing impairment appears to be more consistent in age of onset and progression than the neurologic, visual, and neuropsychiatric features, which vary in degree of severity and rate of progression. Life span may show extreme variation, even within a family. For example, in one large family, one member had rapidly progressive dystonia ("dystonia musculorum deformans") and died at age 16 years; other affected family members died in their sixties [ The hearing impairment results from an auditory neuropathy as shown by intact otoacoustic emissions associated with absent auditory brain stem responses in some individuals and convincing histopathologic evidence in five males with molecularly proven DDON syndrome with near-total loss of cochlear neurons and severe loss of vestibular neurons [ Of note, isolated hearing impairment without other manifestations of DDON syndrome has not been reported with Although many affected individuals develop dystonia by their thirties, some, ascertained through severely affected male relatives with a typical phenotype, have no detectable neurologic dysfunction in their thirties [ Dysphagia develops late in the course and often causes aspiration pneumonia and its complications. A mild peripheral sensory neuropathy may be present. Spinal cord dysfunction was present in an individual with DDON syndrome with prolonged somatosensory evoked potentials and disturbed central motor conduction to lower extremities in motor evoked potentials [ Seizures are not characteristic. In childhood, color vision and visual fields are normal [ Slowly progressive decline in visual acuity leads to legal blindness around age 30 to 40 years [ Males with DDON syndrome have normal fertility. Frequent occurrence of hip fractures in affected males appears to be associated with poor neuromuscular coordination and increased risk for stumbling rather than an abnormality in calcium metabolism or intrinsic bone abnormalities [ Cardiomyopathy does not occur. Decrease in respiratory capacity does not occur, except for that related to aspiration pneumonia. Older females from the original family described by Female probands have been reported [ More sophisticated neuroimaging studies such as PET/MRI reveal hypometabolic areas, predominantly over the right striatum and parietal cortex, and marked atrophy of the occipital lobes [ The spinal cord is atrophic with loss of fibers in the dorsal roots and posterior columns, as seen in The limited number of affected individuals, the extremely variable clinical course, and the family-specific nature of each pathogenic variant identified limits detection of genotype-phenotype correlations. It is noteworthy that the clinical features of DDON in individuals with a contiguous gene deletion and in individuals with smaller pathogenic variants are indistinguishable, apart from presence or absence of In 1960, Mohr and Mageroy described an X-linked recessive childhood-onset sensorineural hearing impairment, which was believed to be nonsyndromic and thus was designated DFN-1, indicating that it was the first described X-linked nonsyndromic form of hearing impairment [ Opticoacoustic nerve atrophy (Jensen syndrome), reported by The prevalence of DDON syndrome is unknown. It has been identified in several populations worldwide. A recent comprehensive review chapter identified 91 affected individuals from 37 families [ Dystonia of all types occurs with a prevalence between 70 and 329 per million [ Hearing impairment has a prevalence of 1:800, approximately 1% of which is attributed to X-linked inheritance. • Males with DDON syndrome have normal fertility. • Frequent occurrence of hip fractures in affected males appears to be associated with poor neuromuscular coordination and increased risk for stumbling rather than an abnormality in calcium metabolism or intrinsic bone abnormalities [ • Cardiomyopathy does not occur. • Decrease in respiratory capacity does not occur, except for that related to aspiration pneumonia. ## Clinical Description Deafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive disorder with prelingual or postlingual sensorineural hearing impairment in early childhood. The hearing impairment is always the presenting manifestation. Typically, DDON is associated with slowly progressive dystonia or ataxia in the teens, slowly progressive decreased visual acuity from approximately age 20 years, and dementia from approximately age 40 years. Psychiatric manifestations such as personality change and paranoia may appear in childhood and progress. The deafness and pronounced visual impairment severely compromise communication in late adulthood. Note: The term "neuronopathy" refers to the destruction of the cell bodies of neurons and is different from "neuropathy," which is defined as a functional disturbance in the peripheral nervous system. The hearing impairment appears to be more consistent in age of onset and progression than the neurologic, visual, and neuropsychiatric features, which vary in degree of severity and rate of progression. Life span may show extreme variation, even within a family. For example, in one large family, one member had rapidly progressive dystonia ("dystonia musculorum deformans") and died at age 16 years; other affected family members died in their sixties [ The hearing impairment results from an auditory neuropathy as shown by intact otoacoustic emissions associated with absent auditory brain stem responses in some individuals and convincing histopathologic evidence in five males with molecularly proven DDON syndrome with near-total loss of cochlear neurons and severe loss of vestibular neurons [ Of note, isolated hearing impairment without other manifestations of DDON syndrome has not been reported with Although many affected individuals develop dystonia by their thirties, some, ascertained through severely affected male relatives with a typical phenotype, have no detectable neurologic dysfunction in their thirties [ Dysphagia develops late in the course and often causes aspiration pneumonia and its complications. A mild peripheral sensory neuropathy may be present. Spinal cord dysfunction was present in an individual with DDON syndrome with prolonged somatosensory evoked potentials and disturbed central motor conduction to lower extremities in motor evoked potentials [ Seizures are not characteristic. In childhood, color vision and visual fields are normal [ Slowly progressive decline in visual acuity leads to legal blindness around age 30 to 40 years [ Males with DDON syndrome have normal fertility. Frequent occurrence of hip fractures in affected males appears to be associated with poor neuromuscular coordination and increased risk for stumbling rather than an abnormality in calcium metabolism or intrinsic bone abnormalities [ Cardiomyopathy does not occur. Decrease in respiratory capacity does not occur, except for that related to aspiration pneumonia. Older females from the original family described by Female probands have been reported [ More sophisticated neuroimaging studies such as PET/MRI reveal hypometabolic areas, predominantly over the right striatum and parietal cortex, and marked atrophy of the occipital lobes [ The spinal cord is atrophic with loss of fibers in the dorsal roots and posterior columns, as seen in • Males with DDON syndrome have normal fertility. • Frequent occurrence of hip fractures in affected males appears to be associated with poor neuromuscular coordination and increased risk for stumbling rather than an abnormality in calcium metabolism or intrinsic bone abnormalities [ • Cardiomyopathy does not occur. • Decrease in respiratory capacity does not occur, except for that related to aspiration pneumonia. ## Heterozygotes Older females from the original family described by Female probands have been reported [ ## Other Studies in Affected Males More sophisticated neuroimaging studies such as PET/MRI reveal hypometabolic areas, predominantly over the right striatum and parietal cortex, and marked atrophy of the occipital lobes [ The spinal cord is atrophic with loss of fibers in the dorsal roots and posterior columns, as seen in ## Genotype-Phenotype Correlations The limited number of affected individuals, the extremely variable clinical course, and the family-specific nature of each pathogenic variant identified limits detection of genotype-phenotype correlations. It is noteworthy that the clinical features of DDON in individuals with a contiguous gene deletion and in individuals with smaller pathogenic variants are indistinguishable, apart from presence or absence of ## Nomenclature In 1960, Mohr and Mageroy described an X-linked recessive childhood-onset sensorineural hearing impairment, which was believed to be nonsyndromic and thus was designated DFN-1, indicating that it was the first described X-linked nonsyndromic form of hearing impairment [ Opticoacoustic nerve atrophy (Jensen syndrome), reported by ## Prevalence The prevalence of DDON syndrome is unknown. It has been identified in several populations worldwide. A recent comprehensive review chapter identified 91 affected individuals from 37 families [ Dystonia of all types occurs with a prevalence between 70 and 329 per million [ Hearing impairment has a prevalence of 1:800, approximately 1% of which is attributed to X-linked inheritance. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Note: Other Genes of Interest in the Differential Diagnosis of DDON Syndrome The combination of optic atrophy, hearing loss, & neurologic signs suggests mt disorders such as MELAS. See also Dystonia uncommon in MELAS Short stature, generalized tonic-clonic seizures, recurrent headaches/vomiting, & anorexia common in MELAS Progressive disorder Dystonia & severe hearing impairment Hypotonia, abnormal muscle histopathology, & ↑ methylmalonic acid concentration Ophthalmologic findings normal Several cases reported from Faroe Islands Neurodegenerative basal ganglia disease Neuromuscular manifestations incl (mostly subclinical) sensorimotor axonopathy & clinically relevant muscle weakness or atrophy Hematologic manifestations: RBC acanthocytosis, compensated hemolysis, & McLeod blood group phenotype Dilated cardiomyopathy & arrhythmias Visual & hearing impairment In persons w/DDON, Usher may first be suspected because hearing impairment in DDON may be congenital & in Usher type II may be progressive. Impaired vision results from retinal dystrophy, which first manifests as impaired dark adaptation No neurologic abnormalities Optic atrophy, movement disorder, dementia, & psychiatric abnormalities may occur. Hearing impairment in ~60% of persons by age 20 yrs Consider Wolfram in simplex males (i.e., single case in a family) who appear to have DDON. Juvenile onset of diabetes mellitus Involvement of most organs No dystonia Slowly progressive ataxia w/onset age usually <25 yrs May be assoc w/sensorineural hearing impairment (10% of persons) & often subclinical optic atrophy (25%) Rarely presents w/hearing impairment or optic atrophy (hearing loss is always a presenting finding in DDON) Dystonia & other movement disorders uncommon Tendon reflexes usually (not always) depressed in Friedreich ataxia Cardiomyopathy common AR = autosomal recessive; CNS = central nervous system; ERG = electroretinogram; ID = intellectual disability; Mat = maternal; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MOI = mode of inheritance; mt = mitochondrial; RBC = red blood cell; XL = X-linked Genes are in alphabetic order. The m.3243A>G pathogenic variant in the mitochondrial gene The disorder was identified in a Muslim family and ten remotely related individuals from the Faroe Islands, where a high carrier frequency (1 in 33) is caused by a founder variant [ See also other heredodegenerative X-linked disorders characterized by intellectual impairment, movement disorder, and hearing impairment, including Farlow syndrome (OMIM See Ophthalmoscopy and electroretinography can be used to determine the cause of visual impairment. The presence of immunodeficiency and hearing impairment in a male should raise the possibility of a contiguous gene deletion at Xq22 involving • The combination of optic atrophy, hearing loss, & neurologic signs suggests mt disorders such as MELAS. • See also • Dystonia uncommon in MELAS • Short stature, generalized tonic-clonic seizures, recurrent headaches/vomiting, & anorexia common in MELAS • Progressive disorder • Dystonia & severe hearing impairment • Hypotonia, abnormal muscle histopathology, & ↑ methylmalonic acid concentration • Ophthalmologic findings normal • Several cases reported from Faroe Islands • Neurodegenerative basal ganglia disease • Neuromuscular manifestations incl (mostly subclinical) sensorimotor axonopathy & clinically relevant muscle weakness or atrophy • Hematologic manifestations: RBC acanthocytosis, compensated hemolysis, & McLeod blood group phenotype • Dilated cardiomyopathy & arrhythmias • Visual & hearing impairment • In persons w/DDON, Usher may first be suspected because hearing impairment in DDON may be congenital & in Usher type II may be progressive. • Impaired vision results from retinal dystrophy, which first manifests as impaired dark adaptation • No neurologic abnormalities • Optic atrophy, movement disorder, dementia, & psychiatric abnormalities may occur. • Hearing impairment in ~60% of persons by age 20 yrs • Consider Wolfram in simplex males (i.e., single case in a family) who appear to have DDON. • Juvenile onset of diabetes mellitus • Involvement of most organs • No dystonia • Slowly progressive ataxia w/onset age usually <25 yrs • May be assoc w/sensorineural hearing impairment (10% of persons) & often subclinical optic atrophy (25%) • Rarely presents w/hearing impairment or optic atrophy (hearing loss is always a presenting finding in DDON) • Dystonia & other movement disorders uncommon • Tendon reflexes usually (not always) depressed in Friedreich ataxia • Cardiomyopathy common ## Management Recommended Evaluations Following Initial Diagnosis in Males with DDON Syndrome Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support. OT = occupational therapy; PT = physical therapy; VEP = visual evoked potential Treatment of Manifestations in Individuals with DDON Syndrome Start hearing habituation (auditory & speech training, sign language) as soon as possible. Community hearing services through early intervention or school district CT of bony landmarks & MRI of vestibular & facial nerves as part of pre-cochlear implant assessment Cochlear implants may provide sound awareness & even speech recognition in presence of cochlear abnormalities. Outcome is expected to be variable in auditory neuropathy. To improve gross motor skills & mobility & prevent contractures To improve fine motor skills Provide adaptive devices to improve activities of daily living. ADHD = attention-deficit/hyperactivity disorder; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss 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. 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. Recommended Surveillance for Individuals with DDON Syndrome Effect of hearing impairment, vision impairment, mvmt disorder, changes in behavior &/or cognitive abilities when clinically relevant Be aware of signs of dementia in adults. OT = occupational therapy; PT = physical therapy See Search • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support. • Start hearing habituation (auditory & speech training, sign language) as soon as possible. • Community hearing services through early intervention or school district • CT of bony landmarks & MRI of vestibular & facial nerves as part of pre-cochlear implant assessment • Cochlear implants may provide sound awareness & even speech recognition in presence of cochlear abnormalities. • Outcome is expected to be variable in auditory neuropathy. • To improve gross motor skills & mobility & prevent contractures • To improve fine motor skills • Provide adaptive devices to improve activities of daily living. • 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. • 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 • Effect of hearing impairment, vision impairment, mvmt disorder, changes in behavior &/or cognitive abilities when clinically relevant • Be aware of signs of dementia in adults. ## Evaluations Following Initial Diagnosis Recommended Evaluations Following Initial Diagnosis in Males with DDON Syndrome Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support. OT = occupational therapy; PT = physical therapy; VEP = visual evoked potential • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with DDON Syndrome Start hearing habituation (auditory & speech training, sign language) as soon as possible. Community hearing services through early intervention or school district CT of bony landmarks & MRI of vestibular & facial nerves as part of pre-cochlear implant assessment Cochlear implants may provide sound awareness & even speech recognition in presence of cochlear abnormalities. Outcome is expected to be variable in auditory neuropathy. To improve gross motor skills & mobility & prevent contractures To improve fine motor skills Provide adaptive devices to improve activities of daily living. ADHD = attention-deficit/hyperactivity disorder; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss 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. 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. • Start hearing habituation (auditory & speech training, sign language) as soon as possible. • Community hearing services through early intervention or school district • CT of bony landmarks & MRI of vestibular & facial nerves as part of pre-cochlear implant assessment • Cochlear implants may provide sound awareness & even speech recognition in presence of cochlear abnormalities. • Outcome is expected to be variable in auditory neuropathy. • To improve gross motor skills & mobility & prevent contractures • To improve fine motor skills • Provide adaptive devices to improve activities of daily living. • 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. • 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. 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. ## 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 Recommended Surveillance for Individuals with DDON Syndrome Effect of hearing impairment, vision impairment, mvmt disorder, changes in behavior &/or cognitive abilities when clinically relevant Be aware of signs of dementia in adults. OT = occupational therapy; PT = physical therapy • Effect of hearing impairment, vision impairment, mvmt disorder, changes in behavior &/or cognitive abilities when clinically relevant • Be aware of signs of dementia in adults. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Deafness-dystonia-optic neuronopathy (DDON) syndrome 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 DDON syndrome-causing genetic alteration (i.e., a pathogenic variant in If a male proband has a sib with the same DDON syndrome-causing genetic alteration, the mother of the proband is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the DDON syndrome-causing genetic alteration cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has been suspected but not molecularly proven in any published cases). If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the DDON syndrome-causing genetic alteration or the affected male may have a A female proband may have inherited the DDON syndrome-causing genetic alteration from either her mother or her father, or the DDON syndrome-causing genetic alteration may be Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has a DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing loss or focal dystonia at an older age (see Clinical Description, If the proband represents a simplex case and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. If the mother of the proband has the DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing impairment or focal dystonia at an older age (see Clinical Description, If the father of the proband has a DDON syndrome-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Molecular genetic testing of at-risk female relatives to determine their genetic status is possible if the DDON syndrome-causing genetic alteration in the family has been identified. The progression of individual symptoms shows considerable inter- and intrafamilial variability, making a reliable prediction of the degree of severity difficult. Some families have shown skewed X-chromosome inactivation in heterozygous females, which may explain the occurrence of mild manifestations in some heterozygous females [ The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the DDON syndrome-causing genetic alteration has been identified in the family, 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. • The father of an affected male will not have the disorder nor will he be hemizygous for the DDON syndrome-causing genetic alteration (i.e., a pathogenic variant in • If a male proband has a sib with the same DDON syndrome-causing genetic alteration, the mother of the proband is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the DDON syndrome-causing genetic alteration cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has been suspected but not molecularly proven in any published cases). • If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the DDON syndrome-causing genetic alteration or the affected male may have a • A female proband may have inherited the DDON syndrome-causing genetic alteration from either her mother or her father, or the DDON syndrome-causing genetic alteration may be • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has a DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing loss or focal dystonia at an older age (see Clinical Description, • If the proband represents a simplex case and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. • If the mother of the proband has the DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing impairment or focal dystonia at an older age (see Clinical Description, • If the father of the proband has a DDON syndrome-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Deafness-dystonia-optic neuronopathy (DDON) syndrome 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 DDON syndrome-causing genetic alteration (i.e., a pathogenic variant in If a male proband has a sib with the same DDON syndrome-causing genetic alteration, the mother of the proband is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the DDON syndrome-causing genetic alteration cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has been suspected but not molecularly proven in any published cases). If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the DDON syndrome-causing genetic alteration or the affected male may have a A female proband may have inherited the DDON syndrome-causing genetic alteration from either her mother or her father, or the DDON syndrome-causing genetic alteration may be Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has a DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing loss or focal dystonia at an older age (see Clinical Description, If the proband represents a simplex case and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. If the mother of the proband has the DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing impairment or focal dystonia at an older age (see Clinical Description, If the father of the proband has a DDON syndrome-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. • The father of an affected male will not have the disorder nor will he be hemizygous for the DDON syndrome-causing genetic alteration (i.e., a pathogenic variant in • If a male proband has a sib with the same DDON syndrome-causing genetic alteration, the mother of the proband is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the DDON syndrome-causing genetic alteration cannot be detected in her leukocyte DNA, she most likely has germline mosaicism (maternal germline mosaicism has been suspected but not molecularly proven in any published cases). • If a male is the only affected family member (i.e., a simplex case), the mother may be heterozygous for the DDON syndrome-causing genetic alteration or the affected male may have a • A female proband may have inherited the DDON syndrome-causing genetic alteration from either her mother or her father, or the DDON syndrome-causing genetic alteration may be • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has a DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing loss or focal dystonia at an older age (see Clinical Description, • If the proband represents a simplex case and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is low but greater than that of the general population because of the possibility of maternal germline mosaicism. • If the mother of the proband has the DDON syndrome-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%. Males who inherit the genetic alteration will be affected; females who inherit the genetic alteration will be heterozygotes and may present with mild hearing impairment or focal dystonia at an older age (see Clinical Description, • If the father of the proband has a DDON syndrome-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the DDON syndrome-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. ## Heterozygote Detection Molecular genetic testing of at-risk female relatives to determine their genetic status is possible if the DDON syndrome-causing genetic alteration in the family has been identified. ## Related Genetic Counseling Issues The progression of individual symptoms shows considerable inter- and intrafamilial variability, making a reliable prediction of the degree of severity difficult. Some families have shown skewed X-chromosome inactivation in heterozygous females, which may explain the occurrence of mild manifestations in some heterozygous females [ The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the DDON syndrome-causing genetic alteration has been identified in the family, 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 United Kingdom • • United Kingdom • • • • • • • • • • • • ## Molecular Genetics Deafness-Dystonia-Optic Neuronopathy Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Deafness-Dystonia-Optic Neuronopathy Syndrome ( TIMM8A contains putative Zn-binding domains with four conserved cysteine residues. The product is involved in mitochondrial protein import [ Protein expression and immunocytochemical studies indicate that TIMM8A and TIMM13 are coexpressed at high levels in Purkinje cells in the cerebellum, but not in glial cells [ Deletion of Although some variants are inherited, ## Molecular Pathogenesis TIMM8A contains putative Zn-binding domains with four conserved cysteine residues. The product is involved in mitochondrial protein import [ Protein expression and immunocytochemical studies indicate that TIMM8A and TIMM13 are coexpressed at high levels in Purkinje cells in the cerebellum, but not in glial cells [ Deletion of Although some variants are inherited, ## Chapter Notes 21 November 2019 (bp) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically 3 April 2008 (me) Comprehensive update posted live 8 April 2005 (me) Comprehensive update posted live 5 February 2004 (cd) Revision: change in testing 6 February 2003 (me) Review posted live 23 August 2002 (lt) Original submission • 21 November 2019 (bp) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically • 3 April 2008 (me) Comprehensive update posted live • 8 April 2005 (me) Comprehensive update posted live • 5 February 2004 (cd) Revision: change in testing • 6 February 2003 (me) Review posted live • 23 August 2002 (lt) Original submission ## Revision History 21 November 2019 (bp) Comprehensive update posted live 31 January 2013 (me) Comprehensive update posted live 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically 3 April 2008 (me) Comprehensive update posted live 8 April 2005 (me) Comprehensive update posted live 5 February 2004 (cd) Revision: change in testing 6 February 2003 (me) Review posted live 23 August 2002 (lt) Original submission • 21 November 2019 (bp) Comprehensive update posted live • 31 January 2013 (me) Comprehensive update posted live • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically • 3 April 2008 (me) Comprehensive update posted live • 8 April 2005 (me) Comprehensive update posted live • 5 February 2004 (cd) Revision: change in testing • 6 February 2003 (me) Review posted live • 23 August 2002 (lt) Original submission ## References ## Literature Cited
[ "T Arai, M Zhao, H Kanegane, MC van Zelm, T Futatani, M Yamada, T Ariga, HD Ochs, T Miyawaki, T Oh-ishi. Genetic analysis of contiguous nX-chromosome deletion syndrome encompassing the BTK and TIMM8A genes.. J Hum Genet 2011;56:577-82", "F Bahmad, SN Merchant, JB Nadol, L Tranebjaerg. Otopathology in Mohr-Tranebjaerg syndrome.. Laryngoscope 2007;117:1202-8", "J Binder, S Hofmann, S Kreisel, JC Wohrle, H Bazner, JK Krauss, MG Hennerici, MF Bauer. Clinical and molecular findings in a patient with a novel mutation in the deafness-dystonia peptide (DDP1) gene.. Brain 2003;126:1814-20", "JR Blesa, A Solano, P Briones, JA Prieto-Ruiz, J Hernandez-Yago, F Coria. Molecular genetics of a patient with Mohr-Tranebjaerg Syndrome due to a new mutation in the DDP1 gene.. Neuromolecular Med 2007;9:285-91", "JT Brookes, AB Kanis, LY Tan, L Tranebjaerg, A Vore, RJ Smith. Cochlear implantation in deafness-dystonia-optic neuronopathy (DDON) syndrome.. Int J Pediatr Otorhinolaryngol 2008;72:121-6", "A prevalence study of primary dystonia in eight European countries.. J Neurol. 2000;247:787-92", "AD Ha, KL Parratt, ND Rendtorff, M Lodahl, K Ng, DB Rowe, CM Sue, JG Morris, MW Hayes, L Tranebjaerg, VSC Fung. The phenotypic spectrum of dystonia in Mohr-Tranebjaerg syndrome.. Mov Disord 2012;27:1034-40", "MW Hayes, RA Ouvrier, W Evans, E Somerville, JG Morris. X-linked dystonia-deafness syndrome.. Mov Disord 1998;13:303-8", "PK Jensen. Nerve deafness: optic nerve atrophy, and dementia: a new X-linked recessive syndrome?. Am J Med Genet 1981;9:55-60", "PK Jensen, E Reske-Nielsen, O Hein-Sorensen, M Warburg. The syndrome of opticoacoustic nerve atrophy with dementia.. Am J Med Genet 1987;28:517-8", "J Klempir, O Klempirova, J Hadac, J. Roth. Late-onset severe progressive Mohr-Tranebjaerg syndrome in two female relatives.. Eur J Neurol. 2010;17:S398", "CM Koehler, D Leuenberger, S Merchant, A Renold, T Junne, G Schatz. Human deafness dystonia syndrome is a mitochondrial disease.. Proc Natl Acad Sci USA 1999a;96:2141-6", "CM Koehler, S Merchant, G Schatz. How membrane proteins travel across the mitochondrial intermembrane space.. Trends Biochem Sci 1999b;24:428-32", "SN Merchant, MJ McKenna, JB Nadol, AG Kristiansen, A Tropitzsch, S Lindal, L Tranebjaerg. Temporal bone histopathologic and genetic studies in Mohr-Tranebjaerg syndrome (DFN-1).. Otol Neurotol 2001;22:506-11", "J Mohr, K Mageroy. Sex-linked deafness of a possibly new type.. Acta Genet Stat Med 1960;10:54-62", "S Montaut, C Tranchant, N Drouot, G Rudolf, C Guissart, J Tarabeux, T Stemmelen, A Velt, C Fourrage, P Nitschké, B Gerard, JL Mandel, M Koenig, J Chelly, M Anheim. Assessment of a targeted gene panel for identification of genes associated with movement disorders.. JAMA Neurol. 2018;75:1234-45", "KH Orstavik, RE Orstavik, K Eiklid, L Tranebjaerg. Inheritance of skewed X chromosome inactivation in a large family with X-linked recessive deafness syndrome.. Am J Med Genet 1996;64:31-4", "E Ostergaard, FJ Hansen, N Sorensen, M Duno, J Vissing, PL Larsen, O Faeroe, S Thorgrimsson, F Wibrand, E Christensen, M Schwartz. Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations.. Brain 2007;130:853-61", "SA Paschen, U Rothbauer, K Kaldi, MF Bauer, W Neupert, M Brunner. The role of the TIM8-13 complex in the import of Tim23 into mitochondria.. EMBO J 2000;19:6392-400", "RM Plenge, L Tranebjaerg, PK Jensen, C Schwartz, HF Willard. Evidence that mutations in the X-linked DDP gene cause incompletely penetrant and variable skewed X inactivation.. Am J Hum Genet 1999;64:759-67", "V Ponjavic, S Andreasson, L Tranebjaerg, HA Lubs. Full-field electroretinograms in a family with Mohr-Tranebjaerg syndrome.. Acta Ophthalmol Scand 1996;74:632-5", "E Reske-Nielsen, PK Jensen, O Hein-Sørensen, K Abelskov. Calcification of the central nervous system in a new hereditary neurological syndrome.. Acta Neuropathol 1988;75:590-6", "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 Richter, ME Conley, J Rohrer, LA Myers, K Zahradka, J Kelecic, J Sertic, A Stavljenic-Rukavina. A contiguous deletion syndrome of X-linked agammaglobulinemia and sensorineural deafness.. Pediatr Allergy Immunol 2001;12:107-11", "K Roesch, SP Curran, L Tranebjaerg, CM Koehler. Human deafness dystonia syndrome is caused by a defect in assembly of the DDP1/TIMM8a-TIMM13 complex.. Hum Mol Genet 2002;11:477-86", "K Roesch, PJ Hynds, R Varga, L Tranebjaerg, CM Koehler. The calcium-binding aspartate/glutamate carriers, citrin and aralar1, are new substrates for the DDP1/TIMM8a-TIMM13 complex.. Hum Mol Genet 2004;13:2101-11", "U Rothbauer, S Hofmann, N Muhlenbein, SA Paschen, KD Gerbitz, W Neupert, M Brunner, MF Bauer. Role of the deafness dystonia peptide 1 (DDP1) in import of human Tim23 into the inner membrane of mitochondria.. J Biol Chem 2001;276:37327-34", "N Scribanu, C Kennedy. Familial syndrome with dystonia, neural deafness, and possible intellectual impairment: clinical course and pathological findings.. Adv Neurol 1976;14:235-43", "A Sedivá, CI Smith, AC Asplund, J Hadac, A Janda, J Zeman, H Hansíková, L Dvoráková, L Mrázová, S Velbri, C Koehler, K Roesch, KE Sullivan, T Futatani, HD Ochs. Contiguous X-chromosome deletion syndrome encompassing the BTK, TIMM8A, TAF7L, and DRP2 genes.. J Clin Immunol 2007;27:640-6", "RH Swerdlow, GF Wooten. A novel deafness/dystonia peptide gene mutation that causes dystonia in female carriers of Mohr-Tranebjaerg syndrome.. Ann Neurol 2001;50:537-40", "A Szaflarska, M Rutkowska-Zapała, A Gruca, K Szewczyk, M Bik-Multanowski, M Lenart, M Surman, I Kopyta, E Głuszkiewicz, M Machnikowska-Sokołowska, K Gruszczyńska, A Pituch-Noworolska, M Siedlar. Neurodegenerative changes detected by neuroimaging in a patient with contiguous X-chromosome deletion syndrome encompassing BTK and TIMM8A genes.. Cent Eur J Immunol. 2018;43:139-47", "L Tranebjaerg, BC Hamel, FJ Gabreels, WO Renier, M Van Ghelue. A de novo missense mutation in a critical domain of the X-linked DDP gene causes the typical deafness-dystonia-optic atrophy syndrome.. Eur J Hum Genet 2000a;8:464-7", "L Tranebjaerg, PK Jensen, M van Ghelue. X-linked recessive deafness-dystonia syndrome (Mohr-Tranebjaerg syndrome).. Adv Otorhinolaryngol 2000b;56:176-80", "L Tranebjaerg, PK Jensen, M Van Ghelue, CL Vnencak-Jones, S Sund, K Elgjo, J Jakobsen, S Lindal, M Warburg, A Fuglsang-Frederiksen, K Skullerud. Neuronal cell death in the visual cortex is a prominent feature of the X-linked recessive mitochondrial deafness-dystonia syndrome caused by mutations in the TIMM8a gene.. Ophthalmic Genet 2001;22:207-23", "L Tranebjaerg, C Schwartz, H Eriksen, S Andreasson, V Ponjavic, A Dahl, RE Stevenson, M May, F Arena, D Barker. A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22.. J Med Genet 1995;32:257-63", "L Tranebjaerg, M Van Ghelue, O Nilssen, ME Hodes, SR Dlouhy, MR Farlow, B Hamel, WFM Arts, J Jankovic, J Beach, PKA Jensen. Jensen syndrome is allelic to Mohr-Tranebjaerg syndrome and both are caused by mutations in the DDP gene.. Am J Hum Genet 1997;61S:A349", "H Ujike, Y Tanabe, Y Takehisa, T Hayabara, S Kuroda. A family with X-linked dystonia-deafness syndrome with a novel mutation of the DDP gene.. Arch Neurol 2001;58:1004-7", "H Wang, L Wang, J Yang, L Yin, L Lan, J Li, Q Zhang, D Wang, J Guan, Q. Wang. Phenotype prediction of Mohr-Tranebjaerg syndrome (MTS) by genetic analysis and initial auditory neuropathy.. BMC Med Genet. 2019;20:11" ]
6/2/2003
21/11/2019
24/3/2009
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ddx3x-ndd
ddx3x-ndd
[ "ATP-dependent RNA helicase DDX3X", "DDX3X", "DDX3X-Related Neurodevelopmental Disorder" ]
Bethany Johnson-Kerner, Lot Snijders Blok, Lindsey Suit, Julian Thomas, Tjitske Kleefstra, Elliott H Sherr
Summary The diagnosis of If the proband is female and represents a simplex case and if the Once the
## Diagnosis Formal diagnostic criteria for Developmental delay (DD) or mild to severe intellectual disability (ID) Hypotonia (primarily truncal) Behavior problems: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), inappropriate behavior, self-injurious behavior, poor impulse control and aggression Language impairment, often with significant verbal dyspraxia Borderline microcephaly Dysmorphic facial features. Although there are no characteristic dysmorphic features, a long and/or hypotonic face, a high and/or broad forehead, and a wide nasal bridge and/or bulbous upturned nasal tip are frequently observed ( Corpus callosum hypoplasia ranging from complete agenesis (rare) to a milder malformation with only a thin posterior body and splenium (common) Ventricular enlargement and/or keyhole-shaped temporal horns of the lateral ventricles Polymicrogyria Other. Decreased white matter volume, decreased cingulum bundle density, diminished anterior commissure, small pons and small inferior cerebellar vermis 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 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 small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on gene-targeted deletions/duplications are available. • Developmental delay (DD) or mild to severe intellectual disability (ID) • Hypotonia (primarily truncal) • Behavior problems: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), inappropriate behavior, self-injurious behavior, poor impulse control and aggression • Language impairment, often with significant verbal dyspraxia • Borderline microcephaly • Dysmorphic facial features. Although there are no characteristic dysmorphic features, a long and/or hypotonic face, a high and/or broad forehead, and a wide nasal bridge and/or bulbous upturned nasal tip are frequently observed ( • Corpus callosum hypoplasia ranging from complete agenesis (rare) to a milder malformation with only a thin posterior body and splenium (common) • Ventricular enlargement and/or keyhole-shaped temporal horns of the lateral ventricles • Polymicrogyria • Other. Decreased white matter volume, decreased cingulum bundle density, diminished anterior commissure, small pons and small inferior cerebellar vermis • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Developmental delay (DD) or mild to severe intellectual disability (ID) Hypotonia (primarily truncal) Behavior problems: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), inappropriate behavior, self-injurious behavior, poor impulse control and aggression Language impairment, often with significant verbal dyspraxia Borderline microcephaly Dysmorphic facial features. Although there are no characteristic dysmorphic features, a long and/or hypotonic face, a high and/or broad forehead, and a wide nasal bridge and/or bulbous upturned nasal tip are frequently observed ( Corpus callosum hypoplasia ranging from complete agenesis (rare) to a milder malformation with only a thin posterior body and splenium (common) Ventricular enlargement and/or keyhole-shaped temporal horns of the lateral ventricles Polymicrogyria Other. Decreased white matter volume, decreased cingulum bundle density, diminished anterior commissure, small pons and small inferior cerebellar vermis • Developmental delay (DD) or mild to severe intellectual disability (ID) • Hypotonia (primarily truncal) • Behavior problems: autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), inappropriate behavior, self-injurious behavior, poor impulse control and aggression • Language impairment, often with significant verbal dyspraxia • Borderline microcephaly • Dysmorphic facial features. Although there are no characteristic dysmorphic features, a long and/or hypotonic face, a high and/or broad forehead, and a wide nasal bridge and/or bulbous upturned nasal tip are frequently observed ( • Corpus callosum hypoplasia ranging from complete agenesis (rare) to a milder malformation with only a thin posterior body and splenium (common) • Ventricular enlargement and/or keyhole-shaped temporal horns of the lateral ventricles • Polymicrogyria • Other. Decreased white matter volume, decreased cingulum bundle density, diminished anterior commissure, small pons and small inferior cerebellar vermis ## 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 [ 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 small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on gene-targeted deletions/duplications are available. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Molecular Genetic Testing 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 small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on gene-targeted deletions/duplications are available. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Characteristics typically present are intellectual disability (ID), tone abnormalities, and associated feeding difficulty, joint laxity, and scoliosis. Other common features include ophthalmologic abnormalities, hearing loss, congenital heart defects, and respiratory difficulties. Neuroblastoma has been observed in three individuals, all of whom presented early in life and responded favorably to treatment. Clinical Findings in Females with NA = not applicable Note: Some overlap of participants exists in the three reported cohorts; to address the overlap, cohort 1 has been reported in its entirety and the overlaps subtracted from cohorts 2 and 3. One male overlaps in Reports 1 and 2, but (being male) is not counted in the table. Twenty of the 104 females in Report 3 were previously reported. DD = developmental delay; ID = intellectual disability; NA = not applicable (not specified or reported in the study) In In Evaluated by echocardiogram Systematic IQ testing has not been published for females with In another study, in which the parents of 53 affected girls used the Vineland Adaptive Behavior Scales (VABS) to self-report their child's adaptive behavioral skills, the mean composite standard score was 56.6, which is significantly below the mean score of 100 (standard deviation: 15) in the neurotypical population. In addition, affected individuals with polymicrogyria (PMG) were more delayed developmentally, with an average VABS of 43.8 versus 57.5 in those without PMG (p<0.05) [ Speech-language delays or disorders are common: After age five years, 52% of females with Neuroblastoma has been observed in three females ages 4-7 months [ A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [ To date, males from at least ten different families have been reported with a hemizygous In one report, two of five males had a head circumference more than two standard deviations below the mean [ Additional features similar to those reported in affected females included behavioral findings, spasticity, tremor, hypotonia, vision issues, congenital heart disease, and delayed puberty [ Polymicrogyria has been associated with missense or in-frame deletions [ Although In one study that included more than 6,000 individuals, variants in Another study reported that among approximately 450 genes, the occurrence of • Neuroblastoma has been observed in three females ages 4-7 months [ • A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [ • In one study that included more than 6,000 individuals, variants in • Another study reported that among approximately 450 genes, the occurrence of ## Clinical Description Characteristics typically present are intellectual disability (ID), tone abnormalities, and associated feeding difficulty, joint laxity, and scoliosis. Other common features include ophthalmologic abnormalities, hearing loss, congenital heart defects, and respiratory difficulties. Neuroblastoma has been observed in three individuals, all of whom presented early in life and responded favorably to treatment. Clinical Findings in Females with NA = not applicable Note: Some overlap of participants exists in the three reported cohorts; to address the overlap, cohort 1 has been reported in its entirety and the overlaps subtracted from cohorts 2 and 3. One male overlaps in Reports 1 and 2, but (being male) is not counted in the table. Twenty of the 104 females in Report 3 were previously reported. DD = developmental delay; ID = intellectual disability; NA = not applicable (not specified or reported in the study) In In Evaluated by echocardiogram Systematic IQ testing has not been published for females with In another study, in which the parents of 53 affected girls used the Vineland Adaptive Behavior Scales (VABS) to self-report their child's adaptive behavioral skills, the mean composite standard score was 56.6, which is significantly below the mean score of 100 (standard deviation: 15) in the neurotypical population. In addition, affected individuals with polymicrogyria (PMG) were more delayed developmentally, with an average VABS of 43.8 versus 57.5 in those without PMG (p<0.05) [ Speech-language delays or disorders are common: After age five years, 52% of females with Neuroblastoma has been observed in three females ages 4-7 months [ A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [ To date, males from at least ten different families have been reported with a hemizygous In one report, two of five males had a head circumference more than two standard deviations below the mean [ Additional features similar to those reported in affected females included behavioral findings, spasticity, tremor, hypotonia, vision issues, congenital heart disease, and delayed puberty [ • Neuroblastoma has been observed in three females ages 4-7 months [ • A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [ Systematic IQ testing has not been published for females with In another study, in which the parents of 53 affected girls used the Vineland Adaptive Behavior Scales (VABS) to self-report their child's adaptive behavioral skills, the mean composite standard score was 56.6, which is significantly below the mean score of 100 (standard deviation: 15) in the neurotypical population. In addition, affected individuals with polymicrogyria (PMG) were more delayed developmentally, with an average VABS of 43.8 versus 57.5 in those without PMG (p<0.05) [ Speech-language delays or disorders are common: After age five years, 52% of females with Neuroblastoma has been observed in three females ages 4-7 months [ A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [ • Neuroblastoma has been observed in three females ages 4-7 months [ • A pilocytic astrocytoma, incidentally found on head imaging, was reported in a female age eight years [ To date, males from at least ten different families have been reported with a hemizygous In one report, two of five males had a head circumference more than two standard deviations below the mean [ Additional features similar to those reported in affected females included behavioral findings, spasticity, tremor, hypotonia, vision issues, congenital heart disease, and delayed puberty [ ## Genotype-Phenotype Correlations Polymicrogyria has been associated with missense or in-frame deletions [ ## Prevalence Although In one study that included more than 6,000 individuals, variants in Another study reported that among approximately 450 genes, the occurrence of • In one study that included more than 6,000 individuals, variants in • Another study reported that among approximately 450 genes, the occurrence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic tumors (including medulloblastoma and lymphoma [ ## Differential Diagnosis Because the phenotypic features associated with Two females with features of Toriello-Carey syndrome (T-CS) (anal atresia, congenital heart defects, corpus callosum anomalies, hypotonia, and developmental delay) (OMIM ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Especially those w/FTT & feeding difficulties Consider autonomic instability in those w/syncope, tachycardia, &/or orthostatic hypotension Swallowing, feeding, & nutritional status assessment to determine safety of oral vs gastrostomy feeding Mgmt of constipation, if present Eval for scoliosis if referred by pediatrician Determination of DME needs Community or Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DME = durable medical equipment; FTT = failure to thrive; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment should be targeted to individual needs. Treatment of Manifestations in Individuals with For those w/scoliosis: consider bracing to prevent progression & secondary morbidity (e.g., pain, impaired ambulation, restrictive lung disease). For those w/hypotonia/hypertonia: consider ankle-foot orthoses. If hypertonia is present evaluate need for spasticity treatment (e.g., baclofen, Botox Consider need for positioning & mobility devices, disability parking placard. Many ASMs may be effective; none has been demonstrated effective specifically for 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 for need of home nursing Consider involvement in adaptive sports. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP should be developed by the local public school district based on results of the psychoeducational evaluation and the presence of a qualifying disability. IEP reevaluations will occur on a regular basis. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, residential living, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Families should establish guardianship or power of attorney as appropriate when their child reaches age 18 years. Use of private supportive therapies based on the affected individual's needs may be considered. 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 regardless of income. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) and/or Medicaid waivers for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Depending on the state and insurance type, ABA therapy can be difficult to access without a diagnosis of autism spectrum disorder. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Social/emotional and behavioral support within school can be obtained through the IEP. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Eval for effects of hypotonia PT follow up for gait abnormality If needs are present, PT assessment at least 1x/mo recommended Once stable, gradually ↓ frequency to 1x/yr. Follow up for possible seizures or for seizure mgmt Monitor for abnormal movements. FTT = failure to thrive; PT = physical therapy See Search • Especially those w/FTT & feeding difficulties • Consider autonomic instability in those w/syncope, tachycardia, &/or orthostatic hypotension • Swallowing, feeding, & nutritional status assessment to determine safety of oral vs gastrostomy feeding • Mgmt of constipation, if present • Eval for scoliosis if referred by pediatrician • Determination of DME needs • Community or • Social work involvement for parental support. • For those w/scoliosis: consider bracing to prevent progression & secondary morbidity (e.g., pain, impaired ambulation, restrictive lung disease). • For those w/hypotonia/hypertonia: consider ankle-foot orthoses. If hypertonia is present evaluate need for spasticity treatment (e.g., baclofen, Botox • Consider need for positioning & mobility devices, disability parking placard. • Many ASMs may be effective; none has been demonstrated effective specifically for • 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 for need of home nursing • Consider involvement in adaptive sports. • In the US, an IEP should be developed by the local public school district based on results of the psychoeducational evaluation and the presence of a qualifying disability. IEP reevaluations will occur on a regular basis. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, residential living, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Families should establish guardianship or power of attorney as appropriate when their child reaches age 18 years. • Use of private supportive therapies based on the affected individual's needs may be considered. 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 regardless of income. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) and/or Medicaid waivers for their child with a disability. • Eval for effects of hypotonia • PT follow up for gait abnormality • If needs are present, PT assessment at least 1x/mo recommended • Once stable, gradually ↓ frequency to 1x/yr. • Follow up for possible seizures or for seizure mgmt • Monitor for abnormal movements. ## 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 Especially those w/FTT & feeding difficulties Consider autonomic instability in those w/syncope, tachycardia, &/or orthostatic hypotension Swallowing, feeding, & nutritional status assessment to determine safety of oral vs gastrostomy feeding Mgmt of constipation, if present Eval for scoliosis if referred by pediatrician Determination of DME needs Community or Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DME = durable medical equipment; FTT = failure to thrive; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Especially those w/FTT & feeding difficulties • Consider autonomic instability in those w/syncope, tachycardia, &/or orthostatic hypotension • Swallowing, feeding, & nutritional status assessment to determine safety of oral vs gastrostomy feeding • Mgmt of constipation, if present • Eval for scoliosis if referred by pediatrician • Determination of DME needs • Community or • Social work involvement for parental support. ## Treatment of Manifestations Treatment should be targeted to individual needs. Treatment of Manifestations in Individuals with For those w/scoliosis: consider bracing to prevent progression & secondary morbidity (e.g., pain, impaired ambulation, restrictive lung disease). For those w/hypotonia/hypertonia: consider ankle-foot orthoses. If hypertonia is present evaluate need for spasticity treatment (e.g., baclofen, Botox Consider need for positioning & mobility devices, disability parking placard. Many ASMs may be effective; none has been demonstrated effective specifically for 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 for need of home nursing Consider involvement in adaptive sports. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP should be developed by the local public school district based on results of the psychoeducational evaluation and the presence of a qualifying disability. IEP reevaluations will occur on a regular basis. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, residential living, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Families should establish guardianship or power of attorney as appropriate when their child reaches age 18 years. Use of private supportive therapies based on the affected individual's needs may be considered. 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 regardless of income. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) and/or Medicaid waivers for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. Depending on the state and insurance type, ABA therapy can be difficult to access without a diagnosis of autism spectrum disorder. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Social/emotional and behavioral support within school can be obtained through the IEP. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • For those w/scoliosis: consider bracing to prevent progression & secondary morbidity (e.g., pain, impaired ambulation, restrictive lung disease). • For those w/hypotonia/hypertonia: consider ankle-foot orthoses. If hypertonia is present evaluate need for spasticity treatment (e.g., baclofen, Botox • Consider need for positioning & mobility devices, disability parking placard. • Many ASMs may be effective; none has been demonstrated effective specifically for • 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 for need of home nursing • Consider involvement in adaptive sports. • In the US, an IEP should be developed by the local public school district based on results of the psychoeducational evaluation and the presence of a qualifying disability. IEP reevaluations will occur on a regular basis. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, residential living, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Families should establish guardianship or power of attorney as appropriate when their child reaches age 18 years. • Use of private supportive therapies based on the affected individual's needs may be considered. 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 regardless of income. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) and/or Medicaid waivers for their child with a disability. ## Developmental Delay / Intellectual Disability Educational 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 should be developed by the local public school district based on results of the psychoeducational evaluation and the presence of a qualifying disability. IEP reevaluations will occur on a regular basis. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, residential living, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Families should establish guardianship or power of attorney as appropriate when their child reaches age 18 years. Use of private supportive therapies based on the affected individual's needs may be considered. 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 regardless of income. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) and/or Medicaid waivers for their child with a disability. • In the US, an IEP should be developed by the local public school district based on results of the psychoeducational evaluation and the presence of a qualifying disability. IEP reevaluations will occur on a regular basis. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, residential living, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Families should establish guardianship or power of attorney as appropriate when their child reaches age 18 years. • Use of private supportive therapies based on the affected individual's needs may be considered. 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 regardless of income. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) and/or Medicaid waivers for their child with a disability. ## 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. Depending on the state and insurance type, ABA therapy can be difficult to access without a diagnosis of autism spectrum disorder. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Social/emotional and behavioral support within school can be obtained through the IEP. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Eval for effects of hypotonia PT follow up for gait abnormality If needs are present, PT assessment at least 1x/mo recommended Once stable, gradually ↓ frequency to 1x/yr. Follow up for possible seizures or for seizure mgmt Monitor for abnormal movements. FTT = failure to thrive; PT = physical therapy • Eval for effects of hypotonia • PT follow up for gait abnormality • If needs are present, PT assessment at least 1x/mo recommended • Once stable, gradually ↓ frequency to 1x/yr. • Follow up for possible seizures or for seizure mgmt • Monitor for abnormal movements. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling All female probands reported to date with Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in a female proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred If parents have more than one affected child and if the The father of an affected male will not have the disorder nor will he be hemizygous for the If a male is the only affected family member (i.e., a simplex case), the mother may be an asymptomatic heterozygote or the affected male may have a If parents have more than one affected child and if the If the mother of an affected male has a DDX3X pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and would not be expected to manifest a neurodevelopmental phenotype (see Clinical Description, If a male proband represents a simplex case and if the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All female probands reported to date with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in a female proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred • If parents have more than one affected child and if the • The father of an affected male will not have the disorder nor will he be hemizygous for the • If a male is the only affected family member (i.e., a simplex case), the mother may be an asymptomatic heterozygote or the affected male may have a • If parents have more than one affected child and if the • If the mother of an affected male has a DDX3X pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and would not be expected to manifest a neurodevelopmental phenotype (see Clinical Description, • If a male proband represents a simplex case and if the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance All female probands reported to date with Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in a female proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred If parents have more than one affected child and if the • All female probands reported to date with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in a female proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred • If parents have more than one affected child and if the The father of an affected male will not have the disorder nor will he be hemizygous for the If a male is the only affected family member (i.e., a simplex case), the mother may be an asymptomatic heterozygote or the affected male may have a If parents have more than one affected child and if the If the mother of an affected male has a DDX3X pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and would not be expected to manifest a neurodevelopmental phenotype (see Clinical Description, If a male proband represents a simplex case and if the • The father of an affected male will not have the disorder nor will he be hemizygous for the • If a male is the only affected family member (i.e., a simplex case), the mother may be an asymptomatic heterozygote or the affected male may have a • If parents have more than one affected child and if the • If the mother of an affected male has a DDX3X pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and would not be expected to manifest a neurodevelopmental phenotype (see Clinical Description, • If a male proband represents a simplex case and if the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 100 West 10th Street Suite 115 Wilmington DE 19801 Unique Rare Chromosome Disorder Support Group United Kingdom Speaking out for People with Intellectual and Developmental Disabilities • • 100 West 10th Street • Suite 115 • Wilmington DE 19801 • • • Unique Rare Chromosome Disorder Support Group • • • • • • • • • • • • • United Kingdom • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics DDX3X-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DDX3X-Related Neurodevelopmental Disorder ( Although two studies suggested that Missense variants identified in male probands and unaffected heterozygous female relatives are thought to have a milder effect on protein function than the Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Although two studies suggested that Missense variants identified in male probands and unaffected heterozygous female relatives are thought to have a milder effect on protein function than the Notable Variants listed in the table have been provided by the authors. ## Chapter Notes 27 August 2020 (bp) Review posted live 21 November 2018 (tk,es) Original submission • 27 August 2020 (bp) Review posted live • 21 November 2018 (tk,es) Original submission ## Revision History 27 August 2020 (bp) Review posted live 21 November 2018 (tk,es) Original submission • 27 August 2020 (bp) Review posted live • 21 November 2018 (tk,es) Original submission ## References ## Literature Cited Facial profiles of females heterozygous for a de novo Facial features of 30 of 38 females with a From
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Hum Mutat. 2016;37:804-11", "M Garieri, G Stamoulis, X Blanc, E Falconnet, P Ribaux, C Borel, F Santoni, SE Antonarakis. Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts.. Proceedings of the National Academy of Sciences of the United States of America. 2018;115:13015-20", "L Jiang, ZH Gu, ZX Yan, X Zhao, YY Xie, ZG Zhang, CM Pan, Y Hu, CP Cai, Y Dong. Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma.. Nat Genet. 2015;47:1061-6", "DT Jones, N Jäger, M Kool, T Zichner, B Hutter, M Sultan, YJ Cho, TJ Pugh, V Hovestadt, AM Stütz. Dissecting the genomic complexity underlying medulloblastoma.. Nature. 2012;488:100-5", "Y Kanai, N Dohmae, N. Hirokawa. Kinesin transports RNA: isolation and characterization of an RNA-transporting granule.. Neuron. 2004;43:513-25", "G Kellaris, K Khan, SM Baig, IC Tsai, FM Zamora, P Ruggieri, MR Natowicz, N Katsanis. A hypomorphic inherited pathogenic variant in DDX3X causes male intellectual disability with additional neurodevelopmental and neurodegenerative features.. Hum Genomics. 2018;12:11", "AL Lennox, ML Hoye, R Jiang, BL Johnson-Kerner, LA Suit, S Venkataramanan, CJ Sheehan, FC Alsina, B Fregeau, KA Aldinger, C Moey, I Lobach, A Afenjar, D Babovic-Vuksanovic, S Bézieau, PR Blackburn, J Bunt, L Burglen, PM Campeau, P Charles, BHY Chung, B Cogné, C Curry, MD D'Agostino, N Di Donato, L Faivre, D Héron, AM Innes, B Isidor, B Keren, A Kimball, EW Klee, P Kuentz, S Küry, D Martin-Coignard, G Mirzaa, C Mignot, N Miyake, N Matsumoto, A Fujita, C Nava, M Nizon, D Rodriguez, LS Blok, C Thauvin-Robinet, J Thevenon, M Vincent, A Ziegler, W Dobyns, LJ Richards, AJ Barkovich, SN Floor, DL Silver, EH Sherr. Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development.. 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De novo DDX3X missense variants in males appear viable and contribute to syndromic intellectual disability.. Am J Med Genet A. 2019;179:570-8", "TJ Pugh, SD Weeraratne, TC Archer, DA Pomeranz Krummel, D Auclair, J Bochicchio, MO Carneiro, SL Carter, K Cibulskis, RL Erlich. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations.. Nature. 2012;488:106-10", "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", "G Robinson, M Parker, TA Kranenburg, C Lu, X Chen, L Ding, TN Phoenix, E Hedlund, L Wei, X Zhu. Novel mutations target distinct subgroups of medulloblastoma.. 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27/8/2020
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ddx41-mds
ddx41-mds
[ "DDX41-Related Myeloid Neoplasia", "Myeloid Neoplasms with Germline DDX41 Mutation", "DDX41-Related Myeloid Neoplasia", "Myeloid Neoplasms with Germline DDX41 Mutation", "Probable ATP-dependent RNA helicase DDX41", "DDX41", "DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia" ]
Jane E Churpek, Kelcy Smith-Simmer
Summary The diagnosis of
## Diagnosis Less common myeloid neoplasms include chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms. Unexplained blood count abnormalities including mild single- or multiple-lineage cytopenias and/or macrocytosis (in 40%-66%) In individuals with MDS/AML: Bone marrow hypocellularity Previous history of cytopenia Personal history of hematologic malignancy (including lymphoid) or solid cancer Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology Normal karyotype (in 59%-85%) One or more Absence of a known family history does not preclude the diagnosis; Only 27%-39% of individuals with a germline Penetrance of hematologic malignancies appears higher in males than females (3:1) which may result in a male-predominant familial hematologic malignancy pattern. The diagnosis of Note: (1) Malignant myeloid cells from individuals with a germline 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) Testing for a germline pathogenic variant should not be performed on blood, bone marrow, or other tissues contaminated with peripheral blood such as saliva, buccal cells, or DNA from direct skin biopsy without culture during an active hematologic malignancy or in individuals following allogeneic stem cell transplant. Testing of an uninvolved specimen, such as DNA derived from cultured skin fibroblasts, is imperative. (2) Testing of blood or bone marrow during complete remission from a hematologic malignancy may also be performed to detect a germline variant; however, residual somatic variants, especially those associated with clonal hematopoiesis, may be detected. This testing option should therefore be reserved for rare circumstances and confirmatory testing on DNA derived from cultured skin fibroblasts is recommended for any abnormal results. For an introduction to multigene panels click Given that the 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Less common myeloid neoplasms include chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms. • Unexplained blood count abnormalities including mild single- or multiple-lineage cytopenias and/or macrocytosis (in 40%-66%) • In individuals with MDS/AML: • Bone marrow hypocellularity • Previous history of cytopenia • Personal history of hematologic malignancy (including lymphoid) or solid cancer • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology • Normal karyotype (in 59%-85%) • One or more • Bone marrow hypocellularity • Previous history of cytopenia • Personal history of hematologic malignancy (including lymphoid) or solid cancer • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology • Normal karyotype (in 59%-85%) • One or more • Bone marrow hypocellularity • Previous history of cytopenia • Personal history of hematologic malignancy (including lymphoid) or solid cancer • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology • Normal karyotype (in 59%-85%) • One or more • Absence of a known family history does not preclude the diagnosis; Only 27%-39% of individuals with a germline • Penetrance of hematologic malignancies appears higher in males than females (3:1) which may result in a male-predominant familial hematologic malignancy pattern. ## Suggestive Findings Less common myeloid neoplasms include chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms. Unexplained blood count abnormalities including mild single- or multiple-lineage cytopenias and/or macrocytosis (in 40%-66%) In individuals with MDS/AML: Bone marrow hypocellularity Previous history of cytopenia Personal history of hematologic malignancy (including lymphoid) or solid cancer Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology Normal karyotype (in 59%-85%) One or more Absence of a known family history does not preclude the diagnosis; Only 27%-39% of individuals with a germline Penetrance of hematologic malignancies appears higher in males than females (3:1) which may result in a male-predominant familial hematologic malignancy pattern. • Less common myeloid neoplasms include chronic myelomonocytic leukemia, chronic myeloid leukemia, and myeloproliferative neoplasms. • Unexplained blood count abnormalities including mild single- or multiple-lineage cytopenias and/or macrocytosis (in 40%-66%) • In individuals with MDS/AML: • Bone marrow hypocellularity • Previous history of cytopenia • Personal history of hematologic malignancy (including lymphoid) or solid cancer • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology • Normal karyotype (in 59%-85%) • One or more • Bone marrow hypocellularity • Previous history of cytopenia • Personal history of hematologic malignancy (including lymphoid) or solid cancer • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology • Normal karyotype (in 59%-85%) • One or more • Bone marrow hypocellularity • Previous history of cytopenia • Personal history of hematologic malignancy (including lymphoid) or solid cancer • Prominent erythroid dysplasia, in some instances resulting in a French-American-British Cooperative Group AML Classification subtype M6 or erythroleukemia morphology • Normal karyotype (in 59%-85%) • One or more • Absence of a known family history does not preclude the diagnosis; Only 27%-39% of individuals with a germline • Penetrance of hematologic malignancies appears higher in males than females (3:1) which may result in a male-predominant familial hematologic malignancy pattern. ## Establishing the Diagnosis The diagnosis of Note: (1) Malignant myeloid cells from individuals with a germline 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) Testing for a germline pathogenic variant should not be performed on blood, bone marrow, or other tissues contaminated with peripheral blood such as saliva, buccal cells, or DNA from direct skin biopsy without culture during an active hematologic malignancy or in individuals following allogeneic stem cell transplant. Testing of an uninvolved specimen, such as DNA derived from cultured skin fibroblasts, is imperative. (2) Testing of blood or bone marrow during complete remission from a hematologic malignancy may also be performed to detect a germline variant; however, residual somatic variants, especially those associated with clonal hematopoiesis, may be detected. This testing option should therefore be reserved for rare circumstances and confirmatory testing on DNA derived from cultured skin fibroblasts is recommended for any abnormal results. For an introduction to multigene panels click Given that the 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 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 Given that the 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 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 Individuals with Myeloproliferative neoplasms, chronic myeloid leukemia, and chronic myelomonocytic leukemia with age of onset in late adulthood have also been reported [ There are conflicting data regarding prognosis of MDS/AML in those with Non-Hodgkin lymphoma (especially early-onset follicular lymphoma), Hodgkin lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have been reported in individuals with germline Adult-onset single- or multiple-lineage cytopenias and/or red blood cell macrocytosis are common [ No consistent genotype-phenotype correlations have been identified. Penetrance may be reduced. Only 27%-39% of individuals with a myeloid malignancy and a germline In the 2016 WHO classification of myeloid neoplasms and acute leukemia, Approximately 1.5%-6.1% of individuals presenting with MDS/AML have been found to have a germline ## Clinical Description Individuals with Myeloproliferative neoplasms, chronic myeloid leukemia, and chronic myelomonocytic leukemia with age of onset in late adulthood have also been reported [ There are conflicting data regarding prognosis of MDS/AML in those with Non-Hodgkin lymphoma (especially early-onset follicular lymphoma), Hodgkin lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have been reported in individuals with germline Adult-onset single- or multiple-lineage cytopenias and/or red blood cell macrocytosis are common [ ## Myeloid Neoplasms Individuals with Myeloproliferative neoplasms, chronic myeloid leukemia, and chronic myelomonocytic leukemia with age of onset in late adulthood have also been reported [ There are conflicting data regarding prognosis of MDS/AML in those with ## Lymphoid Neoplasms Non-Hodgkin lymphoma (especially early-onset follicular lymphoma), Hodgkin lymphoma, multiple myeloma, monoclonal gammopathy of undetermined significance, chronic lymphocytic leukemia, and acute lymphoblastic leukemia have been reported in individuals with germline ## Blood Count Abnormalities Adult-onset single- or multiple-lineage cytopenias and/or red blood cell macrocytosis are common [ ## Other ## Genotype-Phenotype Correlations No consistent genotype-phenotype correlations have been identified. ## Penetrance Penetrance may be reduced. Only 27%-39% of individuals with a myeloid malignancy and a germline ## Nomenclature In the 2016 WHO classification of myeloid neoplasms and acute leukemia, ## Prevalence Approximately 1.5%-6.1% of individuals presenting with MDS/AML have been found to have a germline ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Biallelic germline pathogenic variants in ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; AML = acute myeloid leukemia; CMML= chronic myelomonocytic leukemia; ET = essential thrombocythemia; MDS = myelodysplastic syndrome; MOI = mode of inheritance; PMF = primary myelofibrosis; PV = polycythemia vera The leukemic cells of most individuals with Sporadic hematologic malignancy with somatic Hematologic malignancy secondary to environmental exposures (e.g., benzene, radiation, chemotherapy) Note: MDS and AML are relatively rare disorders (~10,000 individuals are diagnosed with MDS and ~13,300 are diagnosed with AML each year in the US); therefore, the more affected individuals in a family (and the closer the relationships), the greater the likelihood of a common cause (i.e., a heritable predisposition or a common exposure) [ • Sporadic hematologic malignancy with somatic • Hematologic malignancy secondary to environmental exposures (e.g., benzene, radiation, chemotherapy) ## 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 In those w/cytopenia(s) &/or macrocytosis Consider in healthy persons w/normal blood counts on an individual basis. AML = acute myeloid leukemia; CBC = complete blood count; MDS = myelodysplastic syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Standard neoplasm-specific therapy Allogeneic HSCT eval early in the course of hematologic malignancy if appropriate based on person's age, malignancy, & health status to allow time for identification & genotyping of potential related donors Related donors w/o a A HSCT = hematopoietic stem cell transplantation Due to lack of data and observation of individuals with A careful risk/benefit discussion with the recipient & donor, taking into account alternative donor options & their known risk/benefit profiles & timelines for recipient’s needs, is necessary. Donor-derived leukemia has occurred w/use of a related donor who had a familial No evidence-based guidelines on the type of testing or frequency of surveillance for Recommended Surveillance for Individuals with AML = acute myeloid leukemia; CBC = complete blood count; MDS = myelodysplastic syndrome Avoid (if possible) stem cell transplant from related donors who have the familial Avoid smoking, chemical exposure, and unnecessary radiation, as these may increase the risk of developing hematologic malignancy. Clinical monitoring (see Note: There are currently no preemptive treatments available for asymptomatic individuals who have a germline See Although hematologic malignancy onset is typically well beyond years overlapping with childbearing, if the family history suggests earlier onset, a complete blood count with differential can be performed prior to pregnancy to ensure no baseline abnormalities that would require additional hematologic evaluation. If new or worsening blood count abnormalities develop during pregnancy, urgent referral to a hematologist with expertise in this disorder is recommended. See Responsiveness to lenalidomide for Search • In those w/cytopenia(s) &/or macrocytosis • Consider in healthy persons w/normal blood counts on an individual basis. • Standard neoplasm-specific therapy • Allogeneic HSCT eval early in the course of hematologic malignancy if appropriate based on person's age, malignancy, & health status to allow time for identification & genotyping of potential related donors • Related donors w/o a • A ## 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 In those w/cytopenia(s) &/or macrocytosis Consider in healthy persons w/normal blood counts on an individual basis. AML = acute myeloid leukemia; CBC = complete blood count; MDS = myelodysplastic syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • In those w/cytopenia(s) &/or macrocytosis • Consider in healthy persons w/normal blood counts on an individual basis. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Standard neoplasm-specific therapy Allogeneic HSCT eval early in the course of hematologic malignancy if appropriate based on person's age, malignancy, & health status to allow time for identification & genotyping of potential related donors Related donors w/o a A HSCT = hematopoietic stem cell transplantation Due to lack of data and observation of individuals with A careful risk/benefit discussion with the recipient & donor, taking into account alternative donor options & their known risk/benefit profiles & timelines for recipient’s needs, is necessary. Donor-derived leukemia has occurred w/use of a related donor who had a familial • Standard neoplasm-specific therapy • Allogeneic HSCT eval early in the course of hematologic malignancy if appropriate based on person's age, malignancy, & health status to allow time for identification & genotyping of potential related donors • Related donors w/o a • A ## Surveillance No evidence-based guidelines on the type of testing or frequency of surveillance for Recommended Surveillance for Individuals with AML = acute myeloid leukemia; CBC = complete blood count; MDS = myelodysplastic syndrome ## Agents/Circumstances to Avoid Avoid (if possible) stem cell transplant from related donors who have the familial Avoid smoking, chemical exposure, and unnecessary radiation, as these may increase the risk of developing hematologic malignancy. ## Evaluation of Relatives at Risk Clinical monitoring (see Note: There are currently no preemptive treatments available for asymptomatic individuals who have a germline See ## Pregnancy Management Although hematologic malignancy onset is typically well beyond years overlapping with childbearing, if the family history suggests earlier onset, a complete blood count with differential can be performed prior to pregnancy to ensure no baseline abnormalities that would require additional hematologic evaluation. If new or worsening blood count abnormalities develop during pregnancy, urgent referral to a hematologist with expertise in this disorder is recommended. See ## Therapies Under Investigation Responsiveness to lenalidomide for Search ## Genetic Counseling To date, all reported 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, if available, to confirm their genetic status and to allow reliable recurrence risk counseling. Since the majority of probands will be adults at the time of diagnosis, parents may be deceased and unavailable. In this situation, testing of extended blood relatives (e.g., aunts, uncles, and first cousins) is recommended. 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 The likelihood that a sib who inherits a familial If the If the parents have not been tested for the Note: If the reproductive partner of a proband is also heterozygous for a germline See Management, Because clinical monitoring of individuals with a familial For more information, see also the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk in offspring of persons with a germline It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of Partners of individuals known to be heterozygous for a germline 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 • To date, all reported 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, if available, to confirm their genetic status and to allow reliable recurrence risk counseling. Since the majority of probands will be adults at the time of diagnosis, parents may be deceased and unavailable. In this situation, testing of extended blood relatives (e.g., aunts, uncles, and first cousins) is recommended. • 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 • The likelihood that a sib who inherits a familial • If the • If the parents have not been tested for the • Because clinical monitoring of individuals with a familial • For more information, see also the National Society of Genetic Counselors • The optimal time for determination of genetic risk in offspring of persons with a germline • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of • Partners of individuals known to be heterozygous for a germline ## Mode of Inheritance ## Risk to Family Members To date, all reported 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, if available, to confirm their genetic status and to allow reliable recurrence risk counseling. Since the majority of probands will be adults at the time of diagnosis, parents may be deceased and unavailable. In this situation, testing of extended blood relatives (e.g., aunts, uncles, and first cousins) is recommended. 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 The likelihood that a sib who inherits a familial If the If the parents have not been tested for the Note: If the reproductive partner of a proband is also heterozygous for a germline • To date, all reported 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, if available, to confirm their genetic status and to allow reliable recurrence risk counseling. Since the majority of probands will be adults at the time of diagnosis, parents may be deceased and unavailable. In this situation, testing of extended blood relatives (e.g., aunts, uncles, and first cousins) is recommended. • 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 • The likelihood that a sib who inherits a familial • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, Because clinical monitoring of individuals with a familial For more information, see also the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk in offspring of persons with a germline It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of Partners of individuals known to be heterozygous for a germline • Because clinical monitoring of individuals with a familial • For more information, see also the National Society of Genetic Counselors • The optimal time for determination of genetic risk in offspring of persons with a germline • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have a molecular diagnosis of • Partners of individuals known to be heterozygous for a germline ## 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 4330 East West Highway Suite 230 Bethesda MD 20814 1311 Mamaroneck Avenue Suite 310 White Plains NY 10605 4573 South Broad Street Suite 150 Yardville NJ 08620 • • 4330 East West Highway • Suite 230 • Bethesda MD 20814 • • • 1311 Mamaroneck Avenue • Suite 310 • White Plains NY 10605 • • • • • 4573 South Broad Street • Suite 150 • Yardville NJ 08620 • ## Molecular Genetics DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DDX41-Associated Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia ( The DDX41 protein has four main structural regions: N-terminal domain, DEAD-box domain, helicase C domain, and C-terminal domain. Known germline pathogenic variants include frameshift variants throughout the gene, missense variants often affecting the highly conserved DEAD-box domain and helicase C domains but also occurring throughout the gene, and splicing region variants [ Notable Variants listed in the table have been provided by the authors. Sporadic hematologic neoplasms (e.g., MDS, AML) may occur as single tumors in the absence of any other findings of ## Molecular Pathogenesis The DDX41 protein has four main structural regions: N-terminal domain, DEAD-box domain, helicase C domain, and C-terminal domain. Known germline pathogenic variants include frameshift variants throughout the gene, missense variants often affecting the highly conserved DEAD-box domain and helicase C domains but also occurring throughout the gene, and splicing region variants [ Notable Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors Sporadic hematologic neoplasms (e.g., MDS, AML) may occur as single tumors in the absence of any other findings of ## Chapter Notes Dr Jane Churpek is hematologist/oncologist whose clinical practice and research focuses on the care of adults with low blood counts due to acquired and inherited causes, including clonal hematopoiesis, myelodysplastic syndrome, inherited bone marrow failure syndromes, and various other hereditary cancer predisposition syndromes. Web page: Kelcy Smith-Simmer is a certified genetic counselor who sees both adult and pediatric patients as well as their family members for germline genetic evaluation of hereditary hematology, inherited bone marrow failure, and hereditary cancer syndromes. Web page: Dr Churpek and Mrs Smith-Simmer are also a part of the North American & Australian We would like to thank the individuals and families with 28 October 2021 (sw) Review posted live 3 July 2021 (jec) Original submission • 28 October 2021 (sw) Review posted live • 3 July 2021 (jec) Original submission ## Author Notes Dr Jane Churpek is hematologist/oncologist whose clinical practice and research focuses on the care of adults with low blood counts due to acquired and inherited causes, including clonal hematopoiesis, myelodysplastic syndrome, inherited bone marrow failure syndromes, and various other hereditary cancer predisposition syndromes. Web page: Kelcy Smith-Simmer is a certified genetic counselor who sees both adult and pediatric patients as well as their family members for germline genetic evaluation of hereditary hematology, inherited bone marrow failure, and hereditary cancer syndromes. Web page: Dr Churpek and Mrs Smith-Simmer are also a part of the North American & Australian ## Acknowledgments We would like to thank the individuals and families with ## Revision History 28 October 2021 (sw) Review posted live 3 July 2021 (jec) Original submission • 28 October 2021 (sw) Review posted live • 3 July 2021 (jec) Original submission ## References ## Literature Cited
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Br J Haematol. 2008;140:123-32", "C Polprasert, I Schulze, MA Sekeres, H Makishima, B Przychodzen, N Hosono, J Singh, RA Padgett, X Gu, JG Phillips, M Clemente, Y Parker, D Lindner, B Dienes, E Jankowsky, Y Saunthararajah, Y Du, K Oakley, N Nguyen, S Mukherjee, C Pabst, LA Godley, JE Churpek, DA Pollyea, U Krug, WE Berdel, HU Klein, M Dugas, Y Shiraishi, K Chiba, H Tanaka, S Miyano, K Yoshida, S Ogawa, C Müller-Tidow, JP Maciejewski. Inherited and somatic defects in DDX41 in myeloid neoplasms.. Cancer Cell. 2015;27:658-70", "C Polprasert, J Takeda, P Niparuck, T Rattanathammethee, A Pirunsarn, A Suksusut, S Kobbuaklee, K Wudhikarn, P Lawasut, S Kongkiatkamon, S Chuncharunee, K Songserm, P Phowthongkum, U Bunworasate, Y Nannya, K Yoshida, H Makishima, S Ogawa, P. Rojnuckarin. Novel DDX41 variants in Thai patients with myeloid neoplasms.. Int J Hematol. 2020;111:241-6", "S Qu, B Li, T Qin, Z Xu, L Pan, N Hu, G Huang, R Peter Gale, Z. Xiao. Molecular and clinical features of myeloid neoplasms with somatic DDX41 mutations.. Br J Haematol. 2021;192:1006-10", "AE Quesada, MJ Routbort, CD DiNardo, CE Bueso-Ramos, R Kanagal-Shamanna, JD Khoury, B Thakral, Z Zuo, CC Yin, S Loghavi, CY Ok, SA Wang, Z Tang, SA Bannon, CB Benton, G Garcia-Manero, H Kantarjian, R Luthra, LJ Medeiros, KP Patel. DDX41 mutations in myeloid neoplasms are associated with male gender, TP53 mutations and high-risk disease.. Am J Hematol. 2019;94:757-66", "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 Sébert, M Passet, A Raimbault, R Rahmé, E Raffoux, F Sicre de Fontbrune, M Cerrano, S Quentin, N Vasquez, M Da Costa, N Boissel, H Dombret, R Peffault de Latour, G Socié, R Itzykson, P Fenaux, J Soulier, L Adès, E. Clappier. 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Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production.. Dev Cell. 2021;56:627-640.e5" ]
28/10/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
deafness-overview
deafness-overview
[ "Nonsyndromic Hearing Loss and Deafness", "Actin, cytoplasmic 2", "Alpha-tectorin", "Barttin", "Cadherin-23", "Claudin-14", "Cochlin", "Coiled-coil domain-containing protein 50", "Collagen alpha-2(XI) chain", "Cytochrome c oxidase subunit 1", "Dentin sialophosphoprotein", "Endosomal transmembrane epsin interactor 1", "Espin", "Gap junction beta-2 protein", "Gap junction beta-3 protein", "Gap junction beta-6 protein", "Gasdermin-E", "Glutaredoxin domain-containing cysteine-rich protein 1", "G-protein-signaling modulator 2", "Grainyhead-like protein 2 homolog", "Harmonin", "Hepatocyte growth factor", "Homeobox protein SIX1", "LHFPL tetraspan subfamily member 5 protein", "Lipoxygenase homology domain-containing protein 1", "MARVEL domain-containing protein 2", "Myosin-14", "Myosin-9", "Myosin-IIIa", "Nesprin-4", "Not applicable", "Otoancorin", "Otoferlin", "P2X purinoceptor 2", "Pejvakin", "Pendrin", "Phosphatidylinositol phosphatase PTPRQ", "Potassium voltage-gated channel subfamily KQT member 4", "POU domain, class 3, transcription factor 4", "POU domain, class 4, transcription factor 3", "Prestin", "Protein diaphanous homolog 1", "Protein phosphatase EYA4", "Protocadherin-15", "Radixin", "Ribose-phosphate pyrophosphokinase 1", "Small muscular protein", "Stereocilin", "Steroid hormone receptor ERR2", "Taperin", "Tight junction protein 2", "Transmembrane channel-like protein 1", "Transmembrane inner ear expressed protein", "Transmembrane O-methyltransferase", "Transmembrane protease serine 3", "TRIO and F-actin-binding protein", "Unconventional myosin-Ia", "Unconventional myosin-VI", "Unconventional myosin-VIIa", "Unconventional myosin-XV", "Vesicular glutamate transporter 3", "Whirlin", "Wolframin", "ACTG1", "BSND", "CCDC50", "CDH23", "CLDN14", "COCH", "COL11A2", "DIAPH1", "DSPP", "ENTREP1", "ESPN", "ESRRB", "EYA4", "GJB2", "GJB3", "GJB6", "GPSM2", "GRHL2", "GRXCR1", "GSDME", "HGF", "KCNQ4", "LHFPL5", "LOXHD1", "LRTOMT", "MARVELD2", "MIR96", "MT-CO1", "MT-RNR1", "MT-TS1", "MYH14", "MYH9", "MYO15A", "MYO1A", "MYO3A", "MYO6", "MYO7A", "OTOA", "OTOF", "P2RX2", "PCDH15", "PJVK", "POU3F4", "POU4F3", "PRPS1", "PTPRQ", "RDX", "SIX1", "SLC17A8", "SLC26A4", "SLC26A5", "SMPX", "STRC", "SYNE4", "TECTA", "TJP2", "TMC1", "TMIE", "TMPRSS3", "TPRN", "TRIOBP", "USH1C", "WFS1", "WHRN", "Genetic Hearing Loss Overview", "Overview" ]
Genetic Hearing Loss Overview
A Eliot Shearer, Michael S Hildebrand, Amanda M Odell, Richard JH Smith
Summary The purpose of this Describe the Review the Review the Explain the Review the Inform the
## Audiometric and Clinical Aspects of Hearing Loss Hearing loss can be characterized by type, onset, severity, and frequency. Conductive hearing loss, due to abnormalities of the external ear and/or the ossicles of the middle ear Sensorineural hearing loss due to malfunction of the inner ear structures (i.e., cochlea or auditory nerve, with potential for vestibular dysfunction) Mixed hearing loss, a combination of conductive and sensorineural hearing loss Central auditory dysfunction, due to damage or dysfunction at the level of the eighth cranial nerve (auditory nerve), the auditory brain stem (medulla, pons, and midbrain), or the cerebral cortex Congenital (present at birth) Prelingual (occurring before the acquisition of speech) Postlingual (occurring after the acquisition of speech) Adult (occurring after age 18 years) Presbycusis (age-related hearing loss that typically occurs after middle age) Severity of Hearing Loss in Decibels (dB) Human Hearing by Frequency of Sound Bilateral symmetric Bilateral asymmetric Unilateral Low frequency, upsloping, or rising Mid-frequency, "cookie bite" High frequency, downsloping Flat Visual response audiometry: age <2.5 years Conditioned play audiometry: age 2.5-5 years Conventional audiometry: age >5 years Auditory brain stem response (ABR, also called brain stem auditory evoked response, or BAER), which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. Automated ABR may be used in newborn hearing screening. Diagnostic ABR is used for assessment of transmission of auditory stimuli from the ear to the brain. Otoacoustic emissions (OAE), which measure the response of the cochlea to auditory stimulus. OAE may be used in newborn hearing screening. Air conduction tests measure responses from auditory stimuli presented through the external auditory canal. Bone conduction tests measure responses from auditory stimuli transmitted through the bone near the inner ear. • Conductive hearing loss, due to abnormalities of the external ear and/or the ossicles of the middle ear • Sensorineural hearing loss due to malfunction of the inner ear structures (i.e., cochlea or auditory nerve, with potential for vestibular dysfunction) • Mixed hearing loss, a combination of conductive and sensorineural hearing loss • Central auditory dysfunction, due to damage or dysfunction at the level of the eighth cranial nerve (auditory nerve), the auditory brain stem (medulla, pons, and midbrain), or the cerebral cortex • Congenital (present at birth) • Prelingual (occurring before the acquisition of speech) • Postlingual (occurring after the acquisition of speech) • Adult (occurring after age 18 years) • Presbycusis (age-related hearing loss that typically occurs after middle age) • Bilateral symmetric • Bilateral asymmetric • Unilateral • Low frequency, upsloping, or rising • Mid-frequency, "cookie bite" • High frequency, downsloping • Flat • Visual response audiometry: age <2.5 years • Conditioned play audiometry: age 2.5-5 years • Conventional audiometry: age >5 years • Visual response audiometry: age <2.5 years • Conditioned play audiometry: age 2.5-5 years • Conventional audiometry: age >5 years • Auditory brain stem response (ABR, also called brain stem auditory evoked response, or BAER), which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. Automated ABR may be used in newborn hearing screening. Diagnostic ABR is used for assessment of transmission of auditory stimuli from the ear to the brain. • Otoacoustic emissions (OAE), which measure the response of the cochlea to auditory stimulus. OAE may be used in newborn hearing screening. • Auditory brain stem response (ABR, also called brain stem auditory evoked response, or BAER), which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. Automated ABR may be used in newborn hearing screening. Diagnostic ABR is used for assessment of transmission of auditory stimuli from the ear to the brain. • Otoacoustic emissions (OAE), which measure the response of the cochlea to auditory stimulus. OAE may be used in newborn hearing screening. • Air conduction tests measure responses from auditory stimuli presented through the external auditory canal. • Bone conduction tests measure responses from auditory stimuli transmitted through the bone near the inner ear. • Air conduction tests measure responses from auditory stimuli presented through the external auditory canal. • Bone conduction tests measure responses from auditory stimuli transmitted through the bone near the inner ear. • Visual response audiometry: age <2.5 years • Conditioned play audiometry: age 2.5-5 years • Conventional audiometry: age >5 years • Auditory brain stem response (ABR, also called brain stem auditory evoked response, or BAER), which measures physiologic response of the auditory nerve, brain stem, and brain to varying auditory stimuli. Automated ABR may be used in newborn hearing screening. Diagnostic ABR is used for assessment of transmission of auditory stimuli from the ear to the brain. • Otoacoustic emissions (OAE), which measure the response of the cochlea to auditory stimulus. OAE may be used in newborn hearing screening. • Air conduction tests measure responses from auditory stimuli presented through the external auditory canal. • Bone conduction tests measure responses from auditory stimuli transmitted through the bone near the inner ear. ## Causes of Genetic Hearing Loss Hearing loss is not a diagnosis; rather, hearing loss is a symptom of an underlying pathologic change to the auditory system. Eighty percent of prelingual hearing loss is attributed to genetic causes; likewise, a genetic cause can be identified in a signification proportion of individuals with adult-onset hearing loss (see As of this writing, more than 125 genes are associated with nonsyndromic hearing loss (a regularly updated, comprehensive list of identified nonsyndromic hearing loss genes is available at the Approximately 70% of prelingual genetic hearing loss is nonsyndromic (see As of this writing, more than 70 genes have been associated with autosomal recessive nonsyndromic hearing loss. In general, autosomal recessive nonsyndromic hearing loss is prelingual and severe to profound. However, there is a spectrum of degrees of hearing loss, and exceptions to this generalization and/or distinctive features associated with selected genes are summarized in Note: Autosomal Recessive Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes HL can be progressive & postlingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL & AR syndromic HL (See HL can be pre- or postlingual, asymmetric, & progressive. Assoc w/phenotypic spectrum incl AR nonsyndromic HL (nonsyndromic enlarged vestibular aqueduct [NSEVA]) & AR syndromic HL (Pendred syndrome [PDS]). When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high, as pathogenic variants in Biallelic genetic alterations involving Biallelic contiguous gene deletions involving See AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss Nonsyndromic deafness loci are designated DFN (for As of this writing, 50 genes have been associated with autosomal dominant nonsyndromic hearing loss. In general, autosomal dominant nonsyndromic hearing loss is postlingual, progressive, and high frequency. Exceptions to this generalization and/or distinctive features associated with selected genes are summarized in Note: Autosomal Dominant Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes HL is prelingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss As of this writing, five genes ( Distinctive features associated with selected genes are summarized in X-Linked Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes Hearing loss = HL; XL = X-linked Nonsyndromic deafness loci are designated DFN (for Mitochondrial DNA-associated hearing loss is inherited in a maternal manner. Most mtDNA hearing loss is syndromic and involves a broad spectrum of multisystem disorders. Exceptions include the genes At the time of this writing, Syndromic hearing loss accounts for about 20% of prelingual genetic hearing loss. The contribution of syndromic hearing loss to later-onset hearing loss is an active focus of research but is not currently known. Select Common Causes of Autosomal Dominant Syndromic Hearing Loss Cranial nerve VIII dysfunction/anomaly: SNHL &/or vestibular dysfunction Cochlear implantation may be difficult or impossible due to altered cochleovestibular anomalies. Other cranial neuropathies may also be present. Ear malformations such as ossicular malformations assoc w/complex mixed HL 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). Conductive HL can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. Most common type of AD syndromic HL Hearing loss, pigmentary anomalies (white forelock), & dystopium canthorum (widely spaced medial canthus) are most commonly seen clinical features. Various temporal bone abnormalities have been identified in persons w/WS1 & HL. WS2, WS3, & WS4 can be inherited in an AD or AR manner. 2nd most common type of AD syndromic HL Kidney abnormalities Branchial anomalies (branchial cleft tags, pits, cysts) Malformations of outer, middle, & inner ear (e.g., preauricular pits) Bilateral vestibular schwannomas w/assoc symptoms of tinnitus, HL, & balance dysfunction Vestibular schwannomas are a rare, potentially treatable type of HL. AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss; SNHL = sensorineural hearing loss; WS = Waardenburg syndrome Select Common Causes of Autosomal Recessive Syndromic Hearing Loss Usher syndrome overall is the most common type of AR syndromic HL. Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. Intact or variable vestibular responses Usher syndrome overall is the most common type of AR syndromic HL; USH1 is the most common type of Usher syndrome. Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. Unless fitted w/cochlear implant, affected persons do not typically develop speech. Severe vestibular dysfunction or vestibular areflexia. Imbalance is assoc w/HL & is defining feature of USH1. Children typically walk later than usual, at age ~18 mos-2 yrs. 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). Conductive hearing loss can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. 3rd most common type of AR syndromic HL HL & cardiac conduction anomalies Classic presentation is a child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of affected persons had cardiac events before age 3 yrs. See ZSD is due to peroxisome disorder & incl hearing & vision loss, hypotonia, & other clinical features. Milder ZSD may first come to attention due to failed hearing screening. RP, anosmia, neuropathy, ataxia, & HL Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brain stem evoked responses. Persons w/auditory nerve involvement may experience hearing difficulty even in presence of normal audiogram. 2nd most common type of AR syndromic HL HL, vestibular dysfunction, & thyroid goiter HL may fluctuate but often progresses. Vestibular dysfunction should be suspected in infants w/delayed walking. Temporal bones are abnormal radiologically in all persons w/PDS & most commonly incl incomplete partition type II anomaly & enlarged vestibular aqueduct. AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HL = hearing loss; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss Digenic inheritance, in which an affected individual has double heterozygosity for a pathogenic variant in Select Common Causes of X-Linked Syndromic Hearing Loss SNHL = sensorineural hearing loss Three modes of inheritance are recognized for Alport syndrome: X-linked ( • HL can be progressive & postlingual. • Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL & AR syndromic HL (See • HL can be pre- or postlingual, asymmetric, & progressive. • Assoc w/phenotypic spectrum incl AR nonsyndromic HL (nonsyndromic enlarged vestibular aqueduct [NSEVA]) & AR syndromic HL (Pendred syndrome [PDS]). When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high, as pathogenic variants in • Biallelic genetic alterations involving • Biallelic contiguous gene deletions involving • See • HL is prelingual. • Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL • Cranial nerve VIII dysfunction/anomaly: SNHL &/or vestibular dysfunction • Cochlear implantation may be difficult or impossible due to altered cochleovestibular anomalies. • Other cranial neuropathies may also be present. • Ear malformations such as ossicular malformations assoc w/complex mixed HL • 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). • Conductive HL can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. • Most common type of AD syndromic HL • Hearing loss, pigmentary anomalies (white forelock), & dystopium canthorum (widely spaced medial canthus) are most commonly seen clinical features. • Various temporal bone abnormalities have been identified in persons w/WS1 & HL. • WS2, WS3, & WS4 can be inherited in an AD or AR manner. • 2nd most common type of AD syndromic HL • Kidney abnormalities • Branchial anomalies (branchial cleft tags, pits, cysts) • Malformations of outer, middle, & inner ear (e.g., preauricular pits) • Bilateral vestibular schwannomas w/assoc symptoms of tinnitus, HL, & balance dysfunction • Vestibular schwannomas are a rare, potentially treatable type of HL. • Usher syndrome overall is the most common type of AR syndromic HL. • Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. • Intact or variable vestibular responses • Usher syndrome overall is the most common type of AR syndromic HL; USH1 is the most common type of Usher syndrome. • Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. • Unless fitted w/cochlear implant, affected persons do not typically develop speech. • Severe vestibular dysfunction or vestibular areflexia. Imbalance is assoc w/HL & is defining feature of USH1. Children typically walk later than usual, at age ~18 mos-2 yrs. • 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). • Conductive hearing loss can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. • 3rd most common type of AR syndromic HL • HL & cardiac conduction anomalies • Classic presentation is a child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of affected persons had cardiac events before age 3 yrs. • See • ZSD is due to peroxisome disorder & incl hearing & vision loss, hypotonia, & other clinical features. • Milder ZSD may first come to attention due to failed hearing screening. • RP, anosmia, neuropathy, ataxia, & HL • Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brain stem evoked responses. Persons w/auditory nerve involvement may experience hearing difficulty even in presence of normal audiogram. • 2nd most common type of AR syndromic HL • HL, vestibular dysfunction, & thyroid goiter • HL may fluctuate but often progresses. • Vestibular dysfunction should be suspected in infants w/delayed walking. • Temporal bones are abnormal radiologically in all persons w/PDS & most commonly incl incomplete partition type II anomaly & enlarged vestibular aqueduct. ## Nonsyndromic Hearing Loss As of this writing, more than 125 genes are associated with nonsyndromic hearing loss (a regularly updated, comprehensive list of identified nonsyndromic hearing loss genes is available at the Approximately 70% of prelingual genetic hearing loss is nonsyndromic (see As of this writing, more than 70 genes have been associated with autosomal recessive nonsyndromic hearing loss. In general, autosomal recessive nonsyndromic hearing loss is prelingual and severe to profound. However, there is a spectrum of degrees of hearing loss, and exceptions to this generalization and/or distinctive features associated with selected genes are summarized in Note: Autosomal Recessive Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes HL can be progressive & postlingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL & AR syndromic HL (See HL can be pre- or postlingual, asymmetric, & progressive. Assoc w/phenotypic spectrum incl AR nonsyndromic HL (nonsyndromic enlarged vestibular aqueduct [NSEVA]) & AR syndromic HL (Pendred syndrome [PDS]). When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high, as pathogenic variants in Biallelic genetic alterations involving Biallelic contiguous gene deletions involving See AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss Nonsyndromic deafness loci are designated DFN (for As of this writing, 50 genes have been associated with autosomal dominant nonsyndromic hearing loss. In general, autosomal dominant nonsyndromic hearing loss is postlingual, progressive, and high frequency. Exceptions to this generalization and/or distinctive features associated with selected genes are summarized in Note: Autosomal Dominant Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes HL is prelingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss As of this writing, five genes ( Distinctive features associated with selected genes are summarized in X-Linked Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes Hearing loss = HL; XL = X-linked Nonsyndromic deafness loci are designated DFN (for Mitochondrial DNA-associated hearing loss is inherited in a maternal manner. Most mtDNA hearing loss is syndromic and involves a broad spectrum of multisystem disorders. Exceptions include the genes • HL can be progressive & postlingual. • Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL & AR syndromic HL (See • HL can be pre- or postlingual, asymmetric, & progressive. • Assoc w/phenotypic spectrum incl AR nonsyndromic HL (nonsyndromic enlarged vestibular aqueduct [NSEVA]) & AR syndromic HL (Pendred syndrome [PDS]). When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high, as pathogenic variants in • Biallelic genetic alterations involving • Biallelic contiguous gene deletions involving • See • HL is prelingual. • Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL ## Autosomal Recessive Nonsyndromic Hearing Loss As of this writing, more than 70 genes have been associated with autosomal recessive nonsyndromic hearing loss. In general, autosomal recessive nonsyndromic hearing loss is prelingual and severe to profound. However, there is a spectrum of degrees of hearing loss, and exceptions to this generalization and/or distinctive features associated with selected genes are summarized in Note: Autosomal Recessive Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes HL can be progressive & postlingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL & AR syndromic HL (See HL can be pre- or postlingual, asymmetric, & progressive. Assoc w/phenotypic spectrum incl AR nonsyndromic HL (nonsyndromic enlarged vestibular aqueduct [NSEVA]) & AR syndromic HL (Pendred syndrome [PDS]). When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high, as pathogenic variants in Biallelic genetic alterations involving Biallelic contiguous gene deletions involving See AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss Nonsyndromic deafness loci are designated DFN (for • HL can be progressive & postlingual. • Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL & AR syndromic HL (See • HL can be pre- or postlingual, asymmetric, & progressive. • Assoc w/phenotypic spectrum incl AR nonsyndromic HL (nonsyndromic enlarged vestibular aqueduct [NSEVA]) & AR syndromic HL (Pendred syndrome [PDS]). When PDS/NSEVA are considered part of the same disease spectrum, prevalence rates are very high, as pathogenic variants in • Biallelic genetic alterations involving • Biallelic contiguous gene deletions involving • See ## Autosomal Dominant Nonsyndromic Hearing Loss As of this writing, 50 genes have been associated with autosomal dominant nonsyndromic hearing loss. In general, autosomal dominant nonsyndromic hearing loss is postlingual, progressive, and high frequency. Exceptions to this generalization and/or distinctive features associated with selected genes are summarized in Note: Autosomal Dominant Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes HL is prelingual. Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss • HL is prelingual. • Assoc w/phenotypic spectrum incl AR & AD nonsyndromic HL ## X-Linked Nonsyndromic Hearing Loss As of this writing, five genes ( Distinctive features associated with selected genes are summarized in X-Linked Nonsyndromic Hearing Loss: Distinctive Features Associated with Selected Genes Hearing loss = HL; XL = X-linked Nonsyndromic deafness loci are designated DFN (for ## Mitochondrial DNA (mtDNA) Hearing Loss Mitochondrial DNA-associated hearing loss is inherited in a maternal manner. Most mtDNA hearing loss is syndromic and involves a broad spectrum of multisystem disorders. Exceptions include the genes ## Syndromic Hearing Loss At the time of this writing, Syndromic hearing loss accounts for about 20% of prelingual genetic hearing loss. The contribution of syndromic hearing loss to later-onset hearing loss is an active focus of research but is not currently known. Select Common Causes of Autosomal Dominant Syndromic Hearing Loss Cranial nerve VIII dysfunction/anomaly: SNHL &/or vestibular dysfunction Cochlear implantation may be difficult or impossible due to altered cochleovestibular anomalies. Other cranial neuropathies may also be present. Ear malformations such as ossicular malformations assoc w/complex mixed HL 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). Conductive HL can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. Most common type of AD syndromic HL Hearing loss, pigmentary anomalies (white forelock), & dystopium canthorum (widely spaced medial canthus) are most commonly seen clinical features. Various temporal bone abnormalities have been identified in persons w/WS1 & HL. WS2, WS3, & WS4 can be inherited in an AD or AR manner. 2nd most common type of AD syndromic HL Kidney abnormalities Branchial anomalies (branchial cleft tags, pits, cysts) Malformations of outer, middle, & inner ear (e.g., preauricular pits) Bilateral vestibular schwannomas w/assoc symptoms of tinnitus, HL, & balance dysfunction Vestibular schwannomas are a rare, potentially treatable type of HL. AD = autosomal dominant; AR = autosomal recessive; HL = hearing loss; SNHL = sensorineural hearing loss; WS = Waardenburg syndrome Select Common Causes of Autosomal Recessive Syndromic Hearing Loss Usher syndrome overall is the most common type of AR syndromic HL. Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. Intact or variable vestibular responses Usher syndrome overall is the most common type of AR syndromic HL; USH1 is the most common type of Usher syndrome. Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. Unless fitted w/cochlear implant, affected persons do not typically develop speech. Severe vestibular dysfunction or vestibular areflexia. Imbalance is assoc w/HL & is defining feature of USH1. Children typically walk later than usual, at age ~18 mos-2 yrs. 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). Conductive hearing loss can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. 3rd most common type of AR syndromic HL HL & cardiac conduction anomalies Classic presentation is a child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of affected persons had cardiac events before age 3 yrs. See ZSD is due to peroxisome disorder & incl hearing & vision loss, hypotonia, & other clinical features. Milder ZSD may first come to attention due to failed hearing screening. RP, anosmia, neuropathy, ataxia, & HL Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brain stem evoked responses. Persons w/auditory nerve involvement may experience hearing difficulty even in presence of normal audiogram. 2nd most common type of AR syndromic HL HL, vestibular dysfunction, & thyroid goiter HL may fluctuate but often progresses. Vestibular dysfunction should be suspected in infants w/delayed walking. Temporal bones are abnormal radiologically in all persons w/PDS & most commonly incl incomplete partition type II anomaly & enlarged vestibular aqueduct. AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; HL = hearing loss; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss Digenic inheritance, in which an affected individual has double heterozygosity for a pathogenic variant in Select Common Causes of X-Linked Syndromic Hearing Loss SNHL = sensorineural hearing loss Three modes of inheritance are recognized for Alport syndrome: X-linked ( • Cranial nerve VIII dysfunction/anomaly: SNHL &/or vestibular dysfunction • Cochlear implantation may be difficult or impossible due to altered cochleovestibular anomalies. • Other cranial neuropathies may also be present. • Ear malformations such as ossicular malformations assoc w/complex mixed HL • 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). • Conductive HL can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. • Most common type of AD syndromic HL • Hearing loss, pigmentary anomalies (white forelock), & dystopium canthorum (widely spaced medial canthus) are most commonly seen clinical features. • Various temporal bone abnormalities have been identified in persons w/WS1 & HL. • WS2, WS3, & WS4 can be inherited in an AD or AR manner. • 2nd most common type of AD syndromic HL • Kidney abnormalities • Branchial anomalies (branchial cleft tags, pits, cysts) • Malformations of outer, middle, & inner ear (e.g., preauricular pits) • Bilateral vestibular schwannomas w/assoc symptoms of tinnitus, HL, & balance dysfunction • Vestibular schwannomas are a rare, potentially treatable type of HL. • Usher syndrome overall is the most common type of AR syndromic HL. • Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. • Intact or variable vestibular responses • Usher syndrome overall is the most common type of AR syndromic HL; USH1 is the most common type of Usher syndrome. • Nonsyndromic HL mimic: HL is congenital; RP begins in late adolescence or early adulthood. • Unless fitted w/cochlear implant, affected persons do not typically develop speech. • Severe vestibular dysfunction or vestibular areflexia. Imbalance is assoc w/HL & is defining feature of USH1. Children typically walk later than usual, at age ~18 mos-2 yrs. • 40% have some degree of sensorineural hearing impairment (typically high tone, often subtle). • Conductive hearing loss can be seen & may be secondary to recurrent ear infections that are often assoc w/cleft palate &/or may be secondary to a defect of the ossicles of the middle ear. • 3rd most common type of AR syndromic HL • HL & cardiac conduction anomalies • Classic presentation is a child who experiences syncopal episodes during periods of stress, exercise, or fright. 50% of affected persons had cardiac events before age 3 yrs. • See • ZSD is due to peroxisome disorder & incl hearing & vision loss, hypotonia, & other clinical features. • Milder ZSD may first come to attention due to failed hearing screening. • RP, anosmia, neuropathy, ataxia, & HL • Auditory nerve involvement (auditory neuropathy) may be evident on testing of auditory brain stem evoked responses. Persons w/auditory nerve involvement may experience hearing difficulty even in presence of normal audiogram. • 2nd most common type of AR syndromic HL • HL, vestibular dysfunction, & thyroid goiter • HL may fluctuate but often progresses. • Vestibular dysfunction should be suspected in infants w/delayed walking. • Temporal bones are abnormal radiologically in all persons w/PDS & most commonly incl incomplete partition type II anomaly & enlarged vestibular aqueduct. ## Differential Diagnosis of Genetic Hearing Loss In developed countries, approximately 65% of prelingual hearing loss is attributed to genetic causes and approximately 35% to acquired/environmental causes (see The most common acquired/environmental cause of prelingual hearing loss is congenital cytomegalovirus (cCMV) infection (the overall birth prevalence of cCMV is approximately 0.64% [ About 10% of infants with cCMV are symptomatic with findings that can include a characteristic rash, hearing loss (in ~50%), neurologic deficits (e.g., seizures, spasticity), and/or hepatic insufficiency. Some infants succumb to their complications. About 90% of infants with cCMV are considered "asymptomatic." Of these up to 10% develop unilateral or bilateral hearing loss. This variability is characteristic of cCMV-related hearing loss. Acquired/environmental hearing loss in children may also result from: Prenatal infections caused by "TORCH" organisms (i.e., Postnatal infections, particularly bacterial meningitis caused by Acquired/environmental hearing loss in adults is most often attributed to factors such as noise and medications. It is likely that complex environmental-genetic interactions affect the age of onset and severity of age-related hearing loss (presbycusis) and noise-induced hearing loss [ • About 10% of infants with cCMV are symptomatic with findings that can include a characteristic rash, hearing loss (in ~50%), neurologic deficits (e.g., seizures, spasticity), and/or hepatic insufficiency. Some infants succumb to their complications. • About 90% of infants with cCMV are considered "asymptomatic." Of these up to 10% develop unilateral or bilateral hearing loss. This variability is characteristic of cCMV-related hearing loss. • Prenatal infections caused by "TORCH" organisms (i.e., • Postnatal infections, particularly bacterial meningitis caused by ## Evaluation Strategy First, abnormal NBHS results must be followed by confirmatory audiometric testing, typically diagnostic auditory brain stem response (ABR). The next step is typically medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss. The otolaryngologist will perform an evaluation to determine cause of hearing loss by differentiating between non-permanent causes like otitis media (fluid in the middle ear), outer and middle ear abnormalities causing conductive hearing loss, and sensorineural hearing loss. The examination will evaluate for syndromic features. The otolaryngologist will consider history, physical examination, audiometric testing, and frequently imaging studies or genetic tests to determine the underlying diagnosis. A genetic cause is identified in up to 60% of children with congenital bilateral severe-to-profound sensorineural hearing loss (SNHL) [ Children considered to have a high chance of hearing loss for reasons such as a family history of hearing loss, a syndrome associated with hearing loss (e.g., trisomy 21 or cleft lip and palate), or exposure to specific environmental risk factors (e.g., care in a neonatal intensive care unit [NICU], exposure to aminoglycoside antibiotics); School-age children who typically have milder hearing loss that was not detected on NBHS and are often identified following: (1) parental concern regarding hearing; (2) delayed speech or language development; and/or (3) hearing screening as part of a well-child examination or school program [ Adults with hearing loss – at the time of presentation – typically are symptomatic with either diminished hearing or tinnitus (ringing in the ears), which may indicate hearing loss. Initial diagnostic evaluation of any individual with hearing loss (see Timing and order of diagnostic evaluation is individual specific and depends on the age of the individual and the anticipated habilitation options. For instance, a child with severe-to-profound SNHL will typically require imaging (CT or MRI) prior to consideration of cochlear implantation. In clinical practice, the diagnostic evaluation is often performed simultaneously with molecular genetic testing given the turnaround time (1-3 months) for genetic testing. Molecular genetic testing is the standard of care in evaluation of individuals with hearing loss. See The diagnosis of a specific genetic cause of hearing loss 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 a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. Isolated chromosomal microarray testing in an individual with apparent nonsyndromic hearing loss also has a low diagnostic yield. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • First, abnormal NBHS results must be followed by confirmatory audiometric testing, typically diagnostic auditory brain stem response (ABR). • The next step is typically medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss. The otolaryngologist will perform an evaluation to determine cause of hearing loss by differentiating between non-permanent causes like otitis media (fluid in the middle ear), outer and middle ear abnormalities causing conductive hearing loss, and sensorineural hearing loss. The examination will evaluate for syndromic features. The otolaryngologist will consider history, physical examination, audiometric testing, and frequently imaging studies or genetic tests to determine the underlying diagnosis. • A genetic cause is identified in up to 60% of children with congenital bilateral severe-to-profound sensorineural hearing loss (SNHL) [ • Children considered to have a high chance of hearing loss for reasons such as a family history of hearing loss, a syndrome associated with hearing loss (e.g., trisomy 21 or cleft lip and palate), or exposure to specific environmental risk factors (e.g., care in a neonatal intensive care unit [NICU], exposure to aminoglycoside antibiotics); • School-age children who typically have milder hearing loss that was not detected on NBHS and are often identified following: (1) parental concern regarding hearing; (2) delayed speech or language development; and/or (3) hearing screening as part of a well-child examination or school program [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Identification of Children with Hearing Loss First, abnormal NBHS results must be followed by confirmatory audiometric testing, typically diagnostic auditory brain stem response (ABR). The next step is typically medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss. The otolaryngologist will perform an evaluation to determine cause of hearing loss by differentiating between non-permanent causes like otitis media (fluid in the middle ear), outer and middle ear abnormalities causing conductive hearing loss, and sensorineural hearing loss. The examination will evaluate for syndromic features. The otolaryngologist will consider history, physical examination, audiometric testing, and frequently imaging studies or genetic tests to determine the underlying diagnosis. A genetic cause is identified in up to 60% of children with congenital bilateral severe-to-profound sensorineural hearing loss (SNHL) [ Children considered to have a high chance of hearing loss for reasons such as a family history of hearing loss, a syndrome associated with hearing loss (e.g., trisomy 21 or cleft lip and palate), or exposure to specific environmental risk factors (e.g., care in a neonatal intensive care unit [NICU], exposure to aminoglycoside antibiotics); School-age children who typically have milder hearing loss that was not detected on NBHS and are often identified following: (1) parental concern regarding hearing; (2) delayed speech or language development; and/or (3) hearing screening as part of a well-child examination or school program [ • First, abnormal NBHS results must be followed by confirmatory audiometric testing, typically diagnostic auditory brain stem response (ABR). • The next step is typically medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss. The otolaryngologist will perform an evaluation to determine cause of hearing loss by differentiating between non-permanent causes like otitis media (fluid in the middle ear), outer and middle ear abnormalities causing conductive hearing loss, and sensorineural hearing loss. The examination will evaluate for syndromic features. The otolaryngologist will consider history, physical examination, audiometric testing, and frequently imaging studies or genetic tests to determine the underlying diagnosis. • A genetic cause is identified in up to 60% of children with congenital bilateral severe-to-profound sensorineural hearing loss (SNHL) [ • Children considered to have a high chance of hearing loss for reasons such as a family history of hearing loss, a syndrome associated with hearing loss (e.g., trisomy 21 or cleft lip and palate), or exposure to specific environmental risk factors (e.g., care in a neonatal intensive care unit [NICU], exposure to aminoglycoside antibiotics); • School-age children who typically have milder hearing loss that was not detected on NBHS and are often identified following: (1) parental concern regarding hearing; (2) delayed speech or language development; and/or (3) hearing screening as part of a well-child examination or school program [ ## Identification of Adults with Hearing Loss Adults with hearing loss – at the time of presentation – typically are symptomatic with either diminished hearing or tinnitus (ringing in the ears), which may indicate hearing loss. ## Initial Diagnostic Evaluation Initial diagnostic evaluation of any individual with hearing loss (see Timing and order of diagnostic evaluation is individual specific and depends on the age of the individual and the anticipated habilitation options. For instance, a child with severe-to-profound SNHL will typically require imaging (CT or MRI) prior to consideration of cochlear implantation. In clinical practice, the diagnostic evaluation is often performed simultaneously with molecular genetic testing given the turnaround time (1-3 months) for genetic testing. ## Molecular Genetic Testing Molecular genetic testing is the standard of care in evaluation of individuals with hearing loss. See The diagnosis of a specific genetic cause of hearing loss 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 a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. Isolated chromosomal microarray testing in an individual with apparent nonsyndromic hearing loss also has a low diagnostic yield. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management Discussion between health care providers and parents/caregivers to solicit the goals and preferences of the family is the first step in establishing a plan for management. Early auditory intervention can include sound amplification with hearing aids, otologic surgery to implant bone conduction devices, and/or cochlear implantation [ Habituation options include the following: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language. Early access to sign language for children with hearing loss often provides a "head start" to auditory communication skills that are used later by such children who will proceed to communicate using spoken language [ A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. Should an individual not qualify for an IEP, a 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Specific medical therapy is available for select disorders (see Specific Medical Therapy for Select Genetic Disorders Cryopyrin-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome, chronic infantile neurologic cutaneous articular syndrome (CINCA), neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome Regular follow up is recommended for all individuals with genetic hearing loss in order to: Monitor individuals with a genetic disorder known to be associated with systemic involvement for emergence of multisystem manifestations; Perform sequential audiologic examinations that: Document the stability or progression of the hearing loss; Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see Identify and treat superimposed acquired hearing loss, such as otitis media. Recommended Follow Up for Select Genetic Causes of Hearing Loss by Progression Type 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, but the US Occupational Safety and Health Administration ( 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: For genetic disorders with specific agents/circumstances to avoid, see Agents/Circumstances to Avoid: Select Genetic Disorders CSF = cerebrospinal fluid; SNHL = sensorineural hearing loss Virtually all persons w/m.1095T>C, m.1494C>T, or m.1555A>G pathogenic variants will have hearing loss after even intermittent exposure to aminoglycosides. Sensitivity to aminoglycosides related to several other variants in this gene are unknown. See The m.7444G>A pathogenic variant located on the boundary of • • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. • Should an individual not qualify for an IEP, a 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. • Monitor individuals with a genetic disorder known to be associated with systemic involvement for emergence of multisystem manifestations; • Perform sequential audiologic examinations that: • Document the stability or progression of the hearing loss; • Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see • Identify and treat superimposed acquired hearing loss, such as otitis media. • Document the stability or progression of the hearing loss; • Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see • Identify and treat superimposed acquired hearing loss, such as otitis media. • Document the stability or progression of the hearing loss; • Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see • Identify and treat superimposed acquired hearing loss, such as otitis media. • In iPhones, under Settings > Sounds & Haptics > Headphone Safety • In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit • • ## Multidisciplinary Supportive Treatment of Hearing Loss Early auditory intervention can include sound amplification with hearing aids, otologic surgery to implant bone conduction devices, and/or cochlear implantation [ Habituation options include the following: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language. Early access to sign language for children with hearing loss often provides a "head start" to auditory communication skills that are used later by such children who will proceed to communicate using spoken language [ A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. Should an individual not qualify for an IEP, a 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. • Should an individual not qualify for an IEP, a 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. ## Habilitation Early auditory intervention can include sound amplification with hearing aids, otologic surgery to implant bone conduction devices, and/or cochlear implantation [ Habituation options include the following: Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with • Cochlear implantation can be considered in children with severe-to-profound hearing loss who are older than age nine months. Children who undergo cochlear implantation early (before age two years) may achieve – by school age – oral speech and language that is indistinguishable from their normal-hearing peers [ • In adults, cochlear implant performance may be compromised when the auditory nerve itself is affected; however, further research is needed in this area [ • Although research has focused on cochlear implant performance based on the gene involved, given the genetic heterogeneity of hearing loss, large sample sizes are difficult to obtain for performance on a per-gene basis. However, data are clear that individuals with ## Communication and Identity Development On initial evaluation of individuals with hearing loss, the goals for communication must be established with a focus on equipping individuals with language and appropriate access to language. Early access to sign language for children with hearing loss often provides a "head start" to auditory communication skills that are used later by such children who will proceed to communicate using spoken language [ A speech-language therapist as well as a neuropsychologist/psychologist for children with hearing loss provides access to resources within the community to aid in speech and language and D/deaf and hard of hearing (DHH) identity development. ## Education IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. Should an individual not qualify for an IEP, a 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. • Should an individual not qualify for an IEP, a 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Physical, occupational, and speech-language therapy services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. • When developmentally appropriate, self-advocacy skills for DHH children can be fostered in a safe and supportive school environment. Access to a DHH mentor and/or DHH adult as well as social-emotional learning are tools that support a student's self-expression, which can lead to positive social interactions with peers and educators. • DHH specialty services should be provided, especially if a child is in a mainstream setting, to ensure appropriate hearing support and promote positive DHH identity development. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For some of those receiving IEP services, the public school district is required to provide services until age 21. ## Targeted Medical Therapy Specific medical therapy is available for select disorders (see Specific Medical Therapy for Select Genetic Disorders Cryopyrin-associated periodic syndrome (CAPS), familial cold autoinflammatory syndrome, chronic infantile neurologic cutaneous articular syndrome (CINCA), neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome ## Surveillance Regular follow up is recommended for all individuals with genetic hearing loss in order to: Monitor individuals with a genetic disorder known to be associated with systemic involvement for emergence of multisystem manifestations; Perform sequential audiologic examinations that: Document the stability or progression of the hearing loss; Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see Identify and treat superimposed acquired hearing loss, such as otitis media. Recommended Follow Up for Select Genetic Causes of Hearing Loss by Progression Type • Monitor individuals with a genetic disorder known to be associated with systemic involvement for emergence of multisystem manifestations; • Perform sequential audiologic examinations that: • Document the stability or progression of the hearing loss; • Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see • Identify and treat superimposed acquired hearing loss, such as otitis media. • Document the stability or progression of the hearing loss; • Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see • Identify and treat superimposed acquired hearing loss, such as otitis media. • Document the stability or progression of the hearing loss; • Are tailored to the genetic diagnosis and expected prognosis for hearing loss (see • Identify and treat superimposed acquired hearing loss, such as otitis media. ## 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, but the US Occupational Safety and Health Administration ( 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: For genetic disorders with specific agents/circumstances to avoid, see Agents/Circumstances to Avoid: Select Genetic Disorders CSF = cerebrospinal fluid; SNHL = sensorineural hearing loss Virtually all persons w/m.1095T>C, m.1494C>T, or m.1555A>G pathogenic variants will have hearing loss after even intermittent exposure to aminoglycosides. Sensitivity to aminoglycosides related to several other variants in this gene are unknown. See The m.7444G>A pathogenic variant located on the boundary of • In iPhones, under Settings > Sounds & Haptics > Headphone Safety • In Android phones, under Settings > Sounds & Vibrations > Volume > Media Volume Limit • • ## Genetic Counseling Genetic hearing loss may be transmitted in an autosomal dominant, autosomal recessive, or X-linked manner or by maternal inheritance. If an individual has a specific genetic syndrome associated with hearing loss (e.g., See The parents of an individual with autosomal recessive hearing loss are presumed to be heterozygous for a hearing loss-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 hearing loss-related pathogenic variant and to allow reliable recurrence 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. Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier. Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same biallelic pathogenic variants; thus, age of onset and/or progression of hearing loss may not be predictable. Note: One exception is See Most individuals with autosomal dominant hearing loss have a parent with hearing loss. Rarely, an individual with hearing loss has hearing loss as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only family member with hearing loss, targeted molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence 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 with autosomal dominant hearing loss may appear to be negative because of unrecognized hearing loss in a family member who is hard of hearing or reduced penetrance / variable expressivity in a heterozygous 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 one of the proband's parents has the pathogenic variant identified in the proband, sibs have a 50% chance of inheriting the pathogenic variant and having hearing loss. If the proband has a known autosomal dominant hearing loss-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the likelihood of recurrence in sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted. See Note: For the purposes of this The father of a male proband will not be hemizygous for the X-linked hearing loss-related pathogenic variant; therefore, he does not require further evaluation/testing. In a family with more than one individual with X-linked hearing loss, the mother of a male with hearing loss is an obligate heterozygote. Note: If a woman has more than one child with hearing loss and no other relatives with hearing loss and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only family member with hearing loss, the mother may be a heterozygote, the male may have a Targeted molecular genetic testing of the mother for the pathogenic variant identified in the proband is recommended to confirm her genetic status and to allow reliable recurrence assessment. A female proband may have inherited the hearing loss-related pathogenic variant from either her mother or her father, or the variant may be Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has the hearing loss-related pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will have hearing loss; Females who inherit the variant will be heterozygotes and may or may not have hearing loss. If the proband is the only family member known to have hearing loss and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the likelihood of hearing loss in sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same pathogenic variant; thus, age of onset and/or progression may not be predictable. If the mother of the proband has the hearing loss-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will have hearing loss; Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. See If a specific diagnosis cannot be established (and/or the mode of inheritance cannot be established in a person with a positive family history of deafness or hearing loss), the following empiric figures can be used for families of northern European ancestry. If the deaf child does not have If the hearing couple is consanguineous or comes from a highly consanguineous community, the subsequent offspring have close to a 25% probability of deafness because of the high likelihood of autosomal recessive inheritance. Most of the probability is attributed to autosomal dominant syndromic deafness. If both syndromic deafness and a family history of autosomal dominant inheritance can be excluded, the probability of deafness is chiefly related to pseudodominant inheritance of recessive deafness. If both parents have If the couple has autosomal recessive deafness known to be caused by deafness-causing variants at two different loci, the chance of deafness in their offspring is lower than that of the general population. If a genetic etiology has been identified in the parent or sib with hearing loss, targeted testing can be pursued for the familial pathogenic variant(s) to determine if genetic hearing loss will occur in asymptomatic family members. In the absence of a molecular diagnosis in the parent or sib with hearing loss, periodic audiologic testing should be performed for family members with an increased chance of hearing loss. 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 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 hearing loss in offspring and reproductive options) to young adults who have hearing loss. Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation genetic testing for genetic hearing loss are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an individual with autosomal recessive hearing loss are presumed to be heterozygous for a hearing loss-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 hearing loss-related pathogenic variant and to allow reliable recurrence 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. • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier. • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. • Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same biallelic pathogenic variants; thus, age of onset and/or progression of hearing loss may not be predictable. Note: One exception is • Most individuals with autosomal dominant hearing loss have a parent with hearing loss. • Rarely, an individual with hearing loss has hearing loss as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only family member with hearing loss, targeted molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence 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 with autosomal dominant hearing loss may appear to be negative because of unrecognized hearing loss in a family member who is hard of hearing or reduced penetrance / variable expressivity in a heterozygous 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. • If one of the proband's parents has the pathogenic variant identified in the proband, sibs have a 50% chance of inheriting the pathogenic variant and having hearing loss. • If the proband has a known autosomal dominant hearing loss-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the likelihood of recurrence in sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted. • The father of a male proband will not be hemizygous for the X-linked hearing loss-related pathogenic variant; therefore, he does not require further evaluation/testing. • In a family with more than one individual with X-linked hearing loss, the mother of a male with hearing loss is an obligate heterozygote. Note: If a woman has more than one child with hearing loss and no other relatives with hearing loss and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only family member with hearing loss, the mother may be a heterozygote, the male may have a • Targeted molecular genetic testing of the mother for the pathogenic variant identified in the proband is recommended to confirm her genetic status and to allow reliable recurrence assessment. • A female proband may have inherited the hearing loss-related pathogenic variant from either her mother or her father, or the variant may be • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has the hearing loss-related pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the variant will be heterozygotes and may or may not have hearing loss. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the variant will be heterozygotes and may or may not have hearing loss. • If the proband is the only family member known to have hearing loss and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the likelihood of hearing loss in sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same pathogenic variant; thus, age of onset and/or progression may not be predictable. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the variant will be heterozygotes and may or may not have hearing loss. • If the mother of the proband has the hearing loss-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. • If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. • If the deaf child does not have • If the hearing couple is consanguineous or comes from a highly consanguineous community, the subsequent offspring have close to a 25% probability of deafness because of the high likelihood of autosomal recessive inheritance. • Most of the probability is attributed to autosomal dominant syndromic deafness. • If both syndromic deafness and a family history of autosomal dominant inheritance can be excluded, the probability of deafness is chiefly related to pseudodominant inheritance of recessive deafness. • If both parents have • If the couple has autosomal recessive deafness known to be caused by deafness-causing variants at two different loci, the chance of deafness in their offspring is lower than that of the general population. • If a genetic etiology has been identified in the parent or sib with hearing loss, targeted testing can be pursued for the familial pathogenic variant(s) to determine if genetic hearing loss will occur in asymptomatic family members. • In the absence of a molecular diagnosis in the parent or sib with hearing loss, periodic audiologic testing should be performed for family members with an increased chance of hearing loss. • 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 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 hearing loss in offspring and reproductive options) to young adults who have hearing loss. ## Mode of Inheritance Genetic hearing loss may be transmitted in an autosomal dominant, autosomal recessive, or X-linked manner or by maternal inheritance. If an individual has a specific genetic syndrome associated with hearing loss (e.g., ## Autosomal Recessive Nonsyndromic Hearing Loss – Risk to Family Members See The parents of an individual with autosomal recessive hearing loss are presumed to be heterozygous for a hearing loss-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 hearing loss-related pathogenic variant and to allow reliable recurrence 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. Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. If both parents are known to be heterozygous for an autosomal recessive hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier. Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same biallelic pathogenic variants; thus, age of onset and/or progression of hearing loss may not be predictable. Note: One exception is • The parents of an individual with autosomal recessive hearing loss are presumed to be heterozygous for a hearing loss-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 hearing loss-related pathogenic variant and to allow reliable recurrence 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. • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 hearing loss-related pathogenic variant, each sib of the proband has at conception a 25% chance of having hearing loss, a 50% chance of having no hearing loss and being a carrier, and a 25% chance of having no hearing loss and not being a carrier. • Individuals who are heterozygous for a pathogenic variant associated with autosomal recessive hearing loss do not have an increased chance of genetic hearing loss. • Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same biallelic pathogenic variants; thus, age of onset and/or progression of hearing loss may not be predictable. Note: One exception is ## Autosomal Dominant Nonsyndromic Hearing Loss – Risk to Family Members See Most individuals with autosomal dominant hearing loss have a parent with hearing loss. Rarely, an individual with hearing loss has hearing loss as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only family member with hearing loss, targeted molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence 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 with autosomal dominant hearing loss may appear to be negative because of unrecognized hearing loss in a family member who is hard of hearing or reduced penetrance / variable expressivity in a heterozygous 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 one of the proband's parents has the pathogenic variant identified in the proband, sibs have a 50% chance of inheriting the pathogenic variant and having hearing loss. If the proband has a known autosomal dominant hearing loss-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the likelihood of recurrence in sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted. • Most individuals with autosomal dominant hearing loss have a parent with hearing loss. • Rarely, an individual with hearing loss has hearing loss as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only family member with hearing loss, targeted molecular genetic testing for the pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence 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 with autosomal dominant hearing loss may appear to be negative because of unrecognized hearing loss in a family member who is hard of hearing or reduced penetrance / variable expressivity in a heterozygous 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. • If one of the proband's parents has the pathogenic variant identified in the proband, sibs have a 50% chance of inheriting the pathogenic variant and having hearing loss. • If the proband has a known autosomal dominant hearing loss-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the likelihood of recurrence in sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [ • Depending on the specific diagnosis, clinical severity and phenotype may differ between sibs with the same pathogenic variant; thus, age of onset and/or progression cannot be reliably predicted. ## X-Linked Nonsyndromic Hearing Loss – Risk to Family Members See Note: For the purposes of this The father of a male proband will not be hemizygous for the X-linked hearing loss-related pathogenic variant; therefore, he does not require further evaluation/testing. In a family with more than one individual with X-linked hearing loss, the mother of a male with hearing loss is an obligate heterozygote. Note: If a woman has more than one child with hearing loss and no other relatives with hearing loss and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only family member with hearing loss, the mother may be a heterozygote, the male may have a Targeted molecular genetic testing of the mother for the pathogenic variant identified in the proband is recommended to confirm her genetic status and to allow reliable recurrence assessment. A female proband may have inherited the hearing loss-related pathogenic variant from either her mother or her father, or the variant may be Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a If the mother of the proband has the hearing loss-related pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will have hearing loss; Females who inherit the variant will be heterozygotes and may or may not have hearing loss. If the proband is the only family member known to have hearing loss and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the likelihood of hearing loss in sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same pathogenic variant; thus, age of onset and/or progression may not be predictable. If the mother of the proband has the hearing loss-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will have hearing loss; Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. • The father of a male proband will not be hemizygous for the X-linked hearing loss-related pathogenic variant; therefore, he does not require further evaluation/testing. • In a family with more than one individual with X-linked hearing loss, the mother of a male with hearing loss is an obligate heterozygote. Note: If a woman has more than one child with hearing loss and no other relatives with hearing loss and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only family member with hearing loss, the mother may be a heterozygote, the male may have a • Targeted molecular genetic testing of the mother for the pathogenic variant identified in the proband is recommended to confirm her genetic status and to allow reliable recurrence assessment. • A female proband may have inherited the hearing loss-related pathogenic variant from either her mother or her father, or the variant may be • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a • If the mother of the proband has the hearing loss-related pathogenic variant, the chance of the mother transmitting it in each pregnancy is 50%. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the variant will be heterozygotes and may or may not have hearing loss. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the variant will be heterozygotes and may or may not have hearing loss. • If the proband is the only family member known to have hearing loss and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the likelihood of hearing loss in sibs is presumed to be low but greater than that of the general population because of the possibility of maternal germline mosaicism. • Depending on the specific diagnosis, clinical severity and phenotype may differ between individuals with the same pathogenic variant; thus, age of onset and/or progression may not be predictable. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the variant will be heterozygotes and may or may not have hearing loss. • If the mother of the proband has the hearing loss-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. • If the father of the proband has a pathogenic variant, he will transmit it to all his daughters and none of his sons. • Males who inherit the pathogenic variant will have hearing loss; • Females who inherit the pathogenic variant will be heterozygotes and may or may not have hearing loss. ## Mitochondrial Nonsyndromic Hearing Loss – Risk to Family Members See ## Empiric Risk to Family Members If a specific diagnosis cannot be established (and/or the mode of inheritance cannot be established in a person with a positive family history of deafness or hearing loss), the following empiric figures can be used for families of northern European ancestry. If the deaf child does not have If the hearing couple is consanguineous or comes from a highly consanguineous community, the subsequent offspring have close to a 25% probability of deafness because of the high likelihood of autosomal recessive inheritance. Most of the probability is attributed to autosomal dominant syndromic deafness. If both syndromic deafness and a family history of autosomal dominant inheritance can be excluded, the probability of deafness is chiefly related to pseudodominant inheritance of recessive deafness. If both parents have If the couple has autosomal recessive deafness known to be caused by deafness-causing variants at two different loci, the chance of deafness in their offspring is lower than that of the general population. • If the deaf child does not have • If the hearing couple is consanguineous or comes from a highly consanguineous community, the subsequent offspring have close to a 25% probability of deafness because of the high likelihood of autosomal recessive inheritance. • Most of the probability is attributed to autosomal dominant syndromic deafness. • If both syndromic deafness and a family history of autosomal dominant inheritance can be excluded, the probability of deafness is chiefly related to pseudodominant inheritance of recessive deafness. • If both parents have • If the couple has autosomal recessive deafness known to be caused by deafness-causing variants at two different loci, the chance of deafness in their offspring is lower than that of the general population. ## Related Genetic Counseling Issues If a genetic etiology has been identified in the parent or sib with hearing loss, targeted testing can be pursued for the familial pathogenic variant(s) to determine if genetic hearing loss will occur in asymptomatic family members. In the absence of a molecular diagnosis in the parent or sib with hearing loss, periodic audiologic testing should be performed for family members with an increased chance of hearing loss. 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 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 hearing loss in offspring and reproductive options) to young adults who have hearing loss. • If a genetic etiology has been identified in the parent or sib with hearing loss, targeted testing can be pursued for the familial pathogenic variant(s) to determine if genetic hearing loss will occur in asymptomatic family members. • In the absence of a molecular diagnosis in the parent or sib with hearing loss, periodic audiologic testing should be performed for family members with an increased chance of hearing loss. • 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 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 hearing loss in offspring and reproductive options) to young adults who have hearing loss. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant(s) have been identified in the family, prenatal and preimplantation genetic testing for genetic hearing loss 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 Health Resources & Services Administration • • • • • • • • • • • • • • • • • • • Health Resources & Services Administration • ## Chapter Notes Thank you to Nicole Salamy, MS, CCC-SLP, Rachel Landsman, PsyD, and Kaitlyn Fitzpatrick, AuD, from the Deaf and Hard of Hearing Program at Boston Children's Hospital for their contributions to the This work was supported in part by NIDCDs R01's DC002842, DC012049, and DC017955 to RJHS. Glenn Edward Green, MD; University of Arizona (1999-2005)Michael S Hildebrand, PhD (2010-present)Amanda M Odell, MS, LGC (2023-present)A Eliot Shearer (2012-present)Richard JH Smith, MD (1999-present) Guy Van Camp, PhD; University of Antwerp (1999-2017) 3 April 2025 (aa) Revision: 28 September 2023 (aes) Revision: removed references to DFNA3; added recommendations for 29 June 2023 (rjs) Revision: removed 27 April 2023 (aa) Revision: removed 6 April 2023 (bp) Comprehensive update posted live 27 July 2017 (bp) Comprehensive update posted live 14 October 2010 (me) Comprehensive update posted live 28 October 2008 (me) Comprehensive update posted live 30 December 2005 (me) Comprehensive update posted live 3 November 2003 (me) Comprehensive update posted live 24 April 2001 (me) Comprehensive update posted live 14 February 1999 (pb) Overview posted live 30 October 1998 (rjs) Original overview submission [Supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS) and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).] • 3 April 2025 (aa) Revision: • 28 September 2023 (aes) Revision: removed references to DFNA3; added recommendations for • 29 June 2023 (rjs) Revision: removed • 27 April 2023 (aa) Revision: removed • 6 April 2023 (bp) Comprehensive update posted live • 27 July 2017 (bp) Comprehensive update posted live • 14 October 2010 (me) Comprehensive update posted live • 28 October 2008 (me) Comprehensive update posted live • 30 December 2005 (me) Comprehensive update posted live • 3 November 2003 (me) Comprehensive update posted live • 24 April 2001 (me) Comprehensive update posted live • 14 February 1999 (pb) Overview posted live • 30 October 1998 (rjs) Original overview submission [Supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS) and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).] ## Author Notes ## Acknowledgments Thank you to Nicole Salamy, MS, CCC-SLP, Rachel Landsman, PsyD, and Kaitlyn Fitzpatrick, AuD, from the Deaf and Hard of Hearing Program at Boston Children's Hospital for their contributions to the This work was supported in part by NIDCDs R01's DC002842, DC012049, and DC017955 to RJHS. ## Author History Glenn Edward Green, MD; University of Arizona (1999-2005)Michael S Hildebrand, PhD (2010-present)Amanda M Odell, MS, LGC (2023-present)A Eliot Shearer (2012-present)Richard JH Smith, MD (1999-present) Guy Van Camp, PhD; University of Antwerp (1999-2017) ## Revision History 3 April 2025 (aa) Revision: 28 September 2023 (aes) Revision: removed references to DFNA3; added recommendations for 29 June 2023 (rjs) Revision: removed 27 April 2023 (aa) Revision: removed 6 April 2023 (bp) Comprehensive update posted live 27 July 2017 (bp) Comprehensive update posted live 14 October 2010 (me) Comprehensive update posted live 28 October 2008 (me) Comprehensive update posted live 30 December 2005 (me) Comprehensive update posted live 3 November 2003 (me) Comprehensive update posted live 24 April 2001 (me) Comprehensive update posted live 14 February 1999 (pb) Overview posted live 30 October 1998 (rjs) Original overview submission [Supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS) and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).] • 3 April 2025 (aa) Revision: • 28 September 2023 (aes) Revision: removed references to DFNA3; added recommendations for • 29 June 2023 (rjs) Revision: removed • 27 April 2023 (aa) Revision: removed • 6 April 2023 (bp) Comprehensive update posted live • 27 July 2017 (bp) Comprehensive update posted live • 14 October 2010 (me) Comprehensive update posted live • 28 October 2008 (me) Comprehensive update posted live • 30 December 2005 (me) Comprehensive update posted live • 3 November 2003 (me) Comprehensive update posted live • 24 April 2001 (me) Comprehensive update posted live • 14 February 1999 (pb) Overview posted live • 30 October 1998 (rjs) Original overview submission [Supported in part by grants 1RO1DC02842 and 1RO1DC03544 (RJHS) and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC).] ## References Li MM, Tayoun AA, DiStefano M, Pandya A, Rehm HL, Robin NH, Schaefer AM, Yoshinaga-Itano C, et al. Clinical evaluation and etiologic diagnosis of hearing loss: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24:1392-406. [ • Li MM, Tayoun AA, DiStefano M, Pandya A, Rehm HL, Robin NH, Schaefer AM, Yoshinaga-Itano C, et al. Clinical evaluation and etiologic diagnosis of hearing loss: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24:1392-406. [ ## Published Guidelines / Consensus Statements Li MM, Tayoun AA, DiStefano M, Pandya A, Rehm HL, Robin NH, Schaefer AM, Yoshinaga-Itano C, et al. Clinical evaluation and etiologic diagnosis of hearing loss: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24:1392-406. [ • Li MM, Tayoun AA, DiStefano M, Pandya A, Rehm HL, Robin NH, Schaefer AM, Yoshinaga-Itano C, et al. Clinical evaluation and etiologic diagnosis of hearing loss: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24:1392-406. [ ## Literature Cited Causes of prelingual hearing loss in developed countries [ Diagnostic algorithm for presumed hereditary nonsyndromic sensorineural hearing loss
[]
14/2/1999
6/4/2023
3/4/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
del16p11_2
del16p11_2
[ "Not applicable", "Not applicable", "16p11.2 Recurrent Deletion" ]
16p11.2 Recurrent Deletion
Cora M Taylor, Rebecca Smith, Christopher Lehman, Marissa W Mitchel, Kaitlyn Singer, W Curtis Weaver, Wendy Chung
Summary The 16p11.2 recurrent deletion phenotype is characterized by motor speech disorder, language disorder, motor coordination difficulties, psychiatric conditions, and autistic features. While most, if not all, individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, the severity varies significantly. Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. Obesity is a feature of this disorder and generally emerges in childhood; BMI in individuals with the 16p11.2 recurrent deletion is significantly higher than in the general population by age five years. Seizures are observed in approximately 25% of individuals with the recurrent deletion. Vertebral anomalies, hearing impairment, macrocephaly, and cardiovascular malformation have each been observed in some individuals. Clinical follow-up data from adults suggests that the greatest medical challenges are obesity and related comorbidities that can be exacerbated by medications used to treat behavioral and psychiatric problems. The diagnosis of 16p11.2 recurrent deletion is established by detection of a heterozygous ~593-kb recurrent deletion at the approximate position of chr16:29638676-30188531 in the reference genome (NCBI Build 38). The 16p11.2 recurrent deletion is Once a 16p11.2 recurrent deletion has been identified in a family member, prenatal and preimplantation genetic testing are possible. Interpretation of results from prenatal testing is challenging given the inherent difficulty in accurately predicting the phenotype.
## Diagnosis The 16p11.2 recurrent deletion Motor speech disorder, especially childhood apraxia of speech Language disorder Learning difficulties / intellectual disability Social impairments with or without a diagnosis of autism spectrum disorder (ASD) Macrocephaly Chiari I malformation / cerebellar tonsillar ectopia Seizures/epilepsy Vertebral anomalies Obesity starting in adolescence, and in the setting of developmental delay The diagnosis of the 16p11.2 recurrent deletion Of note, an adjacent (distal) recurrent 16p11.2 deletion (GRCh38 chr16:28811314-29035178), which is also associated with variable features, is not discussed further, as this Note: (1) Most individuals with the 16p11.2 recurrent deletion are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, or ASD. (2) Prior to 2008 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods. Genomic Testing Used in the 16p11.2 Recurrent Deletion See Standardized ISCN annotation and interpretation for genomic variants from the Chromosome microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 16p11.2 region. Note: The 16p11.2 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms. Targeted deletion analysis methods can include FISH, quantitative PCR, and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted deletion analysis is not appropriate for an individual in whom the 16q11.2 recurrent deletion was not detected by CMA designed to target this region. Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 16q11.2 recurrent deletion. • Motor speech disorder, especially childhood apraxia of speech • Language disorder • Learning difficulties / intellectual disability • Social impairments with or without a diagnosis of autism spectrum disorder (ASD) • Macrocephaly • Chiari I malformation / cerebellar tonsillar ectopia • Seizures/epilepsy • Vertebral anomalies • Obesity starting in adolescence, and in the setting of developmental delay • Note: (1) Most individuals with the 16p11.2 recurrent deletion are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, or ASD. (2) Prior to 2008 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. • Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods. ## Suggestive Findings The 16p11.2 recurrent deletion Motor speech disorder, especially childhood apraxia of speech Language disorder Learning difficulties / intellectual disability Social impairments with or without a diagnosis of autism spectrum disorder (ASD) Macrocephaly Chiari I malformation / cerebellar tonsillar ectopia Seizures/epilepsy Vertebral anomalies Obesity starting in adolescence, and in the setting of developmental delay • Motor speech disorder, especially childhood apraxia of speech • Language disorder • Learning difficulties / intellectual disability • Social impairments with or without a diagnosis of autism spectrum disorder (ASD) • Macrocephaly • Chiari I malformation / cerebellar tonsillar ectopia • Seizures/epilepsy • Vertebral anomalies • Obesity starting in adolescence, and in the setting of developmental delay ## Establishing the Diagnosis The diagnosis of the 16p11.2 recurrent deletion Of note, an adjacent (distal) recurrent 16p11.2 deletion (GRCh38 chr16:28811314-29035178), which is also associated with variable features, is not discussed further, as this Note: (1) Most individuals with the 16p11.2 recurrent deletion are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, or ASD. (2) Prior to 2008 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods. Genomic Testing Used in the 16p11.2 Recurrent Deletion See Standardized ISCN annotation and interpretation for genomic variants from the Chromosome microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 16p11.2 region. Note: The 16p11.2 recurrent deletion may not have been detectable by older oligonucleotide or BAC platforms. Targeted deletion analysis methods can include FISH, quantitative PCR, and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted deletion analysis is not appropriate for an individual in whom the 16q11.2 recurrent deletion was not detected by CMA designed to target this region. Targeted deletion analysis may be used to test at-risk relatives of a proband known to have the 16q11.2 recurrent deletion. • Note: (1) Most individuals with the 16p11.2 recurrent deletion are identified by CMA performed in the context of evaluation of developmental delay, intellectual disability, or ASD. (2) Prior to 2008 many CMA platforms did not include coverage for this region and thus may not have detected this deletion. • Note: (1) Targeted deletion testing is not appropriate for an individual in whom the 16p11.2 recurrent deletion was not detected by CMA designed to target this region. (2) It is not possible to size the deletion routinely by use of targeted methods. ## Clinical Characteristics The 16p11.2 recurrent deletion is one of the most common known genetic causes of neurodevelopmental disorders [ Select Features of the 16p11.2 Recurrent Deletion Most if not all individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, although the severity varies. Developmental coordination (motor) disorder is one of the most common diagnoses in individuals with the 16p11.2 recurrent deletion, followed by phonologic processing disorder, language disorders, and autism spectrum disorder (ASD) [ Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. On average, the IQ of individuals with the 16p11.2 recurrent deletion is approximately 2 SD lower than other family members without the deletion. Average IQ was 82.7, representing a 26.8-point (1.8 SD) shift downward compared to the full scale IQ average of 109.5 of familial controls [ Individuals with the 16p11.2 recurrent deletion are at increased risk for psychiatric diagnoses, with most individuals with the deletion having at least one psychiatric diagnosis [ The majority of children (~80%) with the 16p11.2 recurrent deletion present with a motor speech disorder, such as childhood apraxia of speech (CAS) and dysarthria [ CAS appears to occur independently of other neuropsychiatric diagnoses such as ASD [ More than 80% of children and adults exhibit some degree of language impairment, with the majority demonstrating both receptive and expressive deficits [ The 16p11.2 recurrent deletion is a predisposing factor for overweight (defined as sex-specific BMI for age 85-95th centile) and obesity (defined as sex-specific BMI for age >95th centile). Overall, several studies show that obesity is a feature of the 16p11.2 recurrent deletion, with the prevalence of overweight and obesity in individuals with the 16p11.2 recurrent deletion higher than in the general population [ Individuals with the 16p11.2 recurrent deletion identified in the earliest reported research studies were ascertained primarily through cohorts of individuals with an ASD. Although not all individuals with the 16p11.2 recurrent deletion meet diagnostic criteria for ASD, almost all have some behavioral traits shared with ASD including insistence on sameness, reduced scope of interest, repetitive behaviors, and problems with social communication [ Based on current literature reports, ASD is diagnosed in approximately 20%-25% of individuals with the 16p11.2 recurrent deletion (i.e, with much greater frequency than in the general population, in which ASD is diagnosed in ~1:54 children) [ The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [ Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [ Although consistent patterns of other medical problems are not observed, the following have been reported in individuals with the 16p11.2 recurrent deletion: Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the deletion [ Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals. Cardiac malformations have been reported in some individuals. Although most with a diagnosis of the 16p11.2 recurrent deletion have not had diagnostic cardiac imaging, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent deletion [ The 16p11.2 recurrent deletion has been found to be more common in children with neuroblastoma compared to population controls [ Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight [ Macrocephaly is frequently observed (reported in 17% of affected individuals in the study of Craniosynostosis was observed in 2% of 233 individuals [ A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the 16p11.2 recurrent deletion, although abnormal palpebral fissures are noted in approximately 40% of individuals with the deletion [ No genotype-phenotype correlations have been observed. The most recent estimate is approximately 1:2,000 in the general population [ • The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [ • Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [ • Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the deletion [ • Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals. • Cardiac malformations have been reported in some individuals. Although most with a diagnosis of the 16p11.2 recurrent deletion have not had diagnostic cardiac imaging, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent deletion [ • The 16p11.2 recurrent deletion has been found to be more common in children with neuroblastoma compared to population controls [ • Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight [ • Macrocephaly is frequently observed (reported in 17% of affected individuals in the study of • Craniosynostosis was observed in 2% of 233 individuals [ • A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the 16p11.2 recurrent deletion, although abnormal palpebral fissures are noted in approximately 40% of individuals with the deletion [ ## Clinical Description The 16p11.2 recurrent deletion is one of the most common known genetic causes of neurodevelopmental disorders [ Select Features of the 16p11.2 Recurrent Deletion Most if not all individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, although the severity varies. Developmental coordination (motor) disorder is one of the most common diagnoses in individuals with the 16p11.2 recurrent deletion, followed by phonologic processing disorder, language disorders, and autism spectrum disorder (ASD) [ Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. On average, the IQ of individuals with the 16p11.2 recurrent deletion is approximately 2 SD lower than other family members without the deletion. Average IQ was 82.7, representing a 26.8-point (1.8 SD) shift downward compared to the full scale IQ average of 109.5 of familial controls [ Individuals with the 16p11.2 recurrent deletion are at increased risk for psychiatric diagnoses, with most individuals with the deletion having at least one psychiatric diagnosis [ The majority of children (~80%) with the 16p11.2 recurrent deletion present with a motor speech disorder, such as childhood apraxia of speech (CAS) and dysarthria [ CAS appears to occur independently of other neuropsychiatric diagnoses such as ASD [ More than 80% of children and adults exhibit some degree of language impairment, with the majority demonstrating both receptive and expressive deficits [ The 16p11.2 recurrent deletion is a predisposing factor for overweight (defined as sex-specific BMI for age 85-95th centile) and obesity (defined as sex-specific BMI for age >95th centile). Overall, several studies show that obesity is a feature of the 16p11.2 recurrent deletion, with the prevalence of overweight and obesity in individuals with the 16p11.2 recurrent deletion higher than in the general population [ Individuals with the 16p11.2 recurrent deletion identified in the earliest reported research studies were ascertained primarily through cohorts of individuals with an ASD. Although not all individuals with the 16p11.2 recurrent deletion meet diagnostic criteria for ASD, almost all have some behavioral traits shared with ASD including insistence on sameness, reduced scope of interest, repetitive behaviors, and problems with social communication [ Based on current literature reports, ASD is diagnosed in approximately 20%-25% of individuals with the 16p11.2 recurrent deletion (i.e, with much greater frequency than in the general population, in which ASD is diagnosed in ~1:54 children) [ The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [ Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [ Although consistent patterns of other medical problems are not observed, the following have been reported in individuals with the 16p11.2 recurrent deletion: Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the deletion [ Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals. Cardiac malformations have been reported in some individuals. Although most with a diagnosis of the 16p11.2 recurrent deletion have not had diagnostic cardiac imaging, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent deletion [ The 16p11.2 recurrent deletion has been found to be more common in children with neuroblastoma compared to population controls [ Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight [ Macrocephaly is frequently observed (reported in 17% of affected individuals in the study of Craniosynostosis was observed in 2% of 233 individuals [ A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the 16p11.2 recurrent deletion, although abnormal palpebral fissures are noted in approximately 40% of individuals with the deletion [ • The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [ • Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [ • Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the deletion [ • Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals. • Cardiac malformations have been reported in some individuals. Although most with a diagnosis of the 16p11.2 recurrent deletion have not had diagnostic cardiac imaging, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent deletion [ • The 16p11.2 recurrent deletion has been found to be more common in children with neuroblastoma compared to population controls [ • Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight [ • Macrocephaly is frequently observed (reported in 17% of affected individuals in the study of • Craniosynostosis was observed in 2% of 233 individuals [ • A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the 16p11.2 recurrent deletion, although abnormal palpebral fissures are noted in approximately 40% of individuals with the deletion [ ## Developmental Delay Most if not all individuals with the 16p11.2 recurrent deletion experience some degree of developmental delay, although the severity varies. Developmental coordination (motor) disorder is one of the most common diagnoses in individuals with the 16p11.2 recurrent deletion, followed by phonologic processing disorder, language disorders, and autism spectrum disorder (ASD) [ ## Cognitive Impact Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains. On average, the IQ of individuals with the 16p11.2 recurrent deletion is approximately 2 SD lower than other family members without the deletion. Average IQ was 82.7, representing a 26.8-point (1.8 SD) shift downward compared to the full scale IQ average of 109.5 of familial controls [ ## Psychiatric Disease and Behavioral Issues Individuals with the 16p11.2 recurrent deletion are at increased risk for psychiatric diagnoses, with most individuals with the deletion having at least one psychiatric diagnosis [ ## Motor Speech Disorders The majority of children (~80%) with the 16p11.2 recurrent deletion present with a motor speech disorder, such as childhood apraxia of speech (CAS) and dysarthria [ CAS appears to occur independently of other neuropsychiatric diagnoses such as ASD [ ## Language Disorder More than 80% of children and adults exhibit some degree of language impairment, with the majority demonstrating both receptive and expressive deficits [ ## Obesity The 16p11.2 recurrent deletion is a predisposing factor for overweight (defined as sex-specific BMI for age 85-95th centile) and obesity (defined as sex-specific BMI for age >95th centile). Overall, several studies show that obesity is a feature of the 16p11.2 recurrent deletion, with the prevalence of overweight and obesity in individuals with the 16p11.2 recurrent deletion higher than in the general population [ ## Autistic Features Individuals with the 16p11.2 recurrent deletion identified in the earliest reported research studies were ascertained primarily through cohorts of individuals with an ASD. Although not all individuals with the 16p11.2 recurrent deletion meet diagnostic criteria for ASD, almost all have some behavioral traits shared with ASD including insistence on sameness, reduced scope of interest, repetitive behaviors, and problems with social communication [ Based on current literature reports, ASD is diagnosed in approximately 20%-25% of individuals with the 16p11.2 recurrent deletion (i.e, with much greater frequency than in the general population, in which ASD is diagnosed in ~1:54 children) [ ## Neurologic Issues The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [ Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [ • The most common recurrent structural brain abnormalities are posterior fossa and/or craniocervical junction-related abnormalities (e.g., Chiari I malformation, cerebellar tonsillar ectopia, platybasia) [ • Quantitative structural MRI analysis has shown a pervasive increase in volume throughout the brain, with white matter and thalami being the most dramatically affected [ ## Other Medical Issues Although consistent patterns of other medical problems are not observed, the following have been reported in individuals with the 16p11.2 recurrent deletion: Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the deletion [ Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals. Cardiac malformations have been reported in some individuals. Although most with a diagnosis of the 16p11.2 recurrent deletion have not had diagnostic cardiac imaging, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent deletion [ The 16p11.2 recurrent deletion has been found to be more common in children with neuroblastoma compared to population controls [ Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight [ Macrocephaly is frequently observed (reported in 17% of affected individuals in the study of Craniosynostosis was observed in 2% of 233 individuals [ A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the 16p11.2 recurrent deletion, although abnormal palpebral fissures are noted in approximately 40% of individuals with the deletion [ • Vertebral anomalies (often associated with scoliosis) were observed in 21% of 233 individuals with the deletion [ • Hearing impairment (sensorineural and conductive hearing loss) is seen in up to 11% of individuals. • Cardiac malformations have been reported in some individuals. Although most with a diagnosis of the 16p11.2 recurrent deletion have not had diagnostic cardiac imaging, limited clinical reports suggest that the incidence of cardiac malformations is slightly increased. Congenital heart disease was identified in 6% of 233 individuals with the 16p11.2 recurrent deletion [ • The 16p11.2 recurrent deletion has been found to be more common in children with neuroblastoma compared to population controls [ • Height is slightly below average for individuals who are not overweight and may be average for individuals who are overweight [ • Macrocephaly is frequently observed (reported in 17% of affected individuals in the study of • Craniosynostosis was observed in 2% of 233 individuals [ • A characteristic pattern of dysmorphic features that would facilitate a clinical diagnosis is not observed in individuals with the 16p11.2 recurrent deletion, although abnormal palpebral fissures are noted in approximately 40% of individuals with the deletion [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been observed. ## Prevalence The most recent estimate is approximately 1:2,000 in the general population [ ## Genetically Related (Allelic) Disorders Reciprocal ~593-kb duplication of 16p11.2 is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and decreased BMI [ The phenotype of the 16p11.2 recurrent duplication shows more variability than the phenotype of the 16p11.2 recurrent deletion; however, most individuals with the 16p11.2 recurrent duplication are identified by CMA performed in the evaluation of developmental delay, intellectual disability, or ASD, conferring an ascertainment bias that makes the phenotype associated with the 16p11.2 recurrent duplication difficult to establish. In a study of 270 individuals with the 16p11.2 recurrent duplication, the mean full-scale IQ (FSIQ) was 78.8 with 30% meeting criteria for a diagnosis of intellectual disability. FSIQ measures were significantly lower than in relatives who did not have the 16p11.2 recurrent duplication [ ASD has been found to be slightly more common in those with the 16p11.2 recurrent duplication (20%) than in those with the 16p11.2 recurrent deletion (16%), and individuals with the 16p11.2 recurrent duplication with ASD have lower cognition than those with the 16p11.2 recurrent deletion with ASD [ Seizures are observed in approximately 20% of individuals with the 16p11.2 recurrent duplication [ Head circumference tends to be smaller in individuals with the 16p11.2 recurrent duplication than in their relatives without the duplication [ In addition, the 16p11.2 recurrent duplication is associated with underweight and a lower body mass index (BMI). The reciprocal impact of both the 16p11.2 recurrent deletion and duplication indicate that severe obesity (deletion) and being underweight (duplication) could have mirror etiologies, possibly through contrasting effects on energy balance [ Whereas 16p11.2 recurrent deletions are often At least two individuals with much larger deletions that include the 16p11.2 recurrent deletion region have been described [ • In a study of 270 individuals with the 16p11.2 recurrent duplication, the mean full-scale IQ (FSIQ) was 78.8 with 30% meeting criteria for a diagnosis of intellectual disability. FSIQ measures were significantly lower than in relatives who did not have the 16p11.2 recurrent duplication [ • ASD has been found to be slightly more common in those with the 16p11.2 recurrent duplication (20%) than in those with the 16p11.2 recurrent deletion (16%), and individuals with the 16p11.2 recurrent duplication with ASD have lower cognition than those with the 16p11.2 recurrent deletion with ASD [ • Seizures are observed in approximately 20% of individuals with the 16p11.2 recurrent duplication [ • Head circumference tends to be smaller in individuals with the 16p11.2 recurrent duplication than in their relatives without the duplication [ • In addition, the 16p11.2 recurrent duplication is associated with underweight and a lower body mass index (BMI). The reciprocal impact of both the 16p11.2 recurrent deletion and duplication indicate that severe obesity (deletion) and being underweight (duplication) could have mirror etiologies, possibly through contrasting effects on energy balance [ ## 16p11.2 Recurrent Duplication Reciprocal ~593-kb duplication of 16p11.2 is the copy number variant most frequently associated with autism spectrum disorder (ASD), schizophrenia, and decreased BMI [ The phenotype of the 16p11.2 recurrent duplication shows more variability than the phenotype of the 16p11.2 recurrent deletion; however, most individuals with the 16p11.2 recurrent duplication are identified by CMA performed in the evaluation of developmental delay, intellectual disability, or ASD, conferring an ascertainment bias that makes the phenotype associated with the 16p11.2 recurrent duplication difficult to establish. In a study of 270 individuals with the 16p11.2 recurrent duplication, the mean full-scale IQ (FSIQ) was 78.8 with 30% meeting criteria for a diagnosis of intellectual disability. FSIQ measures were significantly lower than in relatives who did not have the 16p11.2 recurrent duplication [ ASD has been found to be slightly more common in those with the 16p11.2 recurrent duplication (20%) than in those with the 16p11.2 recurrent deletion (16%), and individuals with the 16p11.2 recurrent duplication with ASD have lower cognition than those with the 16p11.2 recurrent deletion with ASD [ Seizures are observed in approximately 20% of individuals with the 16p11.2 recurrent duplication [ Head circumference tends to be smaller in individuals with the 16p11.2 recurrent duplication than in their relatives without the duplication [ In addition, the 16p11.2 recurrent duplication is associated with underweight and a lower body mass index (BMI). The reciprocal impact of both the 16p11.2 recurrent deletion and duplication indicate that severe obesity (deletion) and being underweight (duplication) could have mirror etiologies, possibly through contrasting effects on energy balance [ Whereas 16p11.2 recurrent deletions are often • In a study of 270 individuals with the 16p11.2 recurrent duplication, the mean full-scale IQ (FSIQ) was 78.8 with 30% meeting criteria for a diagnosis of intellectual disability. FSIQ measures were significantly lower than in relatives who did not have the 16p11.2 recurrent duplication [ • ASD has been found to be slightly more common in those with the 16p11.2 recurrent duplication (20%) than in those with the 16p11.2 recurrent deletion (16%), and individuals with the 16p11.2 recurrent duplication with ASD have lower cognition than those with the 16p11.2 recurrent deletion with ASD [ • Seizures are observed in approximately 20% of individuals with the 16p11.2 recurrent duplication [ • Head circumference tends to be smaller in individuals with the 16p11.2 recurrent duplication than in their relatives without the duplication [ • In addition, the 16p11.2 recurrent duplication is associated with underweight and a lower body mass index (BMI). The reciprocal impact of both the 16p11.2 recurrent deletion and duplication indicate that severe obesity (deletion) and being underweight (duplication) could have mirror etiologies, possibly through contrasting effects on energy balance [ ## 16p11.2-p12.2 Deletion At least two individuals with much larger deletions that include the 16p11.2 recurrent deletion region have been described [ ## Differential Diagnosis The differential diagnosis of the 16p11.2 recurrent deletion is broad due to the clinical variability and the presence of relatively common abnormal phenotypes that occur in affected individuals including developmental delay and autism spectrum disorder. All chromosome anomalies and genes known to be associated with intellectual disability (see ## Management No clinical practice guidelines for the 16p11.2 recurrent deletion have been published. To establish the extent of disease and needs in an individual diagnosed with the 16p11.2 recurrent deletion, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with the 16p11.2 Recurrent Deletion To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl brain MRI w/particular assessment for posterior fossa &/or craniocervical junction-related abnormalities Consider EEG if seizures are a concern. Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BMI = body mass index; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Such as chronic headache (especially occipital), neck pain, oropharyngeal dysfunction, sleep apnea, gait disturbance, and scoliosis Including Chiari I malformation, cerebellar tonsillar ectopia, and platybasia Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with the 16p11.2 Recurrent Deletion Control food intake w/normal portion sizes & limitation of intake between meals. Maintain active lifestyle. Esp important in young children before excessive weight gain begins ↑ calories specifically ingested in absence of hunger suggest that close supervision of portion size & meal times can be beneficial. 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; 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. For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of antiparkinsonian medications. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with the 16p11.2 Recurrent Deletion Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & signs/symptoms of spinal cord dysfunction. OT = occupational therapy; PT = physical therapy Such as chronic headache (especially occipital), neck pain, oropharyngeal dysfunction, sleep apnea, gait disturbance, and scoliosis Some medications used to treat behavioral problems (e.g., clozapine, olanzapine) may lead to excessive weight gain. When possible, use medications that are not associated with weight gain. See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl brain MRI w/particular assessment for posterior fossa &/or craniocervical junction-related abnormalities • Consider EEG if seizures are a concern. • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • Control food intake w/normal portion sizes & limitation of intake between meals. • Maintain active lifestyle. • Esp important in young children before excessive weight gain begins • ↑ calories specifically ingested in absence of hunger suggest that close supervision of portion size & meal times can be beneficial. • 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. • For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of antiparkinsonian medications. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & signs/symptoms of spinal cord dysfunction. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with the 16p11.2 recurrent deletion, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with the 16p11.2 Recurrent Deletion To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To incl brain MRI w/particular assessment for posterior fossa &/or craniocervical junction-related abnormalities Consider EEG if seizures are a concern. Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BMI = body mass index; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Such as chronic headache (especially occipital), neck pain, oropharyngeal dysfunction, sleep apnea, gait disturbance, and scoliosis Including Chiari I malformation, cerebellar tonsillar ectopia, and platybasia 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 w/particular assessment for posterior fossa &/or craniocervical junction-related abnormalities • Consider EEG if seizures are a concern. • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with the 16p11.2 Recurrent Deletion Control food intake w/normal portion sizes & limitation of intake between meals. Maintain active lifestyle. Esp important in young children before excessive weight gain begins ↑ calories specifically ingested in absence of hunger suggest that close supervision of portion size & meal times can be beneficial. 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; 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. For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of antiparkinsonian medications. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Control food intake w/normal portion sizes & limitation of intake between meals. • Maintain active lifestyle. • Esp important in young children before excessive weight gain begins • ↑ calories specifically ingested in absence of hunger suggest that close supervision of portion size & meal times can be beneficial. • 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. • For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of antiparkinsonian medications. ## 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. For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of antiparkinsonian medications. • Physical therapy is recommended to maximize mobility. • For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of antiparkinsonian medications. ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with the 16p11.2 Recurrent Deletion Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & signs/symptoms of spinal cord dysfunction. OT = occupational therapy; PT = physical therapy Such as chronic headache (especially occipital), neck pain, oropharyngeal dysfunction, sleep apnea, gait disturbance, and scoliosis • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, mvmt disorders, & signs/symptoms of spinal cord dysfunction. ## Agents/Circumstances to Avoid Some medications used to treat behavioral problems (e.g., clozapine, olanzapine) may lead to excessive weight gain. When possible, use medications that are not associated with weight gain. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The 16p11.2 recurrent deletion is The 16p11.2 recurrent deletion is Approximately 7% of probands inherited the 16p11.2 recurrent deletion from a parent. Parents with a 16p11.2 recurrent deletion typically do not have a history of ID or ASD but may have more subtle neurodevelopmental and behavioral manifestations. Genomic testing that will detect the 16p11.2 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. The 16p11.2 recurrent deletion has been detected in mildly affected and unaffected parents. If the 16p11.2 recurrent deletion identified in the proband is not identified in either confirmed biological parent, 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 genetic alteration that is present in the germ cells only. The 16p11.2 recurrent deletion has not been reported to have a parent-of-origin bias. If one of the parents has the 16p11.2 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 16p11.2 recurrent deletion; family members with the deletion may be mildly affected or have features similar to those of the proband. If the 16p11.2 recurrent deletion identified in the proband cannot be detected in parental leukocyte, the recurrence risk to sibs is approximately 1% because of the possibility of parental germline mosaicism for the deletion [ The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p11.2 recurrent deletion. Once a 16p11.2 recurrent deletion has been identified in a family member, prenatal and preimplantation genetic testing are possible. Although the prenatal finding of a 16p11.2 recurrent deletion cannot be used to reliably predict the phenotype, the majority of individuals with the 16p11.2 recurrent deletion have language delay and cognitive disability. 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 16p11.2 recurrent deletion is • Approximately 7% of probands inherited the 16p11.2 recurrent deletion from a parent. Parents with a 16p11.2 recurrent deletion typically do not have a history of ID or ASD but may have more subtle neurodevelopmental and behavioral manifestations. • Genomic testing that will detect the 16p11.2 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. The 16p11.2 recurrent deletion has been detected in mildly affected and unaffected parents. • If the 16p11.2 recurrent deletion identified in the proband is not identified in either confirmed biological parent, 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 genetic alteration that is present in the germ 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 genetic alteration that is present in the germ cells only. • The 16p11.2 recurrent deletion has not been reported to have a parent-of-origin bias. • 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 genetic alteration that is present in the germ cells only. • If one of the parents has the 16p11.2 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 16p11.2 recurrent deletion; family members with the deletion may be mildly affected or have features similar to those of the proband. • If the 16p11.2 recurrent deletion identified in the proband cannot be detected in parental leukocyte, the recurrence risk to sibs is approximately 1% because of the possibility of parental germline mosaicism for the deletion [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p11.2 recurrent deletion. ## Mode of Inheritance The 16p11.2 recurrent deletion is ## Risk to Family Members The 16p11.2 recurrent deletion is Approximately 7% of probands inherited the 16p11.2 recurrent deletion from a parent. Parents with a 16p11.2 recurrent deletion typically do not have a history of ID or ASD but may have more subtle neurodevelopmental and behavioral manifestations. Genomic testing that will detect the 16p11.2 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. The 16p11.2 recurrent deletion has been detected in mildly affected and unaffected parents. If the 16p11.2 recurrent deletion identified in the proband is not identified in either confirmed biological parent, 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 genetic alteration that is present in the germ cells only. The 16p11.2 recurrent deletion has not been reported to have a parent-of-origin bias. If one of the parents has the 16p11.2 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 16p11.2 recurrent deletion; family members with the deletion may be mildly affected or have features similar to those of the proband. If the 16p11.2 recurrent deletion identified in the proband cannot be detected in parental leukocyte, the recurrence risk to sibs is approximately 1% because of the possibility of parental germline mosaicism for the deletion [ • The 16p11.2 recurrent deletion is • Approximately 7% of probands inherited the 16p11.2 recurrent deletion from a parent. Parents with a 16p11.2 recurrent deletion typically do not have a history of ID or ASD but may have more subtle neurodevelopmental and behavioral manifestations. • Genomic testing that will detect the 16p11.2 recurrent deletion present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. The 16p11.2 recurrent deletion has been detected in mildly affected and unaffected parents. • If the 16p11.2 recurrent deletion identified in the proband is not identified in either confirmed biological parent, 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 genetic alteration that is present in the germ 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 genetic alteration that is present in the germ cells only. • The 16p11.2 recurrent deletion has not been reported to have a parent-of-origin bias. • 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 genetic alteration that is present in the germ cells only. • If one of the parents has the 16p11.2 recurrent deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. It is not possible to predict the phenotype in sibs who inherit a 16p11.2 recurrent deletion; family members with the deletion may be mildly affected or have features similar to those of the proband. • If the 16p11.2 recurrent deletion identified in the proband cannot be detected in parental leukocyte, the recurrence risk to sibs is approximately 1% because of the possibility of parental germline mosaicism for the deletion [ ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p11.2 recurrent deletion. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with the 16p11.2 recurrent deletion. ## Prenatal Testing and Preimplantation Genetic Testing Once a 16p11.2 recurrent deletion has been identified in a family member, prenatal and preimplantation genetic testing are possible. Although the prenatal finding of a 16p11.2 recurrent deletion cannot be used to reliably predict the phenotype, the majority of individuals with the 16p11.2 recurrent deletion have language delay and cognitive disability. 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 16p11.2 Recurrent Deletion: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for 16p11.2 Recurrent Deletion ( The 16p11.2 recurrent deletion is mediated by nonallelic homologous recombination (NAHR) between flanking 147-kb low-copy repeat sequences with 99.5% sequence identity [ How deletion of these genes results in the clinical manifestations associated with the 16p11.2 recurrent deletion is largely unknown, but ongoing investigations have identified the roles of some key genes and their associated functional pathways as responsible for the phenotypic features. While most of the genes at 16p11.2 exhibited dosage-dependent expression pattern [ ## Molecular Pathogenesis The 16p11.2 recurrent deletion is mediated by nonallelic homologous recombination (NAHR) between flanking 147-kb low-copy repeat sequences with 99.5% sequence identity [ How deletion of these genes results in the clinical manifestations associated with the 16p11.2 recurrent deletion is largely unknown, but ongoing investigations have identified the roles of some key genes and their associated functional pathways as responsible for the phenotypic features. While most of the genes at 16p11.2 exhibited dosage-dependent expression pattern [ ## Chapter Notes Wendy Chung, MD, PhD, FACMG (2015-present)Ellen Hanson, PhD; Boston Children's Hospital (2009-2021)Rachel Hundley, PhD; Boston Children's Hospital (2009-2011)Christopher Lehman, MS (2021-present)David T Miller, MD, PhD, FACMG; Boston Children's Hospital (2009-2021)Marissa Mitchel, MS, CCC-SLP (2021-present)Ramzi Nasir, MD, MPH; Boston Children's Hospital (2009-2021)Yiping Shen, PhD, FACMG; Boston Children's Hospital (2009-2021)Kaitlyn Singer, MS (2021-present)Magdi M Sobeih, MD, PhD; Boston Children's Hospital (2009-2015)Kyle J Steinman, MD, MAS; Seattle Children's Hospital / University of Washington (2015-2021)Rebecca Smith, MS, CGC (2021-present)Cora M Taylor, PhD (2021-present)W Curtis Weaver, BS (2021-present)Bai-Lin Wu, MMed, PhD, FACMG; Boston Children's Hospital (2009-2021) 28 October 2021 (ha) Comprehensive update posted live 10 December 2015 (me) Comprehensive update posted live 8 February 2011 (me) Comprehensive update posted live 22 September 2009 (et) Review posted live 6 March 2009 (dtm) Original submission • 28 October 2021 (ha) Comprehensive update posted live • 10 December 2015 (me) Comprehensive update posted live • 8 February 2011 (me) Comprehensive update posted live • 22 September 2009 (et) Review posted live • 6 March 2009 (dtm) Original submission ## Author History Wendy Chung, MD, PhD, FACMG (2015-present)Ellen Hanson, PhD; Boston Children's Hospital (2009-2021)Rachel Hundley, PhD; Boston Children's Hospital (2009-2011)Christopher Lehman, MS (2021-present)David T Miller, MD, PhD, FACMG; Boston Children's Hospital (2009-2021)Marissa Mitchel, MS, CCC-SLP (2021-present)Ramzi Nasir, MD, MPH; Boston Children's Hospital (2009-2021)Yiping Shen, PhD, FACMG; Boston Children's Hospital (2009-2021)Kaitlyn Singer, MS (2021-present)Magdi M Sobeih, MD, PhD; Boston Children's Hospital (2009-2015)Kyle J Steinman, MD, MAS; Seattle Children's Hospital / University of Washington (2015-2021)Rebecca Smith, MS, CGC (2021-present)Cora M Taylor, PhD (2021-present)W Curtis Weaver, BS (2021-present)Bai-Lin Wu, MMed, PhD, FACMG; Boston Children's Hospital (2009-2021) ## Revision History 28 October 2021 (ha) Comprehensive update posted live 10 December 2015 (me) Comprehensive update posted live 8 February 2011 (me) Comprehensive update posted live 22 September 2009 (et) Review posted live 6 March 2009 (dtm) Original submission • 28 October 2021 (ha) Comprehensive update posted live • 10 December 2015 (me) Comprehensive update posted live • 8 February 2011 (me) Comprehensive update posted live • 22 September 2009 (et) Review posted live • 6 March 2009 (dtm) Original submission ## References ## Literature Cited
[]
22/9/2009
28/10/2021
27/10/2011
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
del1p36
del1p36
[ "Monosomy 1p36 Syndrome", "Monosomy 1p36 Syndrome", "Not applicable", "Not applicable", "1p36 Deletion Syndrome" ]
1p36 Deletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Agatino Battaglia
Summary 1p36 deletion syndrome is characterized by typical craniofacial features consisting of straight eyebrows, deeply set eyes, midface retrusion, wide and depressed nasal bridge, long philtrum, pointed chin, large, late-closing anterior fontanel (77%), microbrachycephaly (65%), epicanthal folds (50%), and posteriorly rotated, low-set, abnormal ears. Other characteristic findings include brachy/camptodactyly and short feet. Developmental delay/intellectual disability of variable degree are present in all, and hypotonia in 95%. Seizures occur in 44%-58% of affected individuals. Other findings include structural brain abnormalities (88%), congenital heart defects (71%), eye/vision problems (52%), hearing loss (47%), skeletal anomalies (41%), abnormalities of the external genitalia (25%), and renal abnormalities (22%). The diagnosis of 1p36 deletion syndrome is suggested by clinical findings and confirmed by detection of a deletion of the most distal band of the short arm of chromosome 1 (1p36). Conventional G-banded cytogenetic analysis, FISH, or chromosomal microarray (CMA) can all be used to detect deletions; however, the complexity of some deletions may be detected only by CMA. 1p36 deletion syndrome is caused by deletion of the 1p36 chromosome region by one of several genetic mechanisms. Approximately 52% of individuals with 1p36 deletion syndrome have a
## Diagnosis The diagnosis of 1p36 deletion syndrome is suggested by the characteristic facial appearance, hypotonia, psychomotor retardation, and poor or absent speech and is confirmed by detection of a deletion of the most distal band of the short arm of chromosome 1 (1p36). An apparently "pure" terminal deletion Interstitial deletion More complex rearrangements including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions Derivative chromosome 1 resulting from an unbalanced translocation Note: (1) No common breakpoint or deletion size is present in individuals with monosomy 1p36. (2) Determining whether a cytogenetically visible deletion is a true terminal deletion or a more complex rearrangement may be accomplished using specialized molecular cytogenetic techniques (see Chromosome Abnormalities Seen in 1p36 Deletion Syndrome Including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions affecting chromosome 1p36 The 1p telomeric region is replaced by another chromosome end. Cytogenetic and Molecular Genetic Testing Used in 1p36 Deletion Syndrome Mb = 10 MLPA is not a recommended method of detection of deletions of these sizes. The ability of the test method used to detect a variant that is present in the indicated gene Conventional G-banded cytogenetic studies (routine and high-resolution) Deletions greater than 5 Mb occur at approximately the same frequency as deletions smaller than 5 Mb. FISH using at least two subtelomeric region-specific probes (Vysis 1p subtel probe, Vysis p58 probe; D1Z2 Oncor probe or CEB108/T7) can identify parental rearrangements and may detect terminal and interstitial deletions and derivative chromosomes. 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. Terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes can potentially be detected by CMA. Notes: (1) Subtelomere FISH detects the presence/absence of the two probes used; thus, FISH (a) cannot detect an interstitial deletion proximal to the probes; (b) cannot distinguish between a "true" terminal deletion and a more complex rearrangement; or (c) cannot define the extent of the deletion. However, CMA has the potential to do all three. (2) MLPA, a type of deletion/duplication analysis, is not a recommended method for detection of deletions of these sizes. • An apparently "pure" terminal deletion • Interstitial deletion • More complex rearrangements including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions • Derivative chromosome 1 resulting from an unbalanced translocation ## Clinical Diagnosis The diagnosis of 1p36 deletion syndrome is suggested by the characteristic facial appearance, hypotonia, psychomotor retardation, and poor or absent speech and is confirmed by detection of a deletion of the most distal band of the short arm of chromosome 1 (1p36). ## Testing An apparently "pure" terminal deletion Interstitial deletion More complex rearrangements including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions Derivative chromosome 1 resulting from an unbalanced translocation Note: (1) No common breakpoint or deletion size is present in individuals with monosomy 1p36. (2) Determining whether a cytogenetically visible deletion is a true terminal deletion or a more complex rearrangement may be accomplished using specialized molecular cytogenetic techniques (see Chromosome Abnormalities Seen in 1p36 Deletion Syndrome Including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions affecting chromosome 1p36 The 1p telomeric region is replaced by another chromosome end. Cytogenetic and Molecular Genetic Testing Used in 1p36 Deletion Syndrome Mb = 10 MLPA is not a recommended method of detection of deletions of these sizes. The ability of the test method used to detect a variant that is present in the indicated gene Conventional G-banded cytogenetic studies (routine and high-resolution) Deletions greater than 5 Mb occur at approximately the same frequency as deletions smaller than 5 Mb. FISH using at least two subtelomeric region-specific probes (Vysis 1p subtel probe, Vysis p58 probe; D1Z2 Oncor probe or CEB108/T7) can identify parental rearrangements and may detect terminal and interstitial deletions and derivative chromosomes. 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. Terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes can potentially be detected by CMA. • An apparently "pure" terminal deletion • Interstitial deletion • More complex rearrangements including more than one deletion or deletions with duplications, triplications, insertions, and/or inversions • Derivative chromosome 1 resulting from an unbalanced translocation ## Molecular Genetic Testing Cytogenetic and Molecular Genetic Testing Used in 1p36 Deletion Syndrome Mb = 10 MLPA is not a recommended method of detection of deletions of these sizes. The ability of the test method used to detect a variant that is present in the indicated gene Conventional G-banded cytogenetic studies (routine and high-resolution) Deletions greater than 5 Mb occur at approximately the same frequency as deletions smaller than 5 Mb. FISH using at least two subtelomeric region-specific probes (Vysis 1p subtel probe, Vysis p58 probe; D1Z2 Oncor probe or CEB108/T7) can identify parental rearrangements and may detect terminal and interstitial deletions and derivative chromosomes. 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. Terminal deletions, interstitial deletions, complex rearrangements, and derivative chromosomes can potentially be detected by CMA. ## Testing Strategy Notes: (1) Subtelomere FISH detects the presence/absence of the two probes used; thus, FISH (a) cannot detect an interstitial deletion proximal to the probes; (b) cannot distinguish between a "true" terminal deletion and a more complex rearrangement; or (c) cannot define the extent of the deletion. However, CMA has the potential to do all three. (2) MLPA, a type of deletion/duplication analysis, is not a recommended method for detection of deletions of these sizes. ## Clinical Characteristics The frequencies of the major clinical findings associated with 1p36 deletion syndrome are summarized in Frequency of Major Clinical Findings in 1p36 Deletion Syndrome Distinctive facial features (see Intellectual disability Poor/absent speech Hypotonia Brachycamptodactyly Short feet Brain abnormalities Congenital heart defects Eye/vision problems including visual inattention Seizures Skeletal anomalies Sensorineural deafness Gastrointestinal anomalies Abnormalities of the external genitalia Behavior disorders Non-compaction cardiomyopathy Renal anomalies Anal anomalies Hypothyroidism Behavior disorders, present in 50%, include poor social interaction, temper tantrums, self-biting of hands and wrists, a number of stereotypies, and, less frequently, hyperphagia. Central nervous system defects, present in 88% of affected individuals, mainly include dilatation of the lateral ventricles and subarachnoid spaces; cortical atrophy; diffuse brain atrophy; and hypoplasia, thinning, and total or partial absence of the corpus callosum. Other reported anomalies are delay in myelination, multifocal hyperintensity areas in the white matter [ Of note, epileptic apneas can also occur in some children [ A variety of EEG abnormalities are present in nearly all affected individuals [ Cryptorchidism, hypospadias, scrotal hypoplasia, and micropenis are seen in a minority of males [ Small labia minora and small clitoris, labia majora hypertrophy, and uterine hypoplasia have been reported in females [ Hypothyroidism has been reported in 15% to 20% of persons of varied ages with deletion 1p36 syndrome in whom TSH and T4 levels were studied [ Telangiectatic skin lesions and hyperpigmented macules [ Polydactyly [ Congenital spinal stenosis [ Congenital fiber type disproportion myopathy [ Redundant skin on the nape of the neck [ Intestinal malrotation, anular pancreas, and anomalous arrangement of the pancreaticobiliary duct [ Liver steatosis [ Hypertrophic pyloric stenosis Anteriorly placed or imperforate anus, hooked or bilobed gallbladder, and small spleen [ Neuroblastoma (in 3 individuals) [ Pemphigus vulgaris (in 1 individual) [ To explain the phenotypic variability of 1p36 deletion syndrome, investigators have searched for correlations between size of the 1p deletion and severity of clinical manifestations. The prevalence of 1p36 deletion syndrome is estimated at between 1:5,000 and 1:10,000 births, with a 2:1 female to male ratio [ • Distinctive facial features (see • Intellectual disability • Poor/absent speech • Hypotonia • Brachycamptodactyly • Short feet • Brain abnormalities • Congenital heart defects • Eye/vision problems including visual inattention • Seizures • Skeletal anomalies • Sensorineural deafness • Gastrointestinal anomalies • Abnormalities of the external genitalia • Behavior disorders • Non-compaction cardiomyopathy • Renal anomalies • Anal anomalies • Hypothyroidism • Telangiectatic skin lesions and hyperpigmented macules [ • Polydactyly [ • Congenital spinal stenosis [ • Congenital fiber type disproportion myopathy [ • Redundant skin on the nape of the neck [ • Intestinal malrotation, anular pancreas, and anomalous arrangement of the pancreaticobiliary duct [ • Liver steatosis [ • Hypertrophic pyloric stenosis • Anteriorly placed or imperforate anus, hooked or bilobed gallbladder, and small spleen [ • Neuroblastoma (in 3 individuals) [ • Pemphigus vulgaris (in 1 individual) [ ## Clinical Description The frequencies of the major clinical findings associated with 1p36 deletion syndrome are summarized in Frequency of Major Clinical Findings in 1p36 Deletion Syndrome Distinctive facial features (see Intellectual disability Poor/absent speech Hypotonia Brachycamptodactyly Short feet Brain abnormalities Congenital heart defects Eye/vision problems including visual inattention Seizures Skeletal anomalies Sensorineural deafness Gastrointestinal anomalies Abnormalities of the external genitalia Behavior disorders Non-compaction cardiomyopathy Renal anomalies Anal anomalies Hypothyroidism Behavior disorders, present in 50%, include poor social interaction, temper tantrums, self-biting of hands and wrists, a number of stereotypies, and, less frequently, hyperphagia. Central nervous system defects, present in 88% of affected individuals, mainly include dilatation of the lateral ventricles and subarachnoid spaces; cortical atrophy; diffuse brain atrophy; and hypoplasia, thinning, and total or partial absence of the corpus callosum. Other reported anomalies are delay in myelination, multifocal hyperintensity areas in the white matter [ Of note, epileptic apneas can also occur in some children [ A variety of EEG abnormalities are present in nearly all affected individuals [ Cryptorchidism, hypospadias, scrotal hypoplasia, and micropenis are seen in a minority of males [ Small labia minora and small clitoris, labia majora hypertrophy, and uterine hypoplasia have been reported in females [ Hypothyroidism has been reported in 15% to 20% of persons of varied ages with deletion 1p36 syndrome in whom TSH and T4 levels were studied [ Telangiectatic skin lesions and hyperpigmented macules [ Polydactyly [ Congenital spinal stenosis [ Congenital fiber type disproportion myopathy [ Redundant skin on the nape of the neck [ Intestinal malrotation, anular pancreas, and anomalous arrangement of the pancreaticobiliary duct [ Liver steatosis [ Hypertrophic pyloric stenosis Anteriorly placed or imperforate anus, hooked or bilobed gallbladder, and small spleen [ Neuroblastoma (in 3 individuals) [ Pemphigus vulgaris (in 1 individual) [ • Distinctive facial features (see • Intellectual disability • Poor/absent speech • Hypotonia • Brachycamptodactyly • Short feet • Brain abnormalities • Congenital heart defects • Eye/vision problems including visual inattention • Seizures • Skeletal anomalies • Sensorineural deafness • Gastrointestinal anomalies • Abnormalities of the external genitalia • Behavior disorders • Non-compaction cardiomyopathy • Renal anomalies • Anal anomalies • Hypothyroidism • Telangiectatic skin lesions and hyperpigmented macules [ • Polydactyly [ • Congenital spinal stenosis [ • Congenital fiber type disproportion myopathy [ • Redundant skin on the nape of the neck [ • Intestinal malrotation, anular pancreas, and anomalous arrangement of the pancreaticobiliary duct [ • Liver steatosis [ • Hypertrophic pyloric stenosis • Anteriorly placed or imperforate anus, hooked or bilobed gallbladder, and small spleen [ • Neuroblastoma (in 3 individuals) [ • Pemphigus vulgaris (in 1 individual) [ ## Genotype-Phenotype Correlations To explain the phenotypic variability of 1p36 deletion syndrome, investigators have searched for correlations between size of the 1p deletion and severity of clinical manifestations. ## Prevalence The prevalence of 1p36 deletion syndrome is estimated at between 1:5,000 and 1:10,000 births, with a 2:1 female to male ratio [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The clinical phenotype and the facial gestalt of 1p36 deletion syndrome are characteristic. However, some individuals may be misdiagnosed because of features that overlap with the following disorders: ## Management To establish the extent of disease and needs in an individual diagnosed with 1p36 deletion syndrome, the following evaluations are recommended: Measurements of growth parameters and plotting on standard growth charts Note: No growth charts are available specifically for 1p36 deletion syndrome. Physical and neurologic examination Evaluation of cognitive, language, and motor development and social skills Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy Waking/sleeping video-EEG-polygraphic studies (mainly in infancy) to detect infantile spasms with hypsarrhythmia Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team Ophthalmology consultation in infancy or at diagnosis even in the absence of overt anomalies Physical examination for skeletal anomalies (e.g., scoliosis, lower-limb asymmetry); if anomalies are present, referral for orthopedic and physical therapy evaluation Comprehensive otolaryngologic evaluation and audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies Periodic thyroid function screening Consultation with a clinical geneticist and/or genetic counselor In most individuals, all seizure types are well controlled by standard antiepileptic drugs (AEDs), provided that the first-choice drug is started as early as possible. Systematic follow up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change [ See Search • Measurements of growth parameters and plotting on standard growth charts • Note: No growth charts are available specifically for 1p36 deletion syndrome. • Physical and neurologic examination • Evaluation of cognitive, language, and motor development and social skills • Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy • Waking/sleeping video-EEG-polygraphic studies (mainly in infancy) to detect infantile spasms with hypsarrhythmia • Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team • Ophthalmology consultation in infancy or at diagnosis even in the absence of overt anomalies • Physical examination for skeletal anomalies (e.g., scoliosis, lower-limb asymmetry); if anomalies are present, referral for orthopedic and physical therapy evaluation • Comprehensive otolaryngologic evaluation and audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions • Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies • Periodic thyroid function screening • 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 1p36 deletion syndrome, the following evaluations are recommended: Measurements of growth parameters and plotting on standard growth charts Note: No growth charts are available specifically for 1p36 deletion syndrome. Physical and neurologic examination Evaluation of cognitive, language, and motor development and social skills Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy Waking/sleeping video-EEG-polygraphic studies (mainly in infancy) to detect infantile spasms with hypsarrhythmia Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team Ophthalmology consultation in infancy or at diagnosis even in the absence of overt anomalies Physical examination for skeletal anomalies (e.g., scoliosis, lower-limb asymmetry); if anomalies are present, referral for orthopedic and physical therapy evaluation Comprehensive otolaryngologic evaluation and audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies Periodic thyroid function screening Consultation with a clinical geneticist and/or genetic counselor • Measurements of growth parameters and plotting on standard growth charts • Note: No growth charts are available specifically for 1p36 deletion syndrome. • Physical and neurologic examination • Evaluation of cognitive, language, and motor development and social skills • Examination of the heart (auscultation, electrocardiogram, echocardiography) in infancy • Waking/sleeping video-EEG-polygraphic studies (mainly in infancy) to detect infantile spasms with hypsarrhythmia • Evaluation for feeding problems and gastroesophageal reflux with referral to a dysphagia team • Ophthalmology consultation in infancy or at diagnosis even in the absence of overt anomalies • Physical examination for skeletal anomalies (e.g., scoliosis, lower-limb asymmetry); if anomalies are present, referral for orthopedic and physical therapy evaluation • Comprehensive otolaryngologic evaluation and audiologic screening (brain stem auditory evoked responses) as early as possible to allow appropriate interventions • Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies • Periodic thyroid function screening • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations In most individuals, all seizure types are well controlled by standard antiepileptic drugs (AEDs), provided that the first-choice drug is started as early as possible. ## Surveillance Systematic follow up allows for adjustment of rehabilitation and treatment as skills improve or deteriorate and medical needs change [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling 1p36 deletion syndrome can be the result of an inherited or The parents of a proband with 1p36 deletion syndrome are unaffected but may carry a balanced rearrangement involving 1p36 (see Sixty percent of In approximately one third of individuals with a derivative chromosome 1, the derivative chromosome 1 results from malsegregation of a balanced parental translocation. Parents of individuals with 1p36 deletion syndrome should have cytogenetic analysis looking for a translocation involving 1p36. CMA would not be recommended for this as the rearrangement would be expected to be balanced, and thus not detected. Subtelomeric analysis of both parents of a proband with an apparently The risk to the sibs of a proband depends on the genetic status of the parents. If the deletion in the proband is If a parent is a balanced translocation carrier, the risk to sibs of being affected with 1p monosomy (i.e., 1p36 deletion syndrome) or 1p trisomy is increased over the general population risk. If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by the method used to identify the rearrangement in the parent (i.e., chromosome analysis or subtelomeric FISH analysis). 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 known to be or at risk of being carriers of a chromosome rearrangement. • The parents of a proband with 1p36 deletion syndrome are unaffected but may carry a balanced rearrangement involving 1p36 (see • Sixty percent of • In approximately one third of individuals with a derivative chromosome 1, the derivative chromosome 1 results from malsegregation of a balanced parental translocation. • Parents of individuals with 1p36 deletion syndrome should have cytogenetic analysis looking for a translocation involving 1p36. CMA would not be recommended for this as the rearrangement would be expected to be balanced, and thus not detected. • Subtelomeric analysis of both parents of a proband with an apparently • The risk to the sibs of a proband depends on the genetic status of the parents. • If the deletion in the proband is • If a parent is a balanced translocation carrier, the risk to sibs of being affected with 1p monosomy (i.e., 1p36 deletion syndrome) or 1p trisomy is increased over the general population risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are known to be or at risk of being carriers of a chromosome rearrangement. ## Mode of Inheritance 1p36 deletion syndrome can be the result of an inherited or ## Risk to Family Members The parents of a proband with 1p36 deletion syndrome are unaffected but may carry a balanced rearrangement involving 1p36 (see Sixty percent of In approximately one third of individuals with a derivative chromosome 1, the derivative chromosome 1 results from malsegregation of a balanced parental translocation. Parents of individuals with 1p36 deletion syndrome should have cytogenetic analysis looking for a translocation involving 1p36. CMA would not be recommended for this as the rearrangement would be expected to be balanced, and thus not detected. Subtelomeric analysis of both parents of a proband with an apparently The risk to the sibs of a proband depends on the genetic status of the parents. If the deletion in the proband is If a parent is a balanced translocation carrier, the risk to sibs of being affected with 1p monosomy (i.e., 1p36 deletion syndrome) or 1p trisomy is increased over the general population risk. • The parents of a proband with 1p36 deletion syndrome are unaffected but may carry a balanced rearrangement involving 1p36 (see • Sixty percent of • In approximately one third of individuals with a derivative chromosome 1, the derivative chromosome 1 results from malsegregation of a balanced parental translocation. • Parents of individuals with 1p36 deletion syndrome should have cytogenetic analysis looking for a translocation involving 1p36. CMA would not be recommended for this as the rearrangement would be expected to be balanced, and thus not detected. • Subtelomeric analysis of both parents of a proband with an apparently • The risk to the sibs of a proband depends on the genetic status of the parents. • If the deletion in the proband is • If a parent is a balanced translocation carrier, the risk to sibs of being affected with 1p monosomy (i.e., 1p36 deletion syndrome) or 1p trisomy is increased over the general population risk. ## Carrier Detection If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by the method used to identify the rearrangement in the parent (i.e., chromosome analysis or subtelomeric FISH analysis). ## 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 known to be or at risk of being carriers of a chromosome rearrangement. • 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 known to be or at risk of being carriers of a chromosome rearrangement. ## Prenatal Testing and Preimplantation Genetic Testing ## Resources PO Box 724 Boca Raton FL 33429-0724 G1 The Stables Station Road West Oxted Surrey RH8 9EE United Kingdom • • • • PO Box 724 • Boca Raton FL 33429-0724 • • • G1 The Stables • Station Road West • Oxted Surrey RH8 9EE • United Kingdom • ## Molecular Genetics 1p36 Deletion Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for 1p36 Deletion Syndrome ( No genes have been conclusively determined to be associated with the clinical features that characterize 1p36 deletion syndrome. ## Molecular Pathogenesis No genes have been conclusively determined to be associated with the clinical features that characterize 1p36 deletion syndrome. ## References ## Literature Cited ## Chapter Notes Agatino Battaglia, MD (2008-present)Lisa G Shaffer, PhD, FACMG; Signature Genomic Laboratories (2008-2013) 8 August 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population 6 June 2013 (me) Comprehensive update posted live 1 February 2008 (me) Review posted live 24 August 2007 (ab) Original submission • 8 August 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population • 6 June 2013 (me) Comprehensive update posted live • 1 February 2008 (me) Review posted live • 24 August 2007 (ab) Original submission ## Author History Agatino Battaglia, MD (2008-present)Lisa G Shaffer, PhD, FACMG; Signature Genomic Laboratories (2008-2013) ## Revision History 8 August 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population 6 June 2013 (me) Comprehensive update posted live 1 February 2008 (me) Review posted live 24 August 2007 (ab) Original submission • 8 August 2019 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population • 6 June 2013 (me) Comprehensive update posted live • 1 February 2008 (me) Review posted live • 24 August 2007 (ab) Original submission Two unrelated children showing microbrachycephaly, straight eyebrows, deeply set eyes, wide and depressed nasal bridge, midface retrusion, elongated philtrum, pointed chin, and hypotonic face A. Girl age 9.5 years B. Boy age 6.5 years; also showing grade II left microtia with atresia of the external auditory canal and preauricular tag
[ "J Anderson, H Kempski, L Hill, D Rampling, T Gordon, A Michalski. Neuroblastoma in monozygotic twins--a case of probable twin-to-twin metastasis.. Br J Cancer 2001;85:493-6", "N Bahi-Buisson, E Gutierrez-Delicado, C Soufflet, M Rio, V Cormier Daire, D Lacombe, D Heron, A Verloes, SM Zuberi, L Burglen, A Afenjar, LM Moutard, P Edery, O Dulac, R Nabbout, P Plouin, A Battaglia. Spectrum of epilepsy in terminal 1p36 deletion syndrome.. Epilepsia 2008;49:509-15", "A Battaglia. Del 1p36 syndrome: a newly emerging clinical entity.. Brain Dev 2005;27:358-61", "A Battaglia, HE Hoyme, B Dallapiccola, E Zackai, L Hudgins, D McDonald-McGinn, N Bahi-Buisson, C Romano, CA Williams, LL Braley, SM Zuberi, JC Carey. Further delineation of deletion 1p36 syndrome in 60 patients: a recognizable phenotype and common cause of developmental delay and mental retardation.. Pediatrics 2008;121:404-10", "JA Biegel, PS White, HN Marshall, M Fujimori, EH Zackai, CD Scher, GM Brodeur, BS Emanuel. Constitutional 1p36 deletion in a child with neuroblastoma.. Am J Hum Genet 1993;52:176-82", "N Bolognini, F Rasi, M Coccia, E Ladavas. Visual search improvement in hemianopic patients after audio-visual stimulation.. Brain 2005;128:2830-42", "M Descartes, FM Mikhail, JC Franklin, TM McGrath, M Bebin. Monosomy1p36.3 and trisomy 19p13.3 in a child with periventricular nodular heterotopia.. Pediatr Neurol. 2011;45:274-8", "WB Dobyns, G Mirzaa, SL Christian, K Petras, J Roseberry, GD Clark, CJR Curry, D McDonald-McGinn, L Medne, E Zackai, J Parsons, DJ Zand, FM Hisama, CA Walsh, RJ Leventer, CL Martin, M Gajecka, LG Shaffer. Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2.. Am J Med Genet A 2008;146A:1637-54", "M Gajecka, KL Mackay, LG Shaffer. Monosomy 1p36 deletion syndrome.. Am J Med Genet C Semin Med Genet. 2007;145C:346-56", "M Gajecka, SC Saitta, AJ Gentles, L Campbell, K Ciprero, E Geiger, A Catherwood, JA Rosenfeld, T Shaikh, LG Shaffer. Recurrent interstitial 1p36 deletions: evidence for germline mosaicism and complex rearrangement breakpoints.. Am J Med Genet A 2010;152A:3074-83", "M Haimi, TC Iancu, LG Shaffer, A Lerner. Severe lysosomal storage disease of liver in del(1)(p36): a new presentation.. Eur J Med Genet 2011;54:209-13", "AV Halpern, A Bansal, WR Heymann. Pemphigus vulgaris in a patient with 1p36 deletion syndrome.. J Am Acad Dermatol 2006;55:98-9", "HA Heilstedt, BC Ballif, LA Howard, CD Kashork, LG Shaffer. Population data suggest that deletions of 1p36 are a relatively common chromosome abnormality.. Clin Genet 2003a;64:310-6", "HA Heilstedt, BC Ballif, LA Howard, RA Lewis, S Stal, CD Kashork, CA Bacino, SK Shapira, LG Shaffer. Physical map of 1p36, placement of breakpoints in monosomy 1p36, and clinical characterization of the syndrome.. Am J Hum Genet 2003b;72:1200-12", "HA Heilstedt, DL Burgess, AE Anderson, A Chedrawi, B Tharp, O Lee, CD Kashork, DE Starkey, YQ Wu, JL Noebels, LG Shaffer, SK Shapira. Loss of the potassium channel beta-subunit gene, KCNAB2, is associated with epilepsy in patients with 1p36 deletion syndrome.. Epilepsia 2001;42:1103-11", "G Kanabar, S Boyd, A Schugal, S Bhate. Multiple causes of apnea in 1p36 deletion syndrome include seizures.. Seizure 2012;21:402-6", "H Kawashima, N Kinjo, H Uejima, H Ioi, K Takekuma, I Nagae, K Ishii, T Itoi, H Numabe. A case of 1p36 deletion syndrome accompanied with anomalous arrangement of the pancreaticobiliary duct.. Pancreas 2011;40:171-3", "KM Keppler-Noreuil, AJ Carroll, WH Finley, SL Rutledge. Chromosome 1p terminal deletion: report of new findings and confirmation of two characteristic phenotypes.. J Med Genet 1995;32:619-22", "G Laureys, F Speleman, G Opdenakker, Y Benoit, J Leroy. Constitutional translocation t(1;17)(p36;q12-21) in a patient with neuroblastoma.. Genes Chromosomes Cancer 1990;2:252-4", "K Minami, H Boshi, T Minami, A Tamura, T Yanagawa, S Uemura, K Takifuji, K Kurosawa, R Tsukino, G Izumi, N Yoshikawa. 1p36 deletion syndrome with intestinal malrotation and annular pancreas.. Eur J Pediatr 2005;164:193-4", "J Neal, K Apse, M Sahin, CA Walsh, VL Sheen. Deletion of chromosome 1p36 is associated with periventricular nodular heterotopia.. Am J Med Genet A 2006;140:1692-5", "N Okamoto, Y Toribe, T Nakajima, T Okinaga, K Kurosawa, I Nonaka, O Shimokawa, N Matsumoto. A girl with 1p36 deletion syndrome and congenital fiber type disproportion myopathy.. J Hum Genet 2002;47:556-9", "AR Paciorkowski, LL Thio, JA Rosenfeld, M Gajecka, CA Gurnett, S Kulkarni, WK Chung, ED Marsh, M Gentile, JD Reggin, JW Wheless, S Balasubramian, R Kumar, SL Christian, C Marini, R Guerrini, N Maltsev, LG Shaffer, WB Dobyns. Copy number variants and infantile spasms: evidence for abnormalities in ventral forebrain development and pathways of synaptic function.. Eur J Hum Genet 2011;19:1238-45", "R Redon, M Rio, SG Gregory, RA Cooper, H Fiegler, D Sanlaville, R Banerjee, C Scott, P Carr, C Langford, V Cormier-Daire, A Munnich, NP Carter, L Colleaux. Tiling path resolution mapping of constitutional 1p36 deletions by array-CGH: contiguous gene deletion or \"deletion with positional effect\" syndrome?. J Med Genet 2005;42:166-71", "O Reish, SA Berry, B Hirsch. Partial monosomy of chromosome 1p36.3: characterization of the critical region and delineation of a syndrome.. Am J Med Genet. 1995;59:467-75", "SK Shapira, C McCaskill, H Northrup, AS Spikes, FF Elder, VR Sutton, JR Korenberg, F Greenberg, LG Shaffer. Chromosome 1p36 deletions: the clinical phenotype and molecular characterization of a common newly delineated syndrome.. Am J Hum Genet 1997;61:642-50", "A Slavotinek, LG Shaffer, SK Shapira. Monosomy 1p36.. J Med Genet. 1999;36:657-63", "BT Wang, M Chen. Redundant skin over the nape in a girl with monosomy 1p36 caused by a de-novo satellited derivative chromosome: a possible new feature?. Clin Dysmorphol 2004;13:107-9", "YQ Wu, HA Heilstedt, JA Bedell, KM May, DE Starkey, JD McPherson, SK Shapira, LG Shaffer. Molecular refinement of the 1p36 deletion syndrome reveals size diversity and a preponderance of maternally derived deletions.. Hum Mol Genet 1999;8:313-21" ]
1/2/2008
6/6/2013
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
del2q37_2
del2q37_2
[ "Albright Hereditary Osteodystrophy-Like Syndrome", "Brachydactyly-Mental Retardation Syndrome", "Albright Hereditary Osteodystrophy-Like Syndrome", "Brachydactyly-Mental Retardation Syndrome", "Histone deacetylase 4", "Not applicable", "HDAC4", "Not applicable", "2q37 Microdeletion Syndrome" ]
2q37 Microdeletion Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Emily S Doherty, Felicitas L Lacbawan
Summary 2q37 microdeletion syndrome is characterized by mild-moderate developmental delay/intellectual disability, brachymetaphalangy of digits 3-5 (often digit 4 alone) (>50%), short stature, obesity, hypotonia, characteristic facial appearance, autism or autism spectrum disorder (30%), joint hypermobility/dislocation, and scoliosis. Other findings include seizures (20%-35%), congenital heart disease, CNS abnormalities (hydrocephalus, dilated ventricles), umbilical/inguinal hernia, tracheomalacia, situs abnormalities, gastrointestinal abnormalities, and renal malformations. Wilms tumor has been reported in two individuals. Chromosome analysis confirms the diagnosis of 2q37 deletion syndrome in 80%-85% of affected individuals. In about 15%-20% of cases the small size of the deleted region can only be detected using deletion analysis (which relies on a variety of methods). In some individuals, 2q37 microdeletion syndrome results from chromosome rearrangements involving 2q37 (e.g., chromosome 2 inversion, ring chromosome 2, or translocation between chromosome 2 and another chromosome). Mutation of Most individuals with the 2q37 microdeletion syndrome have a
## Diagnosis Developmental delay/intellectual disability Brachymetaphalangy of digits 3-5 (often digit 4 alone), referred to as type E brachydactyly Short stature Obesity Hypotonia Characteristic facial appearance: Round face (variable) Frontal bossing Arched eyebrows Deep-set eyes Upslanted palpebral fissures Epicanthal folds Hypoplastic alae nasi Prominent columella Thin upper lip Minor ear anomalies Autism or autism spectrum disorder Joint hypermobility/dislocation, scoliosis Note: When present together, the first four features (developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity) are often referred to as the Albright hereditary osteodystrophy (AHO)-like phenotype. Seizures Congenital heart disease (atrial/ventricular septal defects, PDA) CNS abnormalities (hydrocephalus, dilated ventricles) Umbilical/inguinal hernia Tracheomalacia Situs abnormalities Gastrointestinal abnormalities Renal malformations Eczema Osteopenia Behavioral problems (hyperactivity, attention deficits) In about 15%-20% of cases, the conventional karyotype is normal because of the small size of the deleted region [ Some individuals with the 2q37 microdeletion syndrome have chromosome rearrangements involving 2q37, including chromosome 2 inversion, ring chromosome 2, or translocation between chromosome 2 and another chromosome that results in deletion of 2q37. Molecular Genetic Testing Used in 2q37 Deletion Syndrome The ability of the test method used to detect a genetic defect that is present in the indicated gene 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. Subtelomeric 2q probes are commercially available. A subtelomeric FISH probe should confirm the vast majority of chromosome 2q37 deletions. Theoretically, an interstitial 2q37 deletion could be missed if the subtelomeric sequence is present [ Chromosomal microarray (CMA) using BAC clones confirmed a cryptic unbalanced translocation involving 2q37.2 in a spontaneously aborted fetus after cultured embryonic tissue failed to grow [ Although submicroscopic deletions are demonstrated using FISH or CMA, concurrent duplication/deletion may be missed by FISH study [ 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 Deletion/duplication analysis could be performed first, as it will detect large deletions, microdeletions, and microduplications of the 2q37 region. In addition, it would screen for other microdeletion/microduplication syndromes (e.g., Note: Deletion/duplication analyses (e.g., CMA) typically do not directly evaluate chromosome structure; thus, when results suggest an unbalanced translocation or a ring chromosome, conventional cytogenetic studies are needed to confirm these structural chromosome anomalies. For familial cases where other chromosome rearrangements may be present, karyotype (i.e., routine cytogenetic study) should be done. If the chromosome study is normal but the index of suspicion is high, targeted deletion analysis of the 2q37 region may be performed. If the proband has clinical features of the 2q37 microdeletion syndrome but no microdeletion or chromosome anomaly involving 2q37 is found on the above testing, sequence analysis of • Developmental delay/intellectual disability • Brachymetaphalangy of digits 3-5 (often digit 4 alone), referred to as type E brachydactyly • Short stature • Obesity • Hypotonia • Characteristic facial appearance: • Round face (variable) • Frontal bossing • Arched eyebrows • Deep-set eyes • Upslanted palpebral fissures • Epicanthal folds • Hypoplastic alae nasi • Prominent columella • Thin upper lip • Minor ear anomalies • Round face (variable) • Frontal bossing • Arched eyebrows • Deep-set eyes • Upslanted palpebral fissures • Epicanthal folds • Hypoplastic alae nasi • Prominent columella • Thin upper lip • Minor ear anomalies • Autism or autism spectrum disorder • Joint hypermobility/dislocation, scoliosis • Round face (variable) • Frontal bossing • Arched eyebrows • Deep-set eyes • Upslanted palpebral fissures • Epicanthal folds • Hypoplastic alae nasi • Prominent columella • Thin upper lip • Minor ear anomalies • Seizures • Congenital heart disease (atrial/ventricular septal defects, PDA) • CNS abnormalities (hydrocephalus, dilated ventricles) • Umbilical/inguinal hernia • Tracheomalacia • Situs abnormalities • Gastrointestinal abnormalities • Renal malformations • Eczema • Osteopenia • Behavioral problems (hyperactivity, attention deficits) • Deletion/duplication analysis could be performed first, as it will detect large deletions, microdeletions, and microduplications of the 2q37 region. In addition, it would screen for other microdeletion/microduplication syndromes (e.g., • Note: Deletion/duplication analyses (e.g., CMA) typically do not directly evaluate chromosome structure; thus, when results suggest an unbalanced translocation or a ring chromosome, conventional cytogenetic studies are needed to confirm these structural chromosome anomalies. • For familial cases where other chromosome rearrangements may be present, karyotype (i.e., routine cytogenetic study) should be done. • If the chromosome study is normal but the index of suspicion is high, targeted deletion analysis of the 2q37 region may be performed. ## Clinical Diagnosis Developmental delay/intellectual disability Brachymetaphalangy of digits 3-5 (often digit 4 alone), referred to as type E brachydactyly Short stature Obesity Hypotonia Characteristic facial appearance: Round face (variable) Frontal bossing Arched eyebrows Deep-set eyes Upslanted palpebral fissures Epicanthal folds Hypoplastic alae nasi Prominent columella Thin upper lip Minor ear anomalies Autism or autism spectrum disorder Joint hypermobility/dislocation, scoliosis Note: When present together, the first four features (developmental delay/intellectual disability, brachymetaphalangy of digits 3-5, short stature, obesity) are often referred to as the Albright hereditary osteodystrophy (AHO)-like phenotype. Seizures Congenital heart disease (atrial/ventricular septal defects, PDA) CNS abnormalities (hydrocephalus, dilated ventricles) Umbilical/inguinal hernia Tracheomalacia Situs abnormalities Gastrointestinal abnormalities Renal malformations Eczema Osteopenia Behavioral problems (hyperactivity, attention deficits) • Developmental delay/intellectual disability • Brachymetaphalangy of digits 3-5 (often digit 4 alone), referred to as type E brachydactyly • Short stature • Obesity • Hypotonia • Characteristic facial appearance: • Round face (variable) • Frontal bossing • Arched eyebrows • Deep-set eyes • Upslanted palpebral fissures • Epicanthal folds • Hypoplastic alae nasi • Prominent columella • Thin upper lip • Minor ear anomalies • Round face (variable) • Frontal bossing • Arched eyebrows • Deep-set eyes • Upslanted palpebral fissures • Epicanthal folds • Hypoplastic alae nasi • Prominent columella • Thin upper lip • Minor ear anomalies • Autism or autism spectrum disorder • Joint hypermobility/dislocation, scoliosis • Round face (variable) • Frontal bossing • Arched eyebrows • Deep-set eyes • Upslanted palpebral fissures • Epicanthal folds • Hypoplastic alae nasi • Prominent columella • Thin upper lip • Minor ear anomalies • Seizures • Congenital heart disease (atrial/ventricular septal defects, PDA) • CNS abnormalities (hydrocephalus, dilated ventricles) • Umbilical/inguinal hernia • Tracheomalacia • Situs abnormalities • Gastrointestinal abnormalities • Renal malformations • Eczema • Osteopenia • Behavioral problems (hyperactivity, attention deficits) ## Testing In about 15%-20% of cases, the conventional karyotype is normal because of the small size of the deleted region [ Some individuals with the 2q37 microdeletion syndrome have chromosome rearrangements involving 2q37, including chromosome 2 inversion, ring chromosome 2, or translocation between chromosome 2 and another chromosome that results in deletion of 2q37. Molecular Genetic Testing Used in 2q37 Deletion Syndrome The ability of the test method used to detect a genetic defect that is present in the indicated gene 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. Subtelomeric 2q probes are commercially available. A subtelomeric FISH probe should confirm the vast majority of chromosome 2q37 deletions. Theoretically, an interstitial 2q37 deletion could be missed if the subtelomeric sequence is present [ Chromosomal microarray (CMA) using BAC clones confirmed a cryptic unbalanced translocation involving 2q37.2 in a spontaneously aborted fetus after cultured embryonic tissue failed to grow [ Although submicroscopic deletions are demonstrated using FISH or CMA, concurrent duplication/deletion may be missed by FISH study [ 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 ## Molecular Genetic Testing Molecular Genetic Testing Used in 2q37 Deletion Syndrome The ability of the test method used to detect a genetic defect that is present in the indicated gene 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. Subtelomeric 2q probes are commercially available. A subtelomeric FISH probe should confirm the vast majority of chromosome 2q37 deletions. Theoretically, an interstitial 2q37 deletion could be missed if the subtelomeric sequence is present [ Chromosomal microarray (CMA) using BAC clones confirmed a cryptic unbalanced translocation involving 2q37.2 in a spontaneously aborted fetus after cultured embryonic tissue failed to grow [ Although submicroscopic deletions are demonstrated using FISH or CMA, concurrent duplication/deletion may be missed by FISH study [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click ## Testing Strategy Deletion/duplication analysis could be performed first, as it will detect large deletions, microdeletions, and microduplications of the 2q37 region. In addition, it would screen for other microdeletion/microduplication syndromes (e.g., Note: Deletion/duplication analyses (e.g., CMA) typically do not directly evaluate chromosome structure; thus, when results suggest an unbalanced translocation or a ring chromosome, conventional cytogenetic studies are needed to confirm these structural chromosome anomalies. For familial cases where other chromosome rearrangements may be present, karyotype (i.e., routine cytogenetic study) should be done. If the chromosome study is normal but the index of suspicion is high, targeted deletion analysis of the 2q37 region may be performed. If the proband has clinical features of the 2q37 microdeletion syndrome but no microdeletion or chromosome anomaly involving 2q37 is found on the above testing, sequence analysis of • Deletion/duplication analysis could be performed first, as it will detect large deletions, microdeletions, and microduplications of the 2q37 region. In addition, it would screen for other microdeletion/microduplication syndromes (e.g., • Note: Deletion/duplication analyses (e.g., CMA) typically do not directly evaluate chromosome structure; thus, when results suggest an unbalanced translocation or a ring chromosome, conventional cytogenetic studies are needed to confirm these structural chromosome anomalies. • For familial cases where other chromosome rearrangements may be present, karyotype (i.e., routine cytogenetic study) should be done. • If the chromosome study is normal but the index of suspicion is high, targeted deletion analysis of the 2q37 region may be performed. ## Clinical Characteristics The 2q37 microdeletion syndrome may present with a broad spectrum of clinical findings as described below [ In individuals with isolated microdeletion 2q37 (i.e., those without an unbalanced translocation), functional outcome was affected by the presence of autism, developmental delay, and/or major congenital anomalies. The phenotype observed in individuals with 2q37 microdeletion syndrome seems variable in earlier reports because the molecular breakpoints were not defined. The published female-to-male ratio is greater than one. Low-set, hypoplastic nipples are often seen. Joint hyperextensibility and skin hyperlaxity may be observed. Cleft palate Congenital hearing loss Congenital heart disease (typically atrial/ventricular septal defects) Situs abnormalities Renal malformations including horseshoe kidney CNS abnormalities including separate cases reported with holoprosencephaly, agenesis of the corpus callosum, and hydrocephalus Gastrointestinal abnormalities, including hiatal hernia, pyloric stenosis, malrotation, anal atresia, and esophageal atresia Joint hypermobility/dislocation and scoliosis Umbilical/inguinal hernia Penetrance is complete in the 2q37 microdeletion syndrome; however, phenotypic variability is observed. Using both cytogenetic and molecular analyses, deletion size does not appear to correlate well with phenotype. Brachymetaphalangy is observed in approximately half of individuals with deletions of the Albright hereditary osteodystrophy (AHO)-like critical region containing Further genotype-phenotype correlations have not been established. A parent-of-origin effect has not been convincingly demonstrated. Clinical characteristics of 2q37 microdeletion syndrome are apparent and no case of mosaicism has been documented to date. The 2q37 microdeletion syndrome has also been referred to as Albright hereditary osteodystrophy 3. The prevalence of the 2q37 microdeletion syndrome is unknown. It is likely that this syndrome is underdiagnosed because of difficulty in recognizing the small terminal deletion on routine cytogenetic studies, and failure to recognize the clinical syndrome on physical examination. It is expected that more individuals will be diagnosed as the clinical use of subtelomeric FISH and CMA studies increases. • Cleft palate • Congenital hearing loss • Congenital heart disease (typically atrial/ventricular septal defects) • Situs abnormalities • Renal malformations including horseshoe kidney • CNS abnormalities including separate cases reported with holoprosencephaly, agenesis of the corpus callosum, and hydrocephalus • Gastrointestinal abnormalities, including hiatal hernia, pyloric stenosis, malrotation, anal atresia, and esophageal atresia • Joint hypermobility/dislocation and scoliosis • Umbilical/inguinal hernia ## Clinical Description The 2q37 microdeletion syndrome may present with a broad spectrum of clinical findings as described below [ In individuals with isolated microdeletion 2q37 (i.e., those without an unbalanced translocation), functional outcome was affected by the presence of autism, developmental delay, and/or major congenital anomalies. The phenotype observed in individuals with 2q37 microdeletion syndrome seems variable in earlier reports because the molecular breakpoints were not defined. The published female-to-male ratio is greater than one. Low-set, hypoplastic nipples are often seen. Joint hyperextensibility and skin hyperlaxity may be observed. Cleft palate Congenital hearing loss Congenital heart disease (typically atrial/ventricular septal defects) Situs abnormalities Renal malformations including horseshoe kidney CNS abnormalities including separate cases reported with holoprosencephaly, agenesis of the corpus callosum, and hydrocephalus Gastrointestinal abnormalities, including hiatal hernia, pyloric stenosis, malrotation, anal atresia, and esophageal atresia Joint hypermobility/dislocation and scoliosis Umbilical/inguinal hernia • Cleft palate • Congenital hearing loss • Congenital heart disease (typically atrial/ventricular septal defects) • Situs abnormalities • Renal malformations including horseshoe kidney • CNS abnormalities including separate cases reported with holoprosencephaly, agenesis of the corpus callosum, and hydrocephalus • Gastrointestinal abnormalities, including hiatal hernia, pyloric stenosis, malrotation, anal atresia, and esophageal atresia • Joint hypermobility/dislocation and scoliosis • Umbilical/inguinal hernia ## Genotype-Phenotype Correlations Penetrance is complete in the 2q37 microdeletion syndrome; however, phenotypic variability is observed. Using both cytogenetic and molecular analyses, deletion size does not appear to correlate well with phenotype. Brachymetaphalangy is observed in approximately half of individuals with deletions of the Albright hereditary osteodystrophy (AHO)-like critical region containing Further genotype-phenotype correlations have not been established. A parent-of-origin effect has not been convincingly demonstrated. ## Penetrance Clinical characteristics of 2q37 microdeletion syndrome are apparent and no case of mosaicism has been documented to date. ## Nomenclature The 2q37 microdeletion syndrome has also been referred to as Albright hereditary osteodystrophy 3. ## Prevalence The prevalence of the 2q37 microdeletion syndrome is unknown. It is likely that this syndrome is underdiagnosed because of difficulty in recognizing the small terminal deletion on routine cytogenetic studies, and failure to recognize the clinical syndrome on physical examination. It is expected that more individuals will be diagnosed as the clinical use of subtelomeric FISH and CMA studies increases. ## Genetically Related (Allelic) Disorders The 2q37 microdeletion syndrome may present with a broad spectrum of clinical findings. Prior to the clinical introduction of chromosomal microarray, subtelomeric FISH identified 2q37 deletions in a number of individuals referred for developmental delay/intellectual disability with or without other dysmorphic features [ A pilot study of children with autism reported one nondysmorphic child with a normal examination and a subtelomeric deletion of 2q [ ## Differential Diagnosis Maternally inherited pathogenic variants are associated with resistance to parathyroid hormone (PTH) (known as pseudohypoparathyroidism type 1A), thyroid stimulating hormone (TSH), and gonadotropins. Paternally inherited pathogenic variants are associated only with AHO (also known as pseudopseudohypoparathyroidism). The clinical overlap between AHO/pseudopseudohypoparathyroidism and the 2q37 microdeletion syndrome may be substantial [ • Maternally inherited pathogenic variants are associated with resistance to parathyroid hormone (PTH) (known as pseudohypoparathyroidism type 1A), thyroid stimulating hormone (TSH), and gonadotropins. • Paternally inherited pathogenic variants are associated only with AHO (also known as pseudopseudohypoparathyroidism). ## Management To establish the extent of disease in an individual diagnosed with the 2q37 microdeletion syndrome, the following evaluations are recommended: Complete medical history to include evidence of any congenital malformations, seizure disorder, or behavioral problems Complete physical and dysmorphology examination Determination of head circumference, height, weight, and other anthropometric measurements Specialty evaluation of obesity or failure to thrive Multidisciplinary developmental and neurologic evaluation to assess motor and cognitive skills as well as autism, autism spectrum behaviors, and other behavioral issues Echocardiogram to evaluate for congenital cardiac anomaly Renal ultrasound examination to evaluate for possible Wilms tumor, renal malformation, or other renal problems Ophthalmology evaluation for strabismus and/or refractive errors Audiologic assessment for possible hearing loss Brain imaging studies (MRI, CT scan) in individuals with abnormal neurologic findings EEG for evaluation of seizures and treatment monitoring X-ray to evaluate for the presence of scoliosis and skeletal anomalies examination. While the clinical implications of osteopenia have not been studied in the 2q37 microdeletion syndrome, clinicians should be aware that this is a common finding. X-rays should be performed at diagnosis and should be repeated as warranted by clinical examination. The youngest individual with osteopenia in the authors' series is age three years. Consultation with a clinical geneticist and/or genetic counselor Depending on the age and presenting concerns of the individual with the 2q37 microdeletion syndrome, care from specialists in the following areas is often necessary: clinical genetics, speech pathology, occupational and physical therapy, child development, neurology, cardiology, gastroenterology, nutrition/feeding in cases of failure to thrive, ophthalmology, and audiology. Medical care may be coordinated by a clinical geneticist or other health care professional skilled at managing patients with complex needs. Infants benefit from enrollment in an early-intervention program. Most school-age children benefit from an individualized educational program (IEP) with input from a multispecialty group of physical, occupational, and speech therapists with pediatric assessment. At this time, it is not known why many individuals with the 2q37 microdeletion syndrome are obese. To the extent that it is feasible, the authors recommend an active lifestyle and good dietary habits to help avoid development of obesity. When the 2q37 microdeletion is identified in early childhood, screening for the development of renal cysts at age four years and again at puberty is suggested [ The following are also appropriate: Ongoing routine pediatric care Periodic reevaluation by a clinical geneticist to provide new recommendations and information about the syndrome Periodic neurodevelopmental and/or developmental/behavioral pediatric evaluation to assist in the management of cognitive and behavioral problems It is reasonable to perform genetic testing of any young child at risk, so that Wilms tumor surveillance can be considered in those with a deletion that includes 2q37.1. See Search • Complete medical history to include evidence of any congenital malformations, seizure disorder, or behavioral problems • Complete physical and dysmorphology examination • Determination of head circumference, height, weight, and other anthropometric measurements • Specialty evaluation of obesity or failure to thrive • Multidisciplinary developmental and neurologic evaluation to assess motor and cognitive skills as well as autism, autism spectrum behaviors, and other behavioral issues • Echocardiogram to evaluate for congenital cardiac anomaly • Renal ultrasound examination to evaluate for possible Wilms tumor, renal malformation, or other renal problems • Ophthalmology evaluation for strabismus and/or refractive errors • Audiologic assessment for possible hearing loss • Brain imaging studies (MRI, CT scan) in individuals with abnormal neurologic findings • EEG for evaluation of seizures and treatment monitoring • X-ray to evaluate for the presence of scoliosis and skeletal anomalies examination. While the clinical implications of osteopenia have not been studied in the 2q37 microdeletion syndrome, clinicians should be aware that this is a common finding. X-rays should be performed at diagnosis and should be repeated as warranted by clinical examination. The youngest individual with osteopenia in the authors' series is age three years. • Consultation with a clinical geneticist and/or genetic counselor • Ongoing routine pediatric care • Periodic reevaluation by a clinical geneticist to provide new recommendations and information about the syndrome • Periodic neurodevelopmental and/or developmental/behavioral pediatric evaluation to assist in the management of cognitive and behavioral problems ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with the 2q37 microdeletion syndrome, the following evaluations are recommended: Complete medical history to include evidence of any congenital malformations, seizure disorder, or behavioral problems Complete physical and dysmorphology examination Determination of head circumference, height, weight, and other anthropometric measurements Specialty evaluation of obesity or failure to thrive Multidisciplinary developmental and neurologic evaluation to assess motor and cognitive skills as well as autism, autism spectrum behaviors, and other behavioral issues Echocardiogram to evaluate for congenital cardiac anomaly Renal ultrasound examination to evaluate for possible Wilms tumor, renal malformation, or other renal problems Ophthalmology evaluation for strabismus and/or refractive errors Audiologic assessment for possible hearing loss Brain imaging studies (MRI, CT scan) in individuals with abnormal neurologic findings EEG for evaluation of seizures and treatment monitoring X-ray to evaluate for the presence of scoliosis and skeletal anomalies examination. While the clinical implications of osteopenia have not been studied in the 2q37 microdeletion syndrome, clinicians should be aware that this is a common finding. X-rays should be performed at diagnosis and should be repeated as warranted by clinical examination. The youngest individual with osteopenia in the authors' series is age three years. Consultation with a clinical geneticist and/or genetic counselor • Complete medical history to include evidence of any congenital malformations, seizure disorder, or behavioral problems • Complete physical and dysmorphology examination • Determination of head circumference, height, weight, and other anthropometric measurements • Specialty evaluation of obesity or failure to thrive • Multidisciplinary developmental and neurologic evaluation to assess motor and cognitive skills as well as autism, autism spectrum behaviors, and other behavioral issues • Echocardiogram to evaluate for congenital cardiac anomaly • Renal ultrasound examination to evaluate for possible Wilms tumor, renal malformation, or other renal problems • Ophthalmology evaluation for strabismus and/or refractive errors • Audiologic assessment for possible hearing loss • Brain imaging studies (MRI, CT scan) in individuals with abnormal neurologic findings • EEG for evaluation of seizures and treatment monitoring • X-ray to evaluate for the presence of scoliosis and skeletal anomalies examination. While the clinical implications of osteopenia have not been studied in the 2q37 microdeletion syndrome, clinicians should be aware that this is a common finding. X-rays should be performed at diagnosis and should be repeated as warranted by clinical examination. The youngest individual with osteopenia in the authors' series is age three years. • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Depending on the age and presenting concerns of the individual with the 2q37 microdeletion syndrome, care from specialists in the following areas is often necessary: clinical genetics, speech pathology, occupational and physical therapy, child development, neurology, cardiology, gastroenterology, nutrition/feeding in cases of failure to thrive, ophthalmology, and audiology. Medical care may be coordinated by a clinical geneticist or other health care professional skilled at managing patients with complex needs. Infants benefit from enrollment in an early-intervention program. Most school-age children benefit from an individualized educational program (IEP) with input from a multispecialty group of physical, occupational, and speech therapists with pediatric assessment. ## Prevention of Secondary Complications At this time, it is not known why many individuals with the 2q37 microdeletion syndrome are obese. To the extent that it is feasible, the authors recommend an active lifestyle and good dietary habits to help avoid development of obesity. ## Surveillance When the 2q37 microdeletion is identified in early childhood, screening for the development of renal cysts at age four years and again at puberty is suggested [ The following are also appropriate: Ongoing routine pediatric care Periodic reevaluation by a clinical geneticist to provide new recommendations and information about the syndrome Periodic neurodevelopmental and/or developmental/behavioral pediatric evaluation to assist in the management of cognitive and behavioral problems • Ongoing routine pediatric care • Periodic reevaluation by a clinical geneticist to provide new recommendations and information about the syndrome • Periodic neurodevelopmental and/or developmental/behavioral pediatric evaluation to assist in the management of cognitive and behavioral problems ## Evaluation of Relatives at Risk It is reasonable to perform genetic testing of any young child at risk, so that Wilms tumor surveillance can be considered in those with a deletion that includes 2q37.1. See ## Therapies Under Investigation Search ## Genetic Counseling 2q37 microdeletion syndrome can be the result of a Instances of deletion or mutation of Most probands have a Most cases of deletion or mutation of Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. The risk to sibs of a proband with 2q37 deletion syndrome depends on the genetic status of the parents. As with other 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. The occurrence of germline mosaicism has not been reported in individuals with 2q37 deletion syndrome, although the possibility cannot be excluded. If a parent has an To date, no individual with a cytogenetically visible 2q37 deletion has been reported to reproduce. An affected female with some features of the 2q37 microdeletion syndrome was born to a "normal" father with a cryptic subtelomeric deletion [ The risk to other family members depends on the genetic status of the proband's parents. If a parent has a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and FISH. If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and/or FISH. 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. Prenatal diagnosis for pregnancies at increased risk is possible by chromosome analysis of fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. It is difficult to visualize terminal chromosome deletions in fetal cells; therefore, confirmation of the result with FISH should be performed. Prenatal diagnosis for pregnancies at increased risk for an Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Preimplantation genetic testing may be an option for some families at increased risk for a pregnancy with 2q37 deletion syndrome or with an • Most probands have a • Most cases of deletion or mutation of • Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. • The risk to sibs of a proband with 2q37 deletion syndrome depends on the genetic status of the parents. • As with other • 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. • The occurrence of germline mosaicism has not been reported in individuals with 2q37 deletion syndrome, although the possibility cannot be excluded. • If a parent has an • To date, no individual with a cytogenetically visible 2q37 deletion has been reported to reproduce. • An affected female with some features of the 2q37 microdeletion syndrome was born to a "normal" father with a cryptic subtelomeric deletion [ • The risk to other family members depends on the genetic status of the proband's parents. • If a parent has a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and FISH. • 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 2q37 microdeletion syndrome can be the result of a Instances of deletion or mutation of ## Risk to Family Members Most probands have a Most cases of deletion or mutation of Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. The risk to sibs of a proband with 2q37 deletion syndrome depends on the genetic status of the parents. As with other 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. The occurrence of germline mosaicism has not been reported in individuals with 2q37 deletion syndrome, although the possibility cannot be excluded. If a parent has an To date, no individual with a cytogenetically visible 2q37 deletion has been reported to reproduce. An affected female with some features of the 2q37 microdeletion syndrome was born to a "normal" father with a cryptic subtelomeric deletion [ The risk to other family members depends on the genetic status of the proband's parents. If a parent has a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and FISH. • Most probands have a • Most cases of deletion or mutation of • Parents of a proband with a structurally unbalanced chromosome constitution (e.g., deletion or translocation) are at risk of having a balanced chromosome rearrangement and should be offered chromosome analysis. • The risk to sibs of a proband with 2q37 deletion syndrome depends on the genetic status of the parents. • As with other • 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. • The occurrence of germline mosaicism has not been reported in individuals with 2q37 deletion syndrome, although the possibility cannot be excluded. • If a parent has an • To date, no individual with a cytogenetically visible 2q37 deletion has been reported to reproduce. • An affected female with some features of the 2q37 microdeletion syndrome was born to a "normal" father with a cryptic subtelomeric deletion [ • The risk to other family members depends on the genetic status of the proband's parents. • If a parent has a balanced chromosome rearrangement, his or her family members may be at risk and should be offered chromosome analysis and FISH. ## Carrier Detection If a parent of the proband has a balanced chromosome rearrangement, at-risk family members can be tested by chromosome analysis and/or FISH. ## 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 Prenatal diagnosis for pregnancies at increased risk is possible by chromosome analysis of fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. It is difficult to visualize terminal chromosome deletions in fetal cells; therefore, confirmation of the result with FISH should be performed. Prenatal diagnosis for pregnancies at increased risk for an Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Preimplantation genetic testing may be an option for some families at increased risk for a pregnancy with 2q37 deletion syndrome or with an ## Resources No specific resources for 2q37 Microdeletion Syndrome have been identified by ## Molecular Genetics 2q37 Microdeletion Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for 2q37 Microdeletion Syndrome ( Proposed candidate genes responsible for the Albright hereditary osteodystrophy (AHO)-like phenotype in individuals with 2q37 microdeletion syndrome include the following: Three individuals with Wilms tumor and constitutional 2q37 or 2q37.1 deletion (without other chromosome anomalies) have been reported [ Genome-wide linkage studies have shown an autism susceptibility region on 2q37 [ Proposed candidate genes responsible for the autistic features in individuals with 2q37 microdeletion syndrome include the following: • Three individuals with Wilms tumor and constitutional 2q37 or 2q37.1 deletion (without other chromosome anomalies) have been reported [ • Genome-wide linkage studies have shown an autism susceptibility region on 2q37 [ ## Molecular Pathogenesis Proposed candidate genes responsible for the Albright hereditary osteodystrophy (AHO)-like phenotype in individuals with 2q37 microdeletion syndrome include the following: Three individuals with Wilms tumor and constitutional 2q37 or 2q37.1 deletion (without other chromosome anomalies) have been reported [ Genome-wide linkage studies have shown an autism susceptibility region on 2q37 [ Proposed candidate genes responsible for the autistic features in individuals with 2q37 microdeletion syndrome include the following: • Three individuals with Wilms tumor and constitutional 2q37 or 2q37.1 deletion (without other chromosome anomalies) have been reported [ • Genome-wide linkage studies have shown an autism susceptibility region on 2q37 [ ## References ## Literature Cited ## Chapter Notes We are indebted to the affected individuals we work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, and National Institutes of Health. Emily S Doherty, MD, FAAP, FACMG (2007-present)Felicitas L Lacbawan, MD, FCAP, FACMG (2007-present)Benjamin D Solomon, MD; National Human Genome Research Institute (2007-2012) 18 January 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population 31 January 2013 (cd) Revision: additional information on the role of 9 August 2012 (me) Comprehensive update posted live 3 May 2007 (me) Review posted live 21 March 2007 (esd) Original submission • 18 January 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population • 31 January 2013 (cd) Revision: additional information on the role of • 9 August 2012 (me) Comprehensive update posted live • 3 May 2007 (me) Review posted live • 21 March 2007 (esd) Original submission ## Acknowledgments We are indebted to the affected individuals we work with and their families. This work was supported by the Division of Intramural Research, National Human Genome Research Institute, and National Institutes of Health. ## Author History Emily S Doherty, MD, FAAP, FACMG (2007-present)Felicitas L Lacbawan, MD, FCAP, FACMG (2007-present)Benjamin D Solomon, MD; National Human Genome Research Institute (2007-2012) ## Revision History 18 January 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population 31 January 2013 (cd) Revision: additional information on the role of 9 August 2012 (me) Comprehensive update posted live 3 May 2007 (me) Review posted live 21 March 2007 (esd) Original submission • 18 January 2018 (ma) Chapter retired: non-recurrent deletions or duplications; refers to deletions/duplications of varying size – in contrast to a recurrent deletion/duplication, defined as a deletion/duplication of a specific size (usually mediated by nonallelic homologous recombination) occurring multiple times in the general population • 31 January 2013 (cd) Revision: additional information on the role of • 9 August 2012 (me) Comprehensive update posted live • 3 May 2007 (me) Review posted live • 21 March 2007 (esd) Original submission
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3/5/2007
9/8/2012
31/1/2013
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dent
dent
[ "H(+)/Cl(-) exchange transporter 5", "Inositol polyphosphate 5-phosphatase OCRL", "CLCN5", "OCRL", "Dent Disease" ]
Dent Disease
John C Lieske, Dawn S Milliner, Lada Beara-Lasic, Peter Harris, Andrea Cogal, Elizabeth Abrash
Summary Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in The diagnosis is established in a male proband with the typical clinical findings and a family history consistent with X-linked inheritance who has a pathogenic variant in either Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be hemizygous for the pathogenic variant. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. Affected males pass the pathogenic variant to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.
## Diagnosis Dent disease LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin. Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors' knowledge, no known cases of Dent disease have been missed using this screening method; however, its use is cautioned since it is not stable in even minimally acidic urine [ Hypercalciuria At least one of the following: Nephrocalcinosis (diffuse renal calcification) Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) Hematuria (microscopic or macroscopic blood in the urine) Hypophosphatemia (low blood phosphorous concentration) Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age Family history consistent with X-linked inheritance Calcium/Creatinine (mg/mg) Reference Values in Children (age <18 yrs) In random urine collections Molecular testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dent 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 a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Of the 245 different Of the 42 different In a cohort of affected individuals, approximately 18% (20/110) of males with a Dent disease phenotype did not have a pathogenic variant identified in • LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin. • Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors' knowledge, no known cases of Dent disease have been missed using this screening method; however, its use is cautioned since it is not stable in even minimally acidic urine [ • Hypercalciuria • At least one of the following: • Nephrocalcinosis (diffuse renal calcification) • Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) • Hematuria (microscopic or macroscopic blood in the urine) • Hypophosphatemia (low blood phosphorous concentration) • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age • Family history consistent with X-linked inheritance • Nephrocalcinosis (diffuse renal calcification) • Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) • Hematuria (microscopic or macroscopic blood in the urine) • Hypophosphatemia (low blood phosphorous concentration) • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age • Family history consistent with X-linked inheritance • Nephrocalcinosis (diffuse renal calcification) • Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) • Hematuria (microscopic or macroscopic blood in the urine) • Hypophosphatemia (low blood phosphorous concentration) • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age • Family history consistent with X-linked inheritance ## Suggestive Findings Dent disease LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin. Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors' knowledge, no known cases of Dent disease have been missed using this screening method; however, its use is cautioned since it is not stable in even minimally acidic urine [ Hypercalciuria At least one of the following: Nephrocalcinosis (diffuse renal calcification) Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) Hematuria (microscopic or macroscopic blood in the urine) Hypophosphatemia (low blood phosphorous concentration) Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age Family history consistent with X-linked inheritance Calcium/Creatinine (mg/mg) Reference Values in Children (age <18 yrs) In random urine collections • LMW proteinuria (the pathognomonic finding of Dent disease) at least five times (and often 10x) above the upper limit of normal. Commonly screened LMW proteins are retinol binding protein and α1 microglobulin. • Note: β2 microglobulin is also often measured to screen for LMW proteinuria. To the authors' knowledge, no known cases of Dent disease have been missed using this screening method; however, its use is cautioned since it is not stable in even minimally acidic urine [ • Hypercalciuria • At least one of the following: • Nephrocalcinosis (diffuse renal calcification) • Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) • Hematuria (microscopic or macroscopic blood in the urine) • Hypophosphatemia (low blood phosphorous concentration) • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age • Family history consistent with X-linked inheritance • Nephrocalcinosis (diffuse renal calcification) • Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) • Hematuria (microscopic or macroscopic blood in the urine) • Hypophosphatemia (low blood phosphorous concentration) • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age • Family history consistent with X-linked inheritance • Nephrocalcinosis (diffuse renal calcification) • Nephrolithiasis (kidney stones; composed of calcium oxalate and/or calcium phosphate) • Hematuria (microscopic or macroscopic blood in the urine) • Hypophosphatemia (low blood phosphorous concentration) • Chronic kidney disease (CKD); measured or estimated glomerular filtration rate (GFR) that is below the normal limits for age • Family history consistent with X-linked inheritance ## Establishing the Diagnosis Molecular testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dent 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 a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Of the 245 different Of the 42 different In a cohort of affected individuals, approximately 18% (20/110) of males with a Dent disease phenotype did not have a pathogenic variant identified in ## Clinical Characteristics LMW proteinuria and/or hypercalciuria can be accompanied by stone disease or nephrocalcinosis, and less frequently by other manifestations of proximal tubular dysfunction including aminoaciduria, phosphaturia, and glycosuria [ Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact parathyroid hormone (PTH) [ Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption. Short stature is common, although not usually profound in Dent disease 1. In one series height was -0.58 SD of the age-appropriate mean value for Dent disease 1, but more significantly reduced at -2.10 SD for Dent disease 2 [ The renal phenotypic findings in Dent 1 vary considerably. Some individuals with a pathogenic variant in It is currently unclear whether Dent disease will be diagnosed among a larger number of individuals with clinical FSGS, although it is now known that focal global sclerosis is very common in Dent disease [ To date, 42 pathogenic variants have been identified in males with a Dent disease 2 phenotype and have been reported in the literature. In addition to the Dent disease-related renal findings, individuals with Dent disease 2 may also have: Mild intellectual disability Cataracts (rare) Elevated muscle enzymes (LDH, CK) There have been occasional reports of renal calculi and moderate LMW proteinuria when carrier females have been studied in large kindreds. Rarely, heterozygous females manifest clinically significant kidney disease resulting from skewed X-chromosome inactivation. One female from a family with Dent disease developed renal insufficiency and nephrocalcinosis; however, she did not have molecular genetic testing [ Although not reported in the literature, a symptomatic female could have an X-chromosome abnormality (e.g., absence of one X chromosome [45,X] and a Although not reported in the literature, a female with biallelic pathogenic variants in Note: Although the renal tubulopathy in Lowe syndrome (which is mainly characterized by altered protein reabsorption) and Dent disease is similar, it is generally milder in Dent disease. Of note, this milder Dent disease phenotype could not be attributed to lesser protein expression or enzyme activity. Frameshift and nonsense Frameshift and nonsense variants associated with Dent disease 2 are in the first seven exons. Missense variants associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain. Frameshift and nonsense variants associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [ To date about 250 affected families have been reported [ • Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact parathyroid hormone (PTH) [ • Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption. • Mild intellectual disability • Cataracts (rare) • Elevated muscle enzymes (LDH, CK) • Frameshift and nonsense variants associated with Dent disease 2 are in the first seven exons. Missense variants associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain. • Frameshift and nonsense variants associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [ ## Clinical Description LMW proteinuria and/or hypercalciuria can be accompanied by stone disease or nephrocalcinosis, and less frequently by other manifestations of proximal tubular dysfunction including aminoaciduria, phosphaturia, and glycosuria [ Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact parathyroid hormone (PTH) [ Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption. Short stature is common, although not usually profound in Dent disease 1. In one series height was -0.58 SD of the age-appropriate mean value for Dent disease 1, but more significantly reduced at -2.10 SD for Dent disease 2 [ The renal phenotypic findings in Dent 1 vary considerably. Some individuals with a pathogenic variant in It is currently unclear whether Dent disease will be diagnosed among a larger number of individuals with clinical FSGS, although it is now known that focal global sclerosis is very common in Dent disease [ To date, 42 pathogenic variants have been identified in males with a Dent disease 2 phenotype and have been reported in the literature. In addition to the Dent disease-related renal findings, individuals with Dent disease 2 may also have: Mild intellectual disability Cataracts (rare) Elevated muscle enzymes (LDH, CK) There have been occasional reports of renal calculi and moderate LMW proteinuria when carrier females have been studied in large kindreds. Rarely, heterozygous females manifest clinically significant kidney disease resulting from skewed X-chromosome inactivation. One female from a family with Dent disease developed renal insufficiency and nephrocalcinosis; however, she did not have molecular genetic testing [ Although not reported in the literature, a symptomatic female could have an X-chromosome abnormality (e.g., absence of one X chromosome [45,X] and a Although not reported in the literature, a female with biallelic pathogenic variants in • Hypercalciuria is typically accompanied by elevated or high-normal levels of 1,25-dihydroxyvitamin D, and depressed or low-normal levels of intact parathyroid hormone (PTH) [ • Hypercalciuria largely or completely resolves with dietary calcium restriction, suggesting that the major component of hypercalciuria is intestinal hyperabsorption. • Mild intellectual disability • Cataracts (rare) • Elevated muscle enzymes (LDH, CK) ## Dent Disease 1 (caused by pathogenic variants in The renal phenotypic findings in Dent 1 vary considerably. Some individuals with a pathogenic variant in It is currently unclear whether Dent disease will be diagnosed among a larger number of individuals with clinical FSGS, although it is now known that focal global sclerosis is very common in Dent disease [ ## Dent Disease 2 (caused by pathogenic variants in To date, 42 pathogenic variants have been identified in males with a Dent disease 2 phenotype and have been reported in the literature. In addition to the Dent disease-related renal findings, individuals with Dent disease 2 may also have: Mild intellectual disability Cataracts (rare) Elevated muscle enzymes (LDH, CK) • Mild intellectual disability • Cataracts (rare) • Elevated muscle enzymes (LDH, CK) ## Symptomatic Females There have been occasional reports of renal calculi and moderate LMW proteinuria when carrier females have been studied in large kindreds. Rarely, heterozygous females manifest clinically significant kidney disease resulting from skewed X-chromosome inactivation. One female from a family with Dent disease developed renal insufficiency and nephrocalcinosis; however, she did not have molecular genetic testing [ Although not reported in the literature, a symptomatic female could have an X-chromosome abnormality (e.g., absence of one X chromosome [45,X] and a Although not reported in the literature, a female with biallelic pathogenic variants in ## Genotype-Phenotype Correlations Note: Although the renal tubulopathy in Lowe syndrome (which is mainly characterized by altered protein reabsorption) and Dent disease is similar, it is generally milder in Dent disease. Of note, this milder Dent disease phenotype could not be attributed to lesser protein expression or enzyme activity. Frameshift and nonsense Frameshift and nonsense variants associated with Dent disease 2 are in the first seven exons. Missense variants associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain. Frameshift and nonsense variants associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [ • Frameshift and nonsense variants associated with Dent disease 2 are in the first seven exons. Missense variants associated with Dent disease 2 are most often, but not exclusively, located in exons 9-15, which encode the catalytic phosphatase domain. • Frameshift and nonsense variants associated with Lowe syndrome are located in the middle and later regions of the gene, exons 8-23, which encode the catalytic phosphatase and the Rho-GAP-like domain [ ## Prevalence To date about 250 affected families have been reported [ ## Genetically Related (Allelic) Disorders Given the finding of ## Differential Diagnosis The differential diagnosis of Dent disease includes other causes of proximal tubular dysfunction. ## Management To establish the extent of disease and needs of an individual diagnosed with Dent disease, the following evaluations are recommended if they have not already been completed: Assessment of renal function (measured or estimated GFR; urine protein excretion) Assessment for nephrocalcinosis and kidney stones by imaging studies, typically low-dose noncontrast CT scan or ultrasound For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion) Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase) Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [ For those with evidence of bone disease and/or growth delay, more complete assessment of bone health (i.e., serum vitamin D concentration and PTH level; x-ray of long bones for evidence of osteomalacia) In children, evaluation of stature using standard growth charts. If short stature is present, evaluation by an endocrinologist for the possibility of growth hormone therapy can be considered. Evaluation for intellectual disability Careful eye exam for cataracts, especially if there is any concern for visual impairment Consultation with a clinical geneticist and/or genetic counselor Although it is not necessary to specifically screen for the possibility, elevated serum muscle enzyme levels are often seen in patients with Dent disease. No guidelines have been established for treatment of Dent disease. The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD). Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease [ Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with proteinuria to prevent or delay further loss of kidney function; however, their effectiveness has not been clear. Although treatment with ACE inhibitors or ARB may be somewhat beneficial for individuals with focal segmental glomerulosclerosis (FSGS), they are not known to be helpful for the focal global glomerulosclerosis that is associated with Dent disease, and angiotensin blockade is not thought to significantly affect LMW proteinuria or any potential ill effects of it. A kidney biopsy to exclude other causes of proteinuria and CKD is reasonable. While a high-citrate diet has been shown to slow progression of CKD in If males with Dent disease progress to ESRD, renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Because Dent disease manifestations are largely localized in the kidney, the disease will not recur. School-aged individuals with mild intellectual disability will benefit from individual educational plans and special educational services. Cataracts, if present, are treated in a standard manner. Bone disease has not been a prominent component of Dent disease in a recent case series based in France [ Limited reports suggest that growth failure can be successfully treated with human growth hormone without adversely affecting kidney function [ Renal function measured as glomerular filtration rate (GFR) should be monitored at least annually together with the parameters used to stage chronic kidney disease (i.e., blood pressure, hematocrit/hemoglobin, urinary calcium excretion, and serum calcium and phosphorus concentrations). More frequent visits and monitoring for complications of chronic kidney disease (i.e., hypertension, anemia, and secondary hyperparathyroidism) as well as consideration of intensified treatment of cardiovascular risk factors may be indicated if GFR falls below 45 mL/min/1.73 m Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided, especially if renal function is below 45 mL/min/1.73 m It is appropriate to evaluate male relatives at risk for Dent disease 1 (caused by mutation of If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test. See Search • Assessment of renal function (measured or estimated GFR; urine protein excretion) • Assessment for nephrocalcinosis and kidney stones by imaging studies, typically low-dose noncontrast CT scan or ultrasound • For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion) • Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase) • Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [ • For those with evidence of bone disease and/or growth delay, more complete assessment of bone health (i.e., serum vitamin D concentration and PTH level; x-ray of long bones for evidence of osteomalacia) • In children, evaluation of stature using standard growth charts. If short stature is present, evaluation by an endocrinologist for the possibility of growth hormone therapy can be considered. • Evaluation for intellectual disability • Careful eye exam for cataracts, especially if there is any concern for visual impairment • Consultation with a clinical geneticist and/or genetic counselor • Although it is not necessary to specifically screen for the possibility, elevated serum muscle enzyme levels are often seen in patients with Dent disease. • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Dent disease, the following evaluations are recommended if they have not already been completed: Assessment of renal function (measured or estimated GFR; urine protein excretion) Assessment for nephrocalcinosis and kidney stones by imaging studies, typically low-dose noncontrast CT scan or ultrasound For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion) Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase) Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [ For those with evidence of bone disease and/or growth delay, more complete assessment of bone health (i.e., serum vitamin D concentration and PTH level; x-ray of long bones for evidence of osteomalacia) In children, evaluation of stature using standard growth charts. If short stature is present, evaluation by an endocrinologist for the possibility of growth hormone therapy can be considered. Evaluation for intellectual disability Careful eye exam for cataracts, especially if there is any concern for visual impairment Consultation with a clinical geneticist and/or genetic counselor Although it is not necessary to specifically screen for the possibility, elevated serum muscle enzyme levels are often seen in patients with Dent disease. • Assessment of renal function (measured or estimated GFR; urine protein excretion) • Assessment for nephrocalcinosis and kidney stones by imaging studies, typically low-dose noncontrast CT scan or ultrasound • For those with evidence of renal stones or nephrocalcinosis, urine studies for kidney stone risk factors (including calcium and citrate excretion) • Assessment of risk for bone disease (serum calcium, phosphorus, and alkaline phosphatase) • Note: Elevated alkaline phosphatase has been reported in all individuals with clinical rickets [ • For those with evidence of bone disease and/or growth delay, more complete assessment of bone health (i.e., serum vitamin D concentration and PTH level; x-ray of long bones for evidence of osteomalacia) • In children, evaluation of stature using standard growth charts. If short stature is present, evaluation by an endocrinologist for the possibility of growth hormone therapy can be considered. • Evaluation for intellectual disability • Careful eye exam for cataracts, especially if there is any concern for visual impairment • Consultation with a clinical geneticist and/or genetic counselor • Although it is not necessary to specifically screen for the possibility, elevated serum muscle enzyme levels are often seen in patients with Dent disease. ## Treatment of Manifestations No guidelines have been established for treatment of Dent disease. The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD). Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease [ Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been used in children with proteinuria to prevent or delay further loss of kidney function; however, their effectiveness has not been clear. Although treatment with ACE inhibitors or ARB may be somewhat beneficial for individuals with focal segmental glomerulosclerosis (FSGS), they are not known to be helpful for the focal global glomerulosclerosis that is associated with Dent disease, and angiotensin blockade is not thought to significantly affect LMW proteinuria or any potential ill effects of it. A kidney biopsy to exclude other causes of proteinuria and CKD is reasonable. While a high-citrate diet has been shown to slow progression of CKD in If males with Dent disease progress to ESRD, renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Because Dent disease manifestations are largely localized in the kidney, the disease will not recur. School-aged individuals with mild intellectual disability will benefit from individual educational plans and special educational services. Cataracts, if present, are treated in a standard manner. ## Prevention of Secondary Complications Bone disease has not been a prominent component of Dent disease in a recent case series based in France [ Limited reports suggest that growth failure can be successfully treated with human growth hormone without adversely affecting kidney function [ ## Surveillance Renal function measured as glomerular filtration rate (GFR) should be monitored at least annually together with the parameters used to stage chronic kidney disease (i.e., blood pressure, hematocrit/hemoglobin, urinary calcium excretion, and serum calcium and phosphorus concentrations). More frequent visits and monitoring for complications of chronic kidney disease (i.e., hypertension, anemia, and secondary hyperparathyroidism) as well as consideration of intensified treatment of cardiovascular risk factors may be indicated if GFR falls below 45 mL/min/1.73 m ## Agents/Circumstances to Avoid Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents) should be avoided, especially if renal function is below 45 mL/min/1.73 m ## Evaluation of Relatives at Risk It is appropriate to evaluate male relatives at risk for Dent disease 1 (caused by mutation of If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test. See • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, measurement of urinary excretion of low molecular weight proteins (e.g., alpha 1 microglobulin, retinol binding protein) is a sensitive and specific test. ## Therapies Under Investigation Search ## Genetic Counseling Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be hemizygous for a In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, 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 slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. All of their daughters, who will be heterozygotes and, in rare cases, manifest clinically significant kidney disease (see Clinical Description, None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a LMW proteins are often found to be elevated in female carriers; however, the sensitivity and specificity of such testing for carrier detection have not been established. 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 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. • The father of an affected male will not have the disease nor will he be hemizygous for a • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, • 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 slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, • All of their daughters, who will be heterozygotes and, in rare cases, manifest clinically significant kidney disease (see Clinical Description, • None of their sons. • 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 Dent disease is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disease nor will he be hemizygous for a In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a If the mother of the proband has a Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, 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 slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. All of their daughters, who will be heterozygotes and, in rare cases, manifest clinically significant kidney disease (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 the disease nor will he be hemizygous for a • In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a • If the mother of the proband has a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, • 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 slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. However, due to the possibility of skewed X-chromosome inactivation, some female heterozygotes may manifest clinically significant kidney disease (see Clinical Description, • All of their daughters, who will be heterozygotes and, in rare cases, manifest clinically significant kidney disease (see Clinical Description, • None of their sons. ## Heterozygote (Carrier) Detection LMW proteins are often found to be elevated in female carriers; however, the sensitivity and specificity of such testing for carrier detection have not been established. ## 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 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 United Kingdom Canada • • United Kingdom • • • Canada • • • • • ## Molecular Genetics Dent Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Dent Disease ( More than 100 different nonsense or missense variants, insertions or deletions, and splicing variants in Most Group 1. Pathogenic variants that lead to the retention of the mutated protein in the endoplasmic reticulum Group 2. Pathogenic variants that generate a functionally defective protein devoid of electric currents and resulting in failure of endosomal acidification Group 3. Pathogenic variants that lead to abnormal subcellular localization of the mature protein Group 4. Pathogenic variants that generate a protein normally localized at the plasma membrane but with reduced membrane currents Variants listed in the table have been provided by the authors. As detailed in The mechanism by which loss of OCRL-1 protein function leads to disease has not yet been elucidated. However, OCRL-1 protein was localized to early endosomes and the The abnormal vesicular trafficking shared with the CLC-5 protein may explain the overlapping clinical features associated with pathogenic variants in • Group 1. Pathogenic variants that lead to the retention of the mutated protein in the endoplasmic reticulum • Group 2. Pathogenic variants that generate a functionally defective protein devoid of electric currents and resulting in failure of endosomal acidification • Group 3. Pathogenic variants that lead to abnormal subcellular localization of the mature protein • Group 4. Pathogenic variants that generate a protein normally localized at the plasma membrane but with reduced membrane currents ## Chapter Notes The Rare Kidney Stone Consortium is a resource for patients, their families, and physicians. The center facilitates collaborative research to provide better understanding of Dent Disease and other rare types of kidney stones. For more information about Dent disease, please email the Rare Kidney Stone Consortium at [email protected] or call 800-270-4637. Elizabeth Abrash, BA (2017-present)Lada Beara-Lasic, MD (2012-present)Andrea Cogal, BS (2014-present) Peter Harris, PhD (2014-present) Katharina Hopp, PhD; Mayo Clinic (2014-2017)John C Lieske, MD (2012-present)Kari Mattison, BS; Mayo Clinic (2014-2017) Dawn S Milliner, MD (2012-present)Sandro Rossetti, MD; Mayo Clinic (2012-2014) 14 December 2017 (ha) Comprehensive update posted live 25 September 2014 (me) Comprehensive update posted live 9 August 2012 (me) Review posted live 1 March 2012 (jcl) Original submission • 14 December 2017 (ha) Comprehensive update posted live • 25 September 2014 (me) Comprehensive update posted live • 9 August 2012 (me) Review posted live • 1 March 2012 (jcl) Original submission ## Author Notes The Rare Kidney Stone Consortium is a resource for patients, their families, and physicians. The center facilitates collaborative research to provide better understanding of Dent Disease and other rare types of kidney stones. For more information about Dent disease, please email the Rare Kidney Stone Consortium at [email protected] or call 800-270-4637. ## Author History Elizabeth Abrash, BA (2017-present)Lada Beara-Lasic, MD (2012-present)Andrea Cogal, BS (2014-present) Peter Harris, PhD (2014-present) Katharina Hopp, PhD; Mayo Clinic (2014-2017)John C Lieske, MD (2012-present)Kari Mattison, BS; Mayo Clinic (2014-2017) Dawn S Milliner, MD (2012-present)Sandro Rossetti, MD; Mayo Clinic (2012-2014) ## Revision History 14 December 2017 (ha) Comprehensive update posted live 25 September 2014 (me) Comprehensive update posted live 9 August 2012 (me) Review posted live 1 March 2012 (jcl) Original submission • 14 December 2017 (ha) Comprehensive update posted live • 25 September 2014 (me) Comprehensive update posted live • 9 August 2012 (me) Review posted live • 1 March 2012 (jcl) Original submission ## References ## Literature Cited
[]
9/8/2012
14/12/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
depdc5-epilepsy
depdc5-epilepsy
[ "DEPDC5-Related Familial Focal Epilepsy with Variable Foci (FFEVF)", "DEPDC5-Related Autosomal Dominant Sleep-Related Hypermotor Epilepsy (ADSHE) (Autosomal Dominant Nocturnal Frontal Lobe Epilepsy [ADNFLE])", "DEPDC5-Related Familial Mesial Temporal Lobe Epilepsy (FMTLE)", "DEPDC5-Related Autosomal Dominant Epilepsy with Auditory Features (ADEAF)", "DEPDC5-Related Infantile Spasms", "DEPDC5-Related Developmental Encephalopathy with Macrocephaly and Polymicrogyria", "DEPDC5-Related Focal Cortical Dysplasia", "DEPDC5-Related Hemimegalencephaly", "GATOR1 complex protein DEPDC5", "DEPDC5", "DEPDC5-Related Epilepsy" ]
Stéphanie Baulac, Sara Baldassari
Summary The diagnosis of
Familial focal epilepsy with variable foci (FFEVF) Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) (previously termed autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE]) Familial mesial temporal lobe epilepsy (FMTLE) Autosomal dominant epilepsy with auditory features (ADEAF) Infantile spasms Developmental encephalopathy with macrocephaly and polymicrogyria Focal cortical dysplasia Hemimegalencephaly For synonyms and outdated names, see For other genetic causes of these phenotypes, see • Familial focal epilepsy with variable foci (FFEVF) • Autosomal dominant sleep-related hypermotor epilepsy (ADSHE) (previously termed autosomal dominant nocturnal frontal lobe epilepsy [ADNFLE]) • Familial mesial temporal lobe epilepsy (FMTLE) • Autosomal dominant epilepsy with auditory features (ADEAF) • Infantile spasms • Developmental encephalopathy with macrocephaly and polymicrogyria • Focal cortical dysplasia • Hemimegalencephaly ## Diagnosis No consensus clinical diagnostic criteria for Epilepsy (familial or sporadic), which may include: Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures Nocturnal or sleep-related seizures Drug-resistant epilepsy Infantile spasms Otherwise normal neurologic examination Normal psychomotor development and cognition in most, although developmental delay, intellectual disability, and/or neuropsychiatric features (autism spectrum disorder, attention-deficit/hyperactivity disorder) have been described rarely. Sudden unexpected death in epilepsy Brain MRI may demonstrate focal cortical dysplasia, hemimegalencephaly, or rarely other malformations (polymicrogyria, pachygyria, heterotopia, hypoplasia of corpus callosum) Note: A normal brain MRI does not preclude the diagnosis. Interictal EEG may show focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time, typically with a background EEG that is normal. The diagnosis of 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 both can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. As the differential diagnosis for genetic causes of epilepsy and brain malformations is broad, single-gene testing (sequence analysis of Molecular genetic testing approaches typically include a Note: As some 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. • Epilepsy (familial or sporadic), which may include: • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures • Nocturnal or sleep-related seizures • Drug-resistant epilepsy • Infantile spasms • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures • Nocturnal or sleep-related seizures • Drug-resistant epilepsy • Infantile spasms • Otherwise normal neurologic examination • Normal psychomotor development and cognition in most, although developmental delay, intellectual disability, and/or neuropsychiatric features (autism spectrum disorder, attention-deficit/hyperactivity disorder) have been described rarely. • Sudden unexpected death in epilepsy • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures • Nocturnal or sleep-related seizures • Drug-resistant epilepsy • Infantile spasms • Brain MRI may demonstrate focal cortical dysplasia, hemimegalencephaly, or rarely other malformations (polymicrogyria, pachygyria, heterotopia, hypoplasia of corpus callosum) • Note: A normal brain MRI does not preclude the diagnosis. • Interictal EEG may show focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time, typically with a background EEG that is normal. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Epilepsy (familial or sporadic), which may include: Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures Nocturnal or sleep-related seizures Drug-resistant epilepsy Infantile spasms Otherwise normal neurologic examination Normal psychomotor development and cognition in most, although developmental delay, intellectual disability, and/or neuropsychiatric features (autism spectrum disorder, attention-deficit/hyperactivity disorder) have been described rarely. Sudden unexpected death in epilepsy Brain MRI may demonstrate focal cortical dysplasia, hemimegalencephaly, or rarely other malformations (polymicrogyria, pachygyria, heterotopia, hypoplasia of corpus callosum) Note: A normal brain MRI does not preclude the diagnosis. Interictal EEG may show focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time, typically with a background EEG that is normal. • Epilepsy (familial or sporadic), which may include: • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures • Nocturnal or sleep-related seizures • Drug-resistant epilepsy • Infantile spasms • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures • Nocturnal or sleep-related seizures • Drug-resistant epilepsy • Infantile spasms • Otherwise normal neurologic examination • Normal psychomotor development and cognition in most, although developmental delay, intellectual disability, and/or neuropsychiatric features (autism spectrum disorder, attention-deficit/hyperactivity disorder) have been described rarely. • Sudden unexpected death in epilepsy • Focal epilepsy (emerging from any cortical region but predominantly from the frontal lobe), variable epilepsy foci (temporal, parietal), or hypermotor seizures • Nocturnal or sleep-related seizures • Drug-resistant epilepsy • Infantile spasms • Brain MRI may demonstrate focal cortical dysplasia, hemimegalencephaly, or rarely other malformations (polymicrogyria, pachygyria, heterotopia, hypoplasia of corpus callosum) • Note: A normal brain MRI does not preclude the diagnosis. • Interictal EEG may show focal (frontal, temporal, parietal, or occipital) epileptiform abnormalities that remain constant over time, typically with a background EEG that is normal. ## Establishing the Diagnosis The diagnosis of 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 both can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. As the differential diagnosis for genetic causes of epilepsy and brain malformations is broad, single-gene testing (sequence analysis of Molecular genetic testing approaches typically include a Note: As some 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. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, nearly 200 symptomatic individuals have been identified with a pathogenic variant in FCD = focal cortical dysplasia; SUDEP = sudden unexpected death in epilepsy Asymptomatic heterozygotes are common in families with Percentages are based on nearly 200 reported symptomatic individuals with heterozygous pathogenic (or likely pathogenic) variants only and do not include individuals with biallelic pathogenic variants in Most symptomatic individuals are diagnosed because they have epilepsy, so this percentage is biased toward those individuals who have epilepsy as a feature. Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. Age of onset, seizure frequency, and drug response may vary considerably within a family. EEGs may show focal interictal abnormalities that typically stay constant in a given individual. About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. It is unclear if ADEAF is part of Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. In individuals with infantile spasms, hypsarrhythmia can be seen. Most reported individuals had focal cortical dysplasia type IIa (characterized by cortical dyslamination frequently associated with the presence of dysmorphic neurons) associated with early-onset drug-resistant seizures. Hemimegalencephaly (characterized typically by enlargement and dysplasia of one cerebral hemisphere) has been reported in several affected individuals. Other reported findings seen in a few individuals include the following: Bilateral symmetric perisylvian polymicrogyria Pachygyria Subtle band heterotopia Hypoplasia of the corpus callosum in addition to focal cortical dysplasia No definitive genotype-phenotype correlations have been identified. In general, individuals with a heterozygous nonsense or frameshift pathogenic variant leading to a premature stop codon are more likely to have brain malformations (focal cortical dysplasia or hemimegalencephaly) [ Individuals with germline biallelic pathogenic variants and a severe multisystemic phenotype are very rare (only a few individuals have been reported), and therefore no definite genotype-phenotype associations can be defined (see Asymptomatic heterozygotes are common in families with Familial focal epilepsy with variable foci (FFEVF) [ The prevalence of • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. • Age of onset, seizure frequency, and drug response may vary considerably within a family. • EEGs may show focal interictal abnormalities that typically stay constant in a given individual. • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. • Age of onset, seizure frequency, and drug response may vary considerably within a family. • EEGs may show focal interictal abnormalities that typically stay constant in a given individual. • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. • It is unclear if ADEAF is part of • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. • It is unclear if ADEAF is part of • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. • In individuals with infantile spasms, hypsarrhythmia can be seen. • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. • In individuals with infantile spasms, hypsarrhythmia can be seen. • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. • Age of onset, seizure frequency, and drug response may vary considerably within a family. • EEGs may show focal interictal abnormalities that typically stay constant in a given individual. • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. • It is unclear if ADEAF is part of • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. • In individuals with infantile spasms, hypsarrhythmia can be seen. • Most reported individuals had focal cortical dysplasia type IIa (characterized by cortical dyslamination frequently associated with the presence of dysmorphic neurons) associated with early-onset drug-resistant seizures. • Hemimegalencephaly (characterized typically by enlargement and dysplasia of one cerebral hemisphere) has been reported in several affected individuals. • Other reported findings seen in a few individuals include the following: • Bilateral symmetric perisylvian polymicrogyria • Pachygyria • Subtle band heterotopia • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia • Bilateral symmetric perisylvian polymicrogyria • Pachygyria • Subtle band heterotopia • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia • Bilateral symmetric perisylvian polymicrogyria • Pachygyria • Subtle band heterotopia • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia • In general, individuals with a heterozygous nonsense or frameshift pathogenic variant leading to a premature stop codon are more likely to have brain malformations (focal cortical dysplasia or hemimegalencephaly) [ • Individuals with germline biallelic pathogenic variants and a severe multisystemic phenotype are very rare (only a few individuals have been reported), and therefore no definite genotype-phenotype associations can be defined (see ## Clinical Description To date, nearly 200 symptomatic individuals have been identified with a pathogenic variant in FCD = focal cortical dysplasia; SUDEP = sudden unexpected death in epilepsy Asymptomatic heterozygotes are common in families with Percentages are based on nearly 200 reported symptomatic individuals with heterozygous pathogenic (or likely pathogenic) variants only and do not include individuals with biallelic pathogenic variants in Most symptomatic individuals are diagnosed because they have epilepsy, so this percentage is biased toward those individuals who have epilepsy as a feature. Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. Age of onset, seizure frequency, and drug response may vary considerably within a family. EEGs may show focal interictal abnormalities that typically stay constant in a given individual. About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. It is unclear if ADEAF is part of Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. In individuals with infantile spasms, hypsarrhythmia can be seen. Most reported individuals had focal cortical dysplasia type IIa (characterized by cortical dyslamination frequently associated with the presence of dysmorphic neurons) associated with early-onset drug-resistant seizures. Hemimegalencephaly (characterized typically by enlargement and dysplasia of one cerebral hemisphere) has been reported in several affected individuals. Other reported findings seen in a few individuals include the following: Bilateral symmetric perisylvian polymicrogyria Pachygyria Subtle band heterotopia Hypoplasia of the corpus callosum in addition to focal cortical dysplasia • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. • Age of onset, seizure frequency, and drug response may vary considerably within a family. • EEGs may show focal interictal abnormalities that typically stay constant in a given individual. • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. • Age of onset, seizure frequency, and drug response may vary considerably within a family. • EEGs may show focal interictal abnormalities that typically stay constant in a given individual. • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. • It is unclear if ADEAF is part of • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. • It is unclear if ADEAF is part of • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. • In individuals with infantile spasms, hypsarrhythmia can be seen. • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. • In individuals with infantile spasms, hypsarrhythmia can be seen. • Average age of seizure onset is 4.5 years, and seizure symptomatology depend on the focal region of the brain in which the seizures originate. • Frontal lobe and temporal lobe seizures are most common; parietal and occipital lobe seizures are also seen. • Age of onset, seizure frequency, and drug response may vary considerably within a family. • EEGs may show focal interictal abnormalities that typically stay constant in a given individual. • About 80% of individuals develop ADSHE within the first two decades of life, with a mean age of onset of about 5 years. • Clinical neurologic examination is usually normal and intellect preserved, but intellectual disability, cognitive deficits, or psychiatric comorbidity may occur. • Within a family, the manifestations of the disorder may vary considerably; however, seizures have a consistent onset within the frontal region. • ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. • Familial mesial temporal lobe epilepsy (FMTLE) is characterized by focal seizures with ictal mesial temporal lobe symptomatology, including psychic symptoms such as déjà vu and fear or autonomic symptoms such as nausea. Hippocampal sclerosis is commonly observed, as are febrile seizures preceding focal seizures. • Autosomal dominant epilepsy with auditory features (ADEAF) is characterized by focal seizures with auditory auras and symptoms suggesting lateral temporal onset. It is considered a mild syndrome, with onset in adolescence or adulthood, low seizure frequency, and only rare secondarily generalized seizures. • It is unclear if ADEAF is part of • Focal seizures occurred later in most affected individuals; four had focal cortical dysplasia. • In individuals with infantile spasms, hypsarrhythmia can be seen. • Most reported individuals had focal cortical dysplasia type IIa (characterized by cortical dyslamination frequently associated with the presence of dysmorphic neurons) associated with early-onset drug-resistant seizures. • Hemimegalencephaly (characterized typically by enlargement and dysplasia of one cerebral hemisphere) has been reported in several affected individuals. • Other reported findings seen in a few individuals include the following: • Bilateral symmetric perisylvian polymicrogyria • Pachygyria • Subtle band heterotopia • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia • Bilateral symmetric perisylvian polymicrogyria • Pachygyria • Subtle band heterotopia • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia • Bilateral symmetric perisylvian polymicrogyria • Pachygyria • Subtle band heterotopia • Hypoplasia of the corpus callosum in addition to focal cortical dysplasia ## Genotype-Phenotype Correlations No definitive genotype-phenotype correlations have been identified. In general, individuals with a heterozygous nonsense or frameshift pathogenic variant leading to a premature stop codon are more likely to have brain malformations (focal cortical dysplasia or hemimegalencephaly) [ Individuals with germline biallelic pathogenic variants and a severe multisystemic phenotype are very rare (only a few individuals have been reported), and therefore no definite genotype-phenotype associations can be defined (see • In general, individuals with a heterozygous nonsense or frameshift pathogenic variant leading to a premature stop codon are more likely to have brain malformations (focal cortical dysplasia or hemimegalencephaly) [ • Individuals with germline biallelic pathogenic variants and a severe multisystemic phenotype are very rare (only a few individuals have been reported), and therefore no definite genotype-phenotype associations can be defined (see ## Penetrance Asymptomatic heterozygotes are common in families with ## Nomenclature Familial focal epilepsy with variable foci (FFEVF) [ ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis for Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; ADEAF = autosomal dominant epilepsy with auditory features; ADSHE = autosomal dominant sleep-related epilepsy; AR = autosomal recessive; EIMFS = epilepsy of infancy with migrating focal seizures; FCD = focal cortical dysplasia; FFEVF = familial focal epilepsy with variable foci; MOI = mode of inheritance Previously referred to as autosomal dominant partial epilepsy with auditory features (ADPEAF) or autosomal dominant lateral temporal lobe epilepsy (ADTLE) [ NPRL2 and NPRL3, together with DEPDC5, form a complex called GATOR1 ( ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support. MOI = mode of inheritance; SUDEP = sudden unexpected death in epilepsy Predictive factors may include frequent generalized clonic-tonic seizures. Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no specific 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 In those w/FCD or hemimegalencephaly, epilepsy surgery should be explored early in disease course. Surgical outcomes have been variable. ABA = applied behavior analysis; ASM = anti-seizure medication; FCD = focal cortical dysplasia; OT = occupational therapy; PT = physical therapy; ST = speech 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 In one study, four of five unrelated individuals who underwent epilepsy surgery with resection of the focal cortical dysplasia had a favorable postoperative outcome [ 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 SUDEP = sudden unexpected death in epilepsy Predictive factors may include frequent generalized clonic-tonic seizures. 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 those who are at risk for the development of seizures as early as possible. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family. 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 medications (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See Loss-of-function pathogenic variants in Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • In those w/FCD or hemimegalencephaly, epilepsy surgery should be explored early in disease course. • Surgical outcomes have been variable. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support. MOI = mode of inheritance; SUDEP = sudden unexpected death in epilepsy Predictive factors may include frequent generalized clonic-tonic seizures. 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. ## Treatment of Manifestations There is no specific 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 In those w/FCD or hemimegalencephaly, epilepsy surgery should be explored early in disease course. Surgical outcomes have been variable. ABA = applied behavior analysis; ASM = anti-seizure medication; FCD = focal cortical dysplasia; OT = occupational therapy; PT = physical therapy; ST = speech 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 In one study, four of five unrelated individuals who underwent epilepsy surgery with resection of the focal cortical dysplasia had a favorable postoperative outcome [ • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • In those w/FCD or hemimegalencephaly, epilepsy surgery should be explored early in disease course. • Surgical outcomes have been variable. ## 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 SUDEP = sudden unexpected death in epilepsy Predictive factors may include frequent generalized clonic-tonic seizures. ## 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 those who are at risk for the development of seizures as early as possible. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family. 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 medications (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See ## Therapies Under Investigation Loss-of-function pathogenic variants in Search ## Genetic Counseling Many individuals diagnosed with A proband with Some individuals with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the constitutional pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the constitutional 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 gonosomal mosaicism [ The family history of some individuals diagnosed with If a parent of the proband is affected and/or is known to have the Reduced penetrance and intrafamilial variable expressivity are observed in May or may not have manifestations of May have different phenotypic manifestations of If the If the parents have not been tested for the Each child of an individual with autosomal dominant The specific phenotype, age of onset, and disease severity cannot be predicted accurately in offspring who inherit a The parents of an affected child are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Heterozygous parents of a proband with autosomal recessive The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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. • Many individuals diagnosed with • A proband with • Some individuals with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the constitutional pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the constitutional 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 gonosomal mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline or gonosomal mosaicism [ • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline or gonosomal mosaicism [ • If a parent of the proband is affected and/or is known to have the • Reduced penetrance and intrafamilial variable expressivity are observed in • May or may not have manifestations of • May have different phenotypic manifestations of • May or may not have manifestations of • May have different phenotypic manifestations of • If the • If the parents have not been tested for the • May or may not have manifestations of • May have different phenotypic manifestations of • Each child of an individual with autosomal dominant • The specific phenotype, age of onset, and disease severity cannot be predicted accurately in offspring who inherit a • The parents of an affected child are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Heterozygous parents of a proband with autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 ## Autosomal Dominant Inheritance – Risk to Family Members Many individuals diagnosed with A proband with Some individuals with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the constitutional pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the constitutional 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 gonosomal mosaicism [ The family history of some individuals diagnosed with If a parent of the proband is affected and/or is known to have the Reduced penetrance and intrafamilial variable expressivity are observed in May or may not have manifestations of May have different phenotypic manifestations of If the If the parents have not been tested for the Each child of an individual with autosomal dominant The specific phenotype, age of onset, and disease severity cannot be predicted accurately in offspring who inherit a • Many individuals diagnosed with • A proband with • Some individuals with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing for the constitutional pathogenic variant identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the constitutional 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 gonosomal mosaicism [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline or gonosomal mosaicism [ • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline or gonosomal mosaicism [ • If a parent of the proband is affected and/or is known to have the • Reduced penetrance and intrafamilial variable expressivity are observed in • May or may not have manifestations of • May have different phenotypic manifestations of • May or may not have manifestations of • May have different phenotypic manifestations of • If the • If the parents have not been tested for the • May or may not have manifestations of • May have different phenotypic manifestations of • Each child of an individual with autosomal dominant • The specific phenotype, age of onset, and disease severity cannot be predicted accurately in offspring who inherit a ## Autosomal Recessive 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. Heterozygous parents of a proband with autosomal recessive • 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. Heterozygous parents of a proband with autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. ## 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 Canada • • • • Canada • • • • • ## Molecular Genetics DEPDC5-Related Epilepsy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DEPDC5-Related Epilepsy ( Preliminary in vitro functional studies investigated the effect on mTORC1 signaling of ten Some individuals with cortical malformations (most frequently focal cortical dysplasia type II or hemimegalencephaly) have been reported to have a brain-specific mosaic (or postzygotic) pathogenic variant in ## Molecular Pathogenesis Preliminary in vitro functional studies investigated the effect on mTORC1 signaling of ten Some individuals with cortical malformations (most frequently focal cortical dysplasia type II or hemimegalencephaly) have been reported to have a brain-specific mosaic (or postzygotic) pathogenic variant in ## Chapter Notes Dr Stéphanie Baulac is a neurogeneticist, research director, and group leader at ICM (Paris Brain Institute) working on the genetics and neurobiology of focal epilepsies with brain malformations. Dr Sara Baldassari is a neurogeneticist and principal investigator working at the ICM (Paris Brain Institute) on the genetics and physiopathology of focal epilepsies with brain malformations. To volunteer for research contact: Stéphanie BaulacInstitut du Cerveau (ICM)-Paris Brain InstitutePitié-Salpêtrière Hospital47 bd de l'Hôpital75013 Paris, FranceEmail: Sara Baldassari, PhD (2023-present)Stéphanie Baulac, PhD (2016-2023)Sarah Weckhuysen, MD, PhD; Vlaams Instituut voor Biotechnologie (2016-2023) 9 March 2023 (gm) Comprehensive update posted live 29 September 2016 (bp) Review posted live 23 December 2015 (sb) Original submission • 9 March 2023 (gm) Comprehensive update posted live • 29 September 2016 (bp) Review posted live • 23 December 2015 (sb) Original submission ## Author Notes Dr Stéphanie Baulac is a neurogeneticist, research director, and group leader at ICM (Paris Brain Institute) working on the genetics and neurobiology of focal epilepsies with brain malformations. Dr Sara Baldassari is a neurogeneticist and principal investigator working at the ICM (Paris Brain Institute) on the genetics and physiopathology of focal epilepsies with brain malformations. To volunteer for research contact: Stéphanie BaulacInstitut du Cerveau (ICM)-Paris Brain InstitutePitié-Salpêtrière Hospital47 bd de l'Hôpital75013 Paris, FranceEmail: ## Author History Sara Baldassari, PhD (2023-present)Stéphanie Baulac, PhD (2016-2023)Sarah Weckhuysen, MD, PhD; Vlaams Instituut voor Biotechnologie (2016-2023) ## Revision History 9 March 2023 (gm) Comprehensive update posted live 29 September 2016 (bp) Review posted live 23 December 2015 (sb) Original submission • 9 March 2023 (gm) Comprehensive update posted live • 29 September 2016 (bp) Review posted live • 23 December 2015 (sb) Original submission ## References ## Literature Cited
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Epilepsia Open. 2018;4:63-72", "M van Kranenburg, M Hoogeveen-Westerveld, M Nellist. Preliminary functional assessment and classification of DEPDC5 variants associated with focal epilepsy.. Hum Mutat. 2015;36:200-9", "A Ververi, S Zagaglia, L Menzies, J Baptista, R Caswell, S Baulac, S Ellard, S Lynch, GER Consortium, TS Jacques, MS Chawla, M Heier, MA Kulseth, IL Mero, AK Våtevik, I Kraoua, HB Rhouma, TB Younes, Z Miladi, IBY Turki, WD Jones, E Clement, C Eltze, K Mankad, A Merve, J Parker, B Hoskins, R Pressler, S Sudhakar, C DeVile, T Homfray, M Kaliakatsos, PP Ponnudas, R Robinson, SMB Keim, I Habibi, A Reymond, SM Sisodiya, JA Hurst. Germline homozygous missense DEPDC5 variants cause severe refractory early-onset epilepsy, macrocephaly and bilateral polymicrogyria.. Hum Mol Genet. 2023;32:580-94", "T Wang, J Wang, Y Ma, H Zhou, D Ding, C Li, X Du, YH Jiang, Y Wang, S Long, S Li, G Lu, W Chen, Y Zhou, S Zhou, Y Wang. High genetic burden in 163 Chinese children with status epilepticus.. Seizure. 2021;84:40-6", "S Weckhuysen, E Marsan, V Lambrecq, C Marchal, M Morin-Brureau, I An-Gourfinkel, M Baulac, M Fohlen, C Kallay Zetchi, M Seeck, P de la Grange, B Dermaut, A Meurs, P Thomas, F Chassoux, E Leguern, F Picard, S. Baulac. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.. Epilepsia. 2016;57:994-1003", "G Wiegand, TW May, I Lehmann, U Stephani, NE Kadish. Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies.. Seizure. 2021;93:111-9", "CJ Yuskaitis, LA Rossitto, S Gurnani, E Bainbridge, A Poduri, M Sahin. Chronic mTORC1 inhibition rescues behavioral and biochemical deficits resulting from neuronal Depdc5 loss in mice.. Hum Mol Genet. 2019;28:2952-64", "X Zhang, Z Huang, J Liu, M Li, X Zhao, J Ye, Y. Wang. Phenotypic and genotypic characterization of DEPDC5-related familial focal epilepsy: case series and literature review.. Front Neurol. 2021;12" ]
29/9/2016
9/3/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
df-lamm
df-lamm
[ "Congenital Deafness with Inner Ear Agenesis, Microtia, and Microdontia", "LAMM Syndrome", "Congenital Deafness with Inner Ear Agenesis, Microtia, and Microdontia", "LAMM Syndrome", "Fibroblast growth factor 3", "FGF3", "Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia" ]
Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia
Jessica Ordonez, Mustafa Tekin
Summary Congenital deafness with The diagnosis of LAMM syndrome is established in a proband by identification of biallelic pathogenic variants in LAMM 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. Once the
## Diagnosis The diagnosis of congenital deafness with Profound congenital sensorineural deafness Severe inner ear anomalies diagnosed by CT scan or MRI of the inner ear. The most common inner ear anomaly is complete labyrinthine aplasia with no recognizable structure in the inner ear (also referred to as Michel aplasia) ( Microtia with shortening of the upper part of the auricles (also referred to as type I microtia) ( Microdontia (small teeth) with widely spaced teeth ( Some individuals may also show gross motor developmental delay during infancy (presumably due to the absence of vestibular system) accompanied by additional features that include: Hypoplasia/dysplasia of middle ear anatomic structures identified by imaging studies; Stenosis of the jugular foramen with enlarged emissary vein identified by imaging studies. The diagnosis of LAMM 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of LAMM syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of LAMM syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of LAMM syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia 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. • Profound congenital sensorineural deafness • Severe inner ear anomalies diagnosed by CT scan or MRI of the inner ear. The most common inner ear anomaly is complete labyrinthine aplasia with no recognizable structure in the inner ear (also referred to as Michel aplasia) ( • Microtia with shortening of the upper part of the auricles (also referred to as type I microtia) ( • Microdontia (small teeth) with widely spaced teeth ( • Hypoplasia/dysplasia of middle ear anatomic structures identified by imaging studies; • Stenosis of the jugular foramen with enlarged emissary vein identified by imaging studies. • For an introduction to multigene panels click ## Suggestive Findings The diagnosis of congenital deafness with Profound congenital sensorineural deafness Severe inner ear anomalies diagnosed by CT scan or MRI of the inner ear. The most common inner ear anomaly is complete labyrinthine aplasia with no recognizable structure in the inner ear (also referred to as Michel aplasia) ( Microtia with shortening of the upper part of the auricles (also referred to as type I microtia) ( Microdontia (small teeth) with widely spaced teeth ( Some individuals may also show gross motor developmental delay during infancy (presumably due to the absence of vestibular system) accompanied by additional features that include: Hypoplasia/dysplasia of middle ear anatomic structures identified by imaging studies; Stenosis of the jugular foramen with enlarged emissary vein identified by imaging studies. • Profound congenital sensorineural deafness • Severe inner ear anomalies diagnosed by CT scan or MRI of the inner ear. The most common inner ear anomaly is complete labyrinthine aplasia with no recognizable structure in the inner ear (also referred to as Michel aplasia) ( • Microtia with shortening of the upper part of the auricles (also referred to as type I microtia) ( • Microdontia (small teeth) with widely spaced teeth ( • Hypoplasia/dysplasia of middle ear anatomic structures identified by imaging studies; • Stenosis of the jugular foramen with enlarged emissary vein identified by imaging studies. ## Establishing the Diagnosis The diagnosis of LAMM 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of LAMM syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of LAMM syndrome, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of LAMM syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia 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 ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of LAMM 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 LAMM syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia 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 Mild micrognathia and excessive caries were noted in one adult. Hypodontia or dental root anomalies have not been observed [ Motor delays during infancy, presumably the result of impaired balance; commonly seen Stenosis of the jugular foramen with enlarged emissary vein diagnosed by cranial imaging with no clinical manifestations Normal growth and physical development Average or above-average cognition; affected individuals often attend and thrive at schools for the hearing impaired. Absence of limb anomalies and lacrimal findings (seen in some Findings that may be incidental to LAMM s The variant Microtia was not observed in eight of 11 individuals homozygous for p.Arg95Trp; in contrast, none of the persons reported with other pathogenic variants had normal-appearing external ears. Inner ear structures were identified in seven of 20 individuals homozygous for p.Arg95Trp; in contrast, persons reported with other pathogenic variants had either no inner ear components or primitive vesicle-like structures. LAMM syndrome is very rare; no prevalence estimates have been established. It has been reported in more than 60 individuals from more than 20 unrelated families. • Motor delays during infancy, presumably the result of impaired balance; commonly seen • Stenosis of the jugular foramen with enlarged emissary vein diagnosed by cranial imaging with no clinical manifestations • Normal growth and physical development • Average or above-average cognition; affected individuals often attend and thrive at schools for the hearing impaired. • Absence of limb anomalies and lacrimal findings (seen in some • Microtia was not observed in eight of 11 individuals homozygous for p.Arg95Trp; in contrast, none of the persons reported with other pathogenic variants had normal-appearing external ears. • Inner ear structures were identified in seven of 20 individuals homozygous for p.Arg95Trp; in contrast, persons reported with other pathogenic variants had either no inner ear components or primitive vesicle-like structures. ## Clinical Description Mild micrognathia and excessive caries were noted in one adult. Hypodontia or dental root anomalies have not been observed [ Motor delays during infancy, presumably the result of impaired balance; commonly seen Stenosis of the jugular foramen with enlarged emissary vein diagnosed by cranial imaging with no clinical manifestations Normal growth and physical development Average or above-average cognition; affected individuals often attend and thrive at schools for the hearing impaired. Absence of limb anomalies and lacrimal findings (seen in some Findings that may be incidental to LAMM s • Motor delays during infancy, presumably the result of impaired balance; commonly seen • Stenosis of the jugular foramen with enlarged emissary vein diagnosed by cranial imaging with no clinical manifestations • Normal growth and physical development • Average or above-average cognition; affected individuals often attend and thrive at schools for the hearing impaired. • Absence of limb anomalies and lacrimal findings (seen in some ## Genotype-Phenotype Correlations The variant Microtia was not observed in eight of 11 individuals homozygous for p.Arg95Trp; in contrast, none of the persons reported with other pathogenic variants had normal-appearing external ears. Inner ear structures were identified in seven of 20 individuals homozygous for p.Arg95Trp; in contrast, persons reported with other pathogenic variants had either no inner ear components or primitive vesicle-like structures. • Microtia was not observed in eight of 11 individuals homozygous for p.Arg95Trp; in contrast, none of the persons reported with other pathogenic variants had normal-appearing external ears. • Inner ear structures were identified in seven of 20 individuals homozygous for p.Arg95Trp; in contrast, persons reported with other pathogenic variants had either no inner ear components or primitive vesicle-like structures. ## Prevalence LAMM syndrome is very rare; no prevalence estimates have been established. It has been reported in more than 60 individuals from more than 20 unrelated families. ## Genetically Related (Allelic) Disorders Chromosome microdeletions at 11q13 containing ## Differential Diagnosis Other Genes of Interest in the Differential Diagnosis of LAMM Syndrome Hearing loss Dental anomalies Aplasia, atresia, or hypoplasia of the lacrimal & salivary systems Cup-shaped ears Digital (particularly thumb) anomalies Branchial fistulae & cysts Renal malformations Hearing loss Strabismus Skeletal anomalies Typical facial features Dermatoglyphic abnormalities Congenital heart defects Mild-to-moderate ID Microtia Hearing loss Imperforate anus or anal stenosis Typical thumb malformations w/o hypoplasia of the radius AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked; LAMM = labyrinthine aplasia, microtia, and microdontia Although Other single-gene disorders or microdeletion/microduplication syndromes should be considered in individuals who have intellectual disability in addition to typical anomalies seen in LAMM syndrome [ • Hearing loss • Dental anomalies • Aplasia, atresia, or hypoplasia of the lacrimal & salivary systems • Cup-shaped ears • Digital (particularly thumb) anomalies • Branchial fistulae & cysts • Renal malformations • Hearing loss • Strabismus • Skeletal anomalies • Typical facial features • Dermatoglyphic abnormalities • Congenital heart defects • Mild-to-moderate ID • Microtia • Hearing loss • Imperforate anus or anal stenosis • Typical thumb malformations w/o hypoplasia of the radius ## Management To establish the extent of disease and needs in an individual diagnosed with congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia Ideally, the team evaluating and treating a deaf individual should include an otolaryngologist with expertise in the management of early-childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a clinical geneticist, and a pediatrician. The expertise of an educator of the Deaf, a neurologist, and a pediatric ophthalmologist may also be required. Enrollment in appropriate early-intervention programs and educational programs for the hearing impaired is appropriate. An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, brain stem implants, and cochlear implantation: Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. Routine ophthalmologic management of strabismus, if present, is indicated. Regardless of its etiology, uncorrected hearing loss has consistent sequelae: Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production. Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention (whether through amplification or cochlear implantation) is effective (see Delayed gross motor development (presumably the result of impaired balance and profound deafness) increases the risk for accidents and trauma. The risk for accidents can be addressed in part by use of visual or vibrotactile alarm systems in homes and schools. The risk for pedestrian injury can be reduced by choosing routes with visual displays of crosswalks. Anticipatory education of parents, health providers, and educational programs about hazards can help address the risk for falls [ Recommended Surveillance for Individuals with Deafness with Congenital Labyrinthine Aplasia, Microtia, and Microdontia Yearly evaluations by the multidisciplinary team mentioned in Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, individuals with LAMM syndrome and a residual cochlea should be counseled appropriately. Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution. It is appropriate to clarify the genetic status of apparently asymptomatic sibs of an affected individual by molecular genetic testing for the See Search • Enrollment in appropriate early-intervention programs and educational programs for the hearing impaired is appropriate. • An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, brain stem implants, and cochlear implantation: • Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ • Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. • Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ • Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. • Routine ophthalmologic management of strabismus, if present, is indicated. • Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ • Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. • The risk for accidents can be addressed in part by use of visual or vibrotactile alarm systems in homes and schools. • The risk for pedestrian injury can be reduced by choosing routes with visual displays of crosswalks. • Anticipatory education of parents, health providers, and educational programs about hazards can help address the risk for falls [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia ## Treatment of Manifestations Ideally, the team evaluating and treating a deaf individual should include an otolaryngologist with expertise in the management of early-childhood otologic disorders, an audiologist experienced in the assessment of hearing loss in children, a clinical geneticist, and a pediatrician. The expertise of an educator of the Deaf, a neurologist, and a pediatric ophthalmologist may also be required. Enrollment in appropriate early-intervention programs and educational programs for the hearing impaired is appropriate. An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, brain stem implants, and cochlear implantation: Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. Routine ophthalmologic management of strabismus, if present, is indicated. • Enrollment in appropriate early-intervention programs and educational programs for the hearing impaired is appropriate. • An important part of the evaluation is determining the appropriate habilitation option. Possibilities include hearing aids, vibrotactile devices, brain stem implants, and cochlear implantation: • Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ • Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. • Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ • Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. • Routine ophthalmologic management of strabismus, if present, is indicated. • Consideration of vibrotactile hearing devices or brain stem implants for individuals with complete labyrinthine aplasia [ • Evaluation for cochlear implantation in those individuals with a cochleovestibular nerve and a cochlear remnant. Cochlear implantation can be considered in children older than age 12 months with severe-to-profound hearing loss. ## Prevention of Secondary Complications Regardless of its etiology, uncorrected hearing loss has consistent sequelae: Auditory deprivation through age two years is associated with poor reading performance, poor communication skills, and poor speech production. Educational intervention is insufficient to completely remediate these deficiencies. In contrast, early auditory intervention (whether through amplification or cochlear implantation) is effective (see Delayed gross motor development (presumably the result of impaired balance and profound deafness) increases the risk for accidents and trauma. The risk for accidents can be addressed in part by use of visual or vibrotactile alarm systems in homes and schools. The risk for pedestrian injury can be reduced by choosing routes with visual displays of crosswalks. Anticipatory education of parents, health providers, and educational programs about hazards can help address the risk for falls [ • The risk for accidents can be addressed in part by use of visual or vibrotactile alarm systems in homes and schools. • The risk for pedestrian injury can be reduced by choosing routes with visual displays of crosswalks. • Anticipatory education of parents, health providers, and educational programs about hazards can help address the risk for falls [ ## Surveillance Recommended Surveillance for Individuals with Deafness with Congenital Labyrinthine Aplasia, Microtia, and Microdontia Yearly evaluations by the multidisciplinary team mentioned in ## Agents/Circumstances to Avoid Noise exposure is a well-recognized environmental cause of hearing loss. Since this risk can be minimized by avoidance, individuals with LAMM syndrome and a residual cochlea should be counseled appropriately. Because of the high risk for disorientation when submerged in water, swimming needs to be undertaken with caution. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic sibs of an affected individual by molecular genetic testing for the See ## Therapies Under Investigation Search ## Genetic Counseling Congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. 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 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are 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 Congenital deafness with labyrinthine aplasia, microtia, and microdontia (LAMM syndrome) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. 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 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • ## Molecular Genetics Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia ( RAS/MAP kinase pathway (the main pathway) Phosphoinositides 3 kinase/AKT pathway Phospholipase C gamma pathway Physiologically, FGF3 binds to the FGF receptor (FGFR) 1b and 2b to activate its signaling cascade, thus regulating cellular proliferation, survival, migration, and differentiation [ Molecular modeling suggests that the p.Arg95Trp pathogenic variant does not impair the interaction of FGF3 with FGFR2b receptors or heparin sulfate binding sites, which may result in residual function of FGF3 [ Notable Variants listed in the table have been provided by the authors. • RAS/MAP kinase pathway (the main pathway) • Phosphoinositides 3 kinase/AKT pathway • Phospholipase C gamma pathway ## Molecular Pathogenesis RAS/MAP kinase pathway (the main pathway) Phosphoinositides 3 kinase/AKT pathway Phospholipase C gamma pathway Physiologically, FGF3 binds to the FGF receptor (FGFR) 1b and 2b to activate its signaling cascade, thus regulating cellular proliferation, survival, migration, and differentiation [ Molecular modeling suggests that the p.Arg95Trp pathogenic variant does not impair the interaction of FGF3 with FGFR2b receptors or heparin sulfate binding sites, which may result in residual function of FGF3 [ Notable Variants listed in the table have been provided by the authors. • RAS/MAP kinase pathway (the main pathway) • Phosphoinositides 3 kinase/AKT pathway • Phospholipase C gamma pathway ## Chapter Notes This work was supported by NIH-NIDCD grant R01DC009645 to M.T. John P Hussman Institute for Human Genomics: Division of Clinical and Translation Genetics: 14 August 2025 (aa) Revision: 4 April 2019 (sw) Comprehensive update posted live 20 September 2012 (me) Review posted live 9 June 2012 (mt) Original submission • 14 August 2025 (aa) Revision: • 4 April 2019 (sw) Comprehensive update posted live • 20 September 2012 (me) Review posted live • 9 June 2012 (mt) Original submission ## Acknowledgments This work was supported by NIH-NIDCD grant R01DC009645 to M.T. ## Author Notes John P Hussman Institute for Human Genomics: Division of Clinical and Translation Genetics: ## Revision History 14 August 2025 (aa) Revision: 4 April 2019 (sw) Comprehensive update posted live 20 September 2012 (me) Review posted live 9 June 2012 (mt) Original submission • 14 August 2025 (aa) Revision: • 4 April 2019 (sw) Comprehensive update posted live • 20 September 2012 (me) Review posted live • 9 June 2012 (mt) Original submission ## References ## Literature Cited Congenital deafness with labyrinthine aplasia, microtia, and microdontia A. Microtia with anteverted ears B. Microdontia with widely spaced teeth C. CT image demonstrating bilateral petrous bone aplasia and absence of inner ear structures. Malleus and incus are seen in the middle ear cavity (black arrows).
[]
20/9/2012
4/4/2019
14/8/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dfn-myop
dfn-myop
[ "SLIT and NTRK-like protein 6", "SLITRK6", "Deafness and Myopia Syndrome" ]
Deafness and Myopia Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Jessica L Ordonez, Mustafa Tekin
Summary Deafness and myopia (DFNMYP) syndrome is characterized by bilateral, congenital or prelingual deafness (sensorineural hearing loss or auditory neuropathy spectrum disorder) and high myopia (>-6 diopters). In individuals with a molecularly confirmed diagnosis reported to date, hearing loss was progressive and severity ranged from moderate to profound. Vestibular testing was normal. Myopia was diagnosed at infancy or early childhood. The diagnosis is established in a proband by identification of biallelic pathogenic variants in DFNMYP 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. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the
## Diagnosis Deafness and myopia (DFNMYP) syndrome Moderate-to-profound, bilateral, congenital or prelingual sensorineural hearing loss or auditory neuropathy spectrum disorder (sensorineural hearing loss originates from problems in the inner ear or the auditory nerve). Auditory neuropathy spectrum disorder is characterized by normal outer hair cell function (present otoacoustic emissions [OAE] and/or cochlear microphonic), suggesting that the hearing loss results from abnormal inner hair cells, synapses, or auditory nerve function that can be demonstrated with an absent or abnormal auditory brain stem response (ABR) test. High myopia (g>-6 diopters) Nondysmorphic facial appearance and normal temporal bone structure No neurologic, connective tissue, or other ocular manifestations No formal clinical diagnostic criteria have been established for DFNMYP syndrome. The diagnosis of DFNMYP Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Deafness and Myopia 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. • Moderate-to-profound, bilateral, congenital or prelingual sensorineural hearing loss or auditory neuropathy spectrum disorder (sensorineural hearing loss originates from problems in the inner ear or the auditory nerve). Auditory neuropathy spectrum disorder is characterized by normal outer hair cell function (present otoacoustic emissions [OAE] and/or cochlear microphonic), suggesting that the hearing loss results from abnormal inner hair cells, synapses, or auditory nerve function that can be demonstrated with an absent or abnormal auditory brain stem response (ABR) test. • High myopia (g>-6 diopters) • Nondysmorphic facial appearance and normal temporal bone structure • No neurologic, connective tissue, or other ocular manifestations • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Deafness and myopia (DFNMYP) syndrome Moderate-to-profound, bilateral, congenital or prelingual sensorineural hearing loss or auditory neuropathy spectrum disorder (sensorineural hearing loss originates from problems in the inner ear or the auditory nerve). Auditory neuropathy spectrum disorder is characterized by normal outer hair cell function (present otoacoustic emissions [OAE] and/or cochlear microphonic), suggesting that the hearing loss results from abnormal inner hair cells, synapses, or auditory nerve function that can be demonstrated with an absent or abnormal auditory brain stem response (ABR) test. High myopia (g>-6 diopters) Nondysmorphic facial appearance and normal temporal bone structure No neurologic, connective tissue, or other ocular manifestations • Moderate-to-profound, bilateral, congenital or prelingual sensorineural hearing loss or auditory neuropathy spectrum disorder (sensorineural hearing loss originates from problems in the inner ear or the auditory nerve). Auditory neuropathy spectrum disorder is characterized by normal outer hair cell function (present otoacoustic emissions [OAE] and/or cochlear microphonic), suggesting that the hearing loss results from abnormal inner hair cells, synapses, or auditory nerve function that can be demonstrated with an absent or abnormal auditory brain stem response (ABR) test. • High myopia (g>-6 diopters) • Nondysmorphic facial appearance and normal temporal bone structure • No neurologic, connective tissue, or other ocular manifestations ## Establishing the Diagnosis No formal clinical diagnostic criteria have been established for DFNMYP syndrome. The diagnosis of DFNMYP Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Deafness and Myopia 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. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Deafness and myopia (DFNMYP) syndrome was described by Sensorineural hearing loss progressed from moderate to profound by early adulthood in nine additional affected individuals from an endogamous Amish population [ Affected individuals had normal gross motor development. None had balance problems, vertigo, or dizziness. Vestibular testing and temporal bone CT were normal in one affected individual from each family. All reported individuals to date with DFNMYP syndrome have homozygous nonsense Due to the rarity of the syndrome, no prevalence estimates have been established. ## Clinical Description Deafness and myopia (DFNMYP) syndrome was described by Sensorineural hearing loss progressed from moderate to profound by early adulthood in nine additional affected individuals from an endogamous Amish population [ Affected individuals had normal gross motor development. None had balance problems, vertigo, or dizziness. Vestibular testing and temporal bone CT were normal in one affected individual from each family. ## Genotype-Phenotype Correlations All reported individuals to date with DFNMYP syndrome have homozygous nonsense ## Prevalence Due to the rarity of the syndrome, no prevalence estimates have been established. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic tumors (including papillary thyroid tumors) occurring as single tumors in the absence of any other findings of deafness and myopia syndrome may have somatic pathogenic variants in ## Differential Diagnosis See Disorders with deafness and myopia to specifically consider include the following: ## Management To establish the extent of disease and needs in an individual diagnosed with deafness and myopia (DFNMYP) syndrome, the following evaluations are recommended if they have not already been completed: Audiology evaluation for sensorineural hearing loss and auditory neuropathy spectrum disorder Ophthalmology evaluation for myopia and other ocular comorbidities Evaluation by early intervention/educational programs for the hearing impaired including baseline speech and language assessment in children Consultation with a clinical geneticist and/or genetic counselor Appropriate treatment includes the following: Implementation of hearing habilitation devices including hearing aids and vibrotactile hearing tools as needed Consideration of cochlear implantation (CI) in individuals with severe-to-profound sensorineural hearing loss and auditory neuropathy spectrum disorder. Although no CI has been reported among individuals with deafness and myopia syndrome, favorable outcome of CI has been reported in children with auditory neuropathy spectrum disorder [ Enrollment in early intervention programs and educational programs for the hearing impaired to maximize long-term speech and language outcomes Routine correction of refractive error The following are appropriate: ENT and audiology evaluations at least yearly Regular speech and language evaluation to monitor language development Regular ophthalmology evaluations to monitor for potential complications from high myopia including cataracts, glaucoma, and retinal detachment Yearly evaluations by a clinical geneticist familiar with hereditary forms of deafness Individuals with hearing loss should avoid the following: Known environmental factors for hearing loss (e.g., loud noises) Ototoxic medications It is appropriate to evaluate older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt treatment of hearing loss and myopia. Evaluations can include: Molecular genetic testing if the Clinical audiology and ophthalmology evaluations if a molecular diagnosis has not been established. See Search • Audiology evaluation for sensorineural hearing loss and auditory neuropathy spectrum disorder • Ophthalmology evaluation for myopia and other ocular comorbidities • Evaluation by early intervention/educational programs for the hearing impaired including baseline speech and language assessment in children • Consultation with a clinical geneticist and/or genetic counselor • Implementation of hearing habilitation devices including hearing aids and vibrotactile hearing tools as needed • Consideration of cochlear implantation (CI) in individuals with severe-to-profound sensorineural hearing loss and auditory neuropathy spectrum disorder. Although no CI has been reported among individuals with deafness and myopia syndrome, favorable outcome of CI has been reported in children with auditory neuropathy spectrum disorder [ • Enrollment in early intervention programs and educational programs for the hearing impaired to maximize long-term speech and language outcomes • Routine correction of refractive error • ENT and audiology evaluations at least yearly • Regular speech and language evaluation to monitor language development • Regular ophthalmology evaluations to monitor for potential complications from high myopia including cataracts, glaucoma, and retinal detachment • Yearly evaluations by a clinical geneticist familiar with hereditary forms of deafness • Known environmental factors for hearing loss (e.g., loud noises) • Ototoxic medications • Molecular genetic testing if the • Clinical audiology and ophthalmology evaluations if a molecular diagnosis has not been established. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with deafness and myopia (DFNMYP) syndrome, the following evaluations are recommended if they have not already been completed: Audiology evaluation for sensorineural hearing loss and auditory neuropathy spectrum disorder Ophthalmology evaluation for myopia and other ocular comorbidities Evaluation by early intervention/educational programs for the hearing impaired including baseline speech and language assessment in children Consultation with a clinical geneticist and/or genetic counselor • Audiology evaluation for sensorineural hearing loss and auditory neuropathy spectrum disorder • Ophthalmology evaluation for myopia and other ocular comorbidities • Evaluation by early intervention/educational programs for the hearing impaired including baseline speech and language assessment in children • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Appropriate treatment includes the following: Implementation of hearing habilitation devices including hearing aids and vibrotactile hearing tools as needed Consideration of cochlear implantation (CI) in individuals with severe-to-profound sensorineural hearing loss and auditory neuropathy spectrum disorder. Although no CI has been reported among individuals with deafness and myopia syndrome, favorable outcome of CI has been reported in children with auditory neuropathy spectrum disorder [ Enrollment in early intervention programs and educational programs for the hearing impaired to maximize long-term speech and language outcomes Routine correction of refractive error • Implementation of hearing habilitation devices including hearing aids and vibrotactile hearing tools as needed • Consideration of cochlear implantation (CI) in individuals with severe-to-profound sensorineural hearing loss and auditory neuropathy spectrum disorder. Although no CI has been reported among individuals with deafness and myopia syndrome, favorable outcome of CI has been reported in children with auditory neuropathy spectrum disorder [ • Enrollment in early intervention programs and educational programs for the hearing impaired to maximize long-term speech and language outcomes • Routine correction of refractive error ## Surveillance The following are appropriate: ENT and audiology evaluations at least yearly Regular speech and language evaluation to monitor language development Regular ophthalmology evaluations to monitor for potential complications from high myopia including cataracts, glaucoma, and retinal detachment Yearly evaluations by a clinical geneticist familiar with hereditary forms of deafness • ENT and audiology evaluations at least yearly • Regular speech and language evaluation to monitor language development • Regular ophthalmology evaluations to monitor for potential complications from high myopia including cataracts, glaucoma, and retinal detachment • Yearly evaluations by a clinical geneticist familiar with hereditary forms of deafness ## Agents/Circumstances to Avoid Individuals with hearing loss should avoid the following: Known environmental factors for hearing loss (e.g., loud noises) Ototoxic medications • Known environmental factors for hearing loss (e.g., loud noises) • Ototoxic medications ## Evaluation of Relatives at Risk It is appropriate to evaluate older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt treatment of hearing loss and myopia. Evaluations can include: Molecular genetic testing if the Clinical audiology and ophthalmology evaluations if a molecular diagnosis has not been established. See • Molecular genetic testing if the • Clinical audiology and ophthalmology evaluations if a molecular diagnosis has not been established. ## Therapies Under Investigation Search ## Genetic Counseling Deafness and myopia (DFNMYP) syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one Although low myopia (<-3 diopters) of early and adult onset has been reported among some carrier parents, 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 and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Although low myopia (<-3 diopters) of early and adult onset has been reported among some carrier parents, • 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 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 Deafness and myopia (DFNMYP) syndrome is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one Although low myopia (<-3 diopters) of early and adult onset has been reported among some carrier parents, 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 and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Although low myopia (<-3 diopters) of early and adult onset has been reported among some carrier parents, • 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 and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources 31 Center Drive MSC 2320 Bethesda MD 20892-2320 • • • • • • • • • • • 31 Center Drive • MSC 2320 • Bethesda MD 20892-2320 • ## Molecular Genetics Deafness and Myopia Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Deafness and Myopia Syndrome ( Variants listed in the table have been provided by the authors. Unlike other members of the Copy number changes were analyzed from human papillary thyroid cancerous tumors (PTC) using array CGH [ ## Cancer and Benign Tumors Copy number changes were analyzed from human papillary thyroid cancerous tumors (PTC) using array CGH [ ## Chapter Notes Hussman Institute of Human Genomics: Division of Clinical and Translation Genetics: This work was supported by an NIH/NIDCD grant R01DC009645 to MT. 17 July 2025 (ma) Chapter retired: extremely rare disorder 14 September 2017 (sw) Comprehensive update posted live 15 January 2015 (me) Review posted live 8 September 2015 (jo) Original submission • 17 July 2025 (ma) Chapter retired: extremely rare disorder • 14 September 2017 (sw) Comprehensive update posted live • 15 January 2015 (me) Review posted live • 8 September 2015 (jo) Original submission ## Author Notes Hussman Institute of Human Genomics: Division of Clinical and Translation Genetics: ## Acknowledgments This work was supported by an NIH/NIDCD grant R01DC009645 to MT. ## Revision History 17 July 2025 (ma) Chapter retired: extremely rare disorder 14 September 2017 (sw) Comprehensive update posted live 15 January 2015 (me) Review posted live 8 September 2015 (jo) Original submission • 17 July 2025 (ma) Chapter retired: extremely rare disorder • 14 September 2017 (sw) Comprehensive update posted live • 15 January 2015 (me) Review posted live • 8 September 2015 (jo) Original submission ## References ## Literature Cited
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15/1/2015
14/9/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dfna2
dfna2
[ "Potassium voltage-gated channel subfamily KQT member 4", "KCNQ4", "DFNA2 Nonsyndromic Hearing Loss" ]
DFNA2 Nonsyndromic Hearing Loss
Richard JH Smith, Michael Hildebrand
Summary DFNA2 nonsyndromic hearing loss is characterized by symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies. At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies; in older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. Although the hearing impairment is often detected during routine hearing assessment of a school-age child, it is likely that hearing is impaired from birth, especially at high frequencies. Most affected persons initially require hearing aids to assist with sound amplification between ages ten and 40 years. By age 70 years, all persons with DFNA2 nonsyndromic hearing loss have severe-to-profound hearing impairment. The diagnosis of DFNA2 nonsyndromic hearing loss is established in an individual with a characteristic audioprofile, a family history consistent with autosomal dominant inheritance, and identification of a heterozygous pathogenic variant in DFNA2 nonsyndromic hearing loss is inherited in an autosomal dominant manner. Most individuals with DFNA2 nonsyndromic hearing loss have a parent with hearing loss; the proportion of individuals with a
## Diagnosis DFNA2 nonsyndromic hearing loss Symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies: At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. Normal physical examination The diagnosis of DFNA2 nonsyndromic hearing loss Because the phenotype of DFNA2 nonsyndromic hearing loss is indistinguishable from many other inherited disorders with hearing loss, recommended molecular genetic testing approaches include use of a Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DFNA2 Nonsyndromic Hearing Loss 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 detects 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. Copy number variants (CNVs) can be detected in virtually any gene included in targeted sequencing panels for deafness. In sequential testing of 2,506 persons with hearing loss using OtoSCOPE, one CNV of • Symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies: • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. • Normal physical examination • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. ## Suggestive Findings DFNA2 nonsyndromic hearing loss Symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies: At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. Normal physical examination • Symmetric, predominantly high-frequency sensorineural hearing loss (SNHL) that is progressive across all frequencies: • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. • Normal physical examination • At younger ages, hearing loss tends to be mild in the low frequencies and moderate in the high frequencies. • In older persons, the hearing loss is moderate in the low frequencies and severe to profound in the high frequencies. ## Establishing the Diagnosis The diagnosis of DFNA2 nonsyndromic hearing loss Because the phenotype of DFNA2 nonsyndromic hearing loss is indistinguishable from many other inherited disorders with hearing loss, recommended molecular genetic testing approaches include use of a Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DFNA2 Nonsyndromic Hearing Loss 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 detects 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. Copy number variants (CNVs) can be detected in virtually any gene included in targeted sequencing panels for deafness. In sequential testing of 2,506 persons with hearing loss using OtoSCOPE, one CNV of ## Clinical Characteristics All individuals with DFNA2 nonsyndromic hearing loss have symmetric, predominantly high-frequency hearing loss that is progressive across all frequencies. Initially, high frequencies are affected; later in life, hearing loss becomes severe to profound across all frequencies. A comprehensive review of the clinical presentation and prognosis of individuals diagnosed with DFNA2 nonsyndromic hearing loss has been provided by Onset of hearing loss is generally reported in early childhood or adolescence; however, it is likely that hearing is impaired from birth, especially at the high frequencies. The hearing loss is often detected during standard hearing assessment of a school-age child or less frequently during the evaluation of a child for delayed speech development. In all affected individuals, the hearing loss is more severe at the high frequencies, resulting in a characteristic downsloping audioprofile with hearing thresholds between 50 and 90 dB at 500 Hz and between 90 and 120 dB at 2-4 kHz by age 50 years. A typical audiogram of an adolescent with DFNA2 nonsyndromic hearing loss is shown in Whereas onset age varies within families, deterioration of annual thresholds for families with DFNA2 nonsyndromic hearing loss has been calculated at a relatively uniform ~1 dB/year [ The phenotype associated with heterozygous Although congenital onset of DFNA2 nonsyndromic hearing loss has been reported in one of the Dutch families with the The phenotype associated with heterozygous The penetrance is complete. All individuals with a heterozygous In a study conducted between 2012 and 2014, the Molecular Otolaryngology and Renal Research Laboratories performed clinical diagnostic testing on a total of 1,119 individuals with hearing loss using the comprehensive genetic testing panel OtoSCOPE. It was determined that among the 440 individuals in whom hearing loss was hereditary, ## Clinical Description All individuals with DFNA2 nonsyndromic hearing loss have symmetric, predominantly high-frequency hearing loss that is progressive across all frequencies. Initially, high frequencies are affected; later in life, hearing loss becomes severe to profound across all frequencies. A comprehensive review of the clinical presentation and prognosis of individuals diagnosed with DFNA2 nonsyndromic hearing loss has been provided by Onset of hearing loss is generally reported in early childhood or adolescence; however, it is likely that hearing is impaired from birth, especially at the high frequencies. The hearing loss is often detected during standard hearing assessment of a school-age child or less frequently during the evaluation of a child for delayed speech development. In all affected individuals, the hearing loss is more severe at the high frequencies, resulting in a characteristic downsloping audioprofile with hearing thresholds between 50 and 90 dB at 500 Hz and between 90 and 120 dB at 2-4 kHz by age 50 years. A typical audiogram of an adolescent with DFNA2 nonsyndromic hearing loss is shown in Whereas onset age varies within families, deterioration of annual thresholds for families with DFNA2 nonsyndromic hearing loss has been calculated at a relatively uniform ~1 dB/year [ ## Genotype-Phenotype Correlations The phenotype associated with heterozygous Although congenital onset of DFNA2 nonsyndromic hearing loss has been reported in one of the Dutch families with the The phenotype associated with heterozygous ## Penetrance The penetrance is complete. All individuals with a heterozygous ## Prevalence In a study conducted between 2012 and 2014, the Molecular Otolaryngology and Renal Research Laboratories performed clinical diagnostic testing on a total of 1,119 individuals with hearing loss using the comprehensive genetic testing panel OtoSCOPE. It was determined that among the 440 individuals in whom hearing loss was hereditary, ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis See ## Management To establish the extent of hearing loss and needs in an individual diagnosed with DFNA2 nonsyndromic hearing loss, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Audiometry, including bone conduction testing Consultation with a clinical geneticist and/or genetic counselor See When hearing loss is mild to moderate, fitting of hearing aids to provide improved amplification is warranted. When the hearing loss becomes severe to profound, cochlear implants (CIs) can be considered. In individuals with preserved or relatively good low-frequency hearing and severe-to-profound high-frequency loss, a hybrid (short) cochlear implant may be considered. Hybrid implants combine two proven technologies – acoustic amplification and implant technology – to provide electroacoustic hearing. The acoustic component, which is coupled to the cochlear implant sound processor, amplifies residual low-frequency hearing; the electrical component uses cochlear implant technology to provide electrostimulation for high-frequency hearing. For school-age children or adolescents, special assistance for the hearing impaired may be warranted and, where available, should be offered. Audiograms should be obtained on an annual basis to follow progression of hearing loss. The rate of progression of high-frequency hearing loss can be reduced by encouraging individuals with DFNA2 nonsyndromic hearing loss to avoid exposure to loud noise in the workplace and during recreation. Determining in infancy or early childhood whether a relative of a person with DFNA2 nonsyndromic hearing loss has inherited the See Search • Audiometry, including bone conduction testing • Consultation with a clinical geneticist and/or genetic counselor ## Evaluations Following Initial Diagnosis To establish the extent of hearing loss and needs in an individual diagnosed with DFNA2 nonsyndromic hearing loss, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Audiometry, including bone conduction testing Consultation with a clinical geneticist and/or genetic counselor • Audiometry, including bone conduction testing • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations See When hearing loss is mild to moderate, fitting of hearing aids to provide improved amplification is warranted. When the hearing loss becomes severe to profound, cochlear implants (CIs) can be considered. In individuals with preserved or relatively good low-frequency hearing and severe-to-profound high-frequency loss, a hybrid (short) cochlear implant may be considered. Hybrid implants combine two proven technologies – acoustic amplification and implant technology – to provide electroacoustic hearing. The acoustic component, which is coupled to the cochlear implant sound processor, amplifies residual low-frequency hearing; the electrical component uses cochlear implant technology to provide electrostimulation for high-frequency hearing. For school-age children or adolescents, special assistance for the hearing impaired may be warranted and, where available, should be offered. ## Surveillance Audiograms should be obtained on an annual basis to follow progression of hearing loss. ## Agents/Circumstances to Avoid The rate of progression of high-frequency hearing loss can be reduced by encouraging individuals with DFNA2 nonsyndromic hearing loss to avoid exposure to loud noise in the workplace and during recreation. ## Evaluation of Relatives at Risk Determining in infancy or early childhood whether a relative of a person with DFNA2 nonsyndromic hearing loss has inherited the See ## Therapies Under Investigation Search ## Genetic Counseling DFNA2 nonsyndromic hearing loss is inherited in an autosomal dominant manner. Most individuals diagnosed with DFNA2 nonsyndromic hearing loss have a deaf parent. A proband with DFNA2 nonsyndromic hearing loss may have deafness as the result of a 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 with DFNA2 nonsyndromic hearing loss may appear to be negative because of failure to diagnosis a parent with a milder phenotypic presentation, early death of the parent before the onset of hearing loss, or late onset of hearing loss in a parent. Therefore, an apparently negative family history cannot be confirmed until the appropriate clinical evaluation and molecular genetic testing have been performed on the parents of the proband. Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and have mild hearing loss. If a parent of the proband is deaf, each sib has a 50% chance of being deaf. If the If the parents have not been tested for the See Management, The following points are noteworthy: Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. 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." Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational and social services, rather than information about prevention, reproduction or family planning. It is important to ascertain and address the questions and concerns of the family/individual. The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. 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 that offspring will be deaf and reproductive options) to young adults who have DFNA2 nonsyndromic hearing loss. 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 DFNA2 nonsyndromic hearing loss have a deaf parent. • A proband with DFNA2 nonsyndromic hearing loss may have deafness as the result of a • 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 with DFNA2 nonsyndromic hearing loss may appear to be negative because of failure to diagnosis a parent with a milder phenotypic presentation, early death of the parent before the onset of hearing loss, or late onset of hearing loss in a parent. Therefore, an apparently negative family history cannot be confirmed until the appropriate clinical evaluation and molecular genetic testing have been performed on the parents of the proband. • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and have mild hearing loss. • If a parent of the proband is deaf, each sib has a 50% chance of being deaf. • If the • If the parents have not been tested for the • Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. • 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." • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational and social services, rather than information about prevention, reproduction or family planning. It is important to ascertain and address the questions and concerns of the family/individual. • The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. • 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 that offspring will be deaf and reproductive options) to young adults who have DFNA2 nonsyndromic hearing loss. ## Mode of Inheritance DFNA2 nonsyndromic hearing loss is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with DFNA2 nonsyndromic hearing loss have a deaf parent. A proband with DFNA2 nonsyndromic hearing loss may have deafness as the result of a 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 with DFNA2 nonsyndromic hearing loss may appear to be negative because of failure to diagnosis a parent with a milder phenotypic presentation, early death of the parent before the onset of hearing loss, or late onset of hearing loss in a parent. Therefore, an apparently negative family history cannot be confirmed until the appropriate clinical evaluation and molecular genetic testing have been performed on the parents of the proband. Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and have mild hearing loss. If a parent of the proband is deaf, each sib has a 50% chance of being deaf. If the If the parents have not been tested for the • Most individuals diagnosed with DFNA2 nonsyndromic hearing loss have a deaf parent. • A proband with DFNA2 nonsyndromic hearing loss may have deafness as the result of a • 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 with DFNA2 nonsyndromic hearing loss may appear to be negative because of failure to diagnosis a parent with a milder phenotypic presentation, early death of the parent before the onset of hearing loss, or late onset of hearing loss in a parent. Therefore, an apparently negative family history cannot be confirmed until the appropriate clinical evaluation and molecular genetic testing have been performed on the parents of the proband. • Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the pathogenic variant and have mild hearing loss. • If a parent of the proband is deaf, each sib has a 50% chance of being deaf. • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The following points are noteworthy: Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. 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." Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational and social services, rather than information about prevention, reproduction or family planning. It is important to ascertain and address the questions and concerns of the family/individual. The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. 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 that offspring will be deaf and reproductive options) to young adults who have DFNA2 nonsyndromic hearing loss. • Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. • 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." • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational and social services, rather than information about prevention, reproduction or family planning. It is important to ascertain and address the questions and concerns of the family/individual. • The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. • 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 that offspring will be deaf and reproductive options) to young adults who have DFNA2 nonsyndromic hearing loss. ## 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 DFNA2 Nonsyndromic Hearing Loss: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DFNA2 Nonsyndromic Hearing Loss ( Variants listed in the table have been provided by the authors. Reference sequences for Pathology was high-frequency hearing impairment and tissue-specific expression was in cochlear outer hair cells and brain for all pathogenic variants described in the table. No effect on protein level is expected. Variants listed in the table have been provided by the authors. Reference sequences for Variant designation that does not conform to current naming conventions Pathology was high-frequency hearing impairment and tissue-specific expression was in cochlear outer hair cells and brain for all pathogenic variants described in the table. Some The evidence associating In both families, other individuals with normal hearing had the reported pathogenic variants in It is doubtful that No other families with autosomal dominant SNHL have been reported to segregate Specific pathogenic variants in • In both families, other individuals with normal hearing had the reported pathogenic variants in • It is doubtful that • No other families with autosomal dominant SNHL have been reported to segregate • Specific pathogenic variants in ## References ## Literature Cited ## Chapter Notes 10 May 2018 (bp) Comprehensive update posted live 20 August 2015 (me) Comprehensive update posted live 20 June 2013 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 4 April 2008 (me) Review posted live 19 December 2007 (rjhs) Original submission • 10 May 2018 (bp) Comprehensive update posted live • 20 August 2015 (me) Comprehensive update posted live • 20 June 2013 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 4 April 2008 (me) Review posted live • 19 December 2007 (rjhs) Original submission ## Author Notes ## Revision History 10 May 2018 (bp) Comprehensive update posted live 20 August 2015 (me) Comprehensive update posted live 20 June 2013 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 4 April 2008 (me) Review posted live 19 December 2007 (rjhs) Original submission • 10 May 2018 (bp) Comprehensive update posted live • 20 August 2015 (me) Comprehensive update posted live • 20 June 2013 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 4 April 2008 (me) Review posted live • 19 December 2007 (rjhs) Original submission Audiogram from an individual age 12 years with DFNA2 hearing loss. Note that the loss is greater in the high frequencies at this age; with time, hearing at all frequencies progressively deteriorates.
[ "J Akita, S Abe, H Shinkawa, WJ Kimberling, S Usami. Clinical and genetic features of nonsyndromic autosomal dominant sensorineural hearing loss: KCNQ4 is a gene responsible in Japanese.. J Hum Genet 2001;46:355-61", "PJ Coucke, P Van Hauwe, PM Kelley, H Kunst, I Schatteman, D Van Velzen, J Meyers, RJ Ensink, M Verstreken, F Declau, H Marres, K Kastury, S Bhasin, WT McGuirt, RJ Smith, CW Cremers, P Van de Heyning, PJ Willems, SD Smith, G Van Camp. Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.. Hum Mol Genet 1999;8:1321-8", "EM De Leenheer, RJ Ensink, HP Kunst, HA Marres, Z Talebizadeh, F Declau, SD Smith, S Usami, PH Van de Heyning, G Van Camp, PL Huygen, CW Cremers. DFNA2/KCNQ4 and its manifestations.. Adv Otorhinolaryngol 2002a;61:41-6", "EM De Leenheer, PL Huygen, PJ Coucke, RJ Admiraal, G van Camp, CW Cremers. Longitudinal and cross-sectional phenotype analysis in a new, large Dutch DFNA2/KCNQ4 family.. Ann Otol Rhinol Laryngol 2002b;111:267-74", "RJ Ensink, PL Huygen, P Van Hauwe, P Coucke, CW Cremers, G Van Camp. A Dutch family with progressive sensorineural hearing impairment linked to the DFNA2 region.. Eur Arch Otorhinolaryngol 2000;257:62-7", "K Ishikawa, T Naito, SY Nishio, Y Iwasa, K Nakamura, S Usami, K Ichimura. A Japanese family showing high-frequency hearing loss with KCNQ4 and TECTA mutations.. Acta Otolaryngol 2014;134:557-63", "F Kamada, S Kure, T Kudo, Y Suzuki, T Oshima, A Ichinohe, K Kojima, T Niihori, J Kanno, Y Narumi, A Narisawa, K Kato, Y Aoki, K Ikeda, T Kobayashi, Y Matsubara. A novel KCNQ4 one-base deletion in a large pedigree with hearing loss: implication for the genotype-phenotype correlation.. J Hum Genet 2006;51:455-60", "C Kubisch, BC Schroeder, T Friedrich, B Lutjohann, A El-Amraoui, S Marlin, C Petit, TJ Jentsch. KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness.. Cell 1999;96:437-46", "H Marres, M van Ewijk, P Huygen, H Kunst, G van Camp, P Coucke, P Willems, C Cremers. Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2.. Arch Otolaryngol Head Neck Surg 1997;123:573-7", "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", "CM Sloan-Heggen, AO Bierer, AE Shearer, DL Kolbe, CJ Nishimura, KL Frees, SS Ephraim, SB Shibata, KT Booth, CA Campbell, PT Ranum, AE Weaver, EA Black-Ziegelbein, D Wang, H Azaiez, RJ Smith. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss.. Hum Genet. 2016;135:441-50", "CC Su, JJ Yang, JC Shieh, MC Su, SY Li. Identification of novel mutations in the KCNQ4 gene of patients with nonsyndromic deafness from Taiwan.. Audiol Neurootol 2007;12:20-6", "Z Talebizadeh, PM Kelley, JW Askew, KW Beisel, SD Smith. Novel mutation in the KCNQ4 gene in a large kindred with dominant progressive hearing loss.. Hum Mutat 1999;14:493-501", "V Topsakal, RJ Pennings, H te Brinke, B Hamel, PL Huygen, H Kremer, CW Cremers. Phenotype determination guides swift genotyping of a DFNA2/KCNQ4 family with a hot spot mutation (W276S).. Otol Neurotol 2005;26:52-8", "G Van Camp, PJ Coucke, J Akita, E Fransen, S Abe, EM De Leenheer, PL Huygen, CW Cremers, S Usami. A mutational hot spot in the KCNQ4 gene responsible for autosomal dominant hearing impairment.. Hum Mutat 2002;20:15-9", "P Van Hauwe, PJ Coucke, RJ Ensink, P Huygen, CW Cremers, G Van Camp. Mutations in the KCNQ4 K+ channel gene, responsible for autosomal dominant hearing loss, cluster in the channel pore region.. Am J Med Genet 2000;93:184-7", "H Wang, Y Zhao, Y Yi, Y Gao, Q Liu, D Wang, Q Li, L Lan, N Li, J Guan, Z Yin, B Han, F Zhao, L Zong, W Xiong, L Yu, L Song, X Yi, L Yang, C Petit, Q Wang. Targeted high-throughput sequencing identifies pathogenic mutations in KCNQ4 in two large Chinese families with autosomal dominant hearing loss.. PLoS One 2014;9", "JH Xia, CY Liu, BS Tang, Q Pan, L Huang, HP Dai, BR Zhang, W Xie, DX Hu, D Zheng, XL Shi, DA Wang, K Xia, KP Yu, XD Liao, Y Feng, YF Yang, JY Xiao, DH Xie, JZ Huang. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment.. Nat Genet 1998;20:370-3" ]
4/4/2008
10/5/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dfna3
dfna3
[ "GJB2-Related DFNA 3 Nonsyndromic Hearing Loss and Deafness", "GJB6-Related DFNA 3 Nonsyndromic Hearing Loss and Deafness", "Gap junction beta-2 protein", "Gap junction beta-6 protein", "GJB2", "GJB6", "Nonsyndromic Hearing Loss and Deafness, DFNA3" ]
Nonsyndromic Hearing Loss and Deafness, DFNA3 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Richard JH Smith, Paul T Ranum
Summary Nonsyndromic hearing loss and deafness, DFNA3 is characterized by pre- or postlingual mild-to-profound progressive high-frequency sensorineural hearing impairment. Affected individuals have no other associated medical findings. Diagnosis of DFNA3 depends on molecular genetic testing to identify a heterozygous pathogenic variant in DFNA3 is inherited in an autosomal dominant manner. Most individuals diagnosed as having DFNA3 have a deaf parent. Each child of an individual with DFNA3 has a 50% chance of inheriting the
## Diagnosis No formal diagnostic criteria have been published for DFNA3-related hearing loss. Nonsyndromic hearing loss and deafness, DFNA3 Pre- or postlingual mild-to-profound progressive sensorineural hearing impairment [ Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 15 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (2000Hz) (see The diagnosis of DFNA3 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 in a person with hearing loss documented on audiogram can include a combination of Gene-targeted testing requires the clinician to determine which gene(s) are likely involved based on phenotypic data, while comprehensive genomic testing does not. Because of the overlapping phenotypes of the many causes of hereditary hearing loss and deafness, most individuals with hereditary hearing loss and deafness are diagnosed by one of two approaches: a multigene panel of ALL genes implicated in nonsyndromic hearing loss and nonsyndromic mimics ( Note: (1) Genes included in available panels and the diagnostic sensitivity of the test used for each gene vary by laboratory and are likely to change over time [ For an introduction to multigene panels click Molecular Genetic Testing Used in Nonsyndromic Hearing Loss and Deafness, DFNA3 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. • Pre- or postlingual mild-to-profound progressive sensorineural hearing impairment [ • Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 15 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (2000Hz) (see ## Suggestive Findings Nonsyndromic hearing loss and deafness, DFNA3 Pre- or postlingual mild-to-profound progressive sensorineural hearing impairment [ Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 15 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (2000Hz) (see • Pre- or postlingual mild-to-profound progressive sensorineural hearing impairment [ • Note: (1) Hearing is measured in decibels (dB). The threshold or 0 dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 15 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90dB), or profound (>90dB). The frequency of hearing loss is designated as low (2000Hz) (see ## Establishing the Diagnosis The diagnosis of DFNA3 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 in a person with hearing loss documented on audiogram can include a combination of Gene-targeted testing requires the clinician to determine which gene(s) are likely involved based on phenotypic data, while comprehensive genomic testing does not. Because of the overlapping phenotypes of the many causes of hereditary hearing loss and deafness, most individuals with hereditary hearing loss and deafness are diagnosed by one of two approaches: a multigene panel of ALL genes implicated in nonsyndromic hearing loss and nonsyndromic mimics ( Note: (1) Genes included in available panels and the diagnostic sensitivity of the test used for each gene vary by laboratory and are likely to change over time [ For an introduction to multigene panels click Molecular Genetic Testing Used in Nonsyndromic Hearing Loss and Deafness, DFNA3 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Recommended Testing Note: (1) Genes included in available panels and the diagnostic sensitivity of the test used for each gene vary by laboratory and are likely to change over time [ For an introduction to multigene panels click ## Testing to Consider Molecular Genetic Testing Used in Nonsyndromic Hearing Loss and Deafness, DFNA3 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 Nonsyndromic hearing loss and deafness, DFNA3 is characterized by progressive mild-to-severe high-frequency sensorineural hearing impairment ( DFNA3 audioprofiles (visual plots of hearing loss severity across a range of frequencies measured by pure tone audiometry) may vary significantly, even within a family. Note that when the hearing loss is postlingual, individuals with DFNA3 may pass the newborn hearing screen. Tests of vestibular function and computed tomography of the temporal bones in persons with DFNA3 are normal [ Individuals with DFNA3 have no other associated medical findings. The majority of pathogenic variants cause progressive prelingual hearing loss ( In contrast, deafness related to the pathogenic variants resulting in the substitutions p.Thr55Asn, p.Asp179Asn, and p.Cys202Phe is postlingual: Other: The different gene loci for nonsyndromic deafness are designated DFN (for Loci are named based on mode of inheritance: The number following the above designations reflects the order of gene mapping and/or discovery. The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare [ Prevalence for different pathogenic variants varies by population [ ## Clinical Description Nonsyndromic hearing loss and deafness, DFNA3 is characterized by progressive mild-to-severe high-frequency sensorineural hearing impairment ( DFNA3 audioprofiles (visual plots of hearing loss severity across a range of frequencies measured by pure tone audiometry) may vary significantly, even within a family. Note that when the hearing loss is postlingual, individuals with DFNA3 may pass the newborn hearing screen. Tests of vestibular function and computed tomography of the temporal bones in persons with DFNA3 are normal [ Individuals with DFNA3 have no other associated medical findings. ## Phenotype Correlations by Gene The majority of pathogenic variants cause progressive prelingual hearing loss ( In contrast, deafness related to the pathogenic variants resulting in the substitutions p.Thr55Asn, p.Asp179Asn, and p.Cys202Phe is postlingual: Other: ## Penetrance ## Nomenclature The different gene loci for nonsyndromic deafness are designated DFN (for Loci are named based on mode of inheritance: The number following the above designations reflects the order of gene mapping and/or discovery. ## Prevalence The relative prevalence of DFNA3 as a cause of autosomal dominant nonsyndromic hearing loss is not known, but it is extremely rare [ Prevalence for different pathogenic variants varies by population [ ## Genetically Related (Allelic) Disorders Allelic Disorders AD= autosomal dominant; AR=autosomal recessive; MOI = mode of Inheritance See hyperlinked The following describes other phenotypes associated with mutation of ## ## ## Differential Diagnosis Other causes of postlingual, acquired forms of hearing loss need to be considered (see Autosomal dominant syndromic forms of hearing loss with: Hearing loss occurs in approximately 57% and is congenital, sensorineural, typically non-progressive, and either unilateral or bilateral. Most commonly, hearing loss is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a white forelock (45%) or graying of the scalp hair before age 30 years. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. The diagnosis is established by clinical findings. Diagnostic criteria rely on the presence of sensorineural hearing loss, pigmentary changes, and calculation of the W index to identify dystopia canthorum. Pathogenic variants in • Hearing loss occurs in approximately 57% and is congenital, sensorineural, typically non-progressive, and either unilateral or bilateral. Most commonly, hearing loss is bilateral and profound (>100 dB). The majority of individuals with WS1 have either a white forelock (45%) or graying of the scalp hair before age 30 years. Affected individuals may have complete heterochromia iridium, partial/segmental heterochromia, or hypoplastic or brilliant blue irides. The diagnosis is established by clinical findings. Diagnostic criteria rely on the presence of sensorineural hearing loss, pigmentary changes, and calculation of the W index to identify dystopia canthorum. Pathogenic variants in ## Management To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss, DFNA3, the following evaluations are recommended: Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry (See Consultation with a clinical geneticist and/or genetic counselor Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming will diminish the likelihood of long-term speech or educational delay. The following are indicated: Fitting with appropriate hearing aids Enrollment in an appropriate educational program for the hearing impaired Consideration of cochlear implantation, an effective habilitation option for persons with preserved residual hearing [ Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [ See The following are appropriate: Semiannual examination by a physician who is familiar with hereditary hearing impairment Repeat audiometry to confirm stability of hearing loss Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important is avoidance of repeated exposure to loud noises. If a See Search • Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry (See • Consultation with a clinical geneticist and/or genetic counselor • Fitting with appropriate hearing aids • Enrollment in an appropriate educational program for the hearing impaired • Consideration of cochlear implantation, an effective habilitation option for persons with preserved residual hearing [ • Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [ • Semiannual examination by a physician who is familiar with hereditary hearing impairment • Repeat audiometry to confirm stability of hearing loss ## Evaluations Following Initial Diagnosis To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss, DFNA3, the following evaluations are recommended: Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry (See Consultation with a clinical geneticist and/or genetic counselor • Complete assessment of auditory acuity using age-appropriate tests including ABR testing, auditory steady-state response (ASSR) testing, and/or pure tone audiometry (See • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Early diagnosis, habilitation with hearing aids or cochlear implantation, and educational programming will diminish the likelihood of long-term speech or educational delay. The following are indicated: Fitting with appropriate hearing aids Enrollment in an appropriate educational program for the hearing impaired Consideration of cochlear implantation, an effective habilitation option for persons with preserved residual hearing [ Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [ See • Fitting with appropriate hearing aids • Enrollment in an appropriate educational program for the hearing impaired • Consideration of cochlear implantation, an effective habilitation option for persons with preserved residual hearing [ • Recognition that unlike with many clinical conditions, management and treatment of mild-to-profound deafness fall largely within the purview of the social welfare and educational systems rather than the medical care system [ ## Surveillance The following are appropriate: Semiannual examination by a physician who is familiar with hereditary hearing impairment Repeat audiometry to confirm stability of hearing loss • Semiannual examination by a physician who is familiar with hereditary hearing impairment • Repeat audiometry to confirm stability of hearing loss ## Agents/Circumstances to Avoid Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important is avoidance of repeated exposure to loud noises. ## Evaluation of Relatives at Risk If a See ## Therapies Under Investigation Search ## Genetic Counseling Nonsyndromic hearing loss and deafness, DFNA3 is inherited in an autosomal dominant manner. Most individuals diagnosed as having DFNA3 have a deaf parent. The proportion of individuals with DFNA3 caused by a 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 likelihood that a sib will have DFNA3 depends on the genetic status of the proband's parents: if one of the proband's parents has a When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If the See Management, The following points are noteworthy: Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter. 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." Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided. 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. 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 as having DFNA3 have a deaf parent. • The proportion of individuals with DFNA3 caused by a • 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 likelihood that a sib will have DFNA3 depends on the genetic status of the proband's parents: if one of the proband's parents has a • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. • If the • Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter. • 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." • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided. • 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. ## Mode of Inheritance Nonsyndromic hearing loss and deafness, DFNA3 is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed as having DFNA3 have a deaf parent. The proportion of individuals with DFNA3 caused by a 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 likelihood that a sib will have DFNA3 depends on the genetic status of the proband's parents: if one of the proband's parents has a When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If the • Most individuals diagnosed as having DFNA3 have a deaf parent. • The proportion of individuals with DFNA3 caused by a • 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 likelihood that a sib will have DFNA3 depends on the genetic status of the proband's parents: if one of the proband's parents has a • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. • If the ## Related Genetic Counseling Issues See Management, The following points are noteworthy: Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter. 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." Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided. 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. • Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter. • 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." • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. • The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided. • 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. ## 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 Nonsyndromic Hearing Loss and Deafness, DFNA3: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nonsyndromic Hearing Loss and Deafness, DFNA3 ( Of note, although the pathogenicity of the Selected Variants listed in the table have been provided by the authors. Variant found in normal hearing persons and family with palmoplantar keratoderma Each connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains (N-terminus, C-terminus, and a cytoplasmic loop located between M2 and M3) [ Selected Variants listed in the table have been provided by the authors. See also Additionally, the p.Ala40Val variant exerts a trans-dominant-negative effect on Cx26, impairing gap junction formation in the cochlea. In functional studies with a mouse model, the p.Thr5Met variant was shown to exert its pathogenic effect through diminished biochemical coupling between cochlear cells [ ## Of note, although the pathogenicity of the Selected Variants listed in the table have been provided by the authors. Variant found in normal hearing persons and family with palmoplantar keratoderma Each connexin protein contains two extracellular (E1-E2), four transmembrane (M1-M4), and three cytoplasmic domains (N-terminus, C-terminus, and a cytoplasmic loop located between M2 and M3) [ ## Selected Variants listed in the table have been provided by the authors. See also Additionally, the p.Ala40Val variant exerts a trans-dominant-negative effect on Cx26, impairing gap junction formation in the cochlea. In functional studies with a mouse model, the p.Thr5Met variant was shown to exert its pathogenic effect through diminished biochemical coupling between cochlear cells [ ## Chapter Notes This work was originally supported in part by research grants 1RO1 DC02842 and DC003544 (RJHS), HG00457 and P50HG00835 (VCS), and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC). Paul T Ranum, BA (2014-present) Daryl A Scott, MD, PhD; University of Iowa (1998-2001) Abraham M Sheffield, MD; University of Iowa (2009-2014) Val C Sheffield, MD, PhD; University of Iowa (1998-2001) Richard JH Smith, MD (1998-present) Guy Van Camp, PhD; University of Antwerp (1998-2016) 7 September 2023 (ma) Chapter retired: outdated 22 December 2016 (bp) Comprehensive update posted live 12 June 2014 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 30 April 2009 (me) Comprehensive update posted live 29 December 2005 (me) Comprehensive update posted live 27 October 2003 (me) Comprehensive update posted live 24 April 2001 (me) Comprehensive update posted live 28 September 1998 (pb) Review posted live 4 April 1998 (rjs) Original submission • 7 September 2023 (ma) Chapter retired: outdated • 22 December 2016 (bp) Comprehensive update posted live • 12 June 2014 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 30 April 2009 (me) Comprehensive update posted live • 29 December 2005 (me) Comprehensive update posted live • 27 October 2003 (me) Comprehensive update posted live • 24 April 2001 (me) Comprehensive update posted live • 28 September 1998 (pb) Review posted live • 4 April 1998 (rjs) Original submission ## Acknowledgments This work was originally supported in part by research grants 1RO1 DC02842 and DC003544 (RJHS), HG00457 and P50HG00835 (VCS), and Belgian National Fonds voor Wetenschappelijk Onderzoek (GVC). ## Author History Paul T Ranum, BA (2014-present) Daryl A Scott, MD, PhD; University of Iowa (1998-2001) Abraham M Sheffield, MD; University of Iowa (2009-2014) Val C Sheffield, MD, PhD; University of Iowa (1998-2001) Richard JH Smith, MD (1998-present) Guy Van Camp, PhD; University of Antwerp (1998-2016) ## Revision History 7 September 2023 (ma) Chapter retired: outdated 22 December 2016 (bp) Comprehensive update posted live 12 June 2014 (me) Comprehensive update posted live 19 April 2012 (me) Comprehensive update posted live 30 April 2009 (me) Comprehensive update posted live 29 December 2005 (me) Comprehensive update posted live 27 October 2003 (me) Comprehensive update posted live 24 April 2001 (me) Comprehensive update posted live 28 September 1998 (pb) Review posted live 4 April 1998 (rjs) Original submission • 7 September 2023 (ma) Chapter retired: outdated • 22 December 2016 (bp) Comprehensive update posted live • 12 June 2014 (me) Comprehensive update posted live • 19 April 2012 (me) Comprehensive update posted live • 30 April 2009 (me) Comprehensive update posted live • 29 December 2005 (me) Comprehensive update posted live • 27 October 2003 (me) Comprehensive update posted live • 24 April 2001 (me) Comprehensive update posted live • 28 September 1998 (pb) Review posted live • 4 April 1998 (rjs) 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 Genetic diagnostic rates in 1119 sequentially accrued persons with hearing loss. No person was excluded based on phenotype, inheritance, or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 individuals (39%). Pathogenic variants were found in 49 genes and included missense variants, large copy number changes, small insertions and deletions, nonsense variants, splice site alterations, and promoter variants. Note that the diagnostic rate for This audioprofile surface shows the anticipated progression of DFNA3 hearing loss with age. Note that the hearing loss is typically congenital and slowly becomes more severe with age [
[]
28/9/1998
22/12/2016
15/7/2004
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dfnb1
dfnb1
[ "DFNB1", "Gap junction beta-2 protein", "GJB2", "GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss" ]
Richard JH Smith, Hela Azaiez, Kevin Booth
Summary The diagnosis of Because children with severe-to-profound hearing loss who are candidates for cochlear implantation can attain levels of social functioning and education indistinguishable from those of normal-hearing peers, cochlear implantation should be performed as soon as possible. Children with mild-to-moderate hearing loss can be treated with hearing aids customized to the child's age and severity of hearing loss. All children with mild-to-moderate
## Diagnosis The diagnosis of Universal NBHS using physiologic screening (either otoacoustic emissions [OAE], which measure the response of cochlear outer hair cells to auditory stimuli, or automated auditory brain stem response [ABR], which measures the physiologic response of cochlear inner hair cells, auditory nerve, brain stem, and brain to auditory stimuli) is required by law or rule in all 50 states in the United States and is performed on >98% of children in the US typically within days after birth (see The following evaluations need to begin immediately on receipt of an abnormal NBHS result: The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see Hearing is measured in Severity of Hearing Loss in Decibels (dB) From The diagnosis of Biallelic OR Compound heterozygosity for one A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of Mosaic uniparental disomy 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 An additional individual with a contiguous gene deletion that includes 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 [ If a single Types 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. • The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see • Biallelic • Compound heterozygosity for one • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of • Mosaic uniparental disomy of • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of • Mosaic uniparental disomy of • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of • Mosaic uniparental disomy of ## Suggestive Findings The diagnosis of Universal NBHS using physiologic screening (either otoacoustic emissions [OAE], which measure the response of cochlear outer hair cells to auditory stimuli, or automated auditory brain stem response [ABR], which measures the physiologic response of cochlear inner hair cells, auditory nerve, brain stem, and brain to auditory stimuli) is required by law or rule in all 50 states in the United States and is performed on >98% of children in the US typically within days after birth (see The following evaluations need to begin immediately on receipt of an abnormal NBHS result: The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see Hearing is measured in Severity of Hearing Loss in Decibels (dB) From • The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see ## Scenario 1: Abnormal Newborn Hearing Screening (NBHS) Result Universal NBHS using physiologic screening (either otoacoustic emissions [OAE], which measure the response of cochlear outer hair cells to auditory stimuli, or automated auditory brain stem response [ABR], which measures the physiologic response of cochlear inner hair cells, auditory nerve, brain stem, and brain to auditory stimuli) is required by law or rule in all 50 states in the United States and is performed on >98% of children in the US typically within days after birth (see The following evaluations need to begin immediately on receipt of an abnormal NBHS result: The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see • The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see ## Scenario 2: Symptomatic Individual Hearing is measured in Severity of Hearing Loss in Decibels (dB) From ## Establishing the Diagnosis The diagnosis of Biallelic OR Compound heterozygosity for one A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of Mosaic uniparental disomy 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 An additional individual with a contiguous gene deletion that includes 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 [ If a single Types 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. • Biallelic • Compound heterozygosity for one • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of • Mosaic uniparental disomy of • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of • Mosaic uniparental disomy of • A deletion that is either (1) an intragenic deletion or (2) a whole-gene deletion (see • A noncoding pathogenic (or likely pathogenic) variant upstream or downstream of • Mosaic uniparental disomy 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 See See An additional individual with a contiguous gene deletion that includes 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 [ If a single Types 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 In two examples, a newborn passed his NBHS auditory brain stem response (ABR)-based test, but was diagnosed as deaf at age 15 months when an ABR test obtained at the request of his parents showed no responses through 90 dB. Another child had a normal free-field audiogram performed by an experienced audiologist at age five months, but at age nine months had ABR-confirmed severe hearing loss [ Severe-to-profound Mild-to-moderate Except for the hearing impairment, individuals with In the T/T class, hearing loss is most typically severe to profound (84%-92% of persons), although moderate (10%-12%) and mild (0%-3%) hearing losses are reported. In the T/NT class, 34%-47% of persons have severe-to-profound hearing loss. In the NT/NT class, only one person in five has severe-to-profound hearing loss, with more than half of persons having mild hearing loss. When a large Homozygosity for a large The prevalence of • In the T/T class, hearing loss is most typically severe to profound (84%-92% of persons), although moderate (10%-12%) and mild (0%-3%) hearing losses are reported. • In the T/NT class, 34%-47% of persons have severe-to-profound hearing loss. • In the NT/NT class, only one person in five has severe-to-profound hearing loss, with more than half of persons having mild hearing loss. • When a large • Homozygosity for a large ## Clinical Description In two examples, a newborn passed his NBHS auditory brain stem response (ABR)-based test, but was diagnosed as deaf at age 15 months when an ABR test obtained at the request of his parents showed no responses through 90 dB. Another child had a normal free-field audiogram performed by an experienced audiologist at age five months, but at age nine months had ABR-confirmed severe hearing loss [ Severe-to-profound Mild-to-moderate Except for the hearing impairment, individuals with ## Genotype-Phenotype Correlations In the T/T class, hearing loss is most typically severe to profound (84%-92% of persons), although moderate (10%-12%) and mild (0%-3%) hearing losses are reported. In the T/NT class, 34%-47% of persons have severe-to-profound hearing loss. In the NT/NT class, only one person in five has severe-to-profound hearing loss, with more than half of persons having mild hearing loss. When a large Homozygosity for a large • In the T/T class, hearing loss is most typically severe to profound (84%-92% of persons), although moderate (10%-12%) and mild (0%-3%) hearing losses are reported. • In the T/NT class, 34%-47% of persons have severe-to-profound hearing loss. • In the NT/NT class, only one person in five has severe-to-profound hearing loss, with more than half of persons having mild hearing loss. • When a large • Homozygosity for a large ## Class of In the T/T class, hearing loss is most typically severe to profound (84%-92% of persons), although moderate (10%-12%) and mild (0%-3%) hearing losses are reported. In the T/NT class, 34%-47% of persons have severe-to-profound hearing loss. In the NT/NT class, only one person in five has severe-to-profound hearing loss, with more than half of persons having mild hearing loss. When a large Homozygosity for a large • In the T/T class, hearing loss is most typically severe to profound (84%-92% of persons), although moderate (10%-12%) and mild (0%-3%) hearing losses are reported. • In the T/NT class, 34%-47% of persons have severe-to-profound hearing loss. • In the NT/NT class, only one person in five has severe-to-profound hearing loss, with more than half of persons having mild hearing loss. • When a large • Homozygosity for a large ## Specific ## Nomenclature ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders Fewer than 30 In most of these case reports, the severity of the hearing loss is variable and is associated with a spectrum of skin manifestations such as keratitis-ichthyosis-deafness syndrome (OMIM Two variants at amino acid residue 75 – p.Arg75Gln and p.Arg75Trp – have been reported to cause autosomal dominant hearing loss. Both of these missense changes affect the same amino acid and are associated with hearing loss that is fully penetrant and a skin phenotype (palmoplantar keratoderma) that is not fully penetrant [ ## Differential Diagnosis As of this writing, more than 70 genes have been associated with autosomal recessive nonsyndromic hearing loss. For a list of selected genes associated with distinctive clinical features, see Genetic Hearing Loss Overview, For a current, comprehensive list of all identified autosomal recessive nonsyndromic hearing loss genes, see ## Management No clinical practice guidelines specific to Management ideally occurs in the context of a multidisciplinary clinic with specialists in otolaryngology, audiology, and genetic counseling. See Genetic Hearing Loss Overview, To establish the extent of involvement and needs in an individual diagnosed with Comprehensive medical history focused on gestational and perinatal events, newborn hearing screen (NBHS) results, and cytomegalic virus (CMV) test results (if performed) Assessment of hearing using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure-tone audiometry to determine severity of hearing loss (see Physical examination including an evaluation for syndromic features (which should be absent) and a thorough examination of the head and neck, including an otomicroscopic evaluation of the ear to evaluate for otitis media Ophthalmologic examination to identify refractive errors (unrelated to 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 Assessment of need for family support and resources including community or online Management of children with Uncorrected hearing loss (regardless of etiology) has consistent sequelae. Auditory deprivation during the first two years of life is associated with poor reading performance, poor communication skills, and poor speech production, deficiencies that cannot be completely remediated even with educational intervention. Early auditory intervention is effective – whether through cochlear implantation or amplification [ To optimize intervention for children with hearing loss, the To monitor the individual's response to habituation and to identify any changes in severity of hearing loss, the following evaluations are recommended. At follow-up appointments, the following may be performed: speech recognition testing, equipment checks (including device adjustment and troubleshooting), and provision of replacement or upgraded equipment [ As the cochlear implant recipient becomes comfortable with the cochlear implant, many of the above tasks can be performed by the family at home, obviating the need for routinely scheduled appointments unless the need for a clinic visit arises. An annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist is recommended to examine the ears, obtain an audiogram, and check hearing aid function. This annual follow up is essential, as progression of hearing loss can occur. For most Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important for persons with 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 NBHS; A newborn sib has a 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 Search • Comprehensive medical history focused on gestational and perinatal events, newborn hearing screen (NBHS) results, and cytomegalic virus (CMV) test results (if performed) • Assessment of hearing using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure-tone audiometry to determine severity of hearing loss (see • Physical examination including an evaluation for syndromic features (which should be absent) and a thorough examination of the head and neck, including an otomicroscopic evaluation of the ear to evaluate for otitis media • Ophthalmologic examination to identify refractive errors (unrelated to • 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 • Assessment of need for family support and resources including community or online • An annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist is recommended to examine the ears, obtain an audiogram, and check hearing aid function. • This annual follow up is essential, as progression of hearing loss can occur. For most • 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 NBHS; • A newborn sib has a • A sib did not undergo NBHS and/or NBHS results are unknown. ## Evaluations Following Initial Diagnosis To establish the extent of involvement and needs in an individual diagnosed with Comprehensive medical history focused on gestational and perinatal events, newborn hearing screen (NBHS) results, and cytomegalic virus (CMV) test results (if performed) Assessment of hearing using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure-tone audiometry to determine severity of hearing loss (see Physical examination including an evaluation for syndromic features (which should be absent) and a thorough examination of the head and neck, including an otomicroscopic evaluation of the ear to evaluate for otitis media Ophthalmologic examination to identify refractive errors (unrelated to 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 Assessment of need for family support and resources including community or online • Comprehensive medical history focused on gestational and perinatal events, newborn hearing screen (NBHS) results, and cytomegalic virus (CMV) test results (if performed) • Assessment of hearing using age-appropriate tests such as auditory brain stem response (ABR) testing, auditory steady-state response (ASSR) testing, and pure-tone audiometry to determine severity of hearing loss (see • Physical examination including an evaluation for syndromic features (which should be absent) and a thorough examination of the head and neck, including an otomicroscopic evaluation of the ear to evaluate for otitis media • Ophthalmologic examination to identify refractive errors (unrelated to • 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 • Assessment of need for family support and resources including community or online ## Treatment of Manifestations Management of children with Uncorrected hearing loss (regardless of etiology) has consistent sequelae. Auditory deprivation during the first two years of life is associated with poor reading performance, poor communication skills, and poor speech production, deficiencies that cannot be completely remediated even with educational intervention. Early auditory intervention is effective – whether through cochlear implantation or amplification [ To optimize intervention for children with hearing loss, the ## Surveillance To monitor the individual's response to habituation and to identify any changes in severity of hearing loss, the following evaluations are recommended. At follow-up appointments, the following may be performed: speech recognition testing, equipment checks (including device adjustment and troubleshooting), and provision of replacement or upgraded equipment [ As the cochlear implant recipient becomes comfortable with the cochlear implant, many of the above tasks can be performed by the family at home, obviating the need for routinely scheduled appointments unless the need for a clinic visit arises. An annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist is recommended to examine the ears, obtain an audiogram, and check hearing aid function. This annual follow up is essential, as progression of hearing loss can occur. For most • An annual evaluation by an otolaryngologist, audiologist, and hearing aid specialist is recommended to examine the ears, obtain an audiogram, and check hearing aid function. • This annual follow up is essential, as progression of hearing loss can occur. For most ## Agents/Circumstances to Avoid Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important for persons with 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 NBHS; A newborn sib has a 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 NBHS; • A newborn sib has a • A sib did not undergo NBHS and/or NBHS results are unknown. ## Therapies Under Investigation Search ## Genetic Counseling By definition, Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) is reported in some families [ The parents of a child with In populations with a high carrier rate (e.g., the East Asian population, in which the carrier frequency for p.Val37Ile is 8.3% [see Molecular genetic testing of the parents is recommended 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 deletion of a portion of Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) of a If both parents are known to be heterozygous for a Strong The majority of sibs (67%) who inherit biallelic Heterozygotes (carriers) of a Unless an affected individual's reproductive partner also has In populations with a high carrier rate (see Carrier testing for relatives of an individual with See Clear communication between individuals with hearing loss, families, and health care providers is key. Deaf and hard-of-hearing persons may use a variety of communication methods, including spoken language, sign language, lip reading, and written notes. For deaf 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. Deaf and hard-of-hearing persons may be interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services. Others may seek information about the chance of deaf/hard-of-hearing children 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 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 hearing loss in offspring and reproductive options) to young adults with hearing loss. Because 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 • In populations with a high carrier rate (e.g., the East Asian population, in which the carrier frequency for p.Val37Ile is 8.3% [see • Molecular genetic testing of the parents is recommended 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 deletion of a portion of • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A deletion of a portion of • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) of a • A deletion of a portion of • 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 • Strong • The majority of sibs (67%) who inherit biallelic • Heterozygotes (carriers) of a • Unless an affected individual's reproductive partner also has • In populations with a high carrier rate (see • Clear communication between individuals with hearing loss, families, and health care providers is key. Deaf and hard-of-hearing persons may use a variety of communication methods, including spoken language, sign language, lip reading, and written notes. For deaf 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. Deaf and hard-of-hearing persons may be interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services. Others may seek information about the chance of deaf/hard-of-hearing children 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 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 hearing loss in offspring and reproductive options) to young adults with hearing loss. • Because ## Mode of Inheritance By definition, Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) is reported in some families [ ## Risk to Family Members The parents of a child with In populations with a high carrier rate (e.g., the East Asian population, in which the carrier frequency for p.Val37Ile is 8.3% [see Molecular genetic testing of the parents is recommended 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 deletion of a portion of Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) of a If both parents are known to be heterozygous for a Strong The majority of sibs (67%) who inherit biallelic Heterozygotes (carriers) of a Unless an affected individual's reproductive partner also has In populations with a high carrier rate (see • The parents of a child with • In populations with a high carrier rate (e.g., the East Asian population, in which the carrier frequency for p.Val37Ile is 8.3% [see • Molecular genetic testing of the parents is recommended 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 deletion of a portion of • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A deletion of a portion of • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) of a • A deletion of a portion of • 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 • Strong • The majority of sibs (67%) who inherit biallelic • Heterozygotes (carriers) of a • Unless an affected individual's reproductive partner also has • In populations with a high carrier rate (see ## Carrier Detection Carrier testing for relatives of an individual with ## Related Genetic Counseling Issues See Clear communication between individuals with hearing loss, families, and health care providers is key. Deaf and hard-of-hearing persons may use a variety of communication methods, including spoken language, sign language, lip reading, and written notes. For deaf 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. Deaf and hard-of-hearing persons may be interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services. Others may seek information about the chance of deaf/hard-of-hearing children 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 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 hearing loss in offspring and reproductive options) to young adults with hearing loss. Because • Clear communication between individuals with hearing loss, families, and health care providers is key. Deaf and hard-of-hearing persons may use a variety of communication methods, including spoken language, sign language, lip reading, and written notes. For deaf 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. Deaf and hard-of-hearing persons may be interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services. Others may seek information about the chance of deaf/hard-of-hearing children 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 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 hearing loss in offspring and reproductive options) to young adults with hearing loss. • Because ## 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 GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for GJB2-Related Autosomal Recessive Nonsyndromic Hearing Loss ( Connexons from adjoining cells covalently bond, forming a channel between cells. Gap junctions permit direct intercellular exchange of ions and molecules through their central aqueous pores and permit synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in nonexcitable tissues. Large deletions have been described, such as sequences upstream of UPD = uniparental disomy Variants listed in the table have been provided by the authors. • Large deletions have been described, such as sequences upstream of ## Molecular Pathogenesis Connexons from adjoining cells covalently bond, forming a channel between cells. Gap junctions permit direct intercellular exchange of ions and molecules through their central aqueous pores and permit synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in nonexcitable tissues. Large deletions have been described, such as sequences upstream of UPD = uniparental disomy Variants listed in the table have been provided by the authors. • Large deletions have been described, such as sequences upstream of ## Chapter Notes Supported in part by grant RO1-DC02842 from the NIDCD (RJHS). Hela Azaiez, MS, PhD (2023-present)Kevin Booth, PhD (2023-present)Mary-Kayt N Jones, BA; University of Iowa (2016-2023)Daryl A Scott, MD, PhD; University of Iowa (1998-2001)Val C Sheffield, MD, PhD; University of Iowa (1998-2001)Richard JH Smith, MD (1998-present)Guy Van Camp, PhD; University of Antwerp (1998-2016) 20 July 2023 (bp) Comprehensive update posted live 18 August 2016 (bp) Comprehensive update posted live 2 January 2014 (me) Comprehensive update posted live 14 July 2011 (me) Comprehensive update posted live 11 July 2008 (me) Comprehensive update posted live 21 December 2005 (me) Comprehensive update posted live 27 October 2003 (me) Comprehensive update posted live 24 April 2001 (me) Comprehensive update posted live 4 April 1998 (rjs) Original submission • 20 July 2023 (bp) Comprehensive update posted live • 18 August 2016 (bp) Comprehensive update posted live • 2 January 2014 (me) Comprehensive update posted live • 14 July 2011 (me) Comprehensive update posted live • 11 July 2008 (me) Comprehensive update posted live • 21 December 2005 (me) Comprehensive update posted live • 27 October 2003 (me) Comprehensive update posted live • 24 April 2001 (me) Comprehensive update posted live • 4 April 1998 (rjs) Original submission ## Author Notes ## Acknowledgments Supported in part by grant RO1-DC02842 from the NIDCD (RJHS). ## Author History Hela Azaiez, MS, PhD (2023-present)Kevin Booth, PhD (2023-present)Mary-Kayt N Jones, BA; University of Iowa (2016-2023)Daryl A Scott, MD, PhD; University of Iowa (1998-2001)Val C Sheffield, MD, PhD; University of Iowa (1998-2001)Richard JH Smith, MD (1998-present)Guy Van Camp, PhD; University of Antwerp (1998-2016) ## Revision History 20 July 2023 (bp) Comprehensive update posted live 18 August 2016 (bp) Comprehensive update posted live 2 January 2014 (me) Comprehensive update posted live 14 July 2011 (me) Comprehensive update posted live 11 July 2008 (me) Comprehensive update posted live 21 December 2005 (me) Comprehensive update posted live 27 October 2003 (me) Comprehensive update posted live 24 April 2001 (me) Comprehensive update posted live 4 April 1998 (rjs) Original submission • 20 July 2023 (bp) Comprehensive update posted live • 18 August 2016 (bp) Comprehensive update posted live • 2 January 2014 (me) Comprehensive update posted live • 14 July 2011 (me) Comprehensive update posted live • 11 July 2008 (me) Comprehensive update posted live • 21 December 2005 (me) Comprehensive update posted live • 27 October 2003 (me) Comprehensive update posted live • 24 April 2001 (me) Comprehensive update posted live • 4 April 1998 (rjs) Original submission ## References The Joint Committee on Infant Hearing. Year 2019 position statement: principles and guidelines for early hearing detection and intervention programs. Available • The Joint Committee on Infant Hearing. Year 2019 position statement: principles and guidelines for early hearing detection and intervention programs. Available ## Published Guidelines / Consensus Statements The Joint Committee on Infant Hearing. Year 2019 position statement: principles and guidelines for early hearing detection and intervention programs. Available • The Joint Committee on Infant Hearing. Year 2019 position statement: principles and guidelines for early hearing detection and intervention programs. Available ## Literature Cited The bar is the carrier frequency for a pathogenic variant in Schematic of large (>10 kilobase) pathogenic deletions associated with Modified from
[]
28/9/1998
20/7/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dfnb9
dfnb9
[ "DFNB9", "Otoferlin-Related Hearing Loss", "DFNB9", "Otoferlin-Related Hearing Loss", "Typical OTOF-Related Hearing Loss", "Atypical (Temperature Sensitive or Progressive) OTOF-Related Hearing Loss", "Otoferlin", "OTOF", "OTOF-Related Hearing Loss" ]
Hela Azaiez, Ryan K Thorpe, Amanda M Odell, Richard JH Smith
Summary The two phenotypes comprising The diagnosis of
For synonyms and outdated names see ## Diagnosis No consensus clinical diagnostic criteria for Universal NBHS using physiologic screening is required by law or rule in all 50 states in the US and is performed on >98% of children in the US typically within days after birth (see Temperature-sensitive Mild-to-moderate progressive Confirmatory audiometric testing, typically diagnostic ABR testing. Hearing is measured in decibels (dB). The threshold, or 0-dB mark, for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing loss in newborns with Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss. The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click To date, if annotating on the transcript 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. There have been six reports of copy number variants (deletion, duplication) involving • Temperature-sensitive • Mild-to-moderate progressive • Confirmatory audiometric testing, typically diagnostic ABR testing. Hearing is measured in decibels (dB). The threshold, or 0-dB mark, for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. • Hearing loss in newborns with • Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss. • The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see ## Suggestive Findings Universal NBHS using physiologic screening is required by law or rule in all 50 states in the US and is performed on >98% of children in the US typically within days after birth (see Temperature-sensitive Mild-to-moderate progressive Confirmatory audiometric testing, typically diagnostic ABR testing. Hearing is measured in decibels (dB). The threshold, or 0-dB mark, for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing loss in newborns with Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss. The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see • Temperature-sensitive • Mild-to-moderate progressive • Confirmatory audiometric testing, typically diagnostic ABR testing. Hearing is measured in decibels (dB). The threshold, or 0-dB mark, for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. • Hearing loss in newborns with • Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss. • The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see ## Scenario 1: Abnormal Newborn Hearing Screening (NBHS) Result Universal NBHS using physiologic screening is required by law or rule in all 50 states in the US and is performed on >98% of children in the US typically within days after birth (see Temperature-sensitive Mild-to-moderate progressive Confirmatory audiometric testing, typically diagnostic ABR testing. Hearing is measured in decibels (dB). The threshold, or 0-dB mark, for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing loss in newborns with Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss. The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see • Temperature-sensitive • Mild-to-moderate progressive • Confirmatory audiometric testing, typically diagnostic ABR testing. Hearing is measured in decibels (dB). The threshold, or 0-dB mark, for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. • Hearing loss in newborns with • Medical evaluation by an otolaryngologist, often the first point of contact for children with newly diagnosed hearing loss, who will perform examinations including: (1) otomicroscopic evaluation for other causes of hearing loss such as conductive hearing loss resulting from otitis media (fluid in the middle ear) and outer and middle ear abnormalities; and (2) evaluation for features of a syndrome that may be associated with hearing loss. • The otolaryngologist will consider family history, gestational history, physical examination, audiometric testing, and molecular genetic testing to determine the underlying diagnosis (see ## Scenario 2: Symptomatic Individual ## 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 To date, if annotating on the transcript 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. There have been six reports of copy number variants (deletion, duplication) involving ## Option 1 For an introduction to multigene panels click ## Option 2 To date, if annotating on the transcript 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. There have been six reports of copy number variants (deletion, duplication) involving ## Clinical Characteristics The two phenotypes comprising Biallelic premature stop and frameshift (truncating) Biallelic nontruncating The presence of one truncating and one nontruncating All individuals with atypical temperature-sensitive Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ Auditory neuropathy can result from a variety of environmental, developmental, and genetic factors. The complex factors involved in the etiology and pathophysiology of auditory neuropathy led to a consensus to use the term auditory neuropathy spectrum disorder (ANSD) (see ANSD can be caused by several different defects in the auditory system including the synaptic region (synaptopathy) and the auditory nerve (neuropathy). Because Temperature-sensitive Auditory dys-synchrony is a historical term used to describe the mismatch between outer hair cell and inner hair cell activity reflected by the difference between ABR and OAE testing. The prevalence of 1%-2% in a Japanese cohort [ 2%-3% in both a Pakistani population [ ~3% of Taiwanese persons with hearing loss. A founder variant, 3%-8% in Spanish populations with autosomal recessive nonsyndromic hearing loss [ 56.5% of The prevalence of temperature-sensitive auditory neuropathy is unknown. • Biallelic premature stop and frameshift (truncating) • Biallelic nontruncating • The presence of one truncating and one nontruncating • Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ • Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ • Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ • Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ • Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ • Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ • Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ • Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ • Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ • 1%-2% in a Japanese cohort [ • 2%-3% in both a Pakistani population [ • ~3% of Taiwanese persons with hearing loss. A founder variant, • 3%-8% in Spanish populations with autosomal recessive nonsyndromic hearing loss [ • 56.5% of ## Clinical Description The two phenotypes comprising ## Genotype-Phenotype Correlations Biallelic premature stop and frameshift (truncating) Biallelic nontruncating The presence of one truncating and one nontruncating All individuals with atypical temperature-sensitive Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ • Biallelic premature stop and frameshift (truncating) • Biallelic nontruncating • The presence of one truncating and one nontruncating • Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ • Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ • Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ • Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ • Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ • Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ • Homozygosity for pathogenic variant p.Ile1573Thr was reported in four children whose hearing impairment was mild (one child at age 9 years), moderate (two children at ages 11 and 13 years), and severe (one child at age 17 years). All children had OAEs. Only the nine-year-old child undergoing ABR testing had absent waves [ • Homozygosity for pathogenic variant p.Glu1700Gln was reported in three Taiwanese families whose hearing impairment was initially mild but became moderate to severe within a few years. In two other families, affected individuals had severe or profound hearing loss at the first hearing assessment at ages one and two years [ • Compound heterozygosity for pathogenic variants p.Ter1998ArgextTer30 and p.Arg1939Gln was reported to result in moderate, predominantly high-frequency hearing loss with progression in one ear [ ## Nomenclature Auditory neuropathy can result from a variety of environmental, developmental, and genetic factors. The complex factors involved in the etiology and pathophysiology of auditory neuropathy led to a consensus to use the term auditory neuropathy spectrum disorder (ANSD) (see ANSD can be caused by several different defects in the auditory system including the synaptic region (synaptopathy) and the auditory nerve (neuropathy). Because Temperature-sensitive Auditory dys-synchrony is a historical term used to describe the mismatch between outer hair cell and inner hair cell activity reflected by the difference between ABR and OAE testing. ## Prevalence The prevalence of 1%-2% in a Japanese cohort [ 2%-3% in both a Pakistani population [ ~3% of Taiwanese persons with hearing loss. A founder variant, 3%-8% in Spanish populations with autosomal recessive nonsyndromic hearing loss [ 56.5% of The prevalence of temperature-sensitive auditory neuropathy is unknown. • 1%-2% in a Japanese cohort [ • 2%-3% in both a Pakistani population [ • ~3% of Taiwanese persons with hearing loss. A founder variant, • 3%-8% in Spanish populations with autosomal recessive nonsyndromic hearing loss [ • 56.5% of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Due to the heterogeneity of auditory neuropathy spectrum disorder (ANSD), it is difficult to estimate the prevalence of environmental versus genetic causes. Environmental causes include cytotoxic agents (e.g., cisplatin), prematurity, hyperbilirubinemia, septicemia, loop diuretics, and aminoglycoside use [ As of this writing, more than 85 genes have been associated with autosomal recessive nonsyndromic hearing loss and seven genes have been associated with nonsyndromic ANSD (see Up to 8% of congenital nonsyndromic hearing loss is associated with pathogenic variants in For a list of selected genes associated with distinctive clinical features, see Genetic Hearing Loss Overview, Loss of otoacoustic emissions (OAEs) over time is found in other forms of genetic auditory neuropathy, such as with Other Nonsyndromic Genetic Auditory Neuropathy Spectrum Disorders Note: Unilateral ## Management No clinical practice guidelines specific for Management ideally occurs in the context of a multidisciplinary clinic with specialists in otolaryngology, audiology, and genetic counseling. See Genetic Hearing Loss Overview, To establish the extent of disease and needs in an individual diagnosed with Assess auditory acuity: Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for Consult with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of Assess the need for family support and resources including community or online See also There is no cure for Hearing aids may be trialed in persons with mild-to-severe hearing loss; however, these are unlikely to be beneficial due to the etiology of auditory synaptopathy. A systematic review of 32 individuals with Cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. A systematic review of 100 individuals with Prevent febrile episodes. Avoid the level of exercise and/or ambient conditions that would cause body temperature to rise. Treat febrile episodes as quickly as possible to return body temperature to normal. Inform individuals with To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time. For example, initial follow up may include audiometry and speech discrimination testing every six months; however, if a child receives a cochlear implant, the scheduled follow up will change. Post implantation, there will be frequent evaluations as recommended by the cochlear implant team (otolaryngologist, audiologist, and speech-language pathologist). At subsequent follow-up appointments, assessments may include speech recognition testing, equipment checks, and provision of replacement or upgraded equipment [ Persons with temperature-sensitive It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband shortly after birth by molecular genetic testing for the See Gene therapy for The first AAV- A single-arm trial with AAV1-hOTOF therapy (AAV serotype 1 carrying human A bilateral AAV1-hOTOF gene therapy trial in five children between ages one and six years with Five ongoing clinical trials are recruiting individuals with Search • Assess auditory acuity: • Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ • Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ • Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for • Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ • Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ • Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for • Consult with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of • Assess the need for family support and resources including community or online • Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ • Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ • Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for • Hearing aids may be trialed in persons with mild-to-severe hearing loss; however, these are unlikely to be beneficial due to the etiology of auditory synaptopathy. A systematic review of 32 individuals with • Cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. A systematic review of 100 individuals with • Prevent febrile episodes. • Avoid the level of exercise and/or ambient conditions that would cause body temperature to rise. • Treat febrile episodes as quickly as possible to return body temperature to normal. • Inform individuals with • The first AAV- • A single-arm trial with AAV1-hOTOF therapy (AAV serotype 1 carrying human • A bilateral AAV1-hOTOF gene therapy trial in five children between ages one and six years with ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Assess auditory acuity: Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for Consult with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of Assess the need for family support and resources including community or online See also • Assess auditory acuity: • Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ • Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ • Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for • Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ • Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ • Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for • Consult with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) to inform affected individuals and their families about the nature, mode of inheritance, and implications of • Assess the need for family support and resources including community or online • Auditory brain stem response (ABR) testing is considered the gold standard for assessing the degree of hearing loss following abnormal newborn hearing screening (NBHS) [ • Pure-tone audiometry is a behavioral test used to assess hearing at selected frequencies, recorded on a graph to create an audiogram [ • Speech discrimination testing in quiet and in background noise (e.g., speech recognition in noise testing) is recommended for ## Treatment of Manifestations There is no cure for Hearing aids may be trialed in persons with mild-to-severe hearing loss; however, these are unlikely to be beneficial due to the etiology of auditory synaptopathy. A systematic review of 32 individuals with Cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. A systematic review of 100 individuals with Prevent febrile episodes. Avoid the level of exercise and/or ambient conditions that would cause body temperature to rise. Treat febrile episodes as quickly as possible to return body temperature to normal. Inform individuals with • Hearing aids may be trialed in persons with mild-to-severe hearing loss; however, these are unlikely to be beneficial due to the etiology of auditory synaptopathy. A systematic review of 32 individuals with • Cochlear implants may provide clinical benefit because they bypass the dysfunctional synapse and stimulate the auditory nerve directly. A systematic review of 100 individuals with • Prevent febrile episodes. • Avoid the level of exercise and/or ambient conditions that would cause body temperature to rise. • Treat febrile episodes as quickly as possible to return body temperature to normal. • Inform individuals with ## Surveillance To monitor the individual's response to supportive care and the emergence of new manifestations, the primary focus should be routine audiometric follow up. The frequency of follow up should be individualized and is likely to vary over time. For example, initial follow up may include audiometry and speech discrimination testing every six months; however, if a child receives a cochlear implant, the scheduled follow up will change. Post implantation, there will be frequent evaluations as recommended by the cochlear implant team (otolaryngologist, audiologist, and speech-language pathologist). At subsequent follow-up appointments, assessments may include speech recognition testing, equipment checks, and provision of replacement or upgraded equipment [ ## Agents/Circumstances to Avoid Persons with temperature-sensitive ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband shortly after birth by molecular genetic testing for the See ## Therapies Under Investigation Gene therapy for The first AAV- A single-arm trial with AAV1-hOTOF therapy (AAV serotype 1 carrying human A bilateral AAV1-hOTOF gene therapy trial in five children between ages one and six years with Five ongoing clinical trials are recruiting individuals with Search • The first AAV- • A single-arm trial with AAV1-hOTOF therapy (AAV serotype 1 carrying human • A bilateral AAV1-hOTOF gene therapy trial in five children between ages one and six years with ## Genetic Counseling The parents of a child with Molecular genetic testing is recommended for the parents of the 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. Individuals who are heterozygous for an If both parents are known to be heterozygous for an Typical Individuals who are heterozygous for an Carrier testing for relatives requires prior identification of the See Management, See Genetic Hearing Loss Overview, 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. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of a child with • Molecular genetic testing is recommended for the parents of the 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. • Individuals who are heterozygous for an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Typical • Individuals who are heterozygous for an • 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. ## Mode of Inheritance ## Risk to Family Members The parents of a child with Molecular genetic testing is recommended for the parents of the 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. Individuals who are heterozygous for an If both parents are known to be heterozygous for an Typical Individuals who are heterozygous for an • The parents of a child with • Molecular genetic testing is recommended for the parents of the 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. • Individuals who are heterozygous for an • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Typical • Individuals who are heterozygous for an ## Carrier Detection Carrier testing for relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, See Genetic Hearing Loss Overview, 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. • 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. ## 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 Health Resources & Services Administration • • • • • • • • • • • • • Health Resources & Services Administration • ## Molecular Genetics OTOF-Related Hearing Loss: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for OTOF-Related Hearing Loss ( Variants listed in the table have been provided by the authors. TS- ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. TS- ## Chapter Notes The The The work in this Hela Azaiez, PhD (2021-present)Jose G Gurrola III, MD; University of Iowa (2007-2015)Philip M Kelley, PhD; Boys Town National Research Hospital (2007-2015)Amanda M Odell, MS, LGCA (2025-present)Eliot Shearer, MD, PhD; University of Iowa (2015-2021)Richard JH Smith, MD (2007-present)Ryan K Thorpe, MD (2021-present) 13 March 2025 (bp) Comprehensive update posted live 21 January 2021 (ha) Comprehensive update posted live 30 July 2015 (me) Comprehensive update posted live 26 April 2011 (me) Comprehensive update posted live 29 February 2008 (me) Review posted live 15 October 2007 (rjhs) Original submission • 13 March 2025 (bp) Comprehensive update posted live • 21 January 2021 (ha) Comprehensive update posted live • 30 July 2015 (me) Comprehensive update posted live • 26 April 2011 (me) Comprehensive update posted live • 29 February 2008 (me) Review posted live • 15 October 2007 (rjhs) Original submission ## Author Notes The The ## Acknowledgments The work in this ## Author History Hela Azaiez, PhD (2021-present)Jose G Gurrola III, MD; University of Iowa (2007-2015)Philip M Kelley, PhD; Boys Town National Research Hospital (2007-2015)Amanda M Odell, MS, LGCA (2025-present)Eliot Shearer, MD, PhD; University of Iowa (2015-2021)Richard JH Smith, MD (2007-present)Ryan K Thorpe, MD (2021-present) ## Revision History 13 March 2025 (bp) Comprehensive update posted live 21 January 2021 (ha) Comprehensive update posted live 30 July 2015 (me) Comprehensive update posted live 26 April 2011 (me) Comprehensive update posted live 29 February 2008 (me) Review posted live 15 October 2007 (rjhs) Original submission • 13 March 2025 (bp) Comprehensive update posted live • 21 January 2021 (ha) Comprehensive update posted live • 30 July 2015 (me) Comprehensive update posted live • 26 April 2011 (me) Comprehensive update posted live • 29 February 2008 (me) Review posted live • 15 October 2007 (rjhs) Original submission ## References ## Literature Cited Genetic spectrum of A. Different types of pathogenic variants have been identified in B. Regardless of variant type – truncating vs nontruncating – pathogenic variants in
[]
29/2/2008
13/3/2025
14/6/2011
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dfnx1
dfnx1
[ "DFN2 Nonsyndromic Hearing Loss and Deafness", "Ribose-phosphate pyrophosphokinase 1", "PRPS1", "DFNX1 Nonsyndromic Hearing Loss and Deafness" ]
DFNX1 Nonsyndromic Hearing Loss and Deafness – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Xue Z Liu, Huijun Yuan, Rahul Mittal, Denise Yan
Summary DFNX1 nonsyndromic hearing loss and deafness is part of the spectrum of Diagnosis relies on the presence of characteristic hearing loss in males and detection of a hemizygous DFNX1 is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be a carrier of the pathogenic variant. If the mother of an affected male has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be carriers and may have hearing loss. Carrier testing for at-risk female relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the
## Diagnosis DFNX1 nonsyndromic hearing loss and deafness, part of the spectrum of Sensorineural hearing loss is: Bilateral moderate to profound; Prelingual or postlingual in onset; Progressive or non-progressive. Audiograms are usually flat across all frequencies. However, some individuals have severe hearing loss in the low frequencies and some have residual hearing in the high frequencies. Vestibular function is normal. 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 DFNX1 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 Sequencing of the seven exons of the coding region and the intron/exon boundaries 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Sensorineural hearing loss is: • Bilateral moderate to profound; • Prelingual or postlingual in onset; • Progressive or non-progressive. • Bilateral moderate to profound; • Prelingual or postlingual in onset; • Progressive or non-progressive. • Audiograms are usually flat across all frequencies. However, some individuals have severe hearing loss in the low frequencies and some have residual hearing in the high frequencies. • Vestibular function is normal. • Bilateral moderate to profound; • Prelingual or postlingual in onset; • Progressive or non-progressive. ## Suggestive Findings DFNX1 nonsyndromic hearing loss and deafness, part of the spectrum of Sensorineural hearing loss is: Bilateral moderate to profound; Prelingual or postlingual in onset; Progressive or non-progressive. Audiograms are usually flat across all frequencies. However, some individuals have severe hearing loss in the low frequencies and some have residual hearing in the high frequencies. Vestibular function is normal. • Sensorineural hearing loss is: • Bilateral moderate to profound; • Prelingual or postlingual in onset; • Progressive or non-progressive. • Bilateral moderate to profound; • Prelingual or postlingual in onset; • Progressive or non-progressive. • Audiograms are usually flat across all frequencies. However, some individuals have severe hearing loss in the low frequencies and some have residual hearing in the high frequencies. • Vestibular function is normal. • Bilateral moderate to profound; • Prelingual or postlingual in onset; • Progressive or non-progressive. ## Establishing the Diagnosis 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 DFNX1 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 Sequencing of the seven exons of the coding region and the intron/exon boundaries 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DFNX1 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 Sequencing of the seven exons of the coding region and the intron/exon boundaries 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Hearing loss in individuals with DFNX1 nonsyndromic hearing loss and deafness can be prelingual or postlingual (in which onset ranges from 3 years to 20 years), progressive or non-progressive, and severe to profound [ In the family described by The established In females, who predictably have a less severe presentation, the ratio of X chromosome inactivation adds an additional variable in predicting clinical outcome [ Prevalence has not been determined. Five families with DFNX1 have been reported [ ## Clinical Description Hearing loss in individuals with DFNX1 nonsyndromic hearing loss and deafness can be prelingual or postlingual (in which onset ranges from 3 years to 20 years), progressive or non-progressive, and severe to profound [ In the family described by ## Genotype-Phenotype Correlations The established In females, who predictably have a less severe presentation, the ratio of X chromosome inactivation adds an additional variable in predicting clinical outcome [ ## Prevalence Prevalence has not been determined. Five families with DFNX1 have been reported [ ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders to Consider in the Differential Diagnosis of DFNX1 Hearing could be normal or abnormal No symptoms In some: isolated &/or milder signs GA = gouty arthritis; ID = intellectual disability; PN = peripheral neuropathy; SNHL = sensorineural hearing loss Other Allelic Disorders (not in the Differential Diagnosis of DFNX1) GA = gouty arthritis; ID = intellectual disability; PN = peripheral neuropathy; SNHL = sensorineural hearing loss ## Differential Diagnosis See ## Management To establish the extent of disease and needs of an individual diagnosed with DFNX1 nonsyndromic hearing loss and deafness, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Pure tone audiograms, auditory brain stem response testing Evaluation for peripheral neuropathy and ophthalmologic findings (optic atrophy and retinitis pigmentosa) Consultation with a clinical geneticist and/or genetic counselor See Hearing loss in DFNX1 is prelingual or postlingual and progressive; regular audiologic evaluation is recommended to assess hearing status and progression of hearing loss. Periodic reevaluation of clinical findings by a neurologist is indicated for males with clinical evidence of peripheral neuropathy. Determining in infancy whether at-risk male and female relatives of a person with DFNX1 nonsyndromic hearing loss and deafness have inherited the Evaluations may include: Molecular genetic testing if the pathogenic Audiometry if molecular genetic testing for the at-risk relative is not available. See Search • Pure tone audiograms, auditory brain stem response testing • Evaluation for peripheral neuropathy and ophthalmologic findings (optic atrophy and retinitis pigmentosa) • Consultation with a clinical geneticist and/or genetic counselor • Molecular genetic testing if the pathogenic • Audiometry if molecular genetic testing for the at-risk relative is not available. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with DFNX1 nonsyndromic hearing loss and deafness, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Pure tone audiograms, auditory brain stem response testing Evaluation for peripheral neuropathy and ophthalmologic findings (optic atrophy and retinitis pigmentosa) Consultation with a clinical geneticist and/or genetic counselor • Pure tone audiograms, auditory brain stem response testing • Evaluation for peripheral neuropathy and ophthalmologic findings (optic atrophy and retinitis pigmentosa) • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations See ## Surveillance Hearing loss in DFNX1 is prelingual or postlingual and progressive; regular audiologic evaluation is recommended to assess hearing status and progression of hearing loss. Periodic reevaluation of clinical findings by a neurologist is indicated for males with clinical evidence of peripheral neuropathy. ## Evaluation of Relatives at Risk Determining in infancy whether at-risk male and female relatives of a person with DFNX1 nonsyndromic hearing loss and deafness have inherited the Evaluations may include: Molecular genetic testing if the pathogenic Audiometry if molecular genetic testing for the at-risk relative is not available. See • Molecular genetic testing if the pathogenic • Audiometry if molecular genetic testing for the at-risk relative is not available. ## Therapies Under Investigation Search ## Genetic Counseling DFNX1 nonsyndromic hearing loss and deafness is inherited in an X-linked manner. The father of an affected male will not have hearing loss 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 If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother of the proband has the Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ 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 heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy and RP as the only manifestations [ None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Molecular genetic testing of female relatives to determine their genetic status requires prior identification of the Note: Females who are heterozygotes for a See Management, The following points are noteworthy: Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. 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." Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. 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 that offspring will be deaf and reproductive options) to young adults who have (or are carriers of) DFNX1 nonsyndromic hearing loss and deafness. 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 hearing loss 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 • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has the • Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ • Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ • Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ • Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ • Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ • All of their daughters, who will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy and RP as the only manifestations [ • None of their sons. • Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. • 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." • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. • The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. • 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 that offspring will be deaf and reproductive options) to young adults who have (or are carriers of) DFNX1 nonsyndromic hearing loss and deafness. ## Mode of Inheritance DFNX1 nonsyndromic hearing loss and deafness is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have hearing loss 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 If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a If the mother of the proband has the Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ 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 heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy and RP as the only manifestations [ 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 hearing loss 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 • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has the • Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ • Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ • Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ • Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Males who inherit the variant will have hearing loss; other features (e.g., mild peripheral neuropathy) may also be observed in hemizygous sibs [ • Females who inherit the variant will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy, as well as retinitis pigmentosa (RP) as the only manifestations [ • All of their daughters, who will be heterozygotes and may be unaffected, have nonsyndromic hearing loss, or have peripheral neuropathy and optic atrophy and RP as the only manifestations [ • None of their sons. ## Heterozygote Detection Molecular genetic testing of female relatives to determine their genetic status requires prior identification of the Note: Females who are heterozygotes for a ## Related Genetic Counseling Issues See Management, The following points are noteworthy: Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. 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." Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. 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 that offspring will be deaf and reproductive options) to young adults who have (or are carriers of) DFNX1 nonsyndromic hearing loss and deafness. • Communication with individuals who are members of the Deaf community and sign requires the services of a skilled interpreter. • 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." • Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. • The use of certain terms is preferred: probability or chance versus risk; deaf and hard-of-hearing versus hearing impaired. Terms such as "abnormal" should be avoided. • 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 that offspring will be deaf and reproductive options) to young adults who have (or are carriers of) DFNX1 nonsyndromic hearing loss and deafness. ## 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 DFNX1 Nonsyndromic Hearing Loss and Deafness: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DFNX1 Nonsyndromic Hearing Loss and Deafness ( Selected Variants listed in the table have been provided by the authors. Phosphoribosylpyrophosphate synthetase (PRS) I enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [ Interestingly, computer-assisted molecular modeling showed that pathogenic variants causing Of note, pathogenic variants that result in ## Chapter Notes 8 June 2023 (ma) Chapter retired: covered in 19 July 2018 (bp) Comprehensive update posted live 4 August 2011 (me) Review posted live 31 March 2011 (xzl) Original submission • 8 June 2023 (ma) Chapter retired: covered in • 19 July 2018 (bp) Comprehensive update posted live • 4 August 2011 (me) Review posted live • 31 March 2011 (xzl) Original submission ## Revision History 8 June 2023 (ma) Chapter retired: covered in 19 July 2018 (bp) Comprehensive update posted live 4 August 2011 (me) Review posted live 31 March 2011 (xzl) Original submission • 8 June 2023 (ma) Chapter retired: covered in • 19 July 2018 (bp) Comprehensive update posted live • 4 August 2011 (me) Review posted live • 31 March 2011 (xzl) Original submission ## References ## Literature Cited
[ "B Almoguera, S He, M Corton, P Fernandez-San Jose, F Blanco-Kelly, MI López-Molina, B García-Sandoval, J Del Val, Y Guo, L Tian, X Liu, L Guan, RJ Torres, JG Puig, H Hakonarson, X Xu, B Keating, C Ayuso. Expanding the phenotype of. Orphanet J Rare Dis. 2014;9:190", "AP de Brouwer, H van Bokhoven, SB Nabuurs, WF Arts, J Christodoulou, J Duley. PRPS1 mutations: four distinct syndromes and potential treatment.. Am J Hum Genet. 2010;86:506-18", "AP de Brouwer, KL Williams, JA Duley, AB van Kuilenburg, SB Nabuurs, M Egmont-Petersen, D Lugtenberg, L Zoetekouw, MJ Banning, M Roeffen, BC Hamel, L Weaving, RA Ouvrier, JA Donald, RA Wevers, J Christodoulou, H van Bokhoven. Arts syndrome is caused by loss-of-function mutations in PRPS1.. Am J Hum Genet. 2007;81:507-18", "M Gandía, J Fernández-Toral, J Solanellas, M Domínguez-Ruiz, E Gómez-Rosas, FJ Del Castillo, M Villamar, MA Moreno-Pelayo, I Del Castillo. Mutations in PRPS1 causing syndromic or nonsyndromic hearing impairment: intrafamilial phenotypic variation complicates genetic counseling.. Pediatr Res. 2015;78:97-102", "HJ Kim, KM Sohn, ME Shy, KM Krajewski, M Hwang, JH Park, SY Jang, HH Won, BO Choi, SH Hong, BJ Kim, YL Suh, CS Ki, SY Lee, SH Kim, JW Kim. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5).. Am J Hum Genet. 2007;81:552-8", "SY Kim, AR Kim, NK Kim, C Lee, JH Han, MY Kim, EH Jeon, WY Park, R Mittal, D Yan, XZ Liu, BY Choi. Functional characterization of a novel loss-of-function mutation of. J Gene Med 2016;18:353-8", "X Liu, D Han, J Li, X Li, B Han, X Ouyang, J Cheng, Z Jin, Y Wang, M Bitner-Glindzicz, X Kong, H Xu, A Kantardzhieva, RD Eavey, CE Seidman, JG Seidman, LL Du, ZY Chen, P Dai, M Teng, D Yan, H Yuan. loss-of-function mutations in the PRPS1 gene cause non-syndromic X-linked sensorineural deafness (DFN2).. Am J Hum Genet 2010;86:65-71", "XZ Liu, D Xie, HJ Yuan, AP de Brouwer, J Christodoulou, D Yan. Hearing loss and PRPS1 mutations: Wide spectrum of phenotypes and potential therapy.. Int J Audiol. 2013;52:23-8", "M Robusto, M Fang, R Asselta, P Castorina, SC Previtali, S Caccia, E Benzoni, R De Cristofaro, C Yu, A Cesarani, X Liu, W Li, P Primignani, U Ambrosetti, X Xu, S Duga, G Soldà. The expanding spectrum of. Eur J Hum Genet. 2015;23:766-73", "M Synofzik, J Muller vom Hagen, TB Haack, C Wilhelm, T Lindig, S Beck-Wodl, SB Nabuurs, AB van Kuilenburg, AP de Brouwer, L Schols. X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation.. Orphanet J Rare Dis. 2014;9:24", "RJ Torres, FA Mateos, JG Puig, M Becker. Determination of phosphoribosylpyrophosphate synthetase activity in human cells by a non-isotopic, one step method.. Clin Chim Acta. 1996;245:105-12" ]
4/8/2011
19/7/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dguok-mtddepl
dguok-mtddepl
[ "DGUOK Deficiency", "DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form", "DGUOK Deficiency", "DGUOK-Related Mitochondrial DNA Depletion Syndrome, Hepatocerebral Form", "Deoxyguanosine kinase, mitochondrial", "DGUOK", "Deoxyguanosine Kinase Deficiency" ]
Deoxyguanosine Kinase Deficiency
Ayman W El-Hattab, Fernando Scaglia
Summary The two forms of deoxyguanosine kinase (DGUOK) deficiency are a neonatal multisystem disorder and an isolated hepatic disorder that presents later in infancy or childhood. The majority of affected individuals have the multisystem illness with hepatic disease (jaundice, cholestasis, hepatomegaly, and elevated transaminases) and neurologic manifestations (hypotonia, nystagmus, and developmental delay) evident within weeks of birth. Those with isolated liver disease may also have renal involvement, and some later develop mild hypotonia. Progressive hepatic disease is the most common cause of death in both forms. The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic variants in DGUOK deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if the
## Diagnosis Deoxyguanosine kinase (DGUOK) deficiency ( Liver disease. Jaundice, cholestasis, and hepatomegaly, progressing to liver failure Neurologic manifestations. Hypotonia, nystagmus, and developmental delay Lactic acidosis and hypoglycemia Elevated transaminases alanine aminotransferase and aspartate aminotransferase In some individuals, elevated serum gammaglutamyltransferase, alpha fetoprotein, and ferritin [ In most individuals, plasma amino acid profile showing elevated tyrosine, phenylalanine, and methionine [ Note: (1) Elevated serum concentration of tyrosine or phenylalanine can be detected on newborn screening in the majority of neonates with multisystem DGUOK deficiency. (2) Infants with DGUOK deficiency do not excrete succinylacetone in the urine, whereas urinary excretion of succinylacetone is diagnostic for Liver histology typically reveals cholestasis, but may show microsteatosis, fibrosis, giant cell hepatitis, or cirrhosis. Electron microscopy may reveal an increase in the number of mitochondria and abnormal cristae, findings common to all hepatocerebral mitochondrial DNA (mtDNA) depletion syndromes [ Mitochondrial DNA content in liver tissue of affected individuals is typically less than 20% of matched control mtDNA content. The liver typically shows a combined deficiency of electron transport chain complexes I, III, and IV [ The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ 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. Children with the distinctive When the phenotypic and laboratory findings suggest the diagnosis of neonatal multisystem disease due to DGUOK deficiency, molecular genetic testing approaches can include Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders with liver disease, molecular genetic testing approaches can include a combination of Molecular Genetic Testing Used in Deoxyguanosine Kinase 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. • Liver disease. Jaundice, cholestasis, and hepatomegaly, progressing to liver failure • Neurologic manifestations. Hypotonia, nystagmus, and developmental delay • Lactic acidosis and hypoglycemia • Elevated transaminases alanine aminotransferase and aspartate aminotransferase • In some individuals, elevated serum gammaglutamyltransferase, alpha fetoprotein, and ferritin [ • In most individuals, plasma amino acid profile showing elevated tyrosine, phenylalanine, and methionine [ • Note: (1) Elevated serum concentration of tyrosine or phenylalanine can be detected on newborn screening in the majority of neonates with multisystem DGUOK deficiency. (2) Infants with DGUOK deficiency do not excrete succinylacetone in the urine, whereas urinary excretion of succinylacetone is diagnostic for • Liver histology typically reveals cholestasis, but may show microsteatosis, fibrosis, giant cell hepatitis, or cirrhosis. Electron microscopy may reveal an increase in the number of mitochondria and abnormal cristae, findings common to all hepatocerebral mitochondrial DNA (mtDNA) depletion syndromes [ • Mitochondrial DNA content in liver tissue of affected individuals is typically less than 20% of matched control mtDNA content. The liver typically shows a combined deficiency of electron transport chain complexes I, III, and IV [ • Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see • For an introduction to multigene panels click ## Suggestive Findings Deoxyguanosine kinase (DGUOK) deficiency ( Liver disease. Jaundice, cholestasis, and hepatomegaly, progressing to liver failure Neurologic manifestations. Hypotonia, nystagmus, and developmental delay Lactic acidosis and hypoglycemia Elevated transaminases alanine aminotransferase and aspartate aminotransferase In some individuals, elevated serum gammaglutamyltransferase, alpha fetoprotein, and ferritin [ In most individuals, plasma amino acid profile showing elevated tyrosine, phenylalanine, and methionine [ Note: (1) Elevated serum concentration of tyrosine or phenylalanine can be detected on newborn screening in the majority of neonates with multisystem DGUOK deficiency. (2) Infants with DGUOK deficiency do not excrete succinylacetone in the urine, whereas urinary excretion of succinylacetone is diagnostic for Liver histology typically reveals cholestasis, but may show microsteatosis, fibrosis, giant cell hepatitis, or cirrhosis. Electron microscopy may reveal an increase in the number of mitochondria and abnormal cristae, findings common to all hepatocerebral mitochondrial DNA (mtDNA) depletion syndromes [ Mitochondrial DNA content in liver tissue of affected individuals is typically less than 20% of matched control mtDNA content. The liver typically shows a combined deficiency of electron transport chain complexes I, III, and IV [ • Liver disease. Jaundice, cholestasis, and hepatomegaly, progressing to liver failure • Neurologic manifestations. Hypotonia, nystagmus, and developmental delay • Lactic acidosis and hypoglycemia • Elevated transaminases alanine aminotransferase and aspartate aminotransferase • In some individuals, elevated serum gammaglutamyltransferase, alpha fetoprotein, and ferritin [ • In most individuals, plasma amino acid profile showing elevated tyrosine, phenylalanine, and methionine [ • Note: (1) Elevated serum concentration of tyrosine or phenylalanine can be detected on newborn screening in the majority of neonates with multisystem DGUOK deficiency. (2) Infants with DGUOK deficiency do not excrete succinylacetone in the urine, whereas urinary excretion of succinylacetone is diagnostic for • Liver histology typically reveals cholestasis, but may show microsteatosis, fibrosis, giant cell hepatitis, or cirrhosis. Electron microscopy may reveal an increase in the number of mitochondria and abnormal cristae, findings common to all hepatocerebral mitochondrial DNA (mtDNA) depletion syndromes [ • Mitochondrial DNA content in liver tissue of affected individuals is typically less than 20% of matched control mtDNA content. The liver typically shows a combined deficiency of electron transport chain complexes I, III, and IV [ ## Establishing the Diagnosis The diagnosis of DGUOK deficiency is established in a proband by the identification of biallelic pathogenic (or likely pathogenic) variants in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ 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. Children with the distinctive When the phenotypic and laboratory findings suggest the diagnosis of neonatal multisystem disease due to DGUOK deficiency, molecular genetic testing approaches can include Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders with liver disease, molecular genetic testing approaches can include a combination of Molecular Genetic Testing Used in Deoxyguanosine Kinase 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. • Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of neonatal multisystem disease due to DGUOK deficiency, molecular genetic testing approaches can include Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see For an introduction to multigene panels click • Note: Targeted analysis for pathogenic variants can be performed first in individuals of Druze ancestry (see • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders with liver disease, molecular genetic testing approaches can include a combination of Molecular Genetic Testing Used in Deoxyguanosine Kinase 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 Deoxyguanosine kinase (DGUOK) deficiency presents in the majority of affected individuals as neonatal multisystem disease and in the minority of affected individuals later in infancy or childhood as isolated hepatic disease. Affected sibs with the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. To date, more than 100 individuals have been identified with pathogenic variants in Most affected infants have lactic acidosis and hypoglycemia in the first week of life. Within weeks of birth, all infants with this form of disease have hepatic disease and neurologic dysfunction. Brain MRI is usually normal. However, subtentorial abnormal myelination and globus pallidus hyperintensity have been reported [ The prognosis for neonatal multisystem disease is poor; most affected children die of liver failure before age four years [ A minority of affected children initially present in infancy or childhood with isolated hepatic disease manifesting as jaundice, cholestasis, hepatomegaly, and elevated transaminases. Compared to neonatal multisystem disease, this form is associated with a less severe and later-onset liver disease. The liver disease, occasionally induced by a viral illness, is typically progressive and can lead to liver failure. However, hepatic disease has undergone reversal in one individual with isolated liver disease [ One individual with isolated liver disease subsequently developed hepatocellular carcinoma [ Although neurologic manifestations are typically absent, long-term follow up suggests that individuals with isolated hepatic disease may subsequently develop mild hypotonia, and some may also have renal involvement manifesting as proteinuria and aminoaciduria [ The following variable phenotypes have occasionally been reported: Noncirrhotic portal hypertension with onset during infancy or childhood [ Neonatal hemochromatosis [ Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [ Juvenile-onset myopathy presenting with weakness and fatigability [ Adult-onset myopathy and parkinsonism presenting with ptosis, ophthalmoplegia, weakness, rigidity, and bradykinesia [ No clear genotype-phenotype correlations are evident among individuals with In contrast, two null variants have been typically associated with multisystem disease and a more severe clinical phenotype [ There is no clear correlation between No large population-based studies have evaluated the prevalence of mitochondrial DNA (mtDNA) depletion in general or DGUOK deficiency specifically. More than 100 individuals with DGUOK deficiency have been reported [ • Noncirrhotic portal hypertension with onset during infancy or childhood [ • Neonatal hemochromatosis [ • Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [ • Juvenile-onset myopathy presenting with weakness and fatigability [ • Adult-onset myopathy and parkinsonism presenting with ptosis, ophthalmoplegia, weakness, rigidity, and bradykinesia [ ## Clinical Description Deoxyguanosine kinase (DGUOK) deficiency presents in the majority of affected individuals as neonatal multisystem disease and in the minority of affected individuals later in infancy or childhood as isolated hepatic disease. Affected sibs with the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. To date, more than 100 individuals have been identified with pathogenic variants in Most affected infants have lactic acidosis and hypoglycemia in the first week of life. Within weeks of birth, all infants with this form of disease have hepatic disease and neurologic dysfunction. Brain MRI is usually normal. However, subtentorial abnormal myelination and globus pallidus hyperintensity have been reported [ The prognosis for neonatal multisystem disease is poor; most affected children die of liver failure before age four years [ A minority of affected children initially present in infancy or childhood with isolated hepatic disease manifesting as jaundice, cholestasis, hepatomegaly, and elevated transaminases. Compared to neonatal multisystem disease, this form is associated with a less severe and later-onset liver disease. The liver disease, occasionally induced by a viral illness, is typically progressive and can lead to liver failure. However, hepatic disease has undergone reversal in one individual with isolated liver disease [ One individual with isolated liver disease subsequently developed hepatocellular carcinoma [ Although neurologic manifestations are typically absent, long-term follow up suggests that individuals with isolated hepatic disease may subsequently develop mild hypotonia, and some may also have renal involvement manifesting as proteinuria and aminoaciduria [ The following variable phenotypes have occasionally been reported: Noncirrhotic portal hypertension with onset during infancy or childhood [ Neonatal hemochromatosis [ Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [ Juvenile-onset myopathy presenting with weakness and fatigability [ Adult-onset myopathy and parkinsonism presenting with ptosis, ophthalmoplegia, weakness, rigidity, and bradykinesia [ • Noncirrhotic portal hypertension with onset during infancy or childhood [ • Neonatal hemochromatosis [ • Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [ • Juvenile-onset myopathy presenting with weakness and fatigability [ • Adult-onset myopathy and parkinsonism presenting with ptosis, ophthalmoplegia, weakness, rigidity, and bradykinesia [ ## Neonatal Multisystem Disease Most affected infants have lactic acidosis and hypoglycemia in the first week of life. Within weeks of birth, all infants with this form of disease have hepatic disease and neurologic dysfunction. Brain MRI is usually normal. However, subtentorial abnormal myelination and globus pallidus hyperintensity have been reported [ The prognosis for neonatal multisystem disease is poor; most affected children die of liver failure before age four years [ ## Isolated Hepatic Disease A minority of affected children initially present in infancy or childhood with isolated hepatic disease manifesting as jaundice, cholestasis, hepatomegaly, and elevated transaminases. Compared to neonatal multisystem disease, this form is associated with a less severe and later-onset liver disease. The liver disease, occasionally induced by a viral illness, is typically progressive and can lead to liver failure. However, hepatic disease has undergone reversal in one individual with isolated liver disease [ One individual with isolated liver disease subsequently developed hepatocellular carcinoma [ Although neurologic manifestations are typically absent, long-term follow up suggests that individuals with isolated hepatic disease may subsequently develop mild hypotonia, and some may also have renal involvement manifesting as proteinuria and aminoaciduria [ ## Other Less Frequent Manifestations The following variable phenotypes have occasionally been reported: Noncirrhotic portal hypertension with onset during infancy or childhood [ Neonatal hemochromatosis [ Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [ Juvenile-onset myopathy presenting with weakness and fatigability [ Adult-onset myopathy and parkinsonism presenting with ptosis, ophthalmoplegia, weakness, rigidity, and bradykinesia [ • Noncirrhotic portal hypertension with onset during infancy or childhood [ • Neonatal hemochromatosis [ • Adult-onset myopathy presenting with limb weakness, ophthalmoplegia, and ptosis [ • Juvenile-onset myopathy presenting with weakness and fatigability [ • Adult-onset myopathy and parkinsonism presenting with ptosis, ophthalmoplegia, weakness, rigidity, and bradykinesia [ ## Genotype-Phenotype Correlations No clear genotype-phenotype correlations are evident among individuals with In contrast, two null variants have been typically associated with multisystem disease and a more severe clinical phenotype [ There is no clear correlation between ## Prevalence No large population-based studies have evaluated the prevalence of mitochondrial DNA (mtDNA) depletion in general or DGUOK deficiency specifically. More than 100 individuals with DGUOK deficiency have been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The neonatal multisystem form of deoxyguanosine kinase (DGUOK) deficiency needs to be differentiated from other mitochondrial DNA (mtDNA) depletion syndromes, a genetically and clinically heterogeneous group of primarily autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. 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 ( Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral (encephalohepatopathic), encephalomyopathic, neurogastrointestinal encephalopathic, encephaloneuropathic, and myopathic forms [ Mitochondrial DNA Depletion Syndromes CSF = cerebrospinal fluid; DD = developmental delay; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; MDMD = mitochondrial DNA maintenance defect; MNGIE = mitochondrial neurogastrointestinal encephalopathy Within each phenotypic category, mtDNA 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 The differential diagnosis of isolated hepatic disease due to DGUOK deficiency includes other genetic and non-genetic age-specific causes of cholestatic liver disease. Inborn errors of bile acid synthesis (See Pediatric Genetic Cholestatic Liver Disease Overview, Wolman disease (See Peroxisomal biogenesis disorders (See Progressive familial intrahepatic cholestasis (See Extrahepatic biliary atresia Choledochal cyst Hypothyroidism Total parenteral nutrition cholestasis Neonatal hemochromatosis • • • • • • Inborn errors of bile acid synthesis (See Pediatric Genetic Cholestatic Liver Disease Overview, • • • Wolman disease (See • Peroxisomal biogenesis disorders (See • Progressive familial intrahepatic cholestasis (See • Extrahepatic biliary atresia • Choledochal cyst • Hypothyroidism • Total parenteral nutrition cholestasis • Neonatal hemochromatosis ## Multisystem Disease The neonatal multisystem form of deoxyguanosine kinase (DGUOK) deficiency needs to be differentiated from other mitochondrial DNA (mtDNA) depletion syndromes, a genetically and clinically heterogeneous group of primarily autosomal recessive disorders that are characterized by a severe reduction in mtDNA content leading to impaired energy production in affected tissues and organs. 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 ( Mitochondrial DNA depletion syndromes are phenotypically classified into hepatocerebral (encephalohepatopathic), encephalomyopathic, neurogastrointestinal encephalopathic, encephaloneuropathic, and myopathic forms [ Mitochondrial DNA Depletion Syndromes CSF = cerebrospinal fluid; DD = developmental delay; GI = gastrointestinal; HCM = hypertrophic cardiomyopathy; IUGR = intrauterine growth restriction; MDMD = mitochondrial DNA maintenance defect; MNGIE = mitochondrial neurogastrointestinal encephalopathy Within each phenotypic category, mtDNA 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 ## Isolated Hepatic Disease The differential diagnosis of isolated hepatic disease due to DGUOK deficiency includes other genetic and non-genetic age-specific causes of cholestatic liver disease. Inborn errors of bile acid synthesis (See Pediatric Genetic Cholestatic Liver Disease Overview, Wolman disease (See Peroxisomal biogenesis disorders (See Progressive familial intrahepatic cholestasis (See Extrahepatic biliary atresia Choledochal cyst Hypothyroidism Total parenteral nutrition cholestasis Neonatal hemochromatosis • • • • • • Inborn errors of bile acid synthesis (See Pediatric Genetic Cholestatic Liver Disease Overview, • • • Wolman disease (See • Peroxisomal biogenesis disorders (See • Progressive familial intrahepatic cholestasis (See • Extrahepatic biliary atresia • Choledochal cyst • Hypothyroidism • Total parenteral nutrition cholestasis • Neonatal hemochromatosis ## Management No clinical practice guidelines for deoxyguanosine kinase (DGUOK) deficiency have been published. To establish the extent of disease and needs in an individual diagnosed with DGUOK deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Deoxyguanosine Kinase Deficiency Comprehensive neurologic exam Developmental/cognitive assessment Brain MRI may be considered. Eval of hepatic status by physician familiar w/care of children w/liver failure Initial testing should incl measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. Nutritional assessment by dietician w/experience in managing children w/hepatic failure Community or Social work involvement for parental support; Home nursing referral. AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyltransferase; HCC = hepatocellular carcinoma; MOI = mode of inheritance Although the value of a highly elevated serum AFP in the detection of hepatocellular carcinoma in DGUOK deficiency is not known, the possibility of hepatocellular carcinoma should be considered in individuals with a solid tumor detected by abdominal ultrasound examination Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management requires a multidisciplinary team including specialists in hepatology, neurology, child development, nutrition, and clinical genetics (see Treatment of Manifestations in Individuals with Deoxyguanosine Kinase Deficiency Formulas w/enriched medium-chain triglyceride content may provide better nutritional support for infants w/cholestasis than formulas w/predominantly long-chain triglycerides. Cornstarch may ↓ symptomatic hypoglycemia in those w/isolated hepatic disease. Fractional meals & enteral nutrition at night can result in good nutritional control. Supplementation w/fat-soluble vitamins & essential fatty acids. Liver transplantation in selected persons w/DGUOK deficiency is not contraindicated, esp in those w/o or w/minimal neurologic abnormalities. Liver transplantation was performed in 20 persons w/DGUOK deficiency at age 1-18 mos. Ten individuals (50%) died 1-21 mos after transplant from procedure-related complications (renal insufficiency, intraventricular hemorrhage, sepsis, pulmonary hypertension, or peritonitis). Among survivors, 8 presented w/good psychomotor development &/or mild hypotonia, 1 presented w/moderate cognitive impairment, & 1 presented w/severe psychomotor impairment. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or 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 No clinical guidelines for surveillance are available. 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 Deoxyguanosine Kinase Deficiency Neurologic assessment Assess developmental progress (particularly gross motor skills) & educational needs. Assess weight gain & nutritional status. Monitor serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyltransferase; HCC = hepatocellular carcinoma See Search • Comprehensive neurologic exam • Developmental/cognitive assessment • Brain MRI may be considered. • Eval of hepatic status by physician familiar w/care of children w/liver failure • Initial testing should incl measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. • Nutritional assessment by dietician w/experience in managing children w/hepatic failure • Community or • Social work involvement for parental support; • Home nursing referral. • Formulas w/enriched medium-chain triglyceride content may provide better nutritional support for infants w/cholestasis than formulas w/predominantly long-chain triglycerides. • Cornstarch may ↓ symptomatic hypoglycemia in those w/isolated hepatic disease. • Fractional meals & enteral nutrition at night can result in good nutritional control. • Supplementation w/fat-soluble vitamins & essential fatty acids. • Liver transplantation in selected persons w/DGUOK deficiency is not contraindicated, esp in those w/o or w/minimal neurologic abnormalities. • Liver transplantation was performed in 20 persons w/DGUOK deficiency at age 1-18 mos. Ten individuals (50%) died 1-21 mos after transplant from procedure-related complications (renal insufficiency, intraventricular hemorrhage, sepsis, pulmonary hypertension, or peritonitis). Among survivors, 8 presented w/good psychomotor development &/or mild hypotonia, 1 presented w/moderate cognitive impairment, & 1 presented w/severe psychomotor impairment. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 • Neurologic assessment • Assess developmental progress (particularly gross motor skills) & educational needs. • Assess weight gain & nutritional status. • Monitor serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DGUOK deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Deoxyguanosine Kinase Deficiency Comprehensive neurologic exam Developmental/cognitive assessment Brain MRI may be considered. Eval of hepatic status by physician familiar w/care of children w/liver failure Initial testing should incl measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. Nutritional assessment by dietician w/experience in managing children w/hepatic failure Community or Social work involvement for parental support; Home nursing referral. AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyltransferase; HCC = hepatocellular carcinoma; MOI = mode of inheritance Although the value of a highly elevated serum AFP in the detection of hepatocellular carcinoma in DGUOK deficiency is not known, the possibility of hepatocellular carcinoma should be considered in individuals with a solid tumor detected by abdominal ultrasound examination Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Comprehensive neurologic exam • Developmental/cognitive assessment • Brain MRI may be considered. • Eval of hepatic status by physician familiar w/care of children w/liver failure • Initial testing should incl measurement of serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. • Nutritional assessment by dietician w/experience in managing children w/hepatic failure • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Management requires a multidisciplinary team including specialists in hepatology, neurology, child development, nutrition, and clinical genetics (see Treatment of Manifestations in Individuals with Deoxyguanosine Kinase Deficiency Formulas w/enriched medium-chain triglyceride content may provide better nutritional support for infants w/cholestasis than formulas w/predominantly long-chain triglycerides. Cornstarch may ↓ symptomatic hypoglycemia in those w/isolated hepatic disease. Fractional meals & enteral nutrition at night can result in good nutritional control. Supplementation w/fat-soluble vitamins & essential fatty acids. Liver transplantation in selected persons w/DGUOK deficiency is not contraindicated, esp in those w/o or w/minimal neurologic abnormalities. Liver transplantation was performed in 20 persons w/DGUOK deficiency at age 1-18 mos. Ten individuals (50%) died 1-21 mos after transplant from procedure-related complications (renal insufficiency, intraventricular hemorrhage, sepsis, pulmonary hypertension, or peritonitis). Among survivors, 8 presented w/good psychomotor development &/or mild hypotonia, 1 presented w/moderate cognitive impairment, & 1 presented w/severe psychomotor impairment. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or 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 • Formulas w/enriched medium-chain triglyceride content may provide better nutritional support for infants w/cholestasis than formulas w/predominantly long-chain triglycerides. • Cornstarch may ↓ symptomatic hypoglycemia in those w/isolated hepatic disease. • Fractional meals & enteral nutrition at night can result in good nutritional control. • Supplementation w/fat-soluble vitamins & essential fatty acids. • Liver transplantation in selected persons w/DGUOK deficiency is not contraindicated, esp in those w/o or w/minimal neurologic abnormalities. • Liver transplantation was performed in 20 persons w/DGUOK deficiency at age 1-18 mos. Ten individuals (50%) died 1-21 mos after transplant from procedure-related complications (renal insufficiency, intraventricular hemorrhage, sepsis, pulmonary hypertension, or peritonitis). Among survivors, 8 presented w/good psychomotor development &/or mild hypotonia, 1 presented w/moderate cognitive impairment, & 1 presented w/severe psychomotor impairment. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 No clinical guidelines for surveillance are available. 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 Deoxyguanosine Kinase Deficiency Neurologic assessment Assess developmental progress (particularly gross motor skills) & educational needs. Assess weight gain & nutritional status. Monitor serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. AFP = alpha fetoprotein; ALT = alanine aminotransferase; AST = aspartate aminotransferase; GGT = gammaglutamyltransferase; HCC = hepatocellular carcinoma • Neurologic assessment • Assess developmental progress (particularly gross motor skills) & educational needs. • Assess weight gain & nutritional status. • Monitor serum concentrations of ALT, AST, GGT, bilirubin, albumin, & coagulation profile. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Deoxyguanosine kinase (DGUOK) 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 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 Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family. Affected sibs sharing the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. 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 reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A 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 • Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family. Affected sibs sharing the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. • 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 reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. A ## Mode of Inheritance Deoxyguanosine kinase (DGUOK) 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 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 Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family. Affected sibs sharing the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. 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 • Although penetrance of DGUOK deficiency is probably complete, age of onset and severity of the clinical symptoms vary, even in the same family. Affected sibs sharing the same pathogenic variants have exhibited both multisystem disease and isolated hepatic disease with divergent long-term outcomes. • 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 reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. 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 carriers or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. 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 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 Deoxyguanosine Kinase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Deoxyguanosine Kinase Deficiency ( Missense, nonsense, and splice site variants result in a reduction or absence of DGUOK enzyme activity, which causes an imbalance of the mitochondrial deoxynucleotide pools. Because the mitochondria depend heavily on the salvage pathway for the supply of deoxynucleotides, DGUOK deficiency results in impaired mitochondrial DNA (mtDNA) synthesis and mtDNA depletion [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Missense, nonsense, and splice site variants result in a reduction or absence of DGUOK enzyme activity, which causes an imbalance of the mitochondrial deoxynucleotide pools. Because the mitochondria depend heavily on the salvage pathway for the supply of deoxynucleotides, DGUOK deficiency results in impaired mitochondrial DNA (mtDNA) synthesis and mtDNA depletion [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes David Dimmock, MD; Medical College of Wisconsin (2009-2016)Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)Fernando Scaglia, MD, FAAP, FACMG (2009-present)Lee-Jun Wong, PhD; Baylor College of Medicine (2009-2023) 9 February 2023 (sw) Comprehensive update posted live 22 December 2016 (bp) Comprehensive update posted live 18 June 2009 (et) Review posted live 10 February 2009 (fs) Original submission • 9 February 2023 (sw) Comprehensive update posted live • 22 December 2016 (bp) Comprehensive update posted live • 18 June 2009 (et) Review posted live • 10 February 2009 (fs) Original submission ## Author History David Dimmock, MD; Medical College of Wisconsin (2009-2016)Ayman W El-Hattab, MD, FAAP, FACMG (2016-present)Fernando Scaglia, MD, FAAP, FACMG (2009-present)Lee-Jun Wong, PhD; Baylor College of Medicine (2009-2023) ## Revision History 9 February 2023 (sw) Comprehensive update posted live 22 December 2016 (bp) Comprehensive update posted live 18 June 2009 (et) Review posted live 10 February 2009 (fs) Original submission • 9 February 2023 (sw) Comprehensive update posted live • 22 December 2016 (bp) Comprehensive update posted live • 18 June 2009 (et) Review posted live • 10 February 2009 (fs) Original submission ## References ## Literature Cited
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18/6/2009
9/2/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
diamond-b
diamond-b
[ "Diamond-Blackfan Anemia (DBA)", "Diamond-Blackfan Syndrome (DBS)", "Diamond-Blackfan Anemia (DBA)", "Diamond-Blackfan Syndrome (DBS)", "Erythroid transcription factor", "HEAT repeat-containing protein 3", "Large ribosomal subunit protein eL15", "Large ribosomal subunit protein eL18", "Large ribosomal subunit protein eL27", "Large ribosomal subunit protein eL31", "Large ribosomal subunit protein eL33", "Large ribosomal subunit protein uL18", "Large ribosomal subunit protein uL24", "Large ribosomal subunit protein uL29", "Large ribosomal subunit protein uL5", "Pre-rRNA-processing protein TSR2 homolog", "Small ribosomal subunit protein eS10", "Small ribosomal subunit protein eS17", "Small ribosomal subunit protein eS19", "Small ribosomal subunit protein eS24", "Small ribosomal subunit protein eS26", "Small ribosomal subunit protein eS27", "Small ribosomal subunit protein eS28", "Small ribosomal subunit protein eS7", "Small ribosomal subunit protein uS14", "Small ribosomal subunit protein uS8", "GATA1", "HEATR3", "RPL11", "RPL15", "RPL18", "RPL26", "RPL27", "RPL31", "RPL35", "RPL35A", "RPL5", "RPS10", "RPS15A", "RPS17", "RPS19", "RPS24", "RPS26", "RPS27", "RPS28", "RPS29", "RPS7", "TSR2", "DBA Syndrome" ]
DBA Syndrome
Colin Sieff
Summary DBA syndrome is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth deficiency in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild or no anemia with only subtle erythroid abnormalities and/or physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA syndrome is associated with an increased risk for acute myelogenous leukemia, myelodysplastic syndrome, and solid tumors including osteogenic sarcoma. The clinical diagnosis of DBA syndrome can be established in a proband with characteristic laboratory, histopathology, and clinical features. The molecular diagnosis of DBA syndrome can be established in a proband by identification of a heterozygous pathogenic variant in a gene associated with autosomal dominant DBA syndrome or biallelic pathogenic variants in Most often, DBA syndrome is inherited in an autosomal dominant manner. Once the DBA syndrome-causing variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
## Diagnosis DBA syndrome Pallor, weakness, poor weight gain Growth deficiency (observed in 30%) Congenital malformations (observed in ~30%-50%); in particular craniofacial, upper-limb (thumb), heart, and genitourinary malformations Macrocytic anemia with no other significant cytopenias Increased erythrocyte mean corpuscular volume Reticulocytopenia Elevated erythrocyte adenosine deaminase activity (observed in 80%-85%) Elevated hemoglobin F concentration Negative parvovirus B19 PCR testing in blood or bone marrow and negative serology Normal marrow cellularity Erythroid hypoplasia with marked reduction in normoblasts Persistence of pronormoblasts on occasion Normal myeloid precursors and megakaryocytes The clinical diagnosis of DBA syndrome Moderate-to-severe macrocytic anemia with typical onset prior to age one year (although DBA syndrome can present later) No other significant cytopenias Reticulocytopenia Normal marrow cellularity with a paucity of erythroid precursors No evidence of another acquired or hereditary disorder of bone marrow function (See Congenital malformation reported in DBA syndrome (e.g., craniofacial, upper limb, heart, and/or genitourinary) The molecular diagnosis A heterozygous pathogenic (or likely pathogenic) variant in Biallelic pathogenic (or likely pathogenic) variants in Rarely, the molecular diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of DBA syndrome, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of DBA syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DBA 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 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. • Pallor, weakness, poor weight gain • Growth deficiency (observed in 30%) • Congenital malformations (observed in ~30%-50%); in particular craniofacial, upper-limb (thumb), heart, and genitourinary malformations • Macrocytic anemia with no other significant cytopenias • Increased erythrocyte mean corpuscular volume • Reticulocytopenia • Elevated erythrocyte adenosine deaminase activity (observed in 80%-85%) • Elevated hemoglobin F concentration • Negative parvovirus B19 PCR testing in blood or bone marrow and negative serology • Normal marrow cellularity • Erythroid hypoplasia with marked reduction in normoblasts • Persistence of pronormoblasts on occasion • Normal myeloid precursors and megakaryocytes • Moderate-to-severe macrocytic anemia with typical onset prior to age one year (although DBA syndrome can present later) • No other significant cytopenias • Reticulocytopenia • Normal marrow cellularity with a paucity of erythroid precursors • No evidence of another acquired or hereditary disorder of bone marrow function (See • Congenital malformation reported in DBA syndrome (e.g., craniofacial, upper limb, heart, and/or genitourinary) • A heterozygous pathogenic (or likely pathogenic) variant in • Biallelic pathogenic (or likely pathogenic) variants in ## Suggestive Findings DBA syndrome Pallor, weakness, poor weight gain Growth deficiency (observed in 30%) Congenital malformations (observed in ~30%-50%); in particular craniofacial, upper-limb (thumb), heart, and genitourinary malformations Macrocytic anemia with no other significant cytopenias Increased erythrocyte mean corpuscular volume Reticulocytopenia Elevated erythrocyte adenosine deaminase activity (observed in 80%-85%) Elevated hemoglobin F concentration Negative parvovirus B19 PCR testing in blood or bone marrow and negative serology Normal marrow cellularity Erythroid hypoplasia with marked reduction in normoblasts Persistence of pronormoblasts on occasion Normal myeloid precursors and megakaryocytes • Pallor, weakness, poor weight gain • Growth deficiency (observed in 30%) • Congenital malformations (observed in ~30%-50%); in particular craniofacial, upper-limb (thumb), heart, and genitourinary malformations • Macrocytic anemia with no other significant cytopenias • Increased erythrocyte mean corpuscular volume • Reticulocytopenia • Elevated erythrocyte adenosine deaminase activity (observed in 80%-85%) • Elevated hemoglobin F concentration • Negative parvovirus B19 PCR testing in blood or bone marrow and negative serology • Normal marrow cellularity • Erythroid hypoplasia with marked reduction in normoblasts • Persistence of pronormoblasts on occasion • Normal myeloid precursors and megakaryocytes ## Establishing the Diagnosis The clinical diagnosis of DBA syndrome Moderate-to-severe macrocytic anemia with typical onset prior to age one year (although DBA syndrome can present later) No other significant cytopenias Reticulocytopenia Normal marrow cellularity with a paucity of erythroid precursors No evidence of another acquired or hereditary disorder of bone marrow function (See Congenital malformation reported in DBA syndrome (e.g., craniofacial, upper limb, heart, and/or genitourinary) The molecular diagnosis A heterozygous pathogenic (or likely pathogenic) variant in Biallelic pathogenic (or likely pathogenic) variants in Rarely, the molecular diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of DBA syndrome, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of DBA syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DBA 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 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. • Moderate-to-severe macrocytic anemia with typical onset prior to age one year (although DBA syndrome can present later) • No other significant cytopenias • Reticulocytopenia • Normal marrow cellularity with a paucity of erythroid precursors • No evidence of another acquired or hereditary disorder of bone marrow function (See • Congenital malformation reported in DBA syndrome (e.g., craniofacial, upper limb, heart, and/or genitourinary) • A heterozygous pathogenic (or likely pathogenic) variant in • Biallelic pathogenic (or likely pathogenic) variants in ## Clinical Diagnosis The clinical diagnosis of DBA syndrome Moderate-to-severe macrocytic anemia with typical onset prior to age one year (although DBA syndrome can present later) No other significant cytopenias Reticulocytopenia Normal marrow cellularity with a paucity of erythroid precursors No evidence of another acquired or hereditary disorder of bone marrow function (See Congenital malformation reported in DBA syndrome (e.g., craniofacial, upper limb, heart, and/or genitourinary) • Moderate-to-severe macrocytic anemia with typical onset prior to age one year (although DBA syndrome can present later) • No other significant cytopenias • Reticulocytopenia • Normal marrow cellularity with a paucity of erythroid precursors • No evidence of another acquired or hereditary disorder of bone marrow function (See • Congenital malformation reported in DBA syndrome (e.g., craniofacial, upper limb, heart, and/or genitourinary) ## Molecular Diagnosis The molecular diagnosis A heterozygous pathogenic (or likely pathogenic) variant in Biallelic pathogenic (or likely pathogenic) variants in Rarely, the molecular diagnosis Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of DBA syndrome, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of DBA syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DBA 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 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 heterozygous pathogenic (or likely pathogenic) variant in • Biallelic pathogenic (or likely pathogenic) variants in ## When the phenotypic and laboratory findings suggest the diagnosis of DBA syndrome, molecular genetic testing approaches can include use of a For an introduction to multigene panels click ## When the diagnosis of DBA syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in DBA 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 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 DBA syndrome is characterized by early-onset hypoplastic anemia. Congenital anomalies are observed in approximately 50% of affected individuals and more than one anomaly is observed in up to 25% of individuals. Additional features include growth deficiency and predisposition to malignancy. DBA Syndrome: Frequency of Select Features 90% in 1st year of life Rarely, DBA syndrome is diagnosed w/o anemia. The Many pathogenic variants are unique to a family and no clinically relevant genotype-phenotype correlations have been confirmed. Penetrance is almost complete with loss-of-function variants in DBA syndrome has previously been known as Diamond-Blackfan anemia, congenital hypoplastic anemia of Blackfan and Diamond, congenital hypoplastic anemia, Blackfan-Diamond syndrome, Aase syndrome, and Aase-Smith syndrome II. The 2024 International Consensus Statement [ The incidence of DBA syndrome is estimated at between 1:100,000 and 1:200,000 live births; incidence remains consistent across ethnicities [ • 90% in 1st year of life • Rarely, DBA syndrome is diagnosed w/o anemia. ## Clinical Description DBA syndrome is characterized by early-onset hypoplastic anemia. Congenital anomalies are observed in approximately 50% of affected individuals and more than one anomaly is observed in up to 25% of individuals. Additional features include growth deficiency and predisposition to malignancy. DBA Syndrome: Frequency of Select Features 90% in 1st year of life Rarely, DBA syndrome is diagnosed w/o anemia. The • 90% in 1st year of life • Rarely, DBA syndrome is diagnosed w/o anemia. ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations Many pathogenic variants are unique to a family and no clinically relevant genotype-phenotype correlations have been confirmed. ## Penetrance Penetrance is almost complete with loss-of-function variants in ## Nomenclature DBA syndrome has previously been known as Diamond-Blackfan anemia, congenital hypoplastic anemia of Blackfan and Diamond, congenital hypoplastic anemia, Blackfan-Diamond syndrome, Aase syndrome, and Aase-Smith syndrome II. The 2024 International Consensus Statement [ ## Prevalence The incidence of DBA syndrome is estimated at between 1:100,000 and 1:200,000 live births; incidence remains consistent across ethnicities [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ HIV and COVID-19 are associated with PRCA. Viral hepatitis Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies Differential Diagnosis of DBA Syndrome: Hereditary Disorders of Bone Marrow Function Broad phenotypic spectrum; includes persons w/classic DC as well as those w/very short telomeres & an isolated physical finding Classic DC is characterized by triad of dysplastic nails, lacy reticular pigmentation of upper chest &/or neck, & oral leukoplakia (triad may not be present in all persons). ↑ risk for progressive BMF, MDS or AML, solid tumors, & pulmonary fibrosis Complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, &/or hematologic abnormalities may predominate. Hematopoietic complications include variably decreased numbers of leukocytes, platelets, & erythrocytes (including PRCA similar to DBA syndrome), as well as pancytopenia due to complete BMF. Physical abnormalities (~75% of affected persons): short stature, abnormal skin pigmentation, skeletal malformations, microcephaly, ophthalmic & genitourinary tract anomalies Progressive BMF w/pancytopenia typically presents in 1st decade, often initially with thrombocytopenia or leukopenia. Incidence of AML is 13% by age 50 yrs. Solid tumors – particularly of head & neck, skin, & genitourinary tract – are more common in persons w/Fanconi anemia. Exocrine pancreatic dysfunction w/malabsorption, malnutrition, poor weight gain, &/or growth delay Hematologic abnormalities w/single- or multilineage cytopenias & susceptibility to MDS & AML Persistent or intermittent neutropenia is an early finding in almost all affected children. Bone abnormalities Short stature & recurrent infections are common. Sideroblastic anemia of childhood, pancytopenia, exocrine pancreatic failure, & renal tubular defects Progressive liver failure & intractable metabolic acidosis typically result in death in infancy. Those who survive may develop neurologic symptoms. SCID w/microcephaly, growth restriction, & sensitivity to ionizing radiation Dysmorphic facies 50% have anemia & thrombocytopenia. Severe disproportionate (short-limb) short stature Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, ↑ risk for malignancy, gastrointestinal dysfunction, & impaired spermatogenesis. Clinical manifestations are variable, even w/in the same family. AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; BMF = bone marrow failure; DBA = Diamond-Blackfan anemia; DD = developmental delay; EPO = erythropoietin; MDS = myelodysplastic syndrome; MOI = mode of inheritance; mt = mitochondrial; PRCA = pure red cell aplasia; SCID = severe combined immunodeficiency; XL = X-linked The proportion of DC/TBD attributed to pathogenic variants in Single large-scale mitochondrial DNA deletion syndromes (such as Pearson syndrome) are almost never inherited, suggesting that these disorders are typically caused by a • • Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ • HIV and COVID-19 are associated with PRCA. • Viral hepatitis • Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 • Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ • HIV and COVID-19 are associated with PRCA. • Viral hepatitis • Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 • Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide • Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide • • Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies • Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies • Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ • HIV and COVID-19 are associated with PRCA. • Viral hepatitis • Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 • Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide • Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies • Broad phenotypic spectrum; includes persons w/classic DC as well as those w/very short telomeres & an isolated physical finding • Classic DC is characterized by triad of dysplastic nails, lacy reticular pigmentation of upper chest &/or neck, & oral leukoplakia (triad may not be present in all persons). • ↑ risk for progressive BMF, MDS or AML, solid tumors, & pulmonary fibrosis • Complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, &/or hematologic abnormalities may predominate. • Hematopoietic complications include variably decreased numbers of leukocytes, platelets, & erythrocytes (including PRCA similar to DBA syndrome), as well as pancytopenia due to complete BMF. • Physical abnormalities (~75% of affected persons): short stature, abnormal skin pigmentation, skeletal malformations, microcephaly, ophthalmic & genitourinary tract anomalies • Progressive BMF w/pancytopenia typically presents in 1st decade, often initially with thrombocytopenia or leukopenia. • Incidence of AML is 13% by age 50 yrs. • Solid tumors – particularly of head & neck, skin, & genitourinary tract – are more common in persons w/Fanconi anemia. • Exocrine pancreatic dysfunction w/malabsorption, malnutrition, poor weight gain, &/or growth delay • Hematologic abnormalities w/single- or multilineage cytopenias & susceptibility to MDS & AML • Persistent or intermittent neutropenia is an early finding in almost all affected children. • Bone abnormalities • Short stature & recurrent infections are common. • Sideroblastic anemia of childhood, pancytopenia, exocrine pancreatic failure, & renal tubular defects • Progressive liver failure & intractable metabolic acidosis typically result in death in infancy. • Those who survive may develop neurologic symptoms. • SCID w/microcephaly, growth restriction, & sensitivity to ionizing radiation • Dysmorphic facies • 50% have anemia & thrombocytopenia. • Severe disproportionate (short-limb) short stature • Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, ↑ risk for malignancy, gastrointestinal dysfunction, & impaired spermatogenesis. • Clinical manifestations are variable, even w/in the same family. ## Acquired Disorders of Bone Marrow Erythroid Hypoplasia Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ HIV and COVID-19 are associated with PRCA. Viral hepatitis Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies • • Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ • HIV and COVID-19 are associated with PRCA. • Viral hepatitis • Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 • Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ • HIV and COVID-19 are associated with PRCA. • Viral hepatitis • Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 • Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide • Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide • • Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies • Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies • Parvovirus B19 infection is usually asymptomatic but can occasionally cause red cell aplasia, which is most often mild and self-limited by production of virus-neutralizing antibodies in the host [ • HIV and COVID-19 are associated with PRCA. • Viral hepatitis • Infectious mononucleosis (EBV) and human T-cell lymphotropic virus type 1 • Anti-seizure medications: diphenylhydantoin, sodium valproate, carbamazepine, sodium dipropylacetate • Others: azathioprine; chloramphenicol and thiamphenicol; sulfonamides; isoniazid; procainamide • Thymoma is most commonly associated with PRCA. Approximately 5%-10% of persons with thymoma develop PRCA. • Myasthenia gravis, systemic lupus erythematosus, and multiple endocrinopathies ## Hereditary Disorders of Bone Marrow Function Differential Diagnosis of DBA Syndrome: Hereditary Disorders of Bone Marrow Function Broad phenotypic spectrum; includes persons w/classic DC as well as those w/very short telomeres & an isolated physical finding Classic DC is characterized by triad of dysplastic nails, lacy reticular pigmentation of upper chest &/or neck, & oral leukoplakia (triad may not be present in all persons). ↑ risk for progressive BMF, MDS or AML, solid tumors, & pulmonary fibrosis Complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, &/or hematologic abnormalities may predominate. Hematopoietic complications include variably decreased numbers of leukocytes, platelets, & erythrocytes (including PRCA similar to DBA syndrome), as well as pancytopenia due to complete BMF. Physical abnormalities (~75% of affected persons): short stature, abnormal skin pigmentation, skeletal malformations, microcephaly, ophthalmic & genitourinary tract anomalies Progressive BMF w/pancytopenia typically presents in 1st decade, often initially with thrombocytopenia or leukopenia. Incidence of AML is 13% by age 50 yrs. Solid tumors – particularly of head & neck, skin, & genitourinary tract – are more common in persons w/Fanconi anemia. Exocrine pancreatic dysfunction w/malabsorption, malnutrition, poor weight gain, &/or growth delay Hematologic abnormalities w/single- or multilineage cytopenias & susceptibility to MDS & AML Persistent or intermittent neutropenia is an early finding in almost all affected children. Bone abnormalities Short stature & recurrent infections are common. Sideroblastic anemia of childhood, pancytopenia, exocrine pancreatic failure, & renal tubular defects Progressive liver failure & intractable metabolic acidosis typically result in death in infancy. Those who survive may develop neurologic symptoms. SCID w/microcephaly, growth restriction, & sensitivity to ionizing radiation Dysmorphic facies 50% have anemia & thrombocytopenia. Severe disproportionate (short-limb) short stature Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, ↑ risk for malignancy, gastrointestinal dysfunction, & impaired spermatogenesis. Clinical manifestations are variable, even w/in the same family. AD = autosomal dominant; AML = acute myeloid leukemia; AR = autosomal recessive; BMF = bone marrow failure; DBA = Diamond-Blackfan anemia; DD = developmental delay; EPO = erythropoietin; MDS = myelodysplastic syndrome; MOI = mode of inheritance; mt = mitochondrial; PRCA = pure red cell aplasia; SCID = severe combined immunodeficiency; XL = X-linked The proportion of DC/TBD attributed to pathogenic variants in Single large-scale mitochondrial DNA deletion syndromes (such as Pearson syndrome) are almost never inherited, suggesting that these disorders are typically caused by a • Broad phenotypic spectrum; includes persons w/classic DC as well as those w/very short telomeres & an isolated physical finding • Classic DC is characterized by triad of dysplastic nails, lacy reticular pigmentation of upper chest &/or neck, & oral leukoplakia (triad may not be present in all persons). • ↑ risk for progressive BMF, MDS or AML, solid tumors, & pulmonary fibrosis • Complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, &/or hematologic abnormalities may predominate. • Hematopoietic complications include variably decreased numbers of leukocytes, platelets, & erythrocytes (including PRCA similar to DBA syndrome), as well as pancytopenia due to complete BMF. • Physical abnormalities (~75% of affected persons): short stature, abnormal skin pigmentation, skeletal malformations, microcephaly, ophthalmic & genitourinary tract anomalies • Progressive BMF w/pancytopenia typically presents in 1st decade, often initially with thrombocytopenia or leukopenia. • Incidence of AML is 13% by age 50 yrs. • Solid tumors – particularly of head & neck, skin, & genitourinary tract – are more common in persons w/Fanconi anemia. • Exocrine pancreatic dysfunction w/malabsorption, malnutrition, poor weight gain, &/or growth delay • Hematologic abnormalities w/single- or multilineage cytopenias & susceptibility to MDS & AML • Persistent or intermittent neutropenia is an early finding in almost all affected children. • Bone abnormalities • Short stature & recurrent infections are common. • Sideroblastic anemia of childhood, pancytopenia, exocrine pancreatic failure, & renal tubular defects • Progressive liver failure & intractable metabolic acidosis typically result in death in infancy. • Those who survive may develop neurologic symptoms. • SCID w/microcephaly, growth restriction, & sensitivity to ionizing radiation • Dysmorphic facies • 50% have anemia & thrombocytopenia. • Severe disproportionate (short-limb) short stature • Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, ↑ risk for malignancy, gastrointestinal dysfunction, & impaired spermatogenesis. • Clinical manifestations are variable, even w/in the same family. ## Management Clinical practice guidelines for treatment and surveillance of individuals with DBA syndrome have been published [ To establish the extent of disease and needs in an individual diagnosed with DBA syndrome, the evaluations summarized in DBA Syndrome: Recommended Evaluations Following Initial Diagnosis Eval by hematologist for macrocytosis & reticulocytopenia Ferritin, LDH, bilirubin, transaminases, creatinine, folate, vitamin B Clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity Upper-limb &/or thumb anomalies Eval by nephrologist & urologist as appropriate Ultrasound exam of kidneys & urinary tract Community or Social work involvement for parental support Home nursing referral LDH = lactate dehydrogenase; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) DBA Syndrome: Targeted Therapies Starting dose: 2 mg/kg/day orally 1x daily in am for 4 weeks. If no response, taper over 2 weeks. Slowly taper responders to minimal effective dose (0.3 mg/kg/day is target daily dose or preferably 0.6 mg/kg every other day to avoid adrenal suppression). In those age ≥12 mos & 10-14 days after RBC transfusion Can improve RBC count in 60%-80% of persons The only curative therapy Persons who are transfusion dependent or develop other cytopenias are often treated w/HSCT. HSCT = hematopoietic stem cell transplantation; RBC = red blood cell In older children a 2.5-mg dose is easily given by splitting a 5 mg tablet in half. To avoid adrenal suppression, 5 mg (or the affected individual's maintenance dose) should be given every other day, i.e., equivalent to 2.5 mg daily for a 10-kg child [C Sieff, personal observation] An increase in hemoglobin and reticulocyte count (>50 x 10 In individuals who respond, corticosteroids should be slowly tapered at four weeks after starting treatment to the minimally effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at or greater than a target of 90 g/L, the minimum required for transfusion independence. The corticosteroid maintenance dose varies and can be extremely low in some individuals. Concerns about the long-term effects of steroids have led to the recommendation of 0.25 mg/kg/day as a preferable minimum daily dose. Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth restriction, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection. In one study of 61 persons with DBA syndrome who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range: 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [ The DBA Registry of North America describes 36 individuals who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Survival greater than five years from HSCT for allogeneic sib transplants was 72.7% ± 10.7% vs survival greater than five years from alternative donor transplants of 17.1% ± 11.9% [ In a French/German HSCT study of 70 children with DBA syndrome, a matched sib donor was available for 45 individuals, a 10/10 HLA-matched unrelated donor in 12 individuals, a 9/10 HLA-matched unrelated donor in seven individuals, and a less compatible or incomplete HLA-matched donor in six individuals. Overall survival was 91% with no difference by donor type. All individuals engrafted; one individual had secondary graft failure. The difference in chronic graft-vs-host disease between children transplanted before age ten years compared with older individuals did not reach statistical significance. Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA syndrome to identify the most suitable bone marrow donor in the event that HSCT is required. (2) Because penetrance of DBA syndrome is reduced, it is possible that a relative considered as a bone marrow donor could have a pathogenic variant but not manifest findings of DBA syndrome. (3) Relatives with a pathogenic variant, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient. 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 DBA Syndrome: Treatment of Manifestations See RBC transfusion in those resistant to corticosteroid therapy Usually started after 10-12 RBC transfusions (170-200 mL/kg of packed RBC), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue Treatment options typically include deferasirox or desferrioxamine. Refer to a center w/experience in T Recommended in those age ≥2 yrs Recommended dose: 20-30 mg/kg/day Side effects are usually mild & include rash, nausea, creatinine elevation, & rarely proteinuria & transaminase elevation. Satisfaction w/deferasirox is greater than w/desferrioxamine, mostly because of ease of administration. Recommended initial dose: 40 mg/kg/day Maximum dose: 50-60 mg/kg/day Dose & frequency of infusion may be modified using serum ferritin concentration or hepatic iron concentration as a guide. Side effects: ocular & auditory toxicity & growth deficiency Adherence is hampered by demanding administration route & schedule. Deferiprone is highly efficacious in removing excess cardiac iron. Agranulocytosis is the most serious adverse event & occurs in ~10% of those w/DBA syndrome. Surgical mgmt of thumb anomalies as recommended by orthopedist Occupational & physical therapy as needed HSCT = hematopoietic stem cell transplantation; RBC = red blood cell Deferiprone is not recommended in the treatment of iron overload in individuals with DBA syndrome except for those with severe cardiac iron overload [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in DBA Syndrome: Recommended Surveillance Monitor blood pressure for risk of hypertension. Assess for gastric ulcers & frequency of infection. T Magnetic biosusceptometry (SQUID) to assess liver iron; noninvasive but not widely available & rarely used Liver biopsy specimen; accurately determines total body iron accumulation but is not practical choice for long-term follow up Every 4-6 mo in those who are otherwise healthy Annually in stable treatment-responsive children RBC = red blood cell; WBC = white blood cell Deferiprone is not recommended in the treatment of iron overload in persons with DBA syndrome except those with severe cardiac iron overload because its side effects include neutropenia [ Individuals with DBA syndrome, especially those on corticosteroid treatment, should take reasonable precautions to avoid infections, as steroid-dependent individuals are more prone to complications resulting from immune system dysfunction. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual to allow early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers. Evaluations include: Molecular genetic testing if the pathogenic variant in the family is known; Consideration of other testing (e.g., mean corpuscular volume, erythrocyte adenosine deaminase activity, and/or fetal hemoglobin concentration) if the pathogenic variant in the family is not known – especially of relatives being considered as bone marrow donors [ Note: Individuals found to have a familial DBA syndrome-causing variant should have a complete blood count to evaluate for anemia. If anemia is identified, further evaluation for manifestations of DBA syndrome is recommended (see See Management of pregnancy in women with DBA syndrome requires obstetricians with expertise in high-risk pregnancies and hematologists with experience with bone marrow failure syndromes [ During pregnancy the maternal hemoglobin level must be monitored. Use of low-dose aspirin up to 37 weeks' gestation may help prevent vasculoplacental complications in women with a history of a previous problematic pregnancy [ A study that surveyed 64 pregnancies in women with DBA syndrome found a high incidence of complications in both mothers and children. Risks include the following [ Intrauterine growth restriction Preeclampsia Retroplacental hematoma In utero fetal death Preterm delivery Search • Eval by hematologist for macrocytosis & reticulocytopenia • Ferritin, LDH, bilirubin, transaminases, creatinine, folate, vitamin B • Clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity • Upper-limb &/or thumb anomalies • Eval by nephrologist & urologist as appropriate • Ultrasound exam of kidneys & urinary tract • Community or • Social work involvement for parental support • Home nursing referral • Starting dose: 2 mg/kg/day orally 1x daily in am for 4 weeks. If no response, taper over 2 weeks. • Slowly taper responders to minimal effective dose (0.3 mg/kg/day is target daily dose or preferably 0.6 mg/kg every other day to avoid adrenal suppression). • In those age ≥12 mos & 10-14 days after RBC transfusion • Can improve RBC count in 60%-80% of persons • The only curative therapy • Persons who are transfusion dependent or develop other cytopenias are often treated w/HSCT. • An increase in hemoglobin and reticulocyte count (>50 x 10 • In individuals who respond, corticosteroids should be slowly tapered at four weeks after starting treatment to the minimally effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at or greater than a target of 90 g/L, the minimum required for transfusion independence. • The corticosteroid maintenance dose varies and can be extremely low in some individuals. Concerns about the long-term effects of steroids have led to the recommendation of 0.25 mg/kg/day as a preferable minimum daily dose. • Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth restriction, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection. • In one study of 61 persons with DBA syndrome who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range: 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [ • The DBA Registry of North America describes 36 individuals who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Survival greater than five years from HSCT for allogeneic sib transplants was 72.7% ± 10.7% vs survival greater than five years from alternative donor transplants of 17.1% ± 11.9% [ • In a French/German HSCT study of 70 children with DBA syndrome, a matched sib donor was available for 45 individuals, a 10/10 HLA-matched unrelated donor in 12 individuals, a 9/10 HLA-matched unrelated donor in seven individuals, and a less compatible or incomplete HLA-matched donor in six individuals. Overall survival was 91% with no difference by donor type. All individuals engrafted; one individual had secondary graft failure. The difference in chronic graft-vs-host disease between children transplanted before age ten years compared with older individuals did not reach statistical significance. • Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA syndrome to identify the most suitable bone marrow donor in the event that HSCT is required. (2) Because penetrance of DBA syndrome is reduced, it is possible that a relative considered as a bone marrow donor could have a pathogenic variant but not manifest findings of DBA syndrome. (3) Relatives with a pathogenic variant, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient. • See • RBC transfusion in those resistant to corticosteroid therapy • Usually started after 10-12 RBC transfusions (170-200 mL/kg of packed RBC), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue • Treatment options typically include deferasirox or desferrioxamine. • Refer to a center w/experience in T • Recommended in those age ≥2 yrs • Recommended dose: 20-30 mg/kg/day • Side effects are usually mild & include rash, nausea, creatinine elevation, & rarely proteinuria & transaminase elevation. • Satisfaction w/deferasirox is greater than w/desferrioxamine, mostly because of ease of administration. • Recommended initial dose: 40 mg/kg/day • Maximum dose: 50-60 mg/kg/day • Dose & frequency of infusion may be modified using serum ferritin concentration or hepatic iron concentration as a guide. • Side effects: ocular & auditory toxicity & growth deficiency • Adherence is hampered by demanding administration route & schedule. • Deferiprone is highly efficacious in removing excess cardiac iron. • Agranulocytosis is the most serious adverse event & occurs in ~10% of those w/DBA syndrome. • Surgical mgmt of thumb anomalies as recommended by orthopedist • Occupational & physical therapy as needed • Monitor blood pressure for risk of hypertension. • Assess for gastric ulcers & frequency of infection. • T • Magnetic biosusceptometry (SQUID) to assess liver iron; noninvasive but not widely available & rarely used • Liver biopsy specimen; accurately determines total body iron accumulation but is not practical choice for long-term follow up • Every 4-6 mo in those who are otherwise healthy • Annually in stable treatment-responsive children • Molecular genetic testing if the pathogenic variant in the family is known; • Consideration of other testing (e.g., mean corpuscular volume, erythrocyte adenosine deaminase activity, and/or fetal hemoglobin concentration) if the pathogenic variant in the family is not known – especially of relatives being considered as bone marrow donors [ • Intrauterine growth restriction • Preeclampsia • Retroplacental hematoma • In utero fetal death • Preterm delivery ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DBA syndrome, the evaluations summarized in DBA Syndrome: Recommended Evaluations Following Initial Diagnosis Eval by hematologist for macrocytosis & reticulocytopenia Ferritin, LDH, bilirubin, transaminases, creatinine, folate, vitamin B Clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity Upper-limb &/or thumb anomalies Eval by nephrologist & urologist as appropriate Ultrasound exam of kidneys & urinary tract Community or Social work involvement for parental support Home nursing referral LDH = lactate dehydrogenase; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Eval by hematologist for macrocytosis & reticulocytopenia • Ferritin, LDH, bilirubin, transaminases, creatinine, folate, vitamin B • Clinical findings suggestive of Klippel-Feil anomaly or Sprengel deformity • Upper-limb &/or thumb anomalies • Eval by nephrologist & urologist as appropriate • Ultrasound exam of kidneys & urinary tract • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations DBA Syndrome: Targeted Therapies Starting dose: 2 mg/kg/day orally 1x daily in am for 4 weeks. If no response, taper over 2 weeks. Slowly taper responders to minimal effective dose (0.3 mg/kg/day is target daily dose or preferably 0.6 mg/kg every other day to avoid adrenal suppression). In those age ≥12 mos & 10-14 days after RBC transfusion Can improve RBC count in 60%-80% of persons The only curative therapy Persons who are transfusion dependent or develop other cytopenias are often treated w/HSCT. HSCT = hematopoietic stem cell transplantation; RBC = red blood cell In older children a 2.5-mg dose is easily given by splitting a 5 mg tablet in half. To avoid adrenal suppression, 5 mg (or the affected individual's maintenance dose) should be given every other day, i.e., equivalent to 2.5 mg daily for a 10-kg child [C Sieff, personal observation] An increase in hemoglobin and reticulocyte count (>50 x 10 In individuals who respond, corticosteroids should be slowly tapered at four weeks after starting treatment to the minimally effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at or greater than a target of 90 g/L, the minimum required for transfusion independence. The corticosteroid maintenance dose varies and can be extremely low in some individuals. Concerns about the long-term effects of steroids have led to the recommendation of 0.25 mg/kg/day as a preferable minimum daily dose. Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth restriction, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection. In one study of 61 persons with DBA syndrome who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range: 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [ The DBA Registry of North America describes 36 individuals who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Survival greater than five years from HSCT for allogeneic sib transplants was 72.7% ± 10.7% vs survival greater than five years from alternative donor transplants of 17.1% ± 11.9% [ In a French/German HSCT study of 70 children with DBA syndrome, a matched sib donor was available for 45 individuals, a 10/10 HLA-matched unrelated donor in 12 individuals, a 9/10 HLA-matched unrelated donor in seven individuals, and a less compatible or incomplete HLA-matched donor in six individuals. Overall survival was 91% with no difference by donor type. All individuals engrafted; one individual had secondary graft failure. The difference in chronic graft-vs-host disease between children transplanted before age ten years compared with older individuals did not reach statistical significance. Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA syndrome to identify the most suitable bone marrow donor in the event that HSCT is required. (2) Because penetrance of DBA syndrome is reduced, it is possible that a relative considered as a bone marrow donor could have a pathogenic variant but not manifest findings of DBA syndrome. (3) Relatives with a pathogenic variant, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient. 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 DBA Syndrome: Treatment of Manifestations See RBC transfusion in those resistant to corticosteroid therapy Usually started after 10-12 RBC transfusions (170-200 mL/kg of packed RBC), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue Treatment options typically include deferasirox or desferrioxamine. Refer to a center w/experience in T Recommended in those age ≥2 yrs Recommended dose: 20-30 mg/kg/day Side effects are usually mild & include rash, nausea, creatinine elevation, & rarely proteinuria & transaminase elevation. Satisfaction w/deferasirox is greater than w/desferrioxamine, mostly because of ease of administration. Recommended initial dose: 40 mg/kg/day Maximum dose: 50-60 mg/kg/day Dose & frequency of infusion may be modified using serum ferritin concentration or hepatic iron concentration as a guide. Side effects: ocular & auditory toxicity & growth deficiency Adherence is hampered by demanding administration route & schedule. Deferiprone is highly efficacious in removing excess cardiac iron. Agranulocytosis is the most serious adverse event & occurs in ~10% of those w/DBA syndrome. Surgical mgmt of thumb anomalies as recommended by orthopedist Occupational & physical therapy as needed HSCT = hematopoietic stem cell transplantation; RBC = red blood cell Deferiprone is not recommended in the treatment of iron overload in individuals with DBA syndrome except for those with severe cardiac iron overload [ • Starting dose: 2 mg/kg/day orally 1x daily in am for 4 weeks. If no response, taper over 2 weeks. • Slowly taper responders to minimal effective dose (0.3 mg/kg/day is target daily dose or preferably 0.6 mg/kg every other day to avoid adrenal suppression). • In those age ≥12 mos & 10-14 days after RBC transfusion • Can improve RBC count in 60%-80% of persons • The only curative therapy • Persons who are transfusion dependent or develop other cytopenias are often treated w/HSCT. • An increase in hemoglobin and reticulocyte count (>50 x 10 • In individuals who respond, corticosteroids should be slowly tapered at four weeks after starting treatment to the minimally effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at or greater than a target of 90 g/L, the minimum required for transfusion independence. • The corticosteroid maintenance dose varies and can be extremely low in some individuals. Concerns about the long-term effects of steroids have led to the recommendation of 0.25 mg/kg/day as a preferable minimum daily dose. • Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth restriction, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection. • In one study of 61 persons with DBA syndrome who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range: 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [ • The DBA Registry of North America describes 36 individuals who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Survival greater than five years from HSCT for allogeneic sib transplants was 72.7% ± 10.7% vs survival greater than five years from alternative donor transplants of 17.1% ± 11.9% [ • In a French/German HSCT study of 70 children with DBA syndrome, a matched sib donor was available for 45 individuals, a 10/10 HLA-matched unrelated donor in 12 individuals, a 9/10 HLA-matched unrelated donor in seven individuals, and a less compatible or incomplete HLA-matched donor in six individuals. Overall survival was 91% with no difference by donor type. All individuals engrafted; one individual had secondary graft failure. The difference in chronic graft-vs-host disease between children transplanted before age ten years compared with older individuals did not reach statistical significance. • Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA syndrome to identify the most suitable bone marrow donor in the event that HSCT is required. (2) Because penetrance of DBA syndrome is reduced, it is possible that a relative considered as a bone marrow donor could have a pathogenic variant but not manifest findings of DBA syndrome. (3) Relatives with a pathogenic variant, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient. • See • RBC transfusion in those resistant to corticosteroid therapy • Usually started after 10-12 RBC transfusions (170-200 mL/kg of packed RBC), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue • Treatment options typically include deferasirox or desferrioxamine. • Refer to a center w/experience in T • Recommended in those age ≥2 yrs • Recommended dose: 20-30 mg/kg/day • Side effects are usually mild & include rash, nausea, creatinine elevation, & rarely proteinuria & transaminase elevation. • Satisfaction w/deferasirox is greater than w/desferrioxamine, mostly because of ease of administration. • Recommended initial dose: 40 mg/kg/day • Maximum dose: 50-60 mg/kg/day • Dose & frequency of infusion may be modified using serum ferritin concentration or hepatic iron concentration as a guide. • Side effects: ocular & auditory toxicity & growth deficiency • Adherence is hampered by demanding administration route & schedule. • Deferiprone is highly efficacious in removing excess cardiac iron. • Agranulocytosis is the most serious adverse event & occurs in ~10% of those w/DBA syndrome. • Surgical mgmt of thumb anomalies as recommended by orthopedist • Occupational & physical therapy as needed ## Targeted Therapies DBA Syndrome: Targeted Therapies Starting dose: 2 mg/kg/day orally 1x daily in am for 4 weeks. If no response, taper over 2 weeks. Slowly taper responders to minimal effective dose (0.3 mg/kg/day is target daily dose or preferably 0.6 mg/kg every other day to avoid adrenal suppression). In those age ≥12 mos & 10-14 days after RBC transfusion Can improve RBC count in 60%-80% of persons The only curative therapy Persons who are transfusion dependent or develop other cytopenias are often treated w/HSCT. HSCT = hematopoietic stem cell transplantation; RBC = red blood cell In older children a 2.5-mg dose is easily given by splitting a 5 mg tablet in half. To avoid adrenal suppression, 5 mg (or the affected individual's maintenance dose) should be given every other day, i.e., equivalent to 2.5 mg daily for a 10-kg child [C Sieff, personal observation] An increase in hemoglobin and reticulocyte count (>50 x 10 In individuals who respond, corticosteroids should be slowly tapered at four weeks after starting treatment to the minimally effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at or greater than a target of 90 g/L, the minimum required for transfusion independence. The corticosteroid maintenance dose varies and can be extremely low in some individuals. Concerns about the long-term effects of steroids have led to the recommendation of 0.25 mg/kg/day as a preferable minimum daily dose. Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth restriction, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection. In one study of 61 persons with DBA syndrome who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range: 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [ The DBA Registry of North America describes 36 individuals who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Survival greater than five years from HSCT for allogeneic sib transplants was 72.7% ± 10.7% vs survival greater than five years from alternative donor transplants of 17.1% ± 11.9% [ In a French/German HSCT study of 70 children with DBA syndrome, a matched sib donor was available for 45 individuals, a 10/10 HLA-matched unrelated donor in 12 individuals, a 9/10 HLA-matched unrelated donor in seven individuals, and a less compatible or incomplete HLA-matched donor in six individuals. Overall survival was 91% with no difference by donor type. All individuals engrafted; one individual had secondary graft failure. The difference in chronic graft-vs-host disease between children transplanted before age ten years compared with older individuals did not reach statistical significance. Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA syndrome to identify the most suitable bone marrow donor in the event that HSCT is required. (2) Because penetrance of DBA syndrome is reduced, it is possible that a relative considered as a bone marrow donor could have a pathogenic variant but not manifest findings of DBA syndrome. (3) Relatives with a pathogenic variant, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient. • Starting dose: 2 mg/kg/day orally 1x daily in am for 4 weeks. If no response, taper over 2 weeks. • Slowly taper responders to minimal effective dose (0.3 mg/kg/day is target daily dose or preferably 0.6 mg/kg every other day to avoid adrenal suppression). • In those age ≥12 mos & 10-14 days after RBC transfusion • Can improve RBC count in 60%-80% of persons • The only curative therapy • Persons who are transfusion dependent or develop other cytopenias are often treated w/HSCT. • An increase in hemoglobin and reticulocyte count (>50 x 10 • In individuals who respond, corticosteroids should be slowly tapered at four weeks after starting treatment to the minimally effective dose. Monitoring of blood counts is needed to ensure that the red cell hemoglobin concentration remains at or greater than a target of 90 g/L, the minimum required for transfusion independence. • The corticosteroid maintenance dose varies and can be extremely low in some individuals. Concerns about the long-term effects of steroids have led to the recommendation of 0.25 mg/kg/day as a preferable minimum daily dose. • Side effects of corticosteroids include osteoporosis, weight gain, cushingoid appearance, hypertension, diabetes mellitus, growth restriction, pathologic bone fractures, gastric ulcers, cataracts, glaucoma, and increased susceptibility to infection. • In one study of 61 persons with DBA syndrome who underwent bone marrow transplantation (BMT), the majority (67%) received their bone marrow grafts from an HLA-matched related donor. The three-year probability of overall survival was 64% (range: 50%-74%). Transplantation from an HLA-identical sib donor was associated with better survival [ • The DBA Registry of North America describes 36 individuals who underwent HSCT: 21 HLA-matched sib HSCTs and 15 alternative donor HSCTs. Survival greater than five years from HSCT for allogeneic sib transplants was 72.7% ± 10.7% vs survival greater than five years from alternative donor transplants of 17.1% ± 11.9% [ • In a French/German HSCT study of 70 children with DBA syndrome, a matched sib donor was available for 45 individuals, a 10/10 HLA-matched unrelated donor in 12 individuals, a 9/10 HLA-matched unrelated donor in seven individuals, and a less compatible or incomplete HLA-matched donor in six individuals. Overall survival was 91% with no difference by donor type. All individuals engrafted; one individual had secondary graft failure. The difference in chronic graft-vs-host disease between children transplanted before age ten years compared with older individuals did not reach statistical significance. • Note: (1) It is recommended that the affected individual, sibs, and parents undergo HLA typing at the time of diagnosis of DBA syndrome to identify the most suitable bone marrow donor in the event that HSCT is required. (2) Because penetrance of DBA syndrome is reduced, it is possible that a relative considered as a bone marrow donor could have a pathogenic variant but not manifest findings of DBA syndrome. (3) Relatives with a pathogenic variant, regardless of their clinical status, are not suitable bone marrow donors, because their donated bone marrow may fail or not engraft in the recipient. ## 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 DBA Syndrome: Treatment of Manifestations See RBC transfusion in those resistant to corticosteroid therapy Usually started after 10-12 RBC transfusions (170-200 mL/kg of packed RBC), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue Treatment options typically include deferasirox or desferrioxamine. Refer to a center w/experience in T Recommended in those age ≥2 yrs Recommended dose: 20-30 mg/kg/day Side effects are usually mild & include rash, nausea, creatinine elevation, & rarely proteinuria & transaminase elevation. Satisfaction w/deferasirox is greater than w/desferrioxamine, mostly because of ease of administration. Recommended initial dose: 40 mg/kg/day Maximum dose: 50-60 mg/kg/day Dose & frequency of infusion may be modified using serum ferritin concentration or hepatic iron concentration as a guide. Side effects: ocular & auditory toxicity & growth deficiency Adherence is hampered by demanding administration route & schedule. Deferiprone is highly efficacious in removing excess cardiac iron. Agranulocytosis is the most serious adverse event & occurs in ~10% of those w/DBA syndrome. Surgical mgmt of thumb anomalies as recommended by orthopedist Occupational & physical therapy as needed HSCT = hematopoietic stem cell transplantation; RBC = red blood cell Deferiprone is not recommended in the treatment of iron overload in individuals with DBA syndrome except for those with severe cardiac iron overload [ • See • RBC transfusion in those resistant to corticosteroid therapy • Usually started after 10-12 RBC transfusions (170-200 mL/kg of packed RBC), when serum ferritin concentration reaches 1,000-1,500 µg/L, or when hepatic iron concentration reaches 6-7 mg/g of dry weight liver tissue • Treatment options typically include deferasirox or desferrioxamine. • Refer to a center w/experience in T • Recommended in those age ≥2 yrs • Recommended dose: 20-30 mg/kg/day • Side effects are usually mild & include rash, nausea, creatinine elevation, & rarely proteinuria & transaminase elevation. • Satisfaction w/deferasirox is greater than w/desferrioxamine, mostly because of ease of administration. • Recommended initial dose: 40 mg/kg/day • Maximum dose: 50-60 mg/kg/day • Dose & frequency of infusion may be modified using serum ferritin concentration or hepatic iron concentration as a guide. • Side effects: ocular & auditory toxicity & growth deficiency • Adherence is hampered by demanding administration route & schedule. • Deferiprone is highly efficacious in removing excess cardiac iron. • Agranulocytosis is the most serious adverse event & occurs in ~10% of those w/DBA syndrome. • Surgical mgmt of thumb anomalies as recommended by orthopedist • Occupational & physical therapy as needed ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in DBA Syndrome: Recommended Surveillance Monitor blood pressure for risk of hypertension. Assess for gastric ulcers & frequency of infection. T Magnetic biosusceptometry (SQUID) to assess liver iron; noninvasive but not widely available & rarely used Liver biopsy specimen; accurately determines total body iron accumulation but is not practical choice for long-term follow up Every 4-6 mo in those who are otherwise healthy Annually in stable treatment-responsive children RBC = red blood cell; WBC = white blood cell • Monitor blood pressure for risk of hypertension. • Assess for gastric ulcers & frequency of infection. • T • Magnetic biosusceptometry (SQUID) to assess liver iron; noninvasive but not widely available & rarely used • Liver biopsy specimen; accurately determines total body iron accumulation but is not practical choice for long-term follow up • Every 4-6 mo in those who are otherwise healthy • Annually in stable treatment-responsive children ## Agents/Circumstances to Avoid Deferiprone is not recommended in the treatment of iron overload in persons with DBA syndrome except those with severe cardiac iron overload because its side effects include neutropenia [ Individuals with DBA syndrome, especially those on corticosteroid treatment, should take reasonable precautions to avoid infections, as steroid-dependent individuals are more prone to complications resulting from immune system dysfunction. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual to allow early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers. Evaluations include: Molecular genetic testing if the pathogenic variant in the family is known; Consideration of other testing (e.g., mean corpuscular volume, erythrocyte adenosine deaminase activity, and/or fetal hemoglobin concentration) if the pathogenic variant in the family is not known – especially of relatives being considered as bone marrow donors [ Note: Individuals found to have a familial DBA syndrome-causing variant should have a complete blood count to evaluate for anemia. If anemia is identified, further evaluation for manifestations of DBA syndrome is recommended (see See • Molecular genetic testing if the pathogenic variant in the family is known; • Consideration of other testing (e.g., mean corpuscular volume, erythrocyte adenosine deaminase activity, and/or fetal hemoglobin concentration) if the pathogenic variant in the family is not known – especially of relatives being considered as bone marrow donors [ ## Pregnancy Management Management of pregnancy in women with DBA syndrome requires obstetricians with expertise in high-risk pregnancies and hematologists with experience with bone marrow failure syndromes [ During pregnancy the maternal hemoglobin level must be monitored. Use of low-dose aspirin up to 37 weeks' gestation may help prevent vasculoplacental complications in women with a history of a previous problematic pregnancy [ A study that surveyed 64 pregnancies in women with DBA syndrome found a high incidence of complications in both mothers and children. Risks include the following [ Intrauterine growth restriction Preeclampsia Retroplacental hematoma In utero fetal death Preterm delivery • Intrauterine growth restriction • Preeclampsia • Retroplacental hematoma • In utero fetal death • Preterm delivery ## Therapies Under Investigation Search ## Genetic Counseling Most often, DBA syndrome is inherited in an autosomal dominant manner. Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome inherited a DBA syndrome-causing variant from a parent who may or may not have manifestations of DBA syndrome [ Approximately 55%-60% of individuals diagnosed with autosomal dominant DBA syndrome 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, allow reliable assessment of risk to offspring and other family members, and determine their need for Note 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. Parental gonadal mosaicism is suggested in a family described by The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see An individual diagnosed with DBA syndrome may appear to be the only affected family member 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, If a parent of the proband is affected with autosomal dominant DBA syndrome 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 penetrance of DBA syndrome in heterozygous sibs is high but may vary somewhat depending on the familial pathogenic variant (see If the DBA syndrome-causing variant found in the proband is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism for the DBA syndrome-causing pathogenic variant [ If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DBA syndrome because of the possibility of parental gonadal mosaicism and the possibility that a parent is heterozygous but does not have apparent manifestations of DBA syndrome because of reduced penetrance or variable expressivity. 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 father of a male with 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 allow reliable recurrence risk assessment. If the mother of an affected male has a If the proband represents a simplex case and 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 DBA syndrome-causing variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for DBA syndrome 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. • Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome inherited a DBA syndrome-causing variant from a parent who may or may not have manifestations of DBA syndrome [ • Approximately 55%-60% of individuals diagnosed with autosomal dominant DBA syndrome 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, allow reliable assessment of risk to offspring and other family members, and determine their need for • Note • 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. Parental gonadal mosaicism is suggested in a family described by • The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism is suggested in a family described by • The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see • An individual diagnosed with DBA syndrome may appear to be the only affected family member 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, • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism is suggested in a family described by • The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see • If a parent of the proband is affected with autosomal dominant DBA syndrome 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 penetrance of DBA syndrome in heterozygous sibs is high but may vary somewhat depending on the familial pathogenic variant (see • If the DBA syndrome-causing variant found in the proband is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism for the DBA syndrome-causing pathogenic variant [ • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DBA syndrome because of the possibility of parental gonadal mosaicism and the possibility that a parent is heterozygous but does not have apparent manifestations of DBA syndrome because of reduced penetrance or variable expressivity. • 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 father of a male with • 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 allow reliable recurrence risk assessment. • If the mother of an affected male has a • If the proband represents a simplex case and 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 Most often, DBA syndrome is inherited in an autosomal dominant manner. ## Autosomal Dominant Inheritance – Risk to Family Members Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome inherited a DBA syndrome-causing variant from a parent who may or may not have manifestations of DBA syndrome [ Approximately 55%-60% of individuals diagnosed with autosomal dominant DBA syndrome 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, allow reliable assessment of risk to offspring and other family members, and determine their need for Note 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. Parental gonadal mosaicism is suggested in a family described by The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see An individual diagnosed with DBA syndrome may appear to be the only affected family member 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, If a parent of the proband is affected with autosomal dominant DBA syndrome 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 penetrance of DBA syndrome in heterozygous sibs is high but may vary somewhat depending on the familial pathogenic variant (see If the DBA syndrome-causing variant found in the proband is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism for the DBA syndrome-causing pathogenic variant [ If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DBA syndrome because of the possibility of parental gonadal mosaicism and the possibility that a parent is heterozygous but does not have apparent manifestations of DBA syndrome because of reduced penetrance or variable expressivity. • Approximately 40%-45% of individuals diagnosed with autosomal dominant DBA syndrome inherited a DBA syndrome-causing variant from a parent who may or may not have manifestations of DBA syndrome [ • Approximately 55%-60% of individuals diagnosed with autosomal dominant DBA syndrome 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, allow reliable assessment of risk to offspring and other family members, and determine their need for • Note • 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. Parental gonadal mosaicism is suggested in a family described by • The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism is suggested in a family described by • The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see • An individual diagnosed with DBA syndrome may appear to be the only affected family member 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, • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Parental gonadal mosaicism is suggested in a family described by • The proband inherited a DBA syndrome-causing variant from a parent with revertant mosaicism (see • If a parent of the proband is affected with autosomal dominant DBA syndrome 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 penetrance of DBA syndrome in heterozygous sibs is high but may vary somewhat depending on the familial pathogenic variant (see • If the DBA syndrome-causing variant found in the proband is not detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be slightly greater than that of the general population because of the possibility of parental gonadal mosaicism for the DBA syndrome-causing pathogenic variant [ • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for DBA syndrome because of the possibility of parental gonadal mosaicism and the possibility that a parent is heterozygous but does not have apparent manifestations of DBA syndrome because of reduced penetrance or variable expressivity. ## Autosomal Recessive 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. ## X-Linked Inheritance – Risk to Family Members The father of a male with 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 allow reliable recurrence risk assessment. If the mother of an affected male has a If the proband represents a simplex case and the • The father of a male with • 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 allow reliable recurrence risk assessment. • If the mother of an affected male has a • If the proband represents a simplex case and 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 DBA syndrome-causing variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for DBA syndrome 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 • • • • • • • • ## Molecular Genetics DBA Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DBA Syndrome ( Ribosomes, consisting of a small 40S subunit and a large 60S subunit, catalyze protein synthesis. Small and large subunits are composed of four RNA species and approximately 80 structurally distinct ribosomal proteins (RPs). The proteins encoded by RPS19 has been demonstrated to play an important role in 18S rRNA maturation in yeast and in human cells [ DBA Syndrome: Gene-Specific Laboratory Considerations Large deletions in ~20% [ Long indels can be missed by exome sequencing [ Large deletions in ~20% [ Six extended or cryptic splicing variants & a 3' UTR variant have been reported [ Genes from • Large deletions in ~20% [ • Long indels can be missed by exome sequencing [ • Large deletions in ~20% [ • Six extended or cryptic splicing variants & a 3' UTR variant have been reported [ ## Molecular Pathogenesis Ribosomes, consisting of a small 40S subunit and a large 60S subunit, catalyze protein synthesis. Small and large subunits are composed of four RNA species and approximately 80 structurally distinct ribosomal proteins (RPs). The proteins encoded by RPS19 has been demonstrated to play an important role in 18S rRNA maturation in yeast and in human cells [ DBA Syndrome: Gene-Specific Laboratory Considerations Large deletions in ~20% [ Long indels can be missed by exome sequencing [ Large deletions in ~20% [ Six extended or cryptic splicing variants & a 3' UTR variant have been reported [ Genes from • Large deletions in ~20% [ • Long indels can be missed by exome sequencing [ • Large deletions in ~20% [ • Six extended or cryptic splicing variants & a 3' UTR variant have been reported [ ## Chapter Notes The author acknowledges the generous support of the Diamond Blackfan Anemia Foundation. Catherine Clinton, MS, CGC; Dana-Farber/Boston Children's Cancer and Blood Disorders Center (2009-2021)Hanna T Gazda, MD, PhD; Boston Children's Hospital (2009-2021)Colin Sieff, MBBCh, FRCPath (2021-present) 31 July 2025 (sw) Comprehensive update posted live 17 June 2021 (sw) Comprehensive update posted live 7 April 2016 (sw) Comprehensive update posted live 25 July 2013 (me) Comprehensive update posted live 27 January 2011 (me) Comprehensive update posted live 25 June 2009 (et) Review posted live 17 February 2009 (hg) Original submission • 31 July 2025 (sw) Comprehensive update posted live • 17 June 2021 (sw) Comprehensive update posted live • 7 April 2016 (sw) Comprehensive update posted live • 25 July 2013 (me) Comprehensive update posted live • 27 January 2011 (me) Comprehensive update posted live • 25 June 2009 (et) Review posted live • 17 February 2009 (hg) Original submission ## Acknowledgments The author acknowledges the generous support of the Diamond Blackfan Anemia Foundation. ## Author History Catherine Clinton, MS, CGC; Dana-Farber/Boston Children's Cancer and Blood Disorders Center (2009-2021)Hanna T Gazda, MD, PhD; Boston Children's Hospital (2009-2021)Colin Sieff, MBBCh, FRCPath (2021-present) ## Revision History 31 July 2025 (sw) Comprehensive update posted live 17 June 2021 (sw) Comprehensive update posted live 7 April 2016 (sw) Comprehensive update posted live 25 July 2013 (me) Comprehensive update posted live 27 January 2011 (me) Comprehensive update posted live 25 June 2009 (et) Review posted live 17 February 2009 (hg) Original submission • 31 July 2025 (sw) Comprehensive update posted live • 17 June 2021 (sw) Comprehensive update posted live • 7 April 2016 (sw) Comprehensive update posted live • 25 July 2013 (me) Comprehensive update posted live • 27 January 2011 (me) Comprehensive update posted live • 25 June 2009 (et) Review posted live • 17 February 2009 (hg) Original submission ## Key Sections in This ## References ## Literature Cited
[]
25/6/2009
31/7/2025
23/3/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
diastrophic-d
diastrophic-d
[ "Diastrophic Dwarfism, SLC26A2-Related Diastrophic Dysplasia", "Diastrophic Dwarfism", "SLC26A2-Related Diastrophic Dysplasia", "Sulfate transporter", "SLC26A2", "Diastrophic Dysplasia" ]
Diastrophic Dysplasia
Sheila Unger, Andrea Superti-Furga
Summary Diastrophic dysplasia (DTD) is characterized by limb shortening, normal-sized head, hitchhiker thumbs, spinal deformities (scoliosis, exaggerated lumbar lordosis, cervical kyphosis), and contractures of the large joints with deformities and early-onset osteoarthritis. Other typical findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. On occasion, the disease can be lethal at birth, but most affected individuals survive the neonatal period and develop physical limitations with normal intelligence. The diagnosis of DTD is established in a proband with characteristic clinical and radiographic features and/or biallelic pathogenic variants in DTD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
## Diagnosis No consensus clinical diagnostic criteria for diastrophic dysplasia (DTD) have been published. However, cystic ear swelling, if present, is pathognomonic. DTD Limb shortening Normal-sized head Slight trunk shortening Hitchhiker thumbs ( Symphalangism with missing interphalangeal creases Small chest Protuberant abdomen Contractures of large joints Dislocation of the radius Cleft palate (in ~1/3 of individuals) Cystic ear swelling in the neonatal period (in ~2/3 of infants) Other common findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead The skull is of normal size with disproportionate short skeleton. Cervical kyphosis is seen in most newborns and children. Ossification of the upper thoracic vertebrae may be incomplete with broadening of cervical spinal canal ("cobra-like" appearance). Coronal clefts may be present in the lumbar and lower thoracic vertebrae. Narrowing of the interpedicular distance from L1 to L5 is a constant finding. The more cephalad ribs are short and the chest can be bell shaped. Sternum may show duplication of the ossification centers. Ilia are hypoplastic with flat acetabula. Long bones appear moderately shortened with some metaphyseal flaring. Distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic. Femur is distally rounded. Patella may appear fragmented or multilayered. Radius and tibia may be bowed. Proximal radial dislocation may be present at birth. Hands may exhibit typical features ( Hitchhiker thumb with ulnar deviation of the fingers Shortness of the first metacarpal Delta-shaped proximal and middle phalanges Symphalangism In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age The diagnosis of DTD 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 phenotype is not clearly distinguishable from other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Diastrophic Dysplasia (DTD) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The four most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ Note: (1) The determination of sulfate uptake is cumbersome and not used for diagnostic purposes. (2) The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is recommended only in the rare instance in which the diagnosis of DTD is strongly suspected but molecular genetic testing fails to detect • Limb shortening • Normal-sized head • Slight trunk shortening • Hitchhiker thumbs ( • Symphalangism with missing interphalangeal creases • Small chest • Protuberant abdomen • Contractures of large joints • Dislocation of the radius • Cleft palate (in ~1/3 of individuals) • Cystic ear swelling in the neonatal period (in ~2/3 of infants) • Other common findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead • The skull is of normal size with disproportionate short skeleton. • Cervical kyphosis is seen in most newborns and children. • Ossification of the upper thoracic vertebrae may be incomplete with broadening of cervical spinal canal ("cobra-like" appearance). • Coronal clefts may be present in the lumbar and lower thoracic vertebrae. • Narrowing of the interpedicular distance from L1 to L5 is a constant finding. • The more cephalad ribs are short and the chest can be bell shaped. • Sternum may show duplication of the ossification centers. • Ilia are hypoplastic with flat acetabula. • Long bones appear moderately shortened with some metaphyseal flaring. • Distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic. • Femur is distally rounded. • Patella may appear fragmented or multilayered. • Radius and tibia may be bowed. • Proximal radial dislocation may be present at birth. • Hands may exhibit typical features ( • Hitchhiker thumb with ulnar deviation of the fingers • Shortness of the first metacarpal • Delta-shaped proximal and middle phalanges • Symphalangism • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age • Hitchhiker thumb with ulnar deviation of the fingers • Shortness of the first metacarpal • Delta-shaped proximal and middle phalanges • Symphalangism • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age • Hitchhiker thumb with ulnar deviation of the fingers • Shortness of the first metacarpal • Delta-shaped proximal and middle phalanges • Symphalangism • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age ## Suggestive Findings DTD Limb shortening Normal-sized head Slight trunk shortening Hitchhiker thumbs ( Symphalangism with missing interphalangeal creases Small chest Protuberant abdomen Contractures of large joints Dislocation of the radius Cleft palate (in ~1/3 of individuals) Cystic ear swelling in the neonatal period (in ~2/3 of infants) Other common findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead The skull is of normal size with disproportionate short skeleton. Cervical kyphosis is seen in most newborns and children. Ossification of the upper thoracic vertebrae may be incomplete with broadening of cervical spinal canal ("cobra-like" appearance). Coronal clefts may be present in the lumbar and lower thoracic vertebrae. Narrowing of the interpedicular distance from L1 to L5 is a constant finding. The more cephalad ribs are short and the chest can be bell shaped. Sternum may show duplication of the ossification centers. Ilia are hypoplastic with flat acetabula. Long bones appear moderately shortened with some metaphyseal flaring. Distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic. Femur is distally rounded. Patella may appear fragmented or multilayered. Radius and tibia may be bowed. Proximal radial dislocation may be present at birth. Hands may exhibit typical features ( Hitchhiker thumb with ulnar deviation of the fingers Shortness of the first metacarpal Delta-shaped proximal and middle phalanges Symphalangism In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age • Limb shortening • Normal-sized head • Slight trunk shortening • Hitchhiker thumbs ( • Symphalangism with missing interphalangeal creases • Small chest • Protuberant abdomen • Contractures of large joints • Dislocation of the radius • Cleft palate (in ~1/3 of individuals) • Cystic ear swelling in the neonatal period (in ~2/3 of infants) • Other common findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead • The skull is of normal size with disproportionate short skeleton. • Cervical kyphosis is seen in most newborns and children. • Ossification of the upper thoracic vertebrae may be incomplete with broadening of cervical spinal canal ("cobra-like" appearance). • Coronal clefts may be present in the lumbar and lower thoracic vertebrae. • Narrowing of the interpedicular distance from L1 to L5 is a constant finding. • The more cephalad ribs are short and the chest can be bell shaped. • Sternum may show duplication of the ossification centers. • Ilia are hypoplastic with flat acetabula. • Long bones appear moderately shortened with some metaphyseal flaring. • Distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic. • Femur is distally rounded. • Patella may appear fragmented or multilayered. • Radius and tibia may be bowed. • Proximal radial dislocation may be present at birth. • Hands may exhibit typical features ( • Hitchhiker thumb with ulnar deviation of the fingers • Shortness of the first metacarpal • Delta-shaped proximal and middle phalanges • Symphalangism • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age • Hitchhiker thumb with ulnar deviation of the fingers • Shortness of the first metacarpal • Delta-shaped proximal and middle phalanges • Symphalangism • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age • Hitchhiker thumb with ulnar deviation of the fingers • Shortness of the first metacarpal • Delta-shaped proximal and middle phalanges • Symphalangism • In some severe cases, ossification of two to three carpal bones in the newborn, simulating advanced skeletal age ## Establishing the Diagnosis The diagnosis of DTD 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 phenotype is not clearly distinguishable from other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Diastrophic Dysplasia (DTD) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The four most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ Note: (1) The determination of sulfate uptake is cumbersome and not used for diagnostic purposes. (2) The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is recommended only in the rare instance in which the diagnosis of DTD is strongly suspected but molecular genetic testing fails to detect ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is not clearly distinguishable from other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Diastrophic Dysplasia (DTD) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The four most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ ## Other Testing Note: (1) The determination of sulfate uptake is cumbersome and not used for diagnostic purposes. (2) The sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is recommended only in the rare instance in which the diagnosis of DTD is strongly suspected but molecular genetic testing fails to detect ## Clinical Characteristics Joint contractures and spine deformity tend to worsen with age. Painful degenerative arthrosis of the hip is common in young adults. Anterior tilting of the pelvis may occur as a consequence and exacerbate the lumbar lordosis. The spine frequently develops excessive lumbar lordosis, thoracolumbar kyphosis, and scoliosis. In anteroposterior radiographs of the lumbar spine, a decrease of the vertebral interpedicular distance is almost invariably observed; however, related neurologic symptoms are only rarely observed [ The knee may be unstable in childhood; flexion contractures develop with progressive valgus deformity and lateral positioning of the patella. The development and position of the patella may determine whether contraction of the quadriceps muscle results in extension of the knee or paradoxic flexion of the knee. If paradoxic flexion occurs, severe difficulty with walking results [ Because of foot deformities (clubfoot) and shortened tendons, many adults with DTD are unable to place their heels on the ground, and thus stand solely on their metatarsals and toes. Brachydactyly, ulnar deviation, phalangeal synostosis, and ankylosis of the fingers with significant disability may be observed. Phalangeal synostosis, usually between proximal and middle phalanges, develops in those fingers that have an abnormal phalangeal patterning at birth, including so-called delta-shaped phalanges that usually lack a proper joint space. Often, newborns with DTD lack phalangeal flexion creases (see In addition to the skeletal abnormalities, a mild degree of muscular hypoplasia of the thighs and legs is common. MRI findings have confirmed that in individuals with DTD, the foramen magnum is of normal size but the cervical spinal canal is narrowed. Individual cervical vertebral bodies (usually C3 to C5) may be hypoplastic, but the frequently observed kyphosis is not explained by changes of the vertebral bodies and may thus be the consequence of abnormal intervertebral disks. The rate of spontaneous correction of cervical kyphosis is rather high. MRI studies have shown a peculiar signal anomaly of intervertebral disks, suggesting reduced water content. This anomaly may be the consequence of reduced proteoglycan sulfation. Cervical spina bifida occulta has been frequently reported in individuals with DTD. Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders, which extends from lethal The pathogenic variant Pathogenic variant Pathogenic variants Pathogenic variant Pathogenic variant The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes ( DTD was recognized as a distinct entity by The existence of clinical variability was recognized early; instances of "severe" or "lethal" DTD are now classified as In the 2023 revised Nosology of Genetic Skeletal Disorders [Unger et al 2023], DTD is referred to as No reliable data exist regarding the prevalence of DTD. In the experience of several genetic and metabolic centers that can compare its incidence with that of other genetic diseases, DTD disorders are generally believed to be in the range of approximately 1:100,000. ## Clinical Description Joint contractures and spine deformity tend to worsen with age. Painful degenerative arthrosis of the hip is common in young adults. Anterior tilting of the pelvis may occur as a consequence and exacerbate the lumbar lordosis. The spine frequently develops excessive lumbar lordosis, thoracolumbar kyphosis, and scoliosis. In anteroposterior radiographs of the lumbar spine, a decrease of the vertebral interpedicular distance is almost invariably observed; however, related neurologic symptoms are only rarely observed [ The knee may be unstable in childhood; flexion contractures develop with progressive valgus deformity and lateral positioning of the patella. The development and position of the patella may determine whether contraction of the quadriceps muscle results in extension of the knee or paradoxic flexion of the knee. If paradoxic flexion occurs, severe difficulty with walking results [ Because of foot deformities (clubfoot) and shortened tendons, many adults with DTD are unable to place their heels on the ground, and thus stand solely on their metatarsals and toes. Brachydactyly, ulnar deviation, phalangeal synostosis, and ankylosis of the fingers with significant disability may be observed. Phalangeal synostosis, usually between proximal and middle phalanges, develops in those fingers that have an abnormal phalangeal patterning at birth, including so-called delta-shaped phalanges that usually lack a proper joint space. Often, newborns with DTD lack phalangeal flexion creases (see In addition to the skeletal abnormalities, a mild degree of muscular hypoplasia of the thighs and legs is common. MRI findings have confirmed that in individuals with DTD, the foramen magnum is of normal size but the cervical spinal canal is narrowed. Individual cervical vertebral bodies (usually C3 to C5) may be hypoplastic, but the frequently observed kyphosis is not explained by changes of the vertebral bodies and may thus be the consequence of abnormal intervertebral disks. The rate of spontaneous correction of cervical kyphosis is rather high. MRI studies have shown a peculiar signal anomaly of intervertebral disks, suggesting reduced water content. This anomaly may be the consequence of reduced proteoglycan sulfation. Cervical spina bifida occulta has been frequently reported in individuals with DTD. ## Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders, which extends from lethal The pathogenic variant Pathogenic variant Pathogenic variants Pathogenic variant Pathogenic variant The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes ( ## Nomenclature DTD was recognized as a distinct entity by The existence of clinical variability was recognized early; instances of "severe" or "lethal" DTD are now classified as In the 2023 revised Nosology of Genetic Skeletal Disorders [Unger et al 2023], DTD is referred to as ## Prevalence No reliable data exist regarding the prevalence of DTD. In the experience of several genetic and metabolic centers that can compare its incidence with that of other genetic diseases, DTD disorders are generally believed to be in the range of approximately 1:100,000. ## Genetically Related (Allelic) Disorders Diastrophic dysplasia (DTD) is one of the more severe allelic phenotypes in the spectrum of Among most severe skeletal disorders in humans Severe hypodysplasia of spine, rib cage, & extremities w/relatively preserved cranium Invariably lethal in perinatal period Commonly lethal in perinatal period Presents around birth or before Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced Joint pain (usually in hips & knees), deformities of hands, feet, & knees, scoliosis ~50% of persons have an abnormal finding at birth (e.g., clubfoot, cleft palate, or cystic ear swelling). Median height in adulthood is at 10th %ile. Usually considered as a differential diagnosis of DTD in toddlers or school-age children DTD = diastrophic dysplasia Disorders are ordered by severity, from most to least severe. • Among most severe skeletal disorders in humans • Severe hypodysplasia of spine, rib cage, & extremities w/relatively preserved cranium • Invariably lethal in perinatal period • Commonly lethal in perinatal period • Presents around birth or before • Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced • Joint pain (usually in hips & knees), deformities of hands, feet, & knees, scoliosis • ~50% of persons have an abnormal finding at birth (e.g., clubfoot, cleft palate, or cystic ear swelling). • Median height in adulthood is at 10th %ile. • Usually considered as a differential diagnosis of DTD in toddlers or school-age children ## Differential Diagnosis Differential diagnosis in the prenatal period must include phenotypes in the Note: The finding of radially deviated thumbs ("hitchhiker thumbs") is suggestive of diastrophic dysplasia (DTD), although not quite pathognomonic. Genes of Interest in the Differential Diagnosis of Diastrophic Dysplasia AD = autosomal dominant; AR = autosomal recessive; DTD = diastrophic dysplasia; MOI = mode of inheritance; XL = X-linked ## Management To establish the extent of disease and needs in an individual diagnosed with diastrophic dysplasia (DTD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Diastrophic Dysplasia DTD = diastrophic dysplasia; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Diastrophic Dysplasia PT may prevent early joint contractures. In children, maintain joint positioning/ mobility as much as possible by physical means (PT & casting, e.g., for clubfeet) Undertake surgery w/caution, as deformities tend to recur. Simple tenotomy does not suffice, & more extensive plasty of tarsal bones may be needed [ Postpubertal surgical correction is best in most cases [ Surgery before puberty may be helpful for those w/severe spinal deformity → respiratory compromise or neurologic signs. DTD = diastrophic dysplasia; PT = physical therapy Indications for surgical correction of have not been established, nor have criteria to define a successful surgical outcome [ Recommended Surveillance for Individuals with Diastrophic Dysplasia Monitor spinal curvature to prevent neurologic complications & joint contractures. Physical medicine, OT/PT assessment of mobility, self-help skills OT = occupational therapy; PT = physical therapy Obesity places an excessive load on the large weight-bearing joints and thus should be avoided. See Although not specific to DTD, women with severe kyphoscoliosis may experience complications related to thoracic compression in later stages of pregnancy and need to be monitored closely. Kyphoscoliosis can also complicate the use of spinal anesthetics; thus, consultation with an anesthesiologist prior to delivery is advisable. See Search • PT may prevent early joint contractures. • In children, maintain joint positioning/ mobility as much as possible by physical means (PT & casting, e.g., for clubfeet) • Undertake surgery w/caution, as deformities tend to recur. • Simple tenotomy does not suffice, & more extensive plasty of tarsal bones may be needed [ • Postpubertal surgical correction is best in most cases [ • Surgery before puberty may be helpful for those w/severe spinal deformity → respiratory compromise or neurologic signs. • Monitor spinal curvature to prevent neurologic complications & 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 diastrophic dysplasia (DTD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Diastrophic Dysplasia DTD = diastrophic dysplasia; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse ## Treatment of Manifestations Treatment of Manifestations in Individuals with Diastrophic Dysplasia PT may prevent early joint contractures. In children, maintain joint positioning/ mobility as much as possible by physical means (PT & casting, e.g., for clubfeet) Undertake surgery w/caution, as deformities tend to recur. Simple tenotomy does not suffice, & more extensive plasty of tarsal bones may be needed [ Postpubertal surgical correction is best in most cases [ Surgery before puberty may be helpful for those w/severe spinal deformity → respiratory compromise or neurologic signs. DTD = diastrophic dysplasia; PT = physical therapy Indications for surgical correction of have not been established, nor have criteria to define a successful surgical outcome [ • PT may prevent early joint contractures. • In children, maintain joint positioning/ mobility as much as possible by physical means (PT & casting, e.g., for clubfeet) • Undertake surgery w/caution, as deformities tend to recur. • Simple tenotomy does not suffice, & more extensive plasty of tarsal bones may be needed [ • Postpubertal surgical correction is best in most cases [ • Surgery before puberty may be helpful for those w/severe spinal deformity → respiratory compromise or neurologic signs. ## Surveillance Recommended Surveillance for Individuals with Diastrophic Dysplasia Monitor spinal curvature to prevent neurologic complications & joint contractures. Physical medicine, OT/PT assessment of mobility, self-help skills OT = occupational therapy; PT = physical therapy • Monitor spinal curvature to prevent neurologic complications & joint contractures. • Physical medicine, OT/PT assessment of mobility, self-help skills ## Agents/Circumstances to Avoid Obesity places an excessive load on the large weight-bearing joints and thus should be avoided. ## Evaluation of Relatives at Risk See ## Pregnancy Management Although not specific to DTD, women with severe kyphoscoliosis may experience complications related to thoracic compression in later stages of pregnancy and need to be monitored closely. Kyphoscoliosis can also complicate the use of spinal anesthetics; thus, consultation with an anesthesiologist prior to delivery is advisable. See ## Therapies Under Investigation Search ## Genetic Counseling Diastrophic dysplasia (DTD) is inherited in an autosomal recessive manner. The parents of an affected child 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 of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are usually asymptomatic and have normal stature. There is no evidence that they are at increased risk for degenerative joint disease. If both parents are known to be heterozygous for an Heterozygotes (carriers) are usually asymptomatic and have normal stature. Carrier testing for at-risk relatives requires prior identification of the Carrier detection in reproductive partners of a heterozygous individual is possible. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Note: While several reports of "successful" early ultrasonographic identification of DTD have been published, the literature is heavily biased toward positive cases [ • The parents of an affected child 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 of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are usually asymptomatic and have normal stature. There is no evidence that they are at increased risk for degenerative joint disease. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are usually asymptomatic and have normal stature. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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 Diastrophic dysplasia (DTD) 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 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 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 usually asymptomatic and have normal stature. There is no evidence that they are at increased risk for degenerative joint disease. If both parents are known to be heterozygous for an Heterozygotes (carriers) are usually asymptomatic and have normal stature. • The parents of an affected child 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 of a proband to confirm that both parents are heterozygous for an • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are usually asymptomatic and have normal stature. There is no evidence that they are at increased risk for degenerative joint disease. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are usually asymptomatic and have normal stature. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the Carrier detection in reproductive partners of a heterozygous individual is possible. ## 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 Note: While several reports of "successful" early ultrasonographic identification of DTD have been published, the literature is heavily biased toward positive cases [ ## High-Risk Pregnancies ## Low-Risk Pregnancies Note: While several reports of "successful" early ultrasonographic identification of DTD have been published, the literature is heavily biased toward positive cases [ ## Resources United Kingdom United Kingdom • • • • • • United Kingdom • • • United Kingdom • • • • • • • • • ## Molecular Genetics Diastrophic Dysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Diastrophic Dysplasia ( In a Notable ACG1B = achondrogenesis 1B; DTD = diastrophic dysplasia; MED = multiple epiphyseal dysplasia Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis In a Notable ACG1B = achondrogenesis 1B; DTD = diastrophic dysplasia; MED = multiple epiphyseal dysplasia Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes Diana Ballhausen, MD; Lausanne University Hospital (2013-2021)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2004-2021)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2013-2021)Andrea Superti-Furga, MD (2004-present)Sheila Unger, MD (2021-present) 16 March 2023 (sw) Revision: " 23 December 2021 (sw) Comprehensive update posted live 18 July 2013 (me) Comprehensive update posted live 12 June 2007 (me) Update posted live 15 November 2004 (me) Review posted live 17 February 2004 (asf) Original submission • 16 March 2023 (sw) Revision: " • 23 December 2021 (sw) Comprehensive update posted live • 18 July 2013 (me) Comprehensive update posted live • 12 June 2007 (me) Update posted live • 15 November 2004 (me) Review posted live • 17 February 2004 (asf) Original submission ## Author History Diana Ballhausen, MD; Lausanne University Hospital (2013-2021)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2004-2021)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2013-2021)Andrea Superti-Furga, MD (2004-present)Sheila Unger, MD (2021-present) ## Revision History 16 March 2023 (sw) Revision: " 23 December 2021 (sw) Comprehensive update posted live 18 July 2013 (me) Comprehensive update posted live 12 June 2007 (me) Update posted live 15 November 2004 (me) Review posted live 17 February 2004 (asf) Original submission • 16 March 2023 (sw) Revision: " • 23 December 2021 (sw) Comprehensive update posted live • 18 July 2013 (me) Comprehensive update posted live • 12 June 2007 (me) Update posted live • 15 November 2004 (me) Review posted live • 17 February 2004 (asf) Original submission ## References ## Literature Cited Hand of a newborn with diastrophic dysplasia, showing brachydactyly (short fingers), absence of flexion creases of the fingers, and proximally placed, abducted "hitchhiker thumb." The thumb deformity results in difficulty with thumb opposition, affecting activities such as writing or opening a screw cap. Radiograph of the hand of a child, age three years, with diastrophic dysplasia. The phalanges are short; some show a "delta"-shape deformity. Ossification of the carpal bones is advanced for age, a phenomenon known as "pseudo-acceleration" of the bone age, because the advanced bone age is not related to hormonal processes, but rather is caused by the biochemical abnormality intrinsic to diastrophic dysplasia.
[]
15/11/2004
23/12/2021
16/3/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dkc
dkc
[ "Zinsser-Cole-Engman Syndrome", "Zinsser-Cole-Engman Syndrome", "Revesz Syndrome", "Classic Dyskeratosis Congenita", "Hoyeraal Hreidarsson Syndrome", "Coats Plus Syndrome", "Adrenocortical dysplasia protein homolog", "CST complex subunit CTC1", "CST complex subunit STN1", "H/ACA ribonucleoprotein complex non-core subunit NAF1", "H/ACA ribonucleoprotein complex subunit 2", "H/ACA ribonucleoprotein complex subunit 3", "H/ACA ribonucleoprotein complex subunit DKC1", "Not applicable", "Poly(A)-specific ribonuclease PARN", "Protection of telomeres protein 1", "Regulator of telomere elongation helicase 1", "Replication protein A 70 kDa DNA-binding subunit", "Telomerase Cajal body protein 1", "Telomerase reverse transcriptase", "TERF1-interacting nuclear factor 2", "Zinc finger CCHC domain-containing protein 8", "ACD", "CTC1", "DKC1", "NAF1", "NHP2", "NOP10", "PARN", "POT1", "RPA1", "RTEL1", "STN1", "TERC", "TERT", "TINF2", "WRAP53", "ZCCHC8", "Dyskeratosis Congenita and Related Telomere Biology Disorders" ]
Dyskeratosis Congenita and Related Telomere Biology Disorders
Sharon A Savage, Marena R Niewisch
Summary Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. A majority of individuals with DC/TBD have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on lymphocyte subsets. To date, The mode of inheritance of DC/TBD varies by gene: X-linked: Autosomal dominant: Autosomal dominant or autosomal recessive: Autosomal recessive: Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Once the DC/TBD-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Classic dyskeratosis congenita Hoyeraal Hreidarsson syndrome Revesz syndrome Coats plus syndrome • Classic dyskeratosis congenita • Hoyeraal Hreidarsson syndrome • Revesz syndrome • Coats plus syndrome ## Diagnosis Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding [ The criteria for classic DC were described by A telomere biology disorder (TBD), including dyskeratosis congenita (DC), At least two features of the classic DC clinical triad ( Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. Oral leukoplakia (white patches in the mouth) One feature of the classic triad or suggestive family history (occurrence of bone marrow failure [BMF], myelodysplastic syndrome [MDS], acute myelogenous leukemia [AML], early-onset head/neck squamous cell cancer [HNSCC], and/or pulmonary fibrosis [PF] in a first- or second-degree relative) in combination with: Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. MDS or AML. May be the presenting sign. Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. PF. See Any feature of the classic triad plus two or more of the following: Epiphora (excessive watering of the eye[s]) Blepharitis (inflammation of the eyelids, often due to epiphora) Abnormal eyelash growth Prematurely gray hair Alopecia Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio Developmental delay Short stature Microcephaly Hypogonadism Esophageal stenosis Urethral stenosis Liver disease Osteoporosis Avascular necrosis of the hips or shoulders Gastrointestinal telangiectasias Pulmonary arteriovenous malformations Note: Individuals with TBDs may have none of the above additional findings or the findings may appear or worsen with age. The diagnosis of DC/TBD is Shortened telomere length as determined by lymphocyte telomere length testing by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) in the six-cell panel assay. Telomere length less than the first centile for age in lymphocytes is 97% sensitive and 91% specific for DC/TBD. In individuals with complex or atypical DC/TBD, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [ Identification of biallelic pathogenic (or likely pathogenic) variants in one of the six genes known to solely cause autosomal recessive DC/TBD; or a heterozygous pathogenic (or likely pathogenic) variant in one of the five genes known to cause autosomal dominant DC/TBD; or a mono- or biallelic pathogenic (or likely pathogenic) variant in one of the four genes associated with autosomal recessive and dominant DC/TBD; or a hemizygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include 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 Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable; XL = X-linked Genes are listed in alphabetic order. See Data from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available for the listed genes. Data derived from the subscription-based professional view of Human Gene Mutation Database [ For heterozygous pathogenic variants, see Approximately 80% of individuals who meet clinical diagnostic criteria for DC/TBD have a pathogenic variant(s) in one of the 15 known DC/TBD-related genes. • At least two features of the classic DC clinical triad ( • Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. • Oral leukoplakia (white patches in the mouth) • Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. • Oral leukoplakia (white patches in the mouth) • One feature of the classic triad or suggestive family history (occurrence of bone marrow failure [BMF], myelodysplastic syndrome [MDS], acute myelogenous leukemia [AML], early-onset head/neck squamous cell cancer [HNSCC], and/or pulmonary fibrosis [PF] in a first- or second-degree relative) in combination with: • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. • MDS or AML. May be the presenting sign. • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. • PF. See • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. • MDS or AML. May be the presenting sign. • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. • PF. See • Any feature of the classic triad plus two or more of the following: • Epiphora (excessive watering of the eye[s]) • Blepharitis (inflammation of the eyelids, often due to epiphora) • Abnormal eyelash growth • Prematurely gray hair • Alopecia • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio • Developmental delay • Short stature • Microcephaly • Hypogonadism • Esophageal stenosis • Urethral stenosis • Liver disease • Osteoporosis • Avascular necrosis of the hips or shoulders • Gastrointestinal telangiectasias • Pulmonary arteriovenous malformations • Note: Individuals with TBDs may have none of the above additional findings or the findings may appear or worsen with age. • Epiphora (excessive watering of the eye[s]) • Blepharitis (inflammation of the eyelids, often due to epiphora) • Abnormal eyelash growth • Prematurely gray hair • Alopecia • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio • Developmental delay • Short stature • Microcephaly • Hypogonadism • Esophageal stenosis • Urethral stenosis • Liver disease • Osteoporosis • Avascular necrosis of the hips or shoulders • Gastrointestinal telangiectasias • Pulmonary arteriovenous malformations • Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. • Oral leukoplakia (white patches in the mouth) • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. • MDS or AML. May be the presenting sign. • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. • PF. See • Epiphora (excessive watering of the eye[s]) • Blepharitis (inflammation of the eyelids, often due to epiphora) • Abnormal eyelash growth • Prematurely gray hair • Alopecia • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio • Developmental delay • Short stature • Microcephaly • Hypogonadism • Esophageal stenosis • Urethral stenosis • Liver disease • Osteoporosis • Avascular necrosis of the hips or shoulders • Gastrointestinal telangiectasias • Pulmonary arteriovenous malformations • Shortened telomere length as determined by lymphocyte telomere length testing by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) in the six-cell panel assay. Telomere length less than the first centile for age in lymphocytes is 97% sensitive and 91% specific for DC/TBD. In individuals with complex or atypical DC/TBD, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [ • Identification of biallelic pathogenic (or likely pathogenic) variants in one of the six genes known to solely cause autosomal recessive DC/TBD; or a heterozygous pathogenic (or likely pathogenic) variant in one of the five genes known to cause autosomal dominant DC/TBD; or a mono- or biallelic pathogenic (or likely pathogenic) variant in one of the four genes associated with autosomal recessive and dominant DC/TBD; or a hemizygous pathogenic (or likely pathogenic) variant in ## Suggestive Findings A telomere biology disorder (TBD), including dyskeratosis congenita (DC), At least two features of the classic DC clinical triad ( Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. Oral leukoplakia (white patches in the mouth) One feature of the classic triad or suggestive family history (occurrence of bone marrow failure [BMF], myelodysplastic syndrome [MDS], acute myelogenous leukemia [AML], early-onset head/neck squamous cell cancer [HNSCC], and/or pulmonary fibrosis [PF] in a first- or second-degree relative) in combination with: Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. MDS or AML. May be the presenting sign. Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. PF. See Any feature of the classic triad plus two or more of the following: Epiphora (excessive watering of the eye[s]) Blepharitis (inflammation of the eyelids, often due to epiphora) Abnormal eyelash growth Prematurely gray hair Alopecia Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio Developmental delay Short stature Microcephaly Hypogonadism Esophageal stenosis Urethral stenosis Liver disease Osteoporosis Avascular necrosis of the hips or shoulders Gastrointestinal telangiectasias Pulmonary arteriovenous malformations Note: Individuals with TBDs may have none of the above additional findings or the findings may appear or worsen with age. • At least two features of the classic DC clinical triad ( • Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. • Oral leukoplakia (white patches in the mouth) • Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. • Oral leukoplakia (white patches in the mouth) • One feature of the classic triad or suggestive family history (occurrence of bone marrow failure [BMF], myelodysplastic syndrome [MDS], acute myelogenous leukemia [AML], early-onset head/neck squamous cell cancer [HNSCC], and/or pulmonary fibrosis [PF] in a first- or second-degree relative) in combination with: • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. • MDS or AML. May be the presenting sign. • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. • PF. See • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. • MDS or AML. May be the presenting sign. • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. • PF. See • Any feature of the classic triad plus two or more of the following: • Epiphora (excessive watering of the eye[s]) • Blepharitis (inflammation of the eyelids, often due to epiphora) • Abnormal eyelash growth • Prematurely gray hair • Alopecia • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio • Developmental delay • Short stature • Microcephaly • Hypogonadism • Esophageal stenosis • Urethral stenosis • Liver disease • Osteoporosis • Avascular necrosis of the hips or shoulders • Gastrointestinal telangiectasias • Pulmonary arteriovenous malformations • Note: Individuals with TBDs may have none of the above additional findings or the findings may appear or worsen with age. • Epiphora (excessive watering of the eye[s]) • Blepharitis (inflammation of the eyelids, often due to epiphora) • Abnormal eyelash growth • Prematurely gray hair • Alopecia • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio • Developmental delay • Short stature • Microcephaly • Hypogonadism • Esophageal stenosis • Urethral stenosis • Liver disease • Osteoporosis • Avascular necrosis of the hips or shoulders • Gastrointestinal telangiectasias • Pulmonary arteriovenous malformations • Dysplastic nails. Findings may be subtle with ridging, flaking, or poor growth, or more diffuse with nearly complete loss of nails. • Lacy reticular pigmentation of the upper chest and/or neck. May be subtle or diffuse hyper- or hypopigmentation. Note that abnormal pigmentation changes are not restricted to the upper chest and neck. • Oral leukoplakia (white patches in the mouth) • Progressive BMF. May appear at any age and may be a presenting sign. Macrocytosis and elevated hemoglobin F levels may be seen. • MDS or AML. May be the presenting sign. • Solid tumors, usually HNSCC or anogenital adenocarcinoma, in persons younger than age 50 years and without other risk factors. Solid tumors may be the first manifestation of DC/TBD in individuals who do not have BMF. • PF. See • Epiphora (excessive watering of the eye[s]) • Blepharitis (inflammation of the eyelids, often due to epiphora) • Abnormal eyelash growth • Prematurely gray hair • Alopecia • Taurodontism (enlarged tooth pulp chambers) or decreased tooth root-to-crown ratio • Developmental delay • Short stature • Microcephaly • Hypogonadism • Esophageal stenosis • Urethral stenosis • Liver disease • Osteoporosis • Avascular necrosis of the hips or shoulders • Gastrointestinal telangiectasias • Pulmonary arteriovenous malformations ## Establishing the Diagnosis The diagnosis of DC/TBD is Shortened telomere length as determined by lymphocyte telomere length testing by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) in the six-cell panel assay. Telomere length less than the first centile for age in lymphocytes is 97% sensitive and 91% specific for DC/TBD. In individuals with complex or atypical DC/TBD, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [ Identification of biallelic pathogenic (or likely pathogenic) variants in one of the six genes known to solely cause autosomal recessive DC/TBD; or a heterozygous pathogenic (or likely pathogenic) variant in one of the five genes known to cause autosomal dominant DC/TBD; or a mono- or biallelic pathogenic (or likely pathogenic) variant in one of the four genes associated with autosomal recessive and dominant DC/TBD; or a hemizygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include 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 Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable; XL = X-linked Genes are listed in alphabetic order. See Data from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available for the listed genes. Data derived from the subscription-based professional view of Human Gene Mutation Database [ For heterozygous pathogenic variants, see Approximately 80% of individuals who meet clinical diagnostic criteria for DC/TBD have a pathogenic variant(s) in one of the 15 known DC/TBD-related genes. • Shortened telomere length as determined by lymphocyte telomere length testing by automated multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) in the six-cell panel assay. Telomere length less than the first centile for age in lymphocytes is 97% sensitive and 91% specific for DC/TBD. In individuals with complex or atypical DC/TBD, the six-cell panel may be more informative than the two-panel test of total lymphocytes and granulocytes [ • Identification of biallelic pathogenic (or likely pathogenic) variants in one of the six genes known to solely cause autosomal recessive DC/TBD; or a heterozygous pathogenic (or likely pathogenic) variant in one of the five genes known to cause autosomal dominant DC/TBD; or a mono- or biallelic pathogenic (or likely pathogenic) variant in one of the four genes associated with autosomal recessive and dominant DC/TBD; or a hemizygous pathogenic (or likely pathogenic) variant in ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; NA = not applicable; XL = X-linked Genes are listed in alphabetic order. See Data from See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available for the listed genes. Data derived from the subscription-based professional view of Human Gene Mutation Database [ For heterozygous pathogenic variants, see Approximately 80% of individuals who meet clinical diagnostic criteria for DC/TBD have a pathogenic variant(s) in one of the 15 known DC/TBD-related genes. ## Clinical Characteristics The classic dyskeratosis congenita (DC) triad of abnormal fingernails and toenails, lacy, reticular pigmentation of the neck and upper chest, and oral leukoplakia is diagnostic ( Three forms of DC/TBD with more severe manifestations have been identified: Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD): Frequency of Select Features HCT = hematopoietic cell transplant Most frequencies based on Dysplastic fingernails and toenails may worsen significantly over time and nails may eventually "disappear." Additional common skin findings in DC/TBD include epiphora, loss of dermatoglyphics, early graying, palmoplantar hyperkeratosis, eyelash loss, and hair loss from scalp [ Hyperhidrosis is noted infrequently in some individuals. Deafness has been reported but is rare. Abnormal eyelash growth includes sparse eyelashes, ectropion, entropion, and trichiasis, which can lead to corneal abrasions, scarring, or infection if not treated. Bilateral exudative retinopathy seen in Revesz syndrome or Coats plus syndrome can lead to blindness. Taurodontism (enlarged pulp chambers of the teeth) may be noted on dental x-ray. Intrauterine growth restriction (IUGR) has been noted in children with the more severe Coats plus syndrome, Hoyeraal Hreidarsson syndrome, or Revesz syndrome. Developmental delay may be present in some. It can be more pronounced in persons with Hoyeraal Hreidarsson syndrome, Revesz syndrome, or Coats plus syndrome. Enteropathy, which may result in poor growth, has been reported, specifically in Hoyeraal Hreidarsson syndrome. Liver disease, including nodular regenerative hyperplasia, fibrosis, cirrhosis, portal hypertension, and hepatopulmonary syndrome, is increasingly recognized as a potential severe complication of DC/TBD and may lead to liver transplant [ Gastrointestinal telangiectasias and bleeding may occur in the context of portal hypertension or independently. Avascular necrosis of the hips and shoulders can result in pain and reduced function. Several individuals have required hip replacement surgery at young ages. Individuals with DC/TBD are at increased risk for leukemia (see Investigators at the National Cancer Institute analyzed data from 15 years of follow up in a longitudinal cohort study to further quantify cancer risk in individuals with DC/TBD (n=197). The median age of onset for all cancers was 38 years (range 18-63 years), with an O/E (observed deaths to expected deaths) ratio of 4.2 compared to the normal population. The most frequent solid tumors were head and neck squamous cell carcinomas (with an O/E ratio of 74), followed by leukemia, non-Hodgkin lymphoma, and anorectal carcinoma. Of note, the risk of tongue cancer was increased by 216-fold over the normal population. In this study, myelodysplastic syndrome (MDS) was observed at a 578-fold increased risk, and the median age of MDS onset was 31 years (range 4-73 years). Pulmonary arteriovenous malformations have recently been reported in individuals with DC/TBD [ Clinical manifestations in females heterozygous for Classic DC with severe bone marrow failure and mucocutaneous triad features is associated with autosomal recessive, X-linked, or Individuals with autosomal recessive or X-linked DC/TBD have been reported to show more neurologic findings than those with autosomal dominant DC/TBD [ Pulmonary fibrosis without prior HCT is more frequently reported in individuals with autosomal dominant forms of DC/TBD [ Due to the rarity of DC/TBD, no specific genotype-phenotype correlations have been identified. The penetrance of DC/TBD and DC/TBD-associated medical complications is not well understood. Due to the variability between individuals (even within the same family) and the observation that medical complications may increase with age, penetrance may appear incomplete. Recent studies report somatic Revesz syndrome [ A few case reports of a syndrome of ataxia and pancytopenia are actually describing DC/TBD caused by pathogenic variants in The prevalence of DC/TBD in the general population is not known; DC/TBD is believed to be rare. As of March 2022, the authors are aware of approximately 800-1,000 affected individuals. ## Clinical Description The classic dyskeratosis congenita (DC) triad of abnormal fingernails and toenails, lacy, reticular pigmentation of the neck and upper chest, and oral leukoplakia is diagnostic ( Three forms of DC/TBD with more severe manifestations have been identified: Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD): Frequency of Select Features HCT = hematopoietic cell transplant Most frequencies based on Dysplastic fingernails and toenails may worsen significantly over time and nails may eventually "disappear." Additional common skin findings in DC/TBD include epiphora, loss of dermatoglyphics, early graying, palmoplantar hyperkeratosis, eyelash loss, and hair loss from scalp [ Hyperhidrosis is noted infrequently in some individuals. Deafness has been reported but is rare. Abnormal eyelash growth includes sparse eyelashes, ectropion, entropion, and trichiasis, which can lead to corneal abrasions, scarring, or infection if not treated. Bilateral exudative retinopathy seen in Revesz syndrome or Coats plus syndrome can lead to blindness. Taurodontism (enlarged pulp chambers of the teeth) may be noted on dental x-ray. Intrauterine growth restriction (IUGR) has been noted in children with the more severe Coats plus syndrome, Hoyeraal Hreidarsson syndrome, or Revesz syndrome. Developmental delay may be present in some. It can be more pronounced in persons with Hoyeraal Hreidarsson syndrome, Revesz syndrome, or Coats plus syndrome. Enteropathy, which may result in poor growth, has been reported, specifically in Hoyeraal Hreidarsson syndrome. Liver disease, including nodular regenerative hyperplasia, fibrosis, cirrhosis, portal hypertension, and hepatopulmonary syndrome, is increasingly recognized as a potential severe complication of DC/TBD and may lead to liver transplant [ Gastrointestinal telangiectasias and bleeding may occur in the context of portal hypertension or independently. Avascular necrosis of the hips and shoulders can result in pain and reduced function. Several individuals have required hip replacement surgery at young ages. Individuals with DC/TBD are at increased risk for leukemia (see Investigators at the National Cancer Institute analyzed data from 15 years of follow up in a longitudinal cohort study to further quantify cancer risk in individuals with DC/TBD (n=197). The median age of onset for all cancers was 38 years (range 18-63 years), with an O/E (observed deaths to expected deaths) ratio of 4.2 compared to the normal population. The most frequent solid tumors were head and neck squamous cell carcinomas (with an O/E ratio of 74), followed by leukemia, non-Hodgkin lymphoma, and anorectal carcinoma. Of note, the risk of tongue cancer was increased by 216-fold over the normal population. In this study, myelodysplastic syndrome (MDS) was observed at a 578-fold increased risk, and the median age of MDS onset was 31 years (range 4-73 years). Pulmonary arteriovenous malformations have recently been reported in individuals with DC/TBD [ Clinical manifestations in females heterozygous for ## Severe Forms of DC/TBD ## Clinical Findings of X-Linked DC/TBD in Females Clinical manifestations in females heterozygous for ## Phenotype Correlations by Gene Classic DC with severe bone marrow failure and mucocutaneous triad features is associated with autosomal recessive, X-linked, or Individuals with autosomal recessive or X-linked DC/TBD have been reported to show more neurologic findings than those with autosomal dominant DC/TBD [ Pulmonary fibrosis without prior HCT is more frequently reported in individuals with autosomal dominant forms of DC/TBD [ ## Genotype-Phenotype Correlations Due to the rarity of DC/TBD, no specific genotype-phenotype correlations have been identified. ## Penetrance The penetrance of DC/TBD and DC/TBD-associated medical complications is not well understood. Due to the variability between individuals (even within the same family) and the observation that medical complications may increase with age, penetrance may appear incomplete. Recent studies report somatic ## Nomenclature Revesz syndrome [ A few case reports of a syndrome of ataxia and pancytopenia are actually describing DC/TBD caused by pathogenic variants in ## Prevalence The prevalence of DC/TBD in the general population is not known; DC/TBD is believed to be rare. As of March 2022, the authors are aware of approximately 800-1,000 affected individuals. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Heterozygous germline pathogenic variants in ## Differential Diagnosis Disorders with clinical features that overlap those of dyskeratosis congenita and related telomere biology disorders (DC/TBD) are described below. Disorders with Nail Dysplasia in the Differential Diagnosis of Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Bone marrow failure syndromes are a complex set of related disorders that may have bone marrow failure as the first presenting sign. Inherited Bone Marrow Failure Syndromes in the Differential Diagnosis of Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AML = acute myelogeneous leukemia; AR = autosomal recessive; BMF = bone marrow failure; DC = dyskeratosis congenita; GI = gastrointestinal; MDS = myelodysplasia syndrome; MOI = mode of inheritance; XL = X-linked Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner ( Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in Diamond-Blackfan anemia (DBA) is most often inherited in an autosomal dominant manner; Characterized by tri-lineage bone marrow cytopenias [ Idiopathic pulmonary fibrosis (IPF) is the most frequent idiopathic interstitial pneumonia. It results in progressive fibrotic lung disease and has high morbidity and mortality. Persons with DC/TBD may develop IPF and it is conceivable that IPF in a young person could be the first manifestation of DC/TBD; thus, DC/TBD should be considered in young persons with IPF. See ## Disorders with Nail Dysplasia Disorders with Nail Dysplasia in the Differential Diagnosis of Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance ## Inherited Bone Marrow Failure Syndromes Bone marrow failure syndromes are a complex set of related disorders that may have bone marrow failure as the first presenting sign. Inherited Bone Marrow Failure Syndromes in the Differential Diagnosis of Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) AD = autosomal dominant; AML = acute myelogeneous leukemia; AR = autosomal recessive; BMF = bone marrow failure; DC = dyskeratosis congenita; GI = gastrointestinal; MDS = myelodysplasia syndrome; MOI = mode of inheritance; XL = X-linked Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner ( Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in Diamond-Blackfan anemia (DBA) is most often inherited in an autosomal dominant manner; ## Acquired Aplastic Anemia Characterized by tri-lineage bone marrow cytopenias [ ## Idiopathic Pulmonary Fibrosis Idiopathic pulmonary fibrosis (IPF) is the most frequent idiopathic interstitial pneumonia. It results in progressive fibrotic lung disease and has high morbidity and mortality. Persons with DC/TBD may develop IPF and it is conceivable that IPF in a young person could be the first manifestation of DC/TBD; thus, DC/TBD should be considered in young persons with IPF. See ## Management To establish the extent of disease and needs in an individual diagnosed with dyskeratosis congenita (DC) or a related telomere biology disorder (TBD), it is important to note that the clinical spectrum of DC/TCB is broad and signs and symptoms develop at various ages and rates. The evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) Baseline PFTs incl carbon monoxide diffusion capacity Consider bubble echocardiography to evaluate for pulmonary arteriovenous malformations. Eval by otolaryngologist & dentist as soon as patient is able to cooperate w/exam Gynecologic exam for females starting by age 16 yrs or when sexually active Lymphocyte subsets, lymphocyte proliferation response, serum IgG, IgM, IgA levels If presenting w/↑ infections: tetanus/diphteria/poliomyelitis/pneumococcal antibodies & IgM isohemagglutinin titer Community resources such as Social work involvement for parental support; Home nursing referral. BMF = bone marrow failure; CBC = complete blood count; HCT = hematopoietic cell transplantation; MOI = mode of inheritance; PFT = pulmonary function test Medical geneticist, certified genetic counselor, certified advanced genetic nurse The specific treatment for DC/TBD-related complications must be tailored to the individual. The recommendations in this section were first discussed at a DC clinical research workshop in 2008 and subsequently at a meeting of experts convened to review the publication of the first edition of the Clinical care guidelines are also available at Treatment of Manifestations in Individuals with Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) Range of clinical phenotypes seen in DC/TBD & possibility of non-manifesting or very mildly affected heterozygotes w/in families may complicate selection of related HCT donors. Test potential related HCT donors either for pathogenic variant(s) present in proband or, if variant(s) are unknown, for telomere length. Persons w/DC/TBD may be more sensitive to androgens than those w/ Side effects, incl liver enzyme abnormalities, need to be monitored carefully. Perform baseline & follow-up liver ultrasound exams for persons receiving androgen therapy because of possibility of liver adenomas & carcinomas, which have been reported in FA & in persons using androgens for benign hematologic diseases or for non-hematologic disorders. Prolonged cytopenias due to underlying BMF; Therapy-related pulmonary & hepatic toxicity (PFTs & liver function should be monitored carefully); Radiotherapy-related complications based on observations in persons undergoing radiotherapy in HCT. BMF = bone marrow failure; FA = Fanconi anemia; HCT = hematopoietic cell transplantation; PFT = pulmonary function test Following the model of the Fanconi anemia consensus guidelines [ HCT is the only curative treatment for severe BMF or leukemia in DC/TBD. It should be performed at centers experienced in treating DC/TBD. Pre- and post-transplant considerations and outcomes have been recently reviewed [ Author, personal observation See The recommendations in this section were discussed at the first DC clinical research workshop in 2008 and updated in 2014 at a consensus conference that led to publication of the first edition of the Recommended Surveillance for Individuals with Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) CBC Bone marrow aspirate & biopsy incl morphologic exam & cytogenetic studies Annually More frequently in case of ↓ blood count detection of clonal cytogenetic abnormality Prior to start Rpt every 4-6 wks When counts are stable, rpt every 2-3 mos Cancer screening by otolaryngologist Gynecologic exam Skin cancer screening by dermatologist Exam by dentist & dental hygienist Monitoring of leukoplakia & biopsy of suspicious lesions BMF = bone marrow failure; CBC = complete blood count; PFT = pulmonary function test Including 5q-, 7q-/monosomy 7, trisomy 8, 20q-, 11q23 translocation, 3q abnormalities Transfusions of red cells or platelets should be avoided or minimized for those who are candidates for hematopoietic cell transplantation (HCT). To minimize the chances of sensitization, family members must not act as blood donors if HCT is being considered. All blood products should be leukodepleted and irradiated. Evaluations include: Telomere length testing; Molecular genetic testing if a molecular diagnosis has been established in the proband. See Individuals with DC/TBD who become pregnant may develop pancytopenia or existing cytopenias may worsen. They should be followed closely by a perinatologist. Search • Baseline PFTs incl carbon monoxide diffusion capacity • Consider bubble echocardiography to evaluate for pulmonary arteriovenous malformations. • Eval by otolaryngologist & dentist as soon as patient is able to cooperate w/exam • Gynecologic exam for females starting by age 16 yrs or when sexually active • Lymphocyte subsets, lymphocyte proliferation response, serum IgG, IgM, IgA levels • If presenting w/↑ infections: tetanus/diphteria/poliomyelitis/pneumococcal antibodies & IgM isohemagglutinin titer • Community resources such as • Social work involvement for parental support; • Home nursing referral. • Range of clinical phenotypes seen in DC/TBD & possibility of non-manifesting or very mildly affected heterozygotes w/in families may complicate selection of related HCT donors. • Test potential related HCT donors either for pathogenic variant(s) present in proband or, if variant(s) are unknown, for telomere length. • Persons w/DC/TBD may be more sensitive to androgens than those w/ • Side effects, incl liver enzyme abnormalities, need to be monitored carefully. • Perform baseline & follow-up liver ultrasound exams for persons receiving androgen therapy because of possibility of liver adenomas & carcinomas, which have been reported in FA & in persons using androgens for benign hematologic diseases or for non-hematologic disorders. • Prolonged cytopenias due to underlying BMF; • Therapy-related pulmonary & hepatic toxicity (PFTs & liver function should be monitored carefully); • Radiotherapy-related complications based on observations in persons undergoing radiotherapy in HCT. • CBC • Bone marrow aspirate & biopsy incl morphologic exam & cytogenetic studies • Annually • More frequently in case of ↓ blood count detection of clonal cytogenetic abnormality • Prior to start • Rpt every 4-6 wks • When counts are stable, rpt every 2-3 mos • Cancer screening by otolaryngologist • Gynecologic exam • Skin cancer screening by dermatologist • Exam by dentist & dental hygienist • Monitoring of leukoplakia & biopsy of suspicious lesions • Transfusions of red cells or platelets should be avoided or minimized for those who are candidates for hematopoietic cell transplantation (HCT). • To minimize the chances of sensitization, family members must not act as blood donors if HCT is being considered. • All blood products should be leukodepleted and irradiated. • Telomere length testing; • Molecular genetic testing if a molecular diagnosis has been established in the proband. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with dyskeratosis congenita (DC) or a related telomere biology disorder (TBD), it is important to note that the clinical spectrum of DC/TCB is broad and signs and symptoms develop at various ages and rates. The evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) Baseline PFTs incl carbon monoxide diffusion capacity Consider bubble echocardiography to evaluate for pulmonary arteriovenous malformations. Eval by otolaryngologist & dentist as soon as patient is able to cooperate w/exam Gynecologic exam for females starting by age 16 yrs or when sexually active Lymphocyte subsets, lymphocyte proliferation response, serum IgG, IgM, IgA levels If presenting w/↑ infections: tetanus/diphteria/poliomyelitis/pneumococcal antibodies & IgM isohemagglutinin titer Community resources such as Social work involvement for parental support; Home nursing referral. BMF = bone marrow failure; CBC = complete blood count; HCT = hematopoietic cell transplantation; MOI = mode of inheritance; PFT = pulmonary function test Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Baseline PFTs incl carbon monoxide diffusion capacity • Consider bubble echocardiography to evaluate for pulmonary arteriovenous malformations. • Eval by otolaryngologist & dentist as soon as patient is able to cooperate w/exam • Gynecologic exam for females starting by age 16 yrs or when sexually active • Lymphocyte subsets, lymphocyte proliferation response, serum IgG, IgM, IgA levels • If presenting w/↑ infections: tetanus/diphteria/poliomyelitis/pneumococcal antibodies & IgM isohemagglutinin titer • Community resources such as • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations The specific treatment for DC/TBD-related complications must be tailored to the individual. The recommendations in this section were first discussed at a DC clinical research workshop in 2008 and subsequently at a meeting of experts convened to review the publication of the first edition of the Clinical care guidelines are also available at Treatment of Manifestations in Individuals with Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) Range of clinical phenotypes seen in DC/TBD & possibility of non-manifesting or very mildly affected heterozygotes w/in families may complicate selection of related HCT donors. Test potential related HCT donors either for pathogenic variant(s) present in proband or, if variant(s) are unknown, for telomere length. Persons w/DC/TBD may be more sensitive to androgens than those w/ Side effects, incl liver enzyme abnormalities, need to be monitored carefully. Perform baseline & follow-up liver ultrasound exams for persons receiving androgen therapy because of possibility of liver adenomas & carcinomas, which have been reported in FA & in persons using androgens for benign hematologic diseases or for non-hematologic disorders. Prolonged cytopenias due to underlying BMF; Therapy-related pulmonary & hepatic toxicity (PFTs & liver function should be monitored carefully); Radiotherapy-related complications based on observations in persons undergoing radiotherapy in HCT. BMF = bone marrow failure; FA = Fanconi anemia; HCT = hematopoietic cell transplantation; PFT = pulmonary function test Following the model of the Fanconi anemia consensus guidelines [ HCT is the only curative treatment for severe BMF or leukemia in DC/TBD. It should be performed at centers experienced in treating DC/TBD. Pre- and post-transplant considerations and outcomes have been recently reviewed [ Author, personal observation See • Range of clinical phenotypes seen in DC/TBD & possibility of non-manifesting or very mildly affected heterozygotes w/in families may complicate selection of related HCT donors. • Test potential related HCT donors either for pathogenic variant(s) present in proband or, if variant(s) are unknown, for telomere length. • Persons w/DC/TBD may be more sensitive to androgens than those w/ • Side effects, incl liver enzyme abnormalities, need to be monitored carefully. • Perform baseline & follow-up liver ultrasound exams for persons receiving androgen therapy because of possibility of liver adenomas & carcinomas, which have been reported in FA & in persons using androgens for benign hematologic diseases or for non-hematologic disorders. • Prolonged cytopenias due to underlying BMF; • Therapy-related pulmonary & hepatic toxicity (PFTs & liver function should be monitored carefully); • Radiotherapy-related complications based on observations in persons undergoing radiotherapy in HCT. ## Surveillance The recommendations in this section were discussed at the first DC clinical research workshop in 2008 and updated in 2014 at a consensus conference that led to publication of the first edition of the Recommended Surveillance for Individuals with Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD) CBC Bone marrow aspirate & biopsy incl morphologic exam & cytogenetic studies Annually More frequently in case of ↓ blood count detection of clonal cytogenetic abnormality Prior to start Rpt every 4-6 wks When counts are stable, rpt every 2-3 mos Cancer screening by otolaryngologist Gynecologic exam Skin cancer screening by dermatologist Exam by dentist & dental hygienist Monitoring of leukoplakia & biopsy of suspicious lesions BMF = bone marrow failure; CBC = complete blood count; PFT = pulmonary function test Including 5q-, 7q-/monosomy 7, trisomy 8, 20q-, 11q23 translocation, 3q abnormalities • CBC • Bone marrow aspirate & biopsy incl morphologic exam & cytogenetic studies • Annually • More frequently in case of ↓ blood count detection of clonal cytogenetic abnormality • Prior to start • Rpt every 4-6 wks • When counts are stable, rpt every 2-3 mos • Cancer screening by otolaryngologist • Gynecologic exam • Skin cancer screening by dermatologist • Exam by dentist & dental hygienist • Monitoring of leukoplakia & biopsy of suspicious lesions ## Agents/Circumstances to Avoid Transfusions of red cells or platelets should be avoided or minimized for those who are candidates for hematopoietic cell transplantation (HCT). To minimize the chances of sensitization, family members must not act as blood donors if HCT is being considered. All blood products should be leukodepleted and irradiated. • Transfusions of red cells or platelets should be avoided or minimized for those who are candidates for hematopoietic cell transplantation (HCT). • To minimize the chances of sensitization, family members must not act as blood donors if HCT is being considered. • All blood products should be leukodepleted and irradiated. ## Evaluation of Relatives at Risk Evaluations include: Telomere length testing; Molecular genetic testing if a molecular diagnosis has been established in the proband. See • Telomere length testing; • Molecular genetic testing if a molecular diagnosis has been established in the proband. ## Pregnancy Management Individuals with DC/TBD who become pregnant may develop pancytopenia or existing cytopenias may worsen. They should be followed closely by a perinatologist. ## Therapies Under Investigation Search ## Genetic Counseling The mode of inheritance of dyskeratosis congenita and related telomere biology disorders (DC/TBD) depends on the associated gene (see Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD): Mode of Inheritance by Gene AD = autosomal dominant; AR = autosomal recessive; XL = X-linked Genes are listed in alphabetic order. Note: If the causative pathogenic variant(s) have not been identified in an affected family member, telomere length testing of first-degree relatives is recommended (see Management, 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 male, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and 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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for If the proband represents a simplex case and if the All their daughters, who will be heterozygotes; None of their sons. Some individuals diagnosed with autosomal dominant DC/TBD have an affected parent. A proband with autosomal dominant DC/TBD may have the disorder as the result of a If the causative pathogenic variant has been identified 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 causative pathogenic variant has not been identified in the proband, telomere length testing of the parents is recommended. If the proband has a known pathogenic variant that cannot be detected 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 mosaicism. Note: Testing of 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline The family history of some individuals diagnosed with autosomal dominant DC/TBD may appear to be negative because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without 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%. The age of onset and manifestations of DC/TBD may vary considerably among heterozygous family members (see If the DC/TBD-causing pathogenic variant found in the proband cannot be detected in the 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 [ A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline If the parents are clinically unaffected but they have not undergone molecular genetic testing or telomere testing, sibs are presumed to be at increased risk for DC/TBD for one of two possible reasons: A parent has germline mosaicism; or A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. The parents of an affected child are presumed to be heterozygous for one DC/TBD-causing pathogenic variant. If the causative pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a DC/TBD-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 may or not may not be affected. Pathogenic variants in Heterozygotes for a pathogenic variant in If both parents are known to be heterozygous for a DC/TBD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two DC/TBD-causing pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial DC/TBD-causing pathogenic variants. The age of onset and manifestations of DC/TBD may vary considerably among family members with biallelic pathogenic variants. Heterozygotes may or not may not be affected. Pathogenic variants in Heterozygotes for a pathogenic variant in See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Once the DC/TBD-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. • 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 male, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and 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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for • 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. Clinical manifestations in females heterozygous for • All their daughters, who will be heterozygotes; • None of their sons. • Some individuals diagnosed with autosomal dominant DC/TBD have an affected parent. • A proband with autosomal dominant DC/TBD may have the disorder as the result of a • If the causative pathogenic variant has been identified 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 causative pathogenic variant has not been identified in the proband, telomere length testing of the parents is recommended. • If the proband has a known pathogenic variant that cannot be detected 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 mosaicism. Note: Testing of 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline • The proband has a • The proband inherited a pathogenic variant from a parent with 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline • The family history of some individuals diagnosed with autosomal dominant DC/TBD may appear to be negative because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without 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 mosaicism. Note: Testing of 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline • 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 age of onset and manifestations of DC/TBD may vary considerably among heterozygous family members (see • If the DC/TBD-causing pathogenic variant found in the proband cannot be detected in the 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 [ • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline • The possibility of parental germline mosaicism [ • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline • If the parents are clinically unaffected but they have not undergone molecular genetic testing or telomere testing, sibs are presumed to be at increased risk for DC/TBD for one of two possible reasons: • A parent has germline mosaicism; or • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. • A parent has germline mosaicism; or • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. • The possibility of parental germline mosaicism [ • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline • A parent has germline mosaicism; or • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. • The parents of an affected child are presumed to be heterozygous for one DC/TBD-causing pathogenic variant. • If the causative pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a DC/TBD-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 may or not may not be affected. • Pathogenic variants in • Heterozygotes for a pathogenic variant in • Pathogenic variants in • Heterozygotes for a pathogenic variant in • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Pathogenic variants in • Heterozygotes for a pathogenic variant in • If both parents are known to be heterozygous for a DC/TBD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two DC/TBD-causing pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial DC/TBD-causing pathogenic variants. • The age of onset and manifestations of DC/TBD may vary considerably among family members with biallelic pathogenic variants. • Heterozygotes may or not may not be affected. • Pathogenic variants in • Heterozygotes for a pathogenic variant in • Pathogenic variants in • Heterozygotes for a pathogenic variant in • Pathogenic variants in • Heterozygotes for a pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance The mode of inheritance of dyskeratosis congenita and related telomere biology disorders (DC/TBD) depends on the associated gene (see Dyskeratosis Congenita and Related Telomere Biology Disorders (DC/TBD): Mode of Inheritance by Gene AD = autosomal dominant; AR = autosomal recessive; XL = X-linked Genes are listed in alphabetic order. Note: If the causative pathogenic variant(s) have not been identified in an affected family member, telomere length testing of first-degree relatives is recommended (see Management, ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected male, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and 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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for If the proband represents a simplex case and if the All their daughters, who will be heterozygotes; 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 male, the mother of an affected male is an obligate heterozygote. If a woman has more than one affected child and 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 pathogenic variant, the chance of transmitting it in each pregnancy is 50%: • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes. Clinical manifestations in females heterozygous for • 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. Clinical manifestations in females heterozygous for • All their daughters, who will be heterozygotes; • None of their sons. ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with autosomal dominant DC/TBD have an affected parent. A proband with autosomal dominant DC/TBD may have the disorder as the result of a If the causative pathogenic variant has been identified 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 causative pathogenic variant has not been identified in the proband, telomere length testing of the parents is recommended. If the proband has a known pathogenic variant that cannot be detected 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 mosaicism. Note: Testing of 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline The family history of some individuals diagnosed with autosomal dominant DC/TBD may appear to be negative because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without 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%. The age of onset and manifestations of DC/TBD may vary considerably among heterozygous family members (see If the DC/TBD-causing pathogenic variant found in the proband cannot be detected in the 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 [ A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline If the parents are clinically unaffected but they have not undergone molecular genetic testing or telomere testing, sibs are presumed to be at increased risk for DC/TBD for one of two possible reasons: A parent has germline mosaicism; or A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. • Some individuals diagnosed with autosomal dominant DC/TBD have an affected parent. • A proband with autosomal dominant DC/TBD may have the disorder as the result of a • If the causative pathogenic variant has been identified 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 causative pathogenic variant has not been identified in the proband, telomere length testing of the parents is recommended. • If the proband has a known pathogenic variant that cannot be detected 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 mosaicism. Note: Testing of 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline • The proband has a • The proband inherited a pathogenic variant from a parent with 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline • The family history of some individuals diagnosed with autosomal dominant DC/TBD may appear to be negative because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without 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 mosaicism. Note: Testing of 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 inherited a DC/TBD-causing pathogenic variant from a parent with somatically acquired loss of heterozygosity with preferential loss of the chromosome with the pathogenic variant. This scenario may cause a false negative molecular result when testing leukocyte DNA. Note: To date, this has only been observed in individuals with germline • 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 age of onset and manifestations of DC/TBD may vary considerably among heterozygous family members (see • If the DC/TBD-causing pathogenic variant found in the proband cannot be detected in the 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 [ • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline • The possibility of parental germline mosaicism [ • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline • If the parents are clinically unaffected but they have not undergone molecular genetic testing or telomere testing, sibs are presumed to be at increased risk for DC/TBD for one of two possible reasons: • A parent has germline mosaicism; or • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. • A parent has germline mosaicism; or • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. • The possibility of parental germline mosaicism [ • A false negative result in a parent due to preferential loss of the chromosome with the DC/TBD-causing pathogenic variant. Note: Revertant mosaicism (i.e., loss of heterozygosity for the deleterious allele) in peripheral blood cells has only been observed in individuals with germline • A parent has germline mosaicism; or • A parent is heterozygous but does not have apparent manifestations of DC/TBD because of phenotypic modification resulting from additional genetic events that confer a protective effect. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are presumed to be heterozygous for one DC/TBD-causing pathogenic variant. If the causative pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a DC/TBD-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 may or not may not be affected. Pathogenic variants in Heterozygotes for a pathogenic variant in If both parents are known to be heterozygous for a DC/TBD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two DC/TBD-causing pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial DC/TBD-causing pathogenic variants. The age of onset and manifestations of DC/TBD may vary considerably among family members with biallelic pathogenic variants. Heterozygotes may or not may not be affected. Pathogenic variants in Heterozygotes for a pathogenic variant in • The parents of an affected child are presumed to be heterozygous for one DC/TBD-causing pathogenic variant. • If the causative pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a DC/TBD-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 may or not may not be affected. • Pathogenic variants in • Heterozygotes for a pathogenic variant in • Pathogenic variants in • Heterozygotes for a pathogenic variant in • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Pathogenic variants in • Heterozygotes for a pathogenic variant in • If both parents are known to be heterozygous for a DC/TBD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two DC/TBD-causing pathogenic variants, a 50% chance of inheriting one pathogenic variant, and a 25% chance of inheriting neither of the familial DC/TBD-causing pathogenic variants. • The age of onset and manifestations of DC/TBD may vary considerably among family members with biallelic pathogenic variants. • Heterozygotes may or not may not be affected. • Pathogenic variants in • Heterozygotes for a pathogenic variant in • Pathogenic variants in • Heterozygotes for a pathogenic variant in • Pathogenic variants in • Heterozygotes for a pathogenic variant in ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the DC/TBD-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 United Kingdom 1562 First Avenue #205-4093 New York NY 10028-4004 • • United Kingdom • • • 1562 First Avenue #205-4093 • New York NY 10028-4004 • • • ## Molecular Genetics Dyskeratosis Congenita and Related Telomere Biology Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Dyskeratosis Congenita and Related Telomere Biology Disorders ( Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The telomere is a complex structure consisting of long nucleotide repeats (TTAGGG)n and a protein complex at chromosome ends that are essential to chromosomal integrity. The TTAGGG nucleotide repeats at the chromosome end fold back to create a T-loop. Many proteins bind to the T-loop and others bind to those proteins to form a stable telomere "cap." Pathogenic variants in 16 different genes ( Note: The DC/TBD: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from ## Molecular Pathogenesis Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The telomere is a complex structure consisting of long nucleotide repeats (TTAGGG)n and a protein complex at chromosome ends that are essential to chromosomal integrity. The TTAGGG nucleotide repeats at the chromosome end fold back to create a T-loop. Many proteins bind to the T-loop and others bind to those proteins to form a stable telomere "cap." Pathogenic variants in 16 different genes ( Note: The DC/TBD: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from ## Chapter Notes Website: Drs Blanche Alter, Neelam Giri, and Lisa McReynolds, NCI, contributed invaluable advice and insight into patient diagnosis and management. This work was supported (in part) by the intramural research program of the National Cancer Institute, National Institutes of Health. 19 January 2023 (sw/sas) Revision: updated number of families with pathogenic variants in 31 March 2022 (ha) Comprehensive update posted live 21 November 2019 (aa) Revision: added mode of inheritance and OMIM links for idiopathic pulmonary fibrosis 26 May 2016 (ha) Comprehensive update posted live 3 January 2013 (cd) Revision: mutations in 13 September 2012 (cd) Revision: sequence analysis of the entire coding regions of 10 May 2012 (me) Comprehensive update posted live 12 November 2009 (me) Review posted live 15 May 2009 (sas) Original submission Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 19 January 2023 (sw/sas) Revision: updated number of families with pathogenic variants in • 31 March 2022 (ha) Comprehensive update posted live • 21 November 2019 (aa) Revision: added mode of inheritance and OMIM links for idiopathic pulmonary fibrosis • 26 May 2016 (ha) Comprehensive update posted live • 3 January 2013 (cd) Revision: mutations in • 13 September 2012 (cd) Revision: sequence analysis of the entire coding regions of • 10 May 2012 (me) Comprehensive update posted live • 12 November 2009 (me) Review posted live • 15 May 2009 (sas) Original submission ## Author Notes Website: ## Acknowledgments Drs Blanche Alter, Neelam Giri, and Lisa McReynolds, NCI, contributed invaluable advice and insight into patient diagnosis and management. This work was supported (in part) by the intramural research program of the National Cancer Institute, National Institutes of Health. ## Revision History 19 January 2023 (sw/sas) Revision: updated number of families with pathogenic variants in 31 March 2022 (ha) Comprehensive update posted live 21 November 2019 (aa) Revision: added mode of inheritance and OMIM links for idiopathic pulmonary fibrosis 26 May 2016 (ha) Comprehensive update posted live 3 January 2013 (cd) Revision: mutations in 13 September 2012 (cd) Revision: sequence analysis of the entire coding regions of 10 May 2012 (me) Comprehensive update posted live 12 November 2009 (me) Review posted live 15 May 2009 (sas) Original submission Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 19 January 2023 (sw/sas) Revision: updated number of families with pathogenic variants in • 31 March 2022 (ha) Comprehensive update posted live • 21 November 2019 (aa) Revision: added mode of inheritance and OMIM links for idiopathic pulmonary fibrosis • 26 May 2016 (ha) Comprehensive update posted live • 3 January 2013 (cd) Revision: mutations in • 13 September 2012 (cd) Revision: sequence analysis of the entire coding regions of • 10 May 2012 (me) Comprehensive update posted live • 12 November 2009 (me) Review posted live • 15 May 2009 (sas) Original submission ## References ## Literature Cited Examples of the dyskeratosis congenita diagnostic triad A. Skin pigmentation B. Dysplastic fingernails and toenails C. Oral leukoplakia MRI of cerebellar hypoplasia in an individual with Hoyeraal Hreidarsson syndrome. Arrow indicates the hypoplastic cerebellum. Schematic of the telomere and the proteins affected in dyskeratosis congenita and related telomere biology disorders Colors refer to reported inheritance pattern in the coding genes of depicted proteins: Red = X-linked Blue = autosomal recessive Yellow = autosomal dominant Green = autosomal dominant and autosomal recessive inheritance reported Gray = not known to cause human disease
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The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "H Takai, E Jenkinson, S Kabir, R Babul-Hirji, N Najm-Tehrani, DA Chitayat, YJ Crow, T. A de Lange. POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus.. Genes Dev. 2016;30:812-26", "DM Townsley, B Dumitriu, NS Young. Danazol treatment for telomere diseases.. N Engl J Med. 2016;375:1095-6", "E Tsangaris, SL Adams, G Yoon, D Chitayat, P Lansdorp, I Dokal, Y Dror. Ataxia and pancytopenia caused by a mutation in TINF2.. Hum Genet 2008;124:507-13", "H Tummala, A Walne, L Collopy, S Cardoso, J de la Fuente, S Lawson, J Powell, N Cooper, A Foster, S Mohammed, V Plagnol, T Vulliamy, I. Dokal. Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita.. J Clin Invest. 2015;125:2151-60", "JJ van der Vis, JJ van der Smagt, FAM Hennekam, JC Grutters, CHM van Moorsel. 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12/11/2009
31/3/2022
19/1/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dld-def
dld-def
[ "DLD Deficiency", "E3 Deficiency", "DLD Deficiency", "E3 Deficiency", "Dihydrolipoyl dehydrogenase, mitochondrial", "DLD", "Dihydrolipoamide Dehydrogenase Deficiency" ]
Dihydrolipoamide Dehydrogenase Deficiency
Shane C Quinonez, Jess G Thoene
Summary The phenotypes of dihydrolipoamide dehydrogenase (DLD) deficiency are an overlapping continuum that ranges from early-onset neurologic manifestations to adult-onset liver involvement and, rarely, a myopathic presentation. Early-onset DLD deficiency typically manifests in infancy as hypotonia with lactic acidosis. Affected infants frequently do not survive their initial metabolic decompensation, or die within the first few years of life during a recurrent metabolic decompensation. Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits (intellectual disability, spasticity, ataxia, and seizures). In contrast, isolated liver involvement can present as early as the neonatal period and as late as the third decade. Evidence of liver injury/failure is preceded by nausea and emesis and frequently associated with encephalopathy and/or coagulopathy. Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes affected individuals frequently return to baseline with no residual neurologic deficit or intellectual disability. Liver failure can result in death, even in those with late-onset disease. Individuals with the myopathic presentation may experience muscle cramps, weakness, and an elevated creatine kinase. The diagnosis of dihydrolipoamide dehydrogenase deficiency (DLD) is established in a proband with suggestive clinical and supportive laboratory findings and/or by identification of biallelic pathogenic variants in Routine daily treatment for those with the early-onset neurologic presentation: protein intake at approximately recommended dietary allowance (RDA); if there is evidence of significant hyperleucinosis, protein intake should consist of branched-chain amino acid (BCAA)-free powder formula with 2-3 g/kg/day natural protein; ketogenic/high-fat diet; dichloroacetate (DCA) supplementation (50-75 mg/kg/day); feeding therapy and consideration of gastrostomy tube for persistent feeding issues; standard treatment for developmental delay / intellectual disability, cardiac dysfunction, and vision impairment / optic atrophy. Acute inpatient treatment for those with early-onset neurologic presentation: address any precipitating factors (infection, fasting, medications); D For hepatic presentation: removal or treatment of precipitating factors; dextrose-containing IV fluids (6-8 mg/kg/min) with age-appropriate electrolytes and/or frequent feedings; consider correction of metabolic acidosis using sodium bicarbonate; consideration of DCA and/or dialysis; consideration of fresh frozen plasma for coagulopathy. For the myopathic presentation: At least one affected individual with severe exercise intolerance responded well to riboflavin supplementation (220 mg/day). DLD deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the
## Diagnosis Dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit of three mitochondrial enzyme complexes: branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, α-ketoglutarate dehydrogenase (αKGDH) complex, and pyruvate dehydrogenase (PDH) complex [ The phenotypic spectrum of DLD deficiency includes an early-onset neurologic presentation, a primarily hepatic presentation, and a primarily myopathic presentation. No formal clinical diagnostic criteria have been established for dihydrolipoamide dehydrogenase (DLD) deficiency. The diagnosis of dihydrolipoamide dehydrogenase (DLD) deficiency In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. Neurologic impairment presents in those who survive the first year of life. Age of onset ranges from the neonatal period to the third decade. Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. While muscle involvement is the main feature in previously reported individuals, additional findings include intermittent acidosis and hepatic involvement [ Note: (1) Newborn screening has failed to identify asymptomatic individuals with DLD deficiency when either dried blood spot citrulline or leucine is used as a primary screening analyte; (2) Individuals with an early-onset or hepatic presentation only occasionally have biochemical evidence of dysfunctional branched chain amino acid (BCAA) metabolism (i.e., elevations of allo-isoleucine and branched chain ketoacids; see Abnormal laboratory findings typically associated with the Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates Hypoglycemia. <40 mg/dL (<2.2 mmol/L) Other metabolic abnormalities listed in Laboratory findings typically associated with the Elevated lactate level (>2.2 µmol/L) Isolated elevated transaminases to fulminant hepatic failure Absence of other metabolic abnormalities (See Laboratory findings typically associated with the Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See Metabolic Abnormalities in DLD Deficiency by Presentation Neonates: 4-524 mmol/mol creatinine Children: 36-117 mmol/mol creatinine Adults: 4-74 mmol/mol creatinine Neonates: <7 mmol/mol creatinine All other ages: not detectable Infants: 46-147 µmol/L Children: 30-246 µmol/L Adolescents-adults: 86-206 µmol/L Infants: 12-77 µmol/L Children: 6-122 µmol/L Adolescents-adults: 34-106 µmol/L Infants: 79-217 µmol/L Children: 132-480 µmol/L Adolescents-adults: 155-343 µmol/L The diagnosis of dihydrolipoamide dehydrogenase deficiency (DLD) Note: The presence of decreased DLD enzymatic activity in fibroblasts, lymphocytes, or liver tissue can also be used to establish the diagnosis but is not recommended as a first-line test, given the general availability of molecular genetic testing. When laboratory findings suggest the diagnosis of DLD, molecular genetic testing approaches can include Targeted analysis for the Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered. For an introduction to multigene panels click Molecular Genetic Testing Used in Dihydrolipoamide Dehydrogenase 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving Variant panels may differ by laboratory. The • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. • Neurologic impairment presents in those who survive the first year of life. • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. • Neurologic impairment presents in those who survive the first year of life. • Age of onset ranges from the neonatal period to the third decade. • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. • Age of onset ranges from the neonatal period to the third decade. • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. • While muscle involvement is the main feature in previously reported individuals, additional findings include intermittent acidosis and hepatic involvement [ • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. • Neurologic impairment presents in those who survive the first year of life. • Age of onset ranges from the neonatal period to the third decade. • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. • Note: (1) Newborn screening has failed to identify asymptomatic individuals with DLD deficiency when either dried blood spot citrulline or leucine is used as a primary screening analyte; (2) Individuals with an early-onset or hepatic presentation only occasionally have biochemical evidence of dysfunctional branched chain amino acid (BCAA) metabolism (i.e., elevations of allo-isoleucine and branched chain ketoacids; see • Abnormal laboratory findings typically associated with the • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates • Hypoglycemia. <40 mg/dL (<2.2 mmol/L) • Other metabolic abnormalities listed in • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates • Hypoglycemia. <40 mg/dL (<2.2 mmol/L) • Other metabolic abnormalities listed in • Laboratory findings typically associated with the • Elevated lactate level (>2.2 µmol/L) • Isolated elevated transaminases to fulminant hepatic failure • Absence of other metabolic abnormalities (See • Elevated lactate level (>2.2 µmol/L) • Isolated elevated transaminases to fulminant hepatic failure • Absence of other metabolic abnormalities (See • Laboratory findings typically associated with the • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates • Hypoglycemia. <40 mg/dL (<2.2 mmol/L) • Other metabolic abnormalities listed in • Elevated lactate level (>2.2 µmol/L) • Isolated elevated transaminases to fulminant hepatic failure • Absence of other metabolic abnormalities (See • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See • Neonates: 4-524 mmol/mol creatinine • Children: 36-117 mmol/mol creatinine • Adults: 4-74 mmol/mol creatinine • Neonates: <7 mmol/mol creatinine • All other ages: not detectable • Infants: 46-147 µmol/L • Children: 30-246 µmol/L • Adolescents-adults: 86-206 µmol/L • Infants: 12-77 µmol/L • Children: 6-122 µmol/L • Adolescents-adults: 34-106 µmol/L • Infants: 79-217 µmol/L • Children: 132-480 µmol/L • Adolescents-adults: 155-343 µmol/L • Targeted analysis for the • Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. • If only one or no variant is detected by the sequencing method used, the gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered. ## Suggestive Findings The diagnosis of dihydrolipoamide dehydrogenase (DLD) deficiency In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. Neurologic impairment presents in those who survive the first year of life. Age of onset ranges from the neonatal period to the third decade. Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. While muscle involvement is the main feature in previously reported individuals, additional findings include intermittent acidosis and hepatic involvement [ Note: (1) Newborn screening has failed to identify asymptomatic individuals with DLD deficiency when either dried blood spot citrulline or leucine is used as a primary screening analyte; (2) Individuals with an early-onset or hepatic presentation only occasionally have biochemical evidence of dysfunctional branched chain amino acid (BCAA) metabolism (i.e., elevations of allo-isoleucine and branched chain ketoacids; see Abnormal laboratory findings typically associated with the Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates Hypoglycemia. <40 mg/dL (<2.2 mmol/L) Other metabolic abnormalities listed in Laboratory findings typically associated with the Elevated lactate level (>2.2 µmol/L) Isolated elevated transaminases to fulminant hepatic failure Absence of other metabolic abnormalities (See Laboratory findings typically associated with the Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See Metabolic Abnormalities in DLD Deficiency by Presentation Neonates: 4-524 mmol/mol creatinine Children: 36-117 mmol/mol creatinine Adults: 4-74 mmol/mol creatinine Neonates: <7 mmol/mol creatinine All other ages: not detectable Infants: 46-147 µmol/L Children: 30-246 µmol/L Adolescents-adults: 86-206 µmol/L Infants: 12-77 µmol/L Children: 6-122 µmol/L Adolescents-adults: 34-106 µmol/L Infants: 79-217 µmol/L Children: 132-480 µmol/L Adolescents-adults: 155-343 µmol/L • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. • Neurologic impairment presents in those who survive the first year of life. • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. • Neurologic impairment presents in those who survive the first year of life. • Age of onset ranges from the neonatal period to the third decade. • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. • Age of onset ranges from the neonatal period to the third decade. • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. • While muscle involvement is the main feature in previously reported individuals, additional findings include intermittent acidosis and hepatic involvement [ • In untreated infants, manifestations progress to deepening encephalopathy (lethargy, tone abnormalities, feeding difficulties, decreased level of alertness, and occasionally seizures) and eventual death. • Neurologic impairment presents in those who survive the first year of life. • Age of onset ranges from the neonatal period to the third decade. • Individuals with the hepatic form typically have normal intellect with no residual neurologic deficit between acute metabolic episodes unless neurologic damage has occurred. • Note: (1) Newborn screening has failed to identify asymptomatic individuals with DLD deficiency when either dried blood spot citrulline or leucine is used as a primary screening analyte; (2) Individuals with an early-onset or hepatic presentation only occasionally have biochemical evidence of dysfunctional branched chain amino acid (BCAA) metabolism (i.e., elevations of allo-isoleucine and branched chain ketoacids; see • Abnormal laboratory findings typically associated with the • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates • Hypoglycemia. <40 mg/dL (<2.2 mmol/L) • Other metabolic abnormalities listed in • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates • Hypoglycemia. <40 mg/dL (<2.2 mmol/L) • Other metabolic abnormalities listed in • Laboratory findings typically associated with the • Elevated lactate level (>2.2 µmol/L) • Isolated elevated transaminases to fulminant hepatic failure • Absence of other metabolic abnormalities (See • Elevated lactate level (>2.2 µmol/L) • Isolated elevated transaminases to fulminant hepatic failure • Absence of other metabolic abnormalities (See • Laboratory findings typically associated with the • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See • Metabolic acidosis. Arterial pH <7.35 or venous pH <7.32 and serum bicarbonate <22 mmol/L in children and adults or <17 mmol/L in neonates • Hypoglycemia. <40 mg/dL (<2.2 mmol/L) • Other metabolic abnormalities listed in • Elevated lactate level (>2.2 µmol/L) • Isolated elevated transaminases to fulminant hepatic failure • Absence of other metabolic abnormalities (See • Normal-to-elevated serum creatinine kinase (CK) level, up to 20 times the normal range during acute episodes (<192 U/L) [ • Occasionally elevated transaminases, lactate, and other metabolic abnormalities (See • Neonates: 4-524 mmol/mol creatinine • Children: 36-117 mmol/mol creatinine • Adults: 4-74 mmol/mol creatinine • Neonates: <7 mmol/mol creatinine • All other ages: not detectable • Infants: 46-147 µmol/L • Children: 30-246 µmol/L • Adolescents-adults: 86-206 µmol/L • Infants: 12-77 µmol/L • Children: 6-122 µmol/L • Adolescents-adults: 34-106 µmol/L • Infants: 79-217 µmol/L • Children: 132-480 µmol/L • Adolescents-adults: 155-343 µmol/L ## Establishing the Diagnosis The diagnosis of dihydrolipoamide dehydrogenase deficiency (DLD) Note: The presence of decreased DLD enzymatic activity in fibroblasts, lymphocytes, or liver tissue can also be used to establish the diagnosis but is not recommended as a first-line test, given the general availability of molecular genetic testing. When laboratory findings suggest the diagnosis of DLD, molecular genetic testing approaches can include Targeted analysis for the Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered. For an introduction to multigene panels click Molecular Genetic Testing Used in Dihydrolipoamide Dehydrogenase 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications involving Variant panels may differ by laboratory. The • Targeted analysis for the • Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. • If only one or no variant is detected by the sequencing method used, the gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered. ## Clinical Characteristics Persons with dihydrolipoamide dehydrogenase (DLD) deficiency exhibit variable phenotypic and biochemical consequences based on the three affected enzyme complexes. While the spectrum of disease ranges from early-onset neurologic manifestations to isolated adult-onset liver involvement, it represents a continuum and differentiation between discretely defined presentations can occasionally be difficult. The most frequent clinical finding in early-onset DLD deficiency is that of a hypotonic infant with lactic acidosis ( Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits including intellectual disability, spasticity (hypertonia and/or hyperreflexia), ataxia, and seizures. Typically, seizures are generalized tonic-clonic and occur during episodes of metabolic decompensation and not during periods when affected individuals are metabolically stable [ Features of the Early-Onset Neurologic Phenotype Includes only individuals biochemically confirmed to have DLD deficiency BCAA = branched-chain amino acids Later physical examination and neurologic findings are likely underrepresented, as children with an early-onset presentation frequently die in the first year(s) of life. Arterial pH <7.35 or venous pH <7.32; serum bicarbonate <22 mmol/L in infants, children, and adults; or <17 mmol/L in neonates See Glucose <40 mg/dL Carnitine (free) <38±22 Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults Some affected individuals have experienced worsening of clinical status with high-fat diets [ Some individuals with DLD deficiency have features of Leigh syndrome [ The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features: Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T Typical neuropathologic changes at postmortem examination Typical neuropathology in a similarly affected sib Between acute episodes both liver size and transaminase levels can return to normal. Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance. Affected individuals with a primarily hepatic presentation can develop signs and symptoms as early as the neonatal period and as late as the third decade of life [ Features of the Hepatic Phenotype Includes only individuals biochemically confirmed to have DLD deficiency BCAA = branched-chain amino acids See Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults Glucose <40 mg/dL Carnitine (free) <38±22 Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes (see Affected individuals frequently experience lifelong recurrent attacks of hepatopathy that decrease with age. Attacks are often precipitated by catabolism, intercurrent illness/fever, and dietary extremes. These individuals additionally are more susceptible to hepatotropic viruses (e.g., Epstein-Barr virus) and medications (e.g., acetaminophen) [ Liver biopsy electron microscopy has shown the presence of lipid droplets [ Two individuals have been described with a phenotype consisting of primarily myopathic symptoms [ Phenotypic severity is difficult to predict based on genotype and residual enzyme function [ Normal intellectual functioning has been reported in individuals with early-onset disease with compound heterozygosity for the All individuals with an exclusively hepatic presentation have been homozygous for the Note: Individuals homozygous for the DLD deficiency is occasionally referred to as maple syrup urine disease (MSUD) type 3 as it functions as the E3 subunit of BCKDH. Note that MSUD type 1 is caused by biallelic pathogenic variants in DLD deficiency may also be referred to as lipoamide dehydrogenase deficiency. In the Ashkenazi Jewish population, the carrier frequency of the The incidence and carrier frequency in other populations are unknown; DLD deficiency is likely very rare. • Some affected individuals have experienced worsening of clinical status with high-fat diets [ • Some individuals with DLD deficiency have features of Leigh syndrome [ • The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features: • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Between acute episodes both liver size and transaminase levels can return to normal. • Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance. • Normal intellectual functioning has been reported in individuals with early-onset disease with compound heterozygosity for the • All individuals with an exclusively hepatic presentation have been homozygous for the • Note: Individuals homozygous for the ## Clinical Description Persons with dihydrolipoamide dehydrogenase (DLD) deficiency exhibit variable phenotypic and biochemical consequences based on the three affected enzyme complexes. While the spectrum of disease ranges from early-onset neurologic manifestations to isolated adult-onset liver involvement, it represents a continuum and differentiation between discretely defined presentations can occasionally be difficult. The most frequent clinical finding in early-onset DLD deficiency is that of a hypotonic infant with lactic acidosis ( Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits including intellectual disability, spasticity (hypertonia and/or hyperreflexia), ataxia, and seizures. Typically, seizures are generalized tonic-clonic and occur during episodes of metabolic decompensation and not during periods when affected individuals are metabolically stable [ Features of the Early-Onset Neurologic Phenotype Includes only individuals biochemically confirmed to have DLD deficiency BCAA = branched-chain amino acids Later physical examination and neurologic findings are likely underrepresented, as children with an early-onset presentation frequently die in the first year(s) of life. Arterial pH <7.35 or venous pH <7.32; serum bicarbonate <22 mmol/L in infants, children, and adults; or <17 mmol/L in neonates See Glucose <40 mg/dL Carnitine (free) <38±22 Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults Some affected individuals have experienced worsening of clinical status with high-fat diets [ Some individuals with DLD deficiency have features of Leigh syndrome [ The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features: Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T Typical neuropathologic changes at postmortem examination Typical neuropathology in a similarly affected sib Between acute episodes both liver size and transaminase levels can return to normal. Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance. Affected individuals with a primarily hepatic presentation can develop signs and symptoms as early as the neonatal period and as late as the third decade of life [ Features of the Hepatic Phenotype Includes only individuals biochemically confirmed to have DLD deficiency BCAA = branched-chain amino acids See Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults Glucose <40 mg/dL Carnitine (free) <38±22 Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes (see Affected individuals frequently experience lifelong recurrent attacks of hepatopathy that decrease with age. Attacks are often precipitated by catabolism, intercurrent illness/fever, and dietary extremes. These individuals additionally are more susceptible to hepatotropic viruses (e.g., Epstein-Barr virus) and medications (e.g., acetaminophen) [ Liver biopsy electron microscopy has shown the presence of lipid droplets [ Two individuals have been described with a phenotype consisting of primarily myopathic symptoms [ • Some affected individuals have experienced worsening of clinical status with high-fat diets [ • Some individuals with DLD deficiency have features of Leigh syndrome [ • The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features: • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Between acute episodes both liver size and transaminase levels can return to normal. • Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance. ## Early-Onset Neurologic Presentation The most frequent clinical finding in early-onset DLD deficiency is that of a hypotonic infant with lactic acidosis ( Children who live beyond the first two to three years frequently exhibit growth deficiencies and residual neurologic deficits including intellectual disability, spasticity (hypertonia and/or hyperreflexia), ataxia, and seizures. Typically, seizures are generalized tonic-clonic and occur during episodes of metabolic decompensation and not during periods when affected individuals are metabolically stable [ Features of the Early-Onset Neurologic Phenotype Includes only individuals biochemically confirmed to have DLD deficiency BCAA = branched-chain amino acids Later physical examination and neurologic findings are likely underrepresented, as children with an early-onset presentation frequently die in the first year(s) of life. Arterial pH <7.35 or venous pH <7.32; serum bicarbonate <22 mmol/L in infants, children, and adults; or <17 mmol/L in neonates See Glucose <40 mg/dL Carnitine (free) <38±22 Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults Some affected individuals have experienced worsening of clinical status with high-fat diets [ Some individuals with DLD deficiency have features of Leigh syndrome [ The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features: Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T Typical neuropathologic changes at postmortem examination Typical neuropathology in a similarly affected sib Between acute episodes both liver size and transaminase levels can return to normal. Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance. • Some affected individuals have experienced worsening of clinical status with high-fat diets [ • Some individuals with DLD deficiency have features of Leigh syndrome [ • The diagnostic criteria for Leigh syndrome include: (1) progressive neurologic disease with motor and intellectual developmental delay; (2) signs and features of brain stem or basal ganglia disease; (3) elevated lactate levels in the blood or cerebrospinal fluid; and (4) one or more of three features: • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Characteristic features of Leigh syndrome on neuroradioimaging (symmetric hypodensities in the basal ganglia on computed tomography, or hyperintense lesions on T • Typical neuropathologic changes at postmortem examination • Typical neuropathology in a similarly affected sib • Between acute episodes both liver size and transaminase levels can return to normal. • Liver biopsies have shown increased glycogen content and mild fibrosis or fatty, acute necrosis with a Reye syndrome-like appearance. ## Hepatic Presentation Affected individuals with a primarily hepatic presentation can develop signs and symptoms as early as the neonatal period and as late as the third decade of life [ Features of the Hepatic Phenotype Includes only individuals biochemically confirmed to have DLD deficiency BCAA = branched-chain amino acids See Ammonia >100 µmol/L in neonates or >60 µmol/L in infants, children, and adults Glucose <40 mg/dL Carnitine (free) <38±22 Acute metabolic episodes are frequently associated with lactate elevations, hyperammonemia, and hepatomegaly. With resolution of the acute episodes (see Affected individuals frequently experience lifelong recurrent attacks of hepatopathy that decrease with age. Attacks are often precipitated by catabolism, intercurrent illness/fever, and dietary extremes. These individuals additionally are more susceptible to hepatotropic viruses (e.g., Epstein-Barr virus) and medications (e.g., acetaminophen) [ Liver biopsy electron microscopy has shown the presence of lipid droplets [ ## Myopathic Presentation Two individuals have been described with a phenotype consisting of primarily myopathic symptoms [ ## Genotype-Phenotype Correlations Phenotypic severity is difficult to predict based on genotype and residual enzyme function [ Normal intellectual functioning has been reported in individuals with early-onset disease with compound heterozygosity for the All individuals with an exclusively hepatic presentation have been homozygous for the Note: Individuals homozygous for the • Normal intellectual functioning has been reported in individuals with early-onset disease with compound heterozygosity for the • All individuals with an exclusively hepatic presentation have been homozygous for the • Note: Individuals homozygous for the ## Nomenclature DLD deficiency is occasionally referred to as maple syrup urine disease (MSUD) type 3 as it functions as the E3 subunit of BCKDH. Note that MSUD type 1 is caused by biallelic pathogenic variants in DLD deficiency may also be referred to as lipoamide dehydrogenase deficiency. ## Prevalence In the Ashkenazi Jewish population, the carrier frequency of the The incidence and carrier frequency in other populations are unknown; DLD deficiency is likely very rare. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency DLD deficiency causes MSUD type 3 & can typically be differentiated from MSUD types 1 & 2 by the presence of severe lactic acidosis, α-ketoglutarate excretion in urine, & liver involvement in DLD deficiency The maple syrup odor frequently assoc w/MSUD types 1 & 2 is not typically assoc w/DLD deficiency. αKGDH = α-ketoglutarate dehydrogenase; AR = autosomal recessive; BCAA = branched-chain amino acid; BCKDH = branched-chain α-ketoacid dehydrogenase; DD = developmental delay; DiffDx = differential diagnosis; DLD = dihydrolipoamide dehydrogenase; MOI = mode of inheritance; PDH = pyruvate dehydrogenase; XL = X-linked Leucine, isoleucine, and valine Lipoic acid is the essential cofactor attached to the E2 subunits of BCKDH, αKGDH, and PDH as well as to the H protein of the glycine cleavage system (see • DLD deficiency causes MSUD type 3 & can typically be differentiated from MSUD types 1 & 2 by the presence of severe lactic acidosis, α-ketoglutarate excretion in urine, & liver involvement in DLD deficiency • The maple syrup odor frequently assoc w/MSUD types 1 & 2 is not typically assoc w/DLD deficiency. ## Management Consensus recommendations for the management of DLD deficiency do not currently exist. Theoretic difficulties exist for the management of affected individuals based on the various metabolic pathways affected by the three involved enzyme complexes. In practice, these difficulties have been experienced and make empiric treatment recommendations challenging. When dihydrolipoamide dehydrogenase (DLD) deficiency is suspected during the diagnostic evaluation, treatment should be initiated immediately. Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center. To establish the extent of disease and needs in an individual diagnosed with dihydrolipoamide dehydrogenase (DLD) deficiency, the evaluations summarized in the following tables (if not performed as part of the evaluation that led to the diagnosis) are recommended. Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Ill Neonate Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in a Stabilized Neonate/Infant Head MRI to assess for brain damage; EEG if seizures a concern; Regular developmental assessments to identify impairments resulting from metabolic decompensations. Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Older Child or Adult Blood gas (arterial or venous), ammonia, lactic acid, CK, & glucose Plasma free & total carnitine, plasma amino acids, & urine organic acids The multiple strategies that have been attempted in children with an early-onset neurologic presentation do not appear to significantly alter the natural history of disease. Even with treatment, children often die in the neonatal/infantile period or, if they survive the initial episode, experience various degrees of chronic neurologic impairment. Routine Daily Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency Leucine tolerance for neonates: 65-85 mg/kg/day Breast milk or regular infant formula can be used as a natural protein source. Dried blood spots by overnight mail for monitoring of amino acid concentrations if available (See Leucine restriction should be maintained until hyperleucinosis resolves. 5 had no clinical benefit, & 2 of the 5 experienced ↑ in acidosis & hypoglycemia; 2 improved clinically. 4 of 5 persons treated w/DCA in the literature experienced at least transient ↓s in lactic acid elevations. Chronic use of DCA can result in polyneuropathy. BCAA = branched-chain amino acids; DCA = dichloroacetate; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; RDA = recommended dietary allowance Recommendations are based on decreased branched-chain α-ketoacid dehydrogenase (BCKDH) complex activity. Restriction of protein to recommended dietary allowances has been attempted with questionable results. Three of the six reported individuals experienced laboratory and/or clinical improvement with the use of protein restriction alone or in combination with medication therapy. For rapidly growing infants, monitoring weekly or twice weekly is recommended. Ketogenic/high-fat diets are frequently employed in individuals who have pyruvate dehydrogenase (PDH) complex deficiency [ One was treated with lipid infusions (instead of high-dextrose infusions) during acute episodes [ Additional therapies used with limited success include the following: Thiamine Coenzyme Q Lipoic acid Riboflavin (though effective in one person with the myopathic form of DLD deficiency) Biotin Acute Inpatient Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency For severe metabolic acidosis (pH <7.20) or if bicarbonate is ≤14 mEq/L, initiate bicarbonate therapy. A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate] Administer 1/2 of calculated dose as slow bolus & remaining 1/2 over 24 hrs. Metabolic acidosis usually improves w/generous fluid & calorie support. Bicarbonate therapy needed for severe metabolic acidosis Maintain glucose concentration in normal range. Intralipids can be added to provide addl calories w/cautious monitoring for acidemia. Withhold protein initially for a maximum of 24 hrs to avoid worsening of catabolism. Then gradually reintroduce protein. Start IV fluid. Maintain blood glucose >100 mg/dL. High-dose glucose needed to avoid catabolism If there is hyperglycemia, start insulin infusion rather than ↓ glucose infusion rate. Hyperammonemia improves w/reversal of catabolism. A high-dose glucose infusion w/insulin infusion is helpful in achieving this goal. If severe hyperammonemia & altered mental status persist after above measures, extracorporeal toxin removal procedures such as hemodialysis & hemofiltration should be considered. If lactate decreases with its introduction Polyneuropathy is a concern w/long-term use. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. As seizures typically occur during acute decompensations, ASM may be discontinued when metabolic control is achieved. ASM = anti-seizure medication; BCAAs = branched-chain amino acids; DCA = dichloroacetate; IV = intravenous; MSUD = maple syrup urine disease; PO = orally Although dextrose infusions may theoretically cause further lactate elevations during acute episodes, provision of dextrose-containing IV fluids is essential for the majority of acutely decompensated individuals. Only one affected individual experienced worsening acidosis with increased dextrose concentrations in the TPN. Note that bicarbonate therapy alone is not sufficient to correct the metabolic acidosis. Correction of metabolic acidosis relies on reversing the catabolic state by providing calorie support from glucose and interlipids. See also If there is no evidence of hyperleucinosis, total protein intake can be at the recommended dietary allowance (RDA). Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement. To help avoid increased intracranial pressure If provision of dextrose-containing fluids worsens metabolic acidosis, consider decreasing the infusion rate and providing the majority of calories in the form of intralipid. Episodes of catabolic stress (e.g., intercurrent illness, surgical procedures, pregnancy) require the assistance/care of a biochemical geneticist. Acute Treatment in Individuals with Acute Liver Injury or Failure Due to Dihydrolipoamide Dehydrogenase Deficiency DCA = dichloroacetate; IV = intravenous Successful in one affected individual Limited data exist for chronic management of individuals with the primarily hepatic presentation. Between episodes, affected individuals typically return to baseline and do not require treatment beyond the avoidance of fasting, catabolic stressors, and liver-toxic medications. At least one affected individual with severe exercise intolerance responded well to riboflavin supplementation (220 mg/day), with resolution of symptoms [ No compelling evidence exists for the prevention of acute episodes, despite multiple attempted dietary strategies and medications. The frequency of acute episodes decreases with age in most patients with all forms of DLD deficiency. Provide protein intake at or around recommended dietary allowance and titrate based on growth and plasma amino acid values. See Supplement with levocarnitine if deficient. Dichloroacetate has been associated with the development of peripheral neuropathy; thus, individuals receiving this medication require close monitoring. Recommended Surveillance for Individuals with Dihydrolipoamide Dehydrogenase Deficiency For rapidly growing infants, monitoring weekly or 2x weekly Routinely in older persons Physical exam &/or US to assess size of liver Blood measurements of liver transaminases & assessment of liver synthetic function OT = occupational therapy; PT = physical therapy; US = ultrasound The frequency of amino acid monitoring varies by age, metabolic stability, compliance, and regional clinical practice and should be guided by a biochemical geneticist in conjunction with a qualified metabolic nutritionist. The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children. School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavioral problems. In individuals receiving dichloroacetate. Avoid the following: Fasting Catabolic stressors Extremes of dietary intake until dietary tolerance/stressors are identified Liver-toxic medications Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of DLD deficiency and to avoid risk factors that may precipitate an acute event. For at-risk newborn sibs when molecular genetic prenatal testing was not performed: in parallel with newborn screening, either test for the familial See Search • Head MRI to assess for brain damage; • EEG if seizures a concern; • Regular developmental assessments to identify impairments resulting from metabolic decompensations. • Blood gas (arterial or venous), ammonia, lactic acid, CK, & glucose • Plasma free & total carnitine, plasma amino acids, & urine organic acids • Leucine tolerance for neonates: 65-85 mg/kg/day • Breast milk or regular infant formula can be used as a natural protein source. • Dried blood spots by overnight mail for monitoring of amino acid concentrations if available (See • Leucine restriction should be maintained until hyperleucinosis resolves. • 5 had no clinical benefit, & 2 of the 5 experienced ↑ in acidosis & hypoglycemia; • 2 improved clinically. • 4 of 5 persons treated w/DCA in the literature experienced at least transient ↓s in lactic acid elevations. • Chronic use of DCA can result in polyneuropathy. • Thiamine • Coenzyme Q • Lipoic acid • Riboflavin (though effective in one person with the myopathic form of DLD deficiency) • Biotin • For severe metabolic acidosis (pH <7.20) or if bicarbonate is ≤14 mEq/L, initiate bicarbonate therapy. • A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate] • Administer 1/2 of calculated dose as slow bolus & remaining 1/2 over 24 hrs. • Metabolic acidosis usually improves w/generous fluid & calorie support. • Bicarbonate therapy needed for severe metabolic acidosis • Maintain glucose concentration in normal range. • Intralipids can be added to provide addl calories w/cautious monitoring for acidemia. • Withhold protein initially for a maximum of 24 hrs to avoid worsening of catabolism. • Then gradually reintroduce protein. • Start IV fluid. • Maintain blood glucose >100 mg/dL. • High-dose glucose needed to avoid catabolism • If there is hyperglycemia, start insulin infusion rather than ↓ glucose infusion rate. • Hyperammonemia improves w/reversal of catabolism. • A high-dose glucose infusion w/insulin infusion is helpful in achieving this goal. • If severe hyperammonemia & altered mental status persist after above measures, extracorporeal toxin removal procedures such as hemodialysis & hemofiltration should be considered. • If lactate decreases with its introduction • Polyneuropathy is a concern w/long-term use. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • As seizures typically occur during acute decompensations, ASM may be discontinued when metabolic control is achieved. • Provide protein intake at or around recommended dietary allowance and titrate based on growth and plasma amino acid values. See • Supplement with levocarnitine if deficient. • For rapidly growing infants, monitoring weekly or 2x weekly • Routinely in older persons • Physical exam &/or US to assess size of liver • Blood measurements of liver transaminases & assessment of liver synthetic function • Fasting • Catabolic stressors • Extremes of dietary intake until dietary tolerance/stressors are identified • Liver-toxic medications ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with dihydrolipoamide dehydrogenase (DLD) deficiency, the evaluations summarized in the following tables (if not performed as part of the evaluation that led to the diagnosis) are recommended. Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Ill Neonate Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in a Stabilized Neonate/Infant Head MRI to assess for brain damage; EEG if seizures a concern; Regular developmental assessments to identify impairments resulting from metabolic decompensations. Recommended Evaluations Following Initial Diagnosis of Dihydrolipoamide Dehydrogenase Deficiency in an Older Child or Adult Blood gas (arterial or venous), ammonia, lactic acid, CK, & glucose Plasma free & total carnitine, plasma amino acids, & urine organic acids • Head MRI to assess for brain damage; • EEG if seizures a concern; • Regular developmental assessments to identify impairments resulting from metabolic decompensations. • Blood gas (arterial or venous), ammonia, lactic acid, CK, & glucose • Plasma free & total carnitine, plasma amino acids, & urine organic acids ## Treatment of Manifestations The multiple strategies that have been attempted in children with an early-onset neurologic presentation do not appear to significantly alter the natural history of disease. Even with treatment, children often die in the neonatal/infantile period or, if they survive the initial episode, experience various degrees of chronic neurologic impairment. Routine Daily Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency Leucine tolerance for neonates: 65-85 mg/kg/day Breast milk or regular infant formula can be used as a natural protein source. Dried blood spots by overnight mail for monitoring of amino acid concentrations if available (See Leucine restriction should be maintained until hyperleucinosis resolves. 5 had no clinical benefit, & 2 of the 5 experienced ↑ in acidosis & hypoglycemia; 2 improved clinically. 4 of 5 persons treated w/DCA in the literature experienced at least transient ↓s in lactic acid elevations. Chronic use of DCA can result in polyneuropathy. BCAA = branched-chain amino acids; DCA = dichloroacetate; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; RDA = recommended dietary allowance Recommendations are based on decreased branched-chain α-ketoacid dehydrogenase (BCKDH) complex activity. Restriction of protein to recommended dietary allowances has been attempted with questionable results. Three of the six reported individuals experienced laboratory and/or clinical improvement with the use of protein restriction alone or in combination with medication therapy. For rapidly growing infants, monitoring weekly or twice weekly is recommended. Ketogenic/high-fat diets are frequently employed in individuals who have pyruvate dehydrogenase (PDH) complex deficiency [ One was treated with lipid infusions (instead of high-dextrose infusions) during acute episodes [ Additional therapies used with limited success include the following: Thiamine Coenzyme Q Lipoic acid Riboflavin (though effective in one person with the myopathic form of DLD deficiency) Biotin Acute Inpatient Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency For severe metabolic acidosis (pH <7.20) or if bicarbonate is ≤14 mEq/L, initiate bicarbonate therapy. A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate] Administer 1/2 of calculated dose as slow bolus & remaining 1/2 over 24 hrs. Metabolic acidosis usually improves w/generous fluid & calorie support. Bicarbonate therapy needed for severe metabolic acidosis Maintain glucose concentration in normal range. Intralipids can be added to provide addl calories w/cautious monitoring for acidemia. Withhold protein initially for a maximum of 24 hrs to avoid worsening of catabolism. Then gradually reintroduce protein. Start IV fluid. Maintain blood glucose >100 mg/dL. High-dose glucose needed to avoid catabolism If there is hyperglycemia, start insulin infusion rather than ↓ glucose infusion rate. Hyperammonemia improves w/reversal of catabolism. A high-dose glucose infusion w/insulin infusion is helpful in achieving this goal. If severe hyperammonemia & altered mental status persist after above measures, extracorporeal toxin removal procedures such as hemodialysis & hemofiltration should be considered. If lactate decreases with its introduction Polyneuropathy is a concern w/long-term use. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. As seizures typically occur during acute decompensations, ASM may be discontinued when metabolic control is achieved. ASM = anti-seizure medication; BCAAs = branched-chain amino acids; DCA = dichloroacetate; IV = intravenous; MSUD = maple syrup urine disease; PO = orally Although dextrose infusions may theoretically cause further lactate elevations during acute episodes, provision of dextrose-containing IV fluids is essential for the majority of acutely decompensated individuals. Only one affected individual experienced worsening acidosis with increased dextrose concentrations in the TPN. Note that bicarbonate therapy alone is not sufficient to correct the metabolic acidosis. Correction of metabolic acidosis relies on reversing the catabolic state by providing calorie support from glucose and interlipids. See also If there is no evidence of hyperleucinosis, total protein intake can be at the recommended dietary allowance (RDA). Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement. To help avoid increased intracranial pressure If provision of dextrose-containing fluids worsens metabolic acidosis, consider decreasing the infusion rate and providing the majority of calories in the form of intralipid. Episodes of catabolic stress (e.g., intercurrent illness, surgical procedures, pregnancy) require the assistance/care of a biochemical geneticist. Acute Treatment in Individuals with Acute Liver Injury or Failure Due to Dihydrolipoamide Dehydrogenase Deficiency DCA = dichloroacetate; IV = intravenous Successful in one affected individual Limited data exist for chronic management of individuals with the primarily hepatic presentation. Between episodes, affected individuals typically return to baseline and do not require treatment beyond the avoidance of fasting, catabolic stressors, and liver-toxic medications. At least one affected individual with severe exercise intolerance responded well to riboflavin supplementation (220 mg/day), with resolution of symptoms [ • Leucine tolerance for neonates: 65-85 mg/kg/day • Breast milk or regular infant formula can be used as a natural protein source. • Dried blood spots by overnight mail for monitoring of amino acid concentrations if available (See • Leucine restriction should be maintained until hyperleucinosis resolves. • 5 had no clinical benefit, & 2 of the 5 experienced ↑ in acidosis & hypoglycemia; • 2 improved clinically. • 4 of 5 persons treated w/DCA in the literature experienced at least transient ↓s in lactic acid elevations. • Chronic use of DCA can result in polyneuropathy. • Thiamine • Coenzyme Q • Lipoic acid • Riboflavin (though effective in one person with the myopathic form of DLD deficiency) • Biotin • For severe metabolic acidosis (pH <7.20) or if bicarbonate is ≤14 mEq/L, initiate bicarbonate therapy. • A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate] • Administer 1/2 of calculated dose as slow bolus & remaining 1/2 over 24 hrs. • Metabolic acidosis usually improves w/generous fluid & calorie support. • Bicarbonate therapy needed for severe metabolic acidosis • Maintain glucose concentration in normal range. • Intralipids can be added to provide addl calories w/cautious monitoring for acidemia. • Withhold protein initially for a maximum of 24 hrs to avoid worsening of catabolism. • Then gradually reintroduce protein. • Start IV fluid. • Maintain blood glucose >100 mg/dL. • High-dose glucose needed to avoid catabolism • If there is hyperglycemia, start insulin infusion rather than ↓ glucose infusion rate. • Hyperammonemia improves w/reversal of catabolism. • A high-dose glucose infusion w/insulin infusion is helpful in achieving this goal. • If severe hyperammonemia & altered mental status persist after above measures, extracorporeal toxin removal procedures such as hemodialysis & hemofiltration should be considered. • If lactate decreases with its introduction • Polyneuropathy is a concern w/long-term use. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • As seizures typically occur during acute decompensations, ASM may be discontinued when metabolic control is achieved. ## Early-Onset Neurologic Presentation The multiple strategies that have been attempted in children with an early-onset neurologic presentation do not appear to significantly alter the natural history of disease. Even with treatment, children often die in the neonatal/infantile period or, if they survive the initial episode, experience various degrees of chronic neurologic impairment. Routine Daily Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency Leucine tolerance for neonates: 65-85 mg/kg/day Breast milk or regular infant formula can be used as a natural protein source. Dried blood spots by overnight mail for monitoring of amino acid concentrations if available (See Leucine restriction should be maintained until hyperleucinosis resolves. 5 had no clinical benefit, & 2 of the 5 experienced ↑ in acidosis & hypoglycemia; 2 improved clinically. 4 of 5 persons treated w/DCA in the literature experienced at least transient ↓s in lactic acid elevations. Chronic use of DCA can result in polyneuropathy. BCAA = branched-chain amino acids; DCA = dichloroacetate; OT = occupational therapy; PDH = pyruvate dehydrogenase; PT = physical therapy; RDA = recommended dietary allowance Recommendations are based on decreased branched-chain α-ketoacid dehydrogenase (BCKDH) complex activity. Restriction of protein to recommended dietary allowances has been attempted with questionable results. Three of the six reported individuals experienced laboratory and/or clinical improvement with the use of protein restriction alone or in combination with medication therapy. For rapidly growing infants, monitoring weekly or twice weekly is recommended. Ketogenic/high-fat diets are frequently employed in individuals who have pyruvate dehydrogenase (PDH) complex deficiency [ One was treated with lipid infusions (instead of high-dextrose infusions) during acute episodes [ Additional therapies used with limited success include the following: Thiamine Coenzyme Q Lipoic acid Riboflavin (though effective in one person with the myopathic form of DLD deficiency) Biotin Acute Inpatient Treatment in Individuals with Early-Onset Neonatal Dihydrolipoamide Dehydrogenase Deficiency For severe metabolic acidosis (pH <7.20) or if bicarbonate is ≤14 mEq/L, initiate bicarbonate therapy. A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate] Administer 1/2 of calculated dose as slow bolus & remaining 1/2 over 24 hrs. Metabolic acidosis usually improves w/generous fluid & calorie support. Bicarbonate therapy needed for severe metabolic acidosis Maintain glucose concentration in normal range. Intralipids can be added to provide addl calories w/cautious monitoring for acidemia. Withhold protein initially for a maximum of 24 hrs to avoid worsening of catabolism. Then gradually reintroduce protein. Start IV fluid. Maintain blood glucose >100 mg/dL. High-dose glucose needed to avoid catabolism If there is hyperglycemia, start insulin infusion rather than ↓ glucose infusion rate. Hyperammonemia improves w/reversal of catabolism. A high-dose glucose infusion w/insulin infusion is helpful in achieving this goal. If severe hyperammonemia & altered mental status persist after above measures, extracorporeal toxin removal procedures such as hemodialysis & hemofiltration should be considered. If lactate decreases with its introduction Polyneuropathy is a concern w/long-term use. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. As seizures typically occur during acute decompensations, ASM may be discontinued when metabolic control is achieved. ASM = anti-seizure medication; BCAAs = branched-chain amino acids; DCA = dichloroacetate; IV = intravenous; MSUD = maple syrup urine disease; PO = orally Although dextrose infusions may theoretically cause further lactate elevations during acute episodes, provision of dextrose-containing IV fluids is essential for the majority of acutely decompensated individuals. Only one affected individual experienced worsening acidosis with increased dextrose concentrations in the TPN. Note that bicarbonate therapy alone is not sufficient to correct the metabolic acidosis. Correction of metabolic acidosis relies on reversing the catabolic state by providing calorie support from glucose and interlipids. See also If there is no evidence of hyperleucinosis, total protein intake can be at the recommended dietary allowance (RDA). Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement. To help avoid increased intracranial pressure If provision of dextrose-containing fluids worsens metabolic acidosis, consider decreasing the infusion rate and providing the majority of calories in the form of intralipid. • Leucine tolerance for neonates: 65-85 mg/kg/day • Breast milk or regular infant formula can be used as a natural protein source. • Dried blood spots by overnight mail for monitoring of amino acid concentrations if available (See • Leucine restriction should be maintained until hyperleucinosis resolves. • 5 had no clinical benefit, & 2 of the 5 experienced ↑ in acidosis & hypoglycemia; • 2 improved clinically. • 4 of 5 persons treated w/DCA in the literature experienced at least transient ↓s in lactic acid elevations. • Chronic use of DCA can result in polyneuropathy. • Thiamine • Coenzyme Q • Lipoic acid • Riboflavin (though effective in one person with the myopathic form of DLD deficiency) • Biotin • For severe metabolic acidosis (pH <7.20) or if bicarbonate is ≤14 mEq/L, initiate bicarbonate therapy. • A common formula for bicarbonate dose: bicarbonate (mEq) = 0.5 x weight (kg) x [desired bicarbonate - measured bicarbonate] • Administer 1/2 of calculated dose as slow bolus & remaining 1/2 over 24 hrs. • Metabolic acidosis usually improves w/generous fluid & calorie support. • Bicarbonate therapy needed for severe metabolic acidosis • Maintain glucose concentration in normal range. • Intralipids can be added to provide addl calories w/cautious monitoring for acidemia. • Withhold protein initially for a maximum of 24 hrs to avoid worsening of catabolism. • Then gradually reintroduce protein. • Start IV fluid. • Maintain blood glucose >100 mg/dL. • High-dose glucose needed to avoid catabolism • If there is hyperglycemia, start insulin infusion rather than ↓ glucose infusion rate. • Hyperammonemia improves w/reversal of catabolism. • A high-dose glucose infusion w/insulin infusion is helpful in achieving this goal. • If severe hyperammonemia & altered mental status persist after above measures, extracorporeal toxin removal procedures such as hemodialysis & hemofiltration should be considered. • If lactate decreases with its introduction • Polyneuropathy is a concern w/long-term use. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • As seizures typically occur during acute decompensations, ASM may be discontinued when metabolic control is achieved. ## Hepatic Presentation Episodes of catabolic stress (e.g., intercurrent illness, surgical procedures, pregnancy) require the assistance/care of a biochemical geneticist. Acute Treatment in Individuals with Acute Liver Injury or Failure Due to Dihydrolipoamide Dehydrogenase Deficiency DCA = dichloroacetate; IV = intravenous Successful in one affected individual Limited data exist for chronic management of individuals with the primarily hepatic presentation. Between episodes, affected individuals typically return to baseline and do not require treatment beyond the avoidance of fasting, catabolic stressors, and liver-toxic medications. ## Myopathic Presentation At least one affected individual with severe exercise intolerance responded well to riboflavin supplementation (220 mg/day), with resolution of symptoms [ ## Prevention of Primary Manifestations No compelling evidence exists for the prevention of acute episodes, despite multiple attempted dietary strategies and medications. The frequency of acute episodes decreases with age in most patients with all forms of DLD deficiency. Provide protein intake at or around recommended dietary allowance and titrate based on growth and plasma amino acid values. See Supplement with levocarnitine if deficient. • Provide protein intake at or around recommended dietary allowance and titrate based on growth and plasma amino acid values. See • Supplement with levocarnitine if deficient. ## Prevention of Secondary Complications Dichloroacetate has been associated with the development of peripheral neuropathy; thus, individuals receiving this medication require close monitoring. ## Surveillance Recommended Surveillance for Individuals with Dihydrolipoamide Dehydrogenase Deficiency For rapidly growing infants, monitoring weekly or 2x weekly Routinely in older persons Physical exam &/or US to assess size of liver Blood measurements of liver transaminases & assessment of liver synthetic function OT = occupational therapy; PT = physical therapy; US = ultrasound The frequency of amino acid monitoring varies by age, metabolic stability, compliance, and regional clinical practice and should be guided by a biochemical geneticist in conjunction with a qualified metabolic nutritionist. The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children. School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavioral problems. In individuals receiving dichloroacetate. • For rapidly growing infants, monitoring weekly or 2x weekly • Routinely in older persons • Physical exam &/or US to assess size of liver • Blood measurements of liver transaminases & assessment of liver synthetic function ## Agents/Circumstances to Avoid Avoid the following: Fasting Catabolic stressors Extremes of dietary intake until dietary tolerance/stressors are identified Liver-toxic medications • Fasting • Catabolic stressors • Extremes of dietary intake until dietary tolerance/stressors are identified • Liver-toxic medications ## Evaluation of Relatives at Risk Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of DLD deficiency and to avoid risk factors that may precipitate an acute event. For at-risk newborn sibs when molecular genetic prenatal testing was not performed: in parallel with newborn screening, either test for the familial See ## Therapies Under Investigation Search ## Genetic Counseling Dihydrolipoamide dehydrogenase (DLD) deficiency is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If each parent is 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, 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., 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 a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If each parent is known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Dihydrolipoamide dehydrogenase (DLD) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If each parent is 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 each parent is heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If each parent is 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, 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 No specific resources for Dihydrolipoamide Dehydrogenase Deficiency have been identified by ## Molecular Genetics Dihydrolipoamide Dehydrogenase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Dihydrolipoamide Dehydrogenase Deficiency ( Dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit in three mitochondrial enzyme complexes (BCKDH, αKGDH, PDH) and the L protein of the glycine cleavage system. As the E3 subunit, it catalyzes the oxidative regeneration of the lipoic acid covalently bound to the E2 subunit, generating NADH in the process. To date no person with DLD deficiency has presented with biochemical evidence of glycine cleavage system dysfunction (see Additionally, multiple Notable Variants listed in the table have been provided by the authors. See ## Molecular Pathogenesis Dihydrolipoamide dehydrogenase (DLD) functions as the E3 subunit in three mitochondrial enzyme complexes (BCKDH, αKGDH, PDH) and the L protein of the glycine cleavage system. As the E3 subunit, it catalyzes the oxidative regeneration of the lipoic acid covalently bound to the E2 subunit, generating NADH in the process. To date no person with DLD deficiency has presented with biochemical evidence of glycine cleavage system dysfunction (see Additionally, multiple Notable Variants listed in the table have been provided by the authors. See ## Chapter Notes 30 September 2021 (sq) Revision: in 9 July 2020 (ma) Comprehensive update posted live 17 July 2014 (me) Review posted live 21 February 2014 (sq) Original submission • 30 September 2021 (sq) Revision: in • 9 July 2020 (ma) Comprehensive update posted live • 17 July 2014 (me) Review posted live • 21 February 2014 (sq) Original submission ## Revision History 30 September 2021 (sq) Revision: in 9 July 2020 (ma) Comprehensive update posted live 17 July 2014 (me) Review posted live 21 February 2014 (sq) Original submission • 30 September 2021 (sq) Revision: in • 9 July 2020 (ma) Comprehensive update posted live • 17 July 2014 (me) Review posted live • 21 February 2014 (sq) Original submission ## References ## Literature Cited
[ "N Ajit Bolar, AV Vanlander, C Wilbrecht, N Van der Aa, J Smet, B De Paepe, G Vandeweyer, F Kooy, F Eyskens, E De Latter, G Delanghe, P Govaert, JG Leroy, B Loeys, R Lill, L Van Laer, R Van Coster. Mutation of the iron-sulfur cluster assembly gene IBA57 causes severe myopathy and encephalopathy.. Hum Mol Genet. 2013;22:2590-602", "A Ambrus, V Adam-Vizi. Molecular dynamics study of the structural basis of dysfunction and the modulation of reactive oxygen species generation by pathogenic mutants of human dihydrolipoamide dehydrogenase.. Arch Biochem Biophys. 2013;538:145-55", "A Brassier, C Ottolenghi, A Boutron, AM Bertrand, S Valmary-Degano, JP Cervoni, D Chretien, JB Arnoux, D Rabier, F Lacaille, Y de Keyzer, V Di Martino, P de Lonlay. Dihydrolipoamide dehydrogenase deficiency: a still overlooked cause of recurrent acute liver failure and Reye-like syndrome.. 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Riboflavin responsive mitochondrial myopathy is a new phenotype of dihydrolipoamide dehydrogenase deficiency. The chaperon-like effect of vitamin B2.. Mitochondrion. 2014;18:49-57", "L Cerna, L Wenchich, H Hansiková, S Kmoch, K Peskova, P Chrastina, J Brynda, J Zeman. Novel mutations in a boy with dihydrolipoamide dehydrogenase deficiency.. Med Sci Monit. 2001;7:1319-25", "TB Haack, B Rolinski, B Haberberger, F Zimmermann, J Schum, V Strecker, E Graf, U Athing, T Hoppen, I Wittig, W Sperl, P Freisinger, JA Mayr, TM Strom, T Meitinger, H Prokisch. Homozygous missense mutation in BOLA3 causes multiple mitochondrial dysfunctions syndrome in two siblings.. J Inherit Metab Dis. 2013;36:55-62", "TB Haack, C Staufner, MG Köpke, BK Straub, S Kölker, C Thiel, P Freisinger, I Baric, PJ McKiernan, N Dikow, I Harting, F Beisse, P Burgard, U Kotzaeridou, J Kühr, U Himbert, RW Taylor, F Distelmaier, J Vockley, L Ghaloul-Gonzalez, J Zschocke, LS Kremer, E Graf, T Schwarzmayr, DM Bader, J Gagneur, T Wieland, C Terrile, TM Strom, T Meitinger, GF Hoffmann, H Prokisch. Biallelic mutations in NBAS cause recurrent acute liver failure with onset in infancy.. Am J Hum Genet. 2015;97:163-9", "R Haviv, A Zeharia, C Belaiche, Y Haimi Cohen, A. Saada. Elevated plasma citrulline: look for dihydrolipoamide dehydrogenase deficiency.. Eur J Pediatr. 2014;173:243-5", "YS Hong, DS Kerr, TC Liu, M Lusk, BR Powell, MS Patel. Deficiency of dihydrolipoamide dehydrogenase due to two mutant alleles (E340K and G101del). Analysis of a family and prenatal testing.. Biochim Biophys Acta. 1997;1362:160-8", "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", "JA Mayr, FA Zimmermann, C Fauth, C Bergheim, D Meierhofer, D Radmayr, J Zschocke, J Koch, W Sperl. Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation.. Am J Hum Genet. 2011;89:792-7", "A Navarro-Sastre, F Tort, O Stehling, MA Uzarska, JA Arranz, M Del Toro, MT Labayru, J Landa, A Font, J Garcia-Villoria, B Merinero, M Ugarte, LG Gutierrez-Solana, J Campistol, A Garcia-Cazorla, J Vaquerizo, E Riudor, P Briones, O Elpeleg, A Ribes, R Lill. A fatal mitochondrial disease is associated with defective NFU1 function in the maturation of a subset of mitochondrial Fe-S proteins.. Am J Hum Genet. 2011;89:656-67", "KP Patel, TW O'Brien, SH Subramony, J Shuster, PW Stacpoole. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients.. Mol Genet Metab. 2012;106:385-94", "SC Quinonez, SM Leber, DM Martin, JG Thoene, JK Bedoyan. Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency.. Pediatr Neurol. 2013;48:67-72", "SC Quinonez, AH Seeley, M Seeterlin, E Stanley, A Ahmad. Newborn screening for dihydrolipoamide dehydrogenase deficiency: citrulline as a useful analyte.. 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Mutations in human lipoyltransferase gene LIPT1 cause a Leigh disease with secondary deficiency for pyruvate and alpha-ketoglutarate dehydrogenase.. Orphanet J Rare Dis. 2013;8:192", "F Tort, X Ferrer-Cortès, M Thió, A Navarro-Sastre, L Matalonga, E Quintana, N Bujan, A Arias, J García-Villoria, C Acquaviva, C Vianey-Saban, R Artuch, A García-Cazorla, P Briones, A Ribes. Mutations in the lipoyltransferase LIPT1 gene cause a fatal disease associated with a specific lipoylation defect of the 2-ketoacid dehydrogenase complexes.. Hum Mol Genet. 2014;23:1907-15", "RA Vaubel, P Rustin, G Isaya. Mutations in the dimer interface of dihydrolipoamide dehydrogenase promote site-specific oxidative damages in yeast and human cells.. J Biol Chem. 2011;286:40232-45" ]
17/7/2014
9/7/2020
30/9/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dlg4-synap
dlg4-synap
[ "Disks large homolog 4", "DLG4", "DLG4-Related Synaptopathy" ]
Zeynep Tümer, Thomas J Dye, Carlos Prada, Alexandre M White-Brown, Alex MacKenzie, Amanda M Levy
Summary The diagnosis of
## Diagnosis No consensus clinical diagnostic criteria for Mild-to-severe developmental delay (DD) or intellectual disability (ID) AND Any of the following features presenting in infancy or childhood: Generalized hypotonia Developmental regression Movement disorder, including stereotypies, ataxia, dystonia, and tremor Generalized or focal epilepsy, with or without epileptic encephalopathy Sleep problems, including issues with sleep onset and/or sleep maintenance Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness Skeletal manifestations, such as joint laxity and scoliosis Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting Nonspecific dysmorphic features (See Brain or cerebellar atrophy Abnormalities of the corpus callosum Abnormalities of the hippocampus, including a dysmorphic appearance 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, unless the testing is on a whole genome sequencing platform. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ For synonymous or deep intronic variants that are predicted to affect splicing by in silico tools, RNA testing (RT-PCR or RNA sequencing) on blood can be considered to establish the pathogenicity of the variant [Z Tümer, personal observation] (see Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 Gene-targeted deletion/duplication analysis has not identified any deletions/duplications to date [ • Mild-to-severe developmental delay (DD) or intellectual disability (ID) • Any of the following features presenting in infancy or childhood: • Generalized hypotonia • Developmental regression • Movement disorder, including stereotypies, ataxia, dystonia, and tremor • Generalized or focal epilepsy, with or without epileptic encephalopathy • Sleep problems, including issues with sleep onset and/or sleep maintenance • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness • Skeletal manifestations, such as joint laxity and scoliosis • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting • Nonspecific dysmorphic features (See • Generalized hypotonia • Developmental regression • Movement disorder, including stereotypies, ataxia, dystonia, and tremor • Generalized or focal epilepsy, with or without epileptic encephalopathy • Sleep problems, including issues with sleep onset and/or sleep maintenance • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness • Skeletal manifestations, such as joint laxity and scoliosis • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting • Nonspecific dysmorphic features (See • Generalized hypotonia • Developmental regression • Movement disorder, including stereotypies, ataxia, dystonia, and tremor • Generalized or focal epilepsy, with or without epileptic encephalopathy • Sleep problems, including issues with sleep onset and/or sleep maintenance • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness • Skeletal manifestations, such as joint laxity and scoliosis • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting • Nonspecific dysmorphic features (See • Brain or cerebellar atrophy • Abnormalities of the corpus callosum • Abnormalities of the hippocampus, including a dysmorphic appearance • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Mild-to-severe developmental delay (DD) or intellectual disability (ID) AND Any of the following features presenting in infancy or childhood: Generalized hypotonia Developmental regression Movement disorder, including stereotypies, ataxia, dystonia, and tremor Generalized or focal epilepsy, with or without epileptic encephalopathy Sleep problems, including issues with sleep onset and/or sleep maintenance Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness Skeletal manifestations, such as joint laxity and scoliosis Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting Nonspecific dysmorphic features (See Brain or cerebellar atrophy Abnormalities of the corpus callosum Abnormalities of the hippocampus, including a dysmorphic appearance • Mild-to-severe developmental delay (DD) or intellectual disability (ID) • Any of the following features presenting in infancy or childhood: • Generalized hypotonia • Developmental regression • Movement disorder, including stereotypies, ataxia, dystonia, and tremor • Generalized or focal epilepsy, with or without epileptic encephalopathy • Sleep problems, including issues with sleep onset and/or sleep maintenance • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness • Skeletal manifestations, such as joint laxity and scoliosis • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting • Nonspecific dysmorphic features (See • Generalized hypotonia • Developmental regression • Movement disorder, including stereotypies, ataxia, dystonia, and tremor • Generalized or focal epilepsy, with or without epileptic encephalopathy • Sleep problems, including issues with sleep onset and/or sleep maintenance • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness • Skeletal manifestations, such as joint laxity and scoliosis • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting • Nonspecific dysmorphic features (See • Generalized hypotonia • Developmental regression • Movement disorder, including stereotypies, ataxia, dystonia, and tremor • Generalized or focal epilepsy, with or without epileptic encephalopathy • Sleep problems, including issues with sleep onset and/or sleep maintenance • Neuropsychiatric/behavioral issues, such as autism spectrum disorder, attention-deficit/hyperactivity disorder, and/or anxiety • Ophthalmologic involvement, including strabismus, nystagmus, hyperopia, and cortical blindness • Skeletal manifestations, such as joint laxity and scoliosis • Gastroenteric disturbances, such as feeding difficulties at birth or in early infancy, gastroesophageal reflux disease, and/or vomiting • Nonspecific dysmorphic features (See • Brain or cerebellar atrophy • Abnormalities of the corpus callosum • Abnormalities of the hippocampus, including a dysmorphic appearance ## 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, unless the testing is on a whole genome sequencing platform. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ For synonymous or deep intronic variants that are predicted to affect splicing by in silico tools, RNA testing (RT-PCR or RNA sequencing) on blood can be considered to establish the pathogenicity of the variant [Z Tümer, personal observation] (see Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 Gene-targeted deletion/duplication analysis has not identified any deletions/duplications to date [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, about 100 individuals have been identified with a pathogenic variant in Select Features of ASD = autism spectrum disorder; ESES = electrical status epilepticus in sleep; ID = intellectual disability The numerator is the number of known individuals with this feature and the denominator is the number of individuals evaluated for the specific feature. Epilepsy can be associated with developmental regression, as about 50% of individuals with epilepsy were reported to have regression, compared to 22% of those without epilepsy. Infection may also be another triggering factor for developmental regression. Hypotonia is observed in about half of affected individuals, while spasticity has only been observed in a few individuals. Movement disorders, most commonly stereotypies and ataxia, develop in about half of affected individuals, often becoming apparent in childhood. Dystonia and tremor are also observed in some affected individuals. Migraine headache is reported by several parents and may be an underdiagnosed feature. Both generalized and focal seizures have been described, although focal seizures are more common. Febrile seizures, infantile spasms, and electrical status epilepticus in sleep (ESES) have also been observed [ The mean age of onset of the first seizure is six years (range: 6 months to 15 years). EEG may show focal abnormalities (which may be multifocal), an abnormal background, or, less frequently, generalized abnormalities. ASD is reported in 56% of affected individuals and is more often diagnosed in those with moderate-to-severe ID than in those with mild ID. ASD is also common in individuals with language regression, but not all those with ASD have language regression. Attention-deficit/hyperactivity disorder (ADHD) is reported in 57% of affected individuals and tends to occur more frequently in those with a co-occurring ASD diagnosis. Anxiety, which can be triggered by different factors such as sound or separation, is reported in about 50% of affected individuals and may be present starting in childhood. Circadian rhythm abnormalities, including advanced sleep-wake phase, have also been seen. The sleep disturbances may overlap with nocturnal epilepsy. No genotype-phenotype correlations have been identified. This condition is sometimes referred to by the acronym SHINE ( • Epilepsy can be associated with developmental regression, as about 50% of individuals with epilepsy were reported to have regression, compared to 22% of those without epilepsy. • Infection may also be another triggering factor for developmental regression. • Hypotonia is observed in about half of affected individuals, while spasticity has only been observed in a few individuals. • Movement disorders, most commonly stereotypies and ataxia, develop in about half of affected individuals, often becoming apparent in childhood. Dystonia and tremor are also observed in some affected individuals. • Migraine headache is reported by several parents and may be an underdiagnosed feature. • Both generalized and focal seizures have been described, although focal seizures are more common. • Febrile seizures, infantile spasms, and electrical status epilepticus in sleep (ESES) have also been observed [ • The mean age of onset of the first seizure is six years (range: 6 months to 15 years). • EEG may show focal abnormalities (which may be multifocal), an abnormal background, or, less frequently, generalized abnormalities. • ASD is reported in 56% of affected individuals and is more often diagnosed in those with moderate-to-severe ID than in those with mild ID. ASD is also common in individuals with language regression, but not all those with ASD have language regression. • Attention-deficit/hyperactivity disorder (ADHD) is reported in 57% of affected individuals and tends to occur more frequently in those with a co-occurring ASD diagnosis. • Anxiety, which can be triggered by different factors such as sound or separation, is reported in about 50% of affected individuals and may be present starting in childhood. • Circadian rhythm abnormalities, including advanced sleep-wake phase, have also been seen. • The sleep disturbances may overlap with nocturnal epilepsy. ## Clinical Description To date, about 100 individuals have been identified with a pathogenic variant in Select Features of ASD = autism spectrum disorder; ESES = electrical status epilepticus in sleep; ID = intellectual disability The numerator is the number of known individuals with this feature and the denominator is the number of individuals evaluated for the specific feature. Epilepsy can be associated with developmental regression, as about 50% of individuals with epilepsy were reported to have regression, compared to 22% of those without epilepsy. Infection may also be another triggering factor for developmental regression. Hypotonia is observed in about half of affected individuals, while spasticity has only been observed in a few individuals. Movement disorders, most commonly stereotypies and ataxia, develop in about half of affected individuals, often becoming apparent in childhood. Dystonia and tremor are also observed in some affected individuals. Migraine headache is reported by several parents and may be an underdiagnosed feature. Both generalized and focal seizures have been described, although focal seizures are more common. Febrile seizures, infantile spasms, and electrical status epilepticus in sleep (ESES) have also been observed [ The mean age of onset of the first seizure is six years (range: 6 months to 15 years). EEG may show focal abnormalities (which may be multifocal), an abnormal background, or, less frequently, generalized abnormalities. ASD is reported in 56% of affected individuals and is more often diagnosed in those with moderate-to-severe ID than in those with mild ID. ASD is also common in individuals with language regression, but not all those with ASD have language regression. Attention-deficit/hyperactivity disorder (ADHD) is reported in 57% of affected individuals and tends to occur more frequently in those with a co-occurring ASD diagnosis. Anxiety, which can be triggered by different factors such as sound or separation, is reported in about 50% of affected individuals and may be present starting in childhood. Circadian rhythm abnormalities, including advanced sleep-wake phase, have also been seen. The sleep disturbances may overlap with nocturnal epilepsy. • Epilepsy can be associated with developmental regression, as about 50% of individuals with epilepsy were reported to have regression, compared to 22% of those without epilepsy. • Infection may also be another triggering factor for developmental regression. • Hypotonia is observed in about half of affected individuals, while spasticity has only been observed in a few individuals. • Movement disorders, most commonly stereotypies and ataxia, develop in about half of affected individuals, often becoming apparent in childhood. Dystonia and tremor are also observed in some affected individuals. • Migraine headache is reported by several parents and may be an underdiagnosed feature. • Both generalized and focal seizures have been described, although focal seizures are more common. • Febrile seizures, infantile spasms, and electrical status epilepticus in sleep (ESES) have also been observed [ • The mean age of onset of the first seizure is six years (range: 6 months to 15 years). • EEG may show focal abnormalities (which may be multifocal), an abnormal background, or, less frequently, generalized abnormalities. • ASD is reported in 56% of affected individuals and is more often diagnosed in those with moderate-to-severe ID than in those with mild ID. ASD is also common in individuals with language regression, but not all those with ASD have language regression. • Attention-deficit/hyperactivity disorder (ADHD) is reported in 57% of affected individuals and tends to occur more frequently in those with a co-occurring ASD diagnosis. • Anxiety, which can be triggered by different factors such as sound or separation, is reported in about 50% of affected individuals and may be present starting in childhood. • Circadian rhythm abnormalities, including advanced sleep-wake phase, have also been seen. • The sleep disturbances may overlap with nocturnal epilepsy. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Nomenclature This condition is sometimes referred to by the acronym SHINE ( ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The phenotypic features associated with All disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series: • • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with If not already performed, brain MRI can be considered in those w/abnormal neurologic exam &/or seizures. Baseline routine EEG Consider 24-hour EEG to evaluate for ESES or subclinical seizure activity, particularly in persons w/developmental regression or abnormal routine EEG. Assess older children, adolescents, & adults for signs/symptoms of migraine headaches. 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 Formal autism eval in those w/findings suggestive of ASD For persons age >12 months: screening for ADHD, anxiety, &/or depression Gross motor & fine motor skills Scoliosis & joint laxity Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Sleep diary for eval of circadian disruption Consider polysomnogram & referral to sleep specialist. Assess for concurrent medications that could be contributing to sleep disruption. Community and Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ESES = electrical status epilepticus in sleep; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Such evaluations may include measurement of vitamin D and vitamin B 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 Adjustments to classroom or therapy setting to allow for better truncal support Mobility, ADL, & need for adaptive devices for home/school Children: through early intervention programs &/or school Adults: low vision clinic &/or community vision services / OT / mobility services Behavioral therapy for insomnia Consider pharmacotherapy for refractory cases 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 consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 and adolescents 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 ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy See Although there has not as yet been documentation of a pregnancy in a person with In general, women with See Search • If not already performed, brain MRI can be considered in those w/abnormal neurologic exam &/or seizures. • Baseline routine EEG • Consider 24-hour EEG to evaluate for ESES or subclinical seizure activity, particularly in persons w/developmental regression or abnormal routine EEG. • Assess older children, adolescents, & adults for signs/symptoms of migraine headaches. • 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 • Formal autism eval in those w/findings suggestive of ASD • For persons age >12 months: screening for ADHD, anxiety, &/or depression • Gross motor & fine motor skills • Scoliosis & joint laxity • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Sleep diary for eval of circadian disruption • Consider polysomnogram & referral to sleep specialist. • Assess for concurrent medications that could be contributing to sleep disruption. • Community and • 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 • Adjustments to classroom or therapy setting to allow for better truncal support • Mobility, ADL, & need for adaptive devices for home/school • Children: through early intervention programs &/or school • Adults: low vision clinic &/or community vision services / OT / mobility services • Behavioral therapy for insomnia • Consider pharmacotherapy for refractory cases • 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 If not already performed, brain MRI can be considered in those w/abnormal neurologic exam &/or seizures. Baseline routine EEG Consider 24-hour EEG to evaluate for ESES or subclinical seizure activity, particularly in persons w/developmental regression or abnormal routine EEG. Assess older children, adolescents, & adults for signs/symptoms of migraine headaches. 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 Formal autism eval in those w/findings suggestive of ASD For persons age >12 months: screening for ADHD, anxiety, &/or depression Gross motor & fine motor skills Scoliosis & joint laxity Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Sleep diary for eval of circadian disruption Consider polysomnogram & referral to sleep specialist. Assess for concurrent medications that could be contributing to sleep disruption. Community and Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ESES = electrical status epilepticus in sleep; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Such evaluations may include measurement of vitamin D and vitamin B Medical geneticist, certified genetic counselor, certified advanced genetic nurse • If not already performed, brain MRI can be considered in those w/abnormal neurologic exam &/or seizures. • Baseline routine EEG • Consider 24-hour EEG to evaluate for ESES or subclinical seizure activity, particularly in persons w/developmental regression or abnormal routine EEG. • Assess older children, adolescents, & adults for signs/symptoms of migraine headaches. • 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 • Formal autism eval in those w/findings suggestive of ASD • For persons age >12 months: screening for ADHD, anxiety, &/or depression • Gross motor & fine motor skills • Scoliosis & joint laxity • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Sleep diary for eval of circadian disruption • Consider polysomnogram & referral to sleep specialist. • Assess for concurrent medications that could be contributing to sleep disruption. • Community and • 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 Adjustments to classroom or therapy setting to allow for better truncal support Mobility, ADL, & need for adaptive devices for home/school Children: through early intervention programs &/or school Adults: low vision clinic &/or community vision services / OT / mobility services Behavioral therapy for insomnia Consider pharmacotherapy for refractory cases 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 consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 and adolescents 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 • Adjustments to classroom or therapy setting to allow for better truncal support • Mobility, ADL, & need for adaptive devices for home/school • Children: through early intervention programs &/or school • Adults: low vision clinic &/or community vision services / OT / mobility services • Behavioral therapy for insomnia • Consider pharmacotherapy for refractory cases • 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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, privatesupportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 and adolescents 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 ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy ## Evaluation of Relatives at Risk See ## Pregnancy Management Although there has not as yet been documentation of a pregnancy in a person with In general, women with See ## Therapies Under Investigation Search ## Genetic Counseling Most probands reported to date with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ If a parent of the proband is known to have the If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • 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 [ • 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 probands reported to date with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ If a parent of the proband is known to have the If the • Most probands reported to date with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • 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 [ • If a parent of the proband is known to have the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • • ## Molecular Genetics Note on Table A, DLG4-Related Synaptopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DLG4-Related Synaptopathy ( There are also a few heterozygous likely pathogenic The main difference between these two transcripts is the presence of two extra exons at the 5' end of the gene in the longer transcript ( In case of synonymous or deep intronic variants that are predicted to affect splicing by in silico tools, RNA testing (RT-PCR or RNA sequencing) could be considered to establish the pathogenicity of the variant. This can be successfully performed using peripheral blood, as the gene is expressed in low levels in this tissue [Z Tümer, personal communication]. ## Molecular Pathogenesis There are also a few heterozygous likely pathogenic The main difference between these two transcripts is the presence of two extra exons at the 5' end of the gene in the longer transcript ( In case of synonymous or deep intronic variants that are predicted to affect splicing by in silico tools, RNA testing (RT-PCR or RNA sequencing) could be considered to establish the pathogenicity of the variant. This can be successfully performed using peripheral blood, as the gene is expressed in low levels in this tissue [Z Tümer, personal communication]. ## Chapter Notes Clinical work: genetic diagnosis of neurodevelopmental disorders and congenital imprinting disorders Research interests: understanding the underlying molecular mechanisms involved in monogenic and complex neurodevelopmental disorders Web page: Clinical work: pediatric sleep medicine, neurodevelopmental disorders, sleep-related movement disorders and epilepsy Research interests: understanding sleep and circadian disruption of neurodevelopmental disorders Web page: Clinical work: neurofibromatosis, RASopathies, lysosomal storage disorders, metabolic disorders, and implementation of genomics in clinical care Research interests: development of biomarkers for rare diseases, clinical trials, and gene discovery Web page: Research interests: development of strategies to improve the diagnostic care of individuals with rare genetic disease; exploring the use of artificial intelligence to identify patients with undiagnosed rare genetic diseases Clinical work: general pediatrician Research interests: therapies for rare neurogenetic disorders Web page: Research interests: understanding the genetic and functional mechanisms of rare neurodevelopmental disorders The patient support group SHINE Syndrome Foundation is acknowledged for collaboration and their contribution to understanding the phenotype and genotype of the condition. The board members of the foundation have also made invaluable suggestions to the chapter. 22 June 2023 (ma) Review posted live 5 December 2022 (zt) Original submission • Clinical work: genetic diagnosis of neurodevelopmental disorders and congenital imprinting disorders • Research interests: understanding the underlying molecular mechanisms involved in monogenic and complex neurodevelopmental disorders • Web page: • Clinical work: pediatric sleep medicine, neurodevelopmental disorders, sleep-related movement disorders and epilepsy • Research interests: understanding sleep and circadian disruption of neurodevelopmental disorders • Web page: • Clinical work: neurofibromatosis, RASopathies, lysosomal storage disorders, metabolic disorders, and implementation of genomics in clinical care • Research interests: development of biomarkers for rare diseases, clinical trials, and gene discovery • Web page: • Research interests: development of strategies to improve the diagnostic care of individuals with rare genetic disease; exploring the use of artificial intelligence to identify patients with undiagnosed rare genetic diseases • Clinical work: general pediatrician • Research interests: therapies for rare neurogenetic disorders • Web page: • Research interests: understanding the genetic and functional mechanisms of rare neurodevelopmental disorders • 22 June 2023 (ma) Review posted live • 5 December 2022 (zt) Original submission ## Author Notes Clinical work: genetic diagnosis of neurodevelopmental disorders and congenital imprinting disorders Research interests: understanding the underlying molecular mechanisms involved in monogenic and complex neurodevelopmental disorders Web page: Clinical work: pediatric sleep medicine, neurodevelopmental disorders, sleep-related movement disorders and epilepsy Research interests: understanding sleep and circadian disruption of neurodevelopmental disorders Web page: Clinical work: neurofibromatosis, RASopathies, lysosomal storage disorders, metabolic disorders, and implementation of genomics in clinical care Research interests: development of biomarkers for rare diseases, clinical trials, and gene discovery Web page: Research interests: development of strategies to improve the diagnostic care of individuals with rare genetic disease; exploring the use of artificial intelligence to identify patients with undiagnosed rare genetic diseases Clinical work: general pediatrician Research interests: therapies for rare neurogenetic disorders Web page: Research interests: understanding the genetic and functional mechanisms of rare neurodevelopmental disorders • Clinical work: genetic diagnosis of neurodevelopmental disorders and congenital imprinting disorders • Research interests: understanding the underlying molecular mechanisms involved in monogenic and complex neurodevelopmental disorders • Web page: • Clinical work: pediatric sleep medicine, neurodevelopmental disorders, sleep-related movement disorders and epilepsy • Research interests: understanding sleep and circadian disruption of neurodevelopmental disorders • Web page: • Clinical work: neurofibromatosis, RASopathies, lysosomal storage disorders, metabolic disorders, and implementation of genomics in clinical care • Research interests: development of biomarkers for rare diseases, clinical trials, and gene discovery • Web page: • Research interests: development of strategies to improve the diagnostic care of individuals with rare genetic disease; exploring the use of artificial intelligence to identify patients with undiagnosed rare genetic diseases • Clinical work: general pediatrician • Research interests: therapies for rare neurogenetic disorders • Web page: • Research interests: understanding the genetic and functional mechanisms of rare neurodevelopmental disorders ## Acknowledgments The patient support group SHINE Syndrome Foundation is acknowledged for collaboration and their contribution to understanding the phenotype and genotype of the condition. The board members of the foundation have also made invaluable suggestions to the chapter. ## Revision History 22 June 2023 (ma) Review posted live 5 December 2022 (zt) Original submission • 22 June 2023 (ma) Review posted live • 5 December 2022 (zt) Original submission ## References ## Literature Cited
[]
22/6/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dmn
dmn
[ "ATP-binding cassette sub-family C member 8", "ATP-sensitive inward rectifier potassium channel 11", "DNA-binding protein RFX6", "Eukaryotic translation initiation factor 2-alpha kinase 3", "Hepatocyte nuclear factor 1-beta", "Hexokinase-4", "Homeobox protein Nkx-2.2", "Insulin", "Motor neuron and pancreas homeobox protein 1", "Neurogenic differentiation factor 1", "Pancreas transcription factor 1 subunit alpha", "Pancreas/duodenum homeobox protein 1", "Solute carrier family 2, facilitated glucose transporter member 2", "Thiamine transporter 1", "Transcription factor GATA-6", "Zinc finger protein GLIS3", "ABCC8", "EIF2AK3", "GATA6", "GCK", "GLIS3", "HNF1B", "INS", "KCNJ11", "MNX1", "NEUROD1", "NKX2-2", "PDX1", "PTF1A", "RFX6", "SLC19A2", "SLC2A2", "Permanent Neonatal Diabetes Mellitus" ]
Permanent Neonatal Diabetes Mellitus
Diva D De León, Sara E Pinney
Summary Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of hyperglycemia within the first six months of life (mean age: 7 weeks; range: birth to age 26 weeks). The diabetes mellitus is associated with partial or complete insulin deficiency. Clinical manifestations at the time of diagnosis include hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and history of intrauterine growth deficiency. Therapy with insulin and/or oral hypoglycemic medications (in some molecular causes of PNDM) can correct the hyperglycemia and result in dramatic catch-up growth. The course of PNDM varies by genotype. The diagnosis of PNDM is established in an infant with diabetes mellitus diagnosed in the first six months of life that does not resolve over time. Molecular genetic testing is recommended, as identification of a specific molecular cause of PNMD can guide treatment. The mode of inheritance of PNDM varies by gene: Once the PNDM-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for PNDM are possible.
## Diagnosis Permanent neonatal diabetes mellitus (PNDM) Persistent hyperglycemia (plasma glucose concentration >250mg/dL) in infants younger than age six months that lasts for longer than seven to ten days [ Features typical of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia) Low or undetectable plasma insulin and C peptide relative to the hyperglycemia Low fecal elastase and high stool fat in infants with pancreatic aplasia or hypoplasia due to pancreatic exocrine insufficiency [ Note: Measurement of hemoglobin A1c (HgA1c) is not suitable for diagnosing diabetes mellitus in infants younger than age six months because of the higher proportion of fetal hemoglobin compared to hemoglobin A. The diagnosis of PNDM 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 Permanent Neonatal Diabetes Mellitus NA = not applicable; PNDM = permanent neonatal diabetes mellitus 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 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. Large deletions/duplication have been reported in individuals with additional phenotypes (see Biallelic Activating pathogenic variants in Analysis of The 26-bp insertion and complex rearrangement in Relative hypomethylation within the 6q24 differentially methylated region (DMR) has been reported in one individual to date with PNDM [ • Persistent hyperglycemia (plasma glucose concentration >250mg/dL) in infants younger than age six months that lasts for longer than seven to ten days [ • Features typical of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia) • Low or undetectable plasma insulin and C peptide relative to the hyperglycemia • Low fecal elastase and high stool fat in infants with pancreatic aplasia or hypoplasia due to pancreatic exocrine insufficiency [ ## Suggestive Findings Permanent neonatal diabetes mellitus (PNDM) Persistent hyperglycemia (plasma glucose concentration >250mg/dL) in infants younger than age six months that lasts for longer than seven to ten days [ Features typical of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia) Low or undetectable plasma insulin and C peptide relative to the hyperglycemia Low fecal elastase and high stool fat in infants with pancreatic aplasia or hypoplasia due to pancreatic exocrine insufficiency [ Note: Measurement of hemoglobin A1c (HgA1c) is not suitable for diagnosing diabetes mellitus in infants younger than age six months because of the higher proportion of fetal hemoglobin compared to hemoglobin A. • Persistent hyperglycemia (plasma glucose concentration >250mg/dL) in infants younger than age six months that lasts for longer than seven to ten days [ • Features typical of diabetes mellitus (e.g., glucosuria, ketonuria, hyperketonemia) • Low or undetectable plasma insulin and C peptide relative to the hyperglycemia • Low fecal elastase and high stool fat in infants with pancreatic aplasia or hypoplasia due to pancreatic exocrine insufficiency [ ## Establishing the Diagnosis The diagnosis of PNDM 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 Permanent Neonatal Diabetes Mellitus NA = not applicable; PNDM = permanent neonatal diabetes mellitus 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 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. Large deletions/duplication have been reported in individuals with additional phenotypes (see Biallelic Activating pathogenic variants in Analysis of The 26-bp insertion and complex rearrangement in Relative hypomethylation within the 6q24 differentially methylated region (DMR) has been reported in one individual to date with PNDM [ ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Permanent Neonatal Diabetes Mellitus NA = not applicable; PNDM = permanent neonatal diabetes mellitus 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 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. Large deletions/duplication have been reported in individuals with additional phenotypes (see Biallelic Activating pathogenic variants in Analysis of The 26-bp insertion and complex rearrangement in Relative hypomethylation within the 6q24 differentially methylated region (DMR) has been reported in one individual to date with PNDM [ ## Clinical Characteristics The diabetes mellitus is associated with partial or complete insulin deficiency. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. Many individuals with Reports of microvascular complications vary among cohorts, with 4%-19% of affected individuals reported to have microalbuminuria and 6% reported to have retinopathy. There was no strong evidence that treatment with sulfonylureas was less effective over time, but there was a trend that later initiation of sulfonylurea treatment was associated with the need for combined treatment with insulin. The course of PNDM is highly variable depending on the causative gene. Additional phenotypic features are associated with pathogenic variants in specific genes (see Permanent Neonatal Diabetes Mellitus: Phenotypes by Gene Most diagnosed age <3 mos Most have low birth weight, symptomatic hyperglycemia, & often DKA Note: PNDM is the most common phenotype; TNDM is also reported. Most diagnosed age ≤6 mos (median: age 2.4 mos) DKA at presentation is common. IUGR Insulin-requiring DM from 1st day of life Hyperglycemia in both parents Low birth weight Hyperglycemia typically presents shortly after birth. PNDM severity is variable even among persons w/same pathogenic variant. Rare cause of PNDM or TNDM presenting w/hyperglycemia at age <6 mos Pancreatic exocrine insufficiency Cystic renal disease / renal dysplasia Median age at diagnosis is 9 wks Persons present w/DKA or marked hyperglycemia. Most newborns are small for gestational age. Most diagnosed age <3 mos Most have low birth weight, symptomatic hyperglycemia, & often DKA Treatment w/sulfonylureas corrects hyperglycemia & can prevent/improve neurologic manifestations (see Note: PNDM is the most common phenotype; TNDM is also reported. 20%-23% have DEND syndrome. Neurologic manifestations also incl muscle weakness, ADHD, & sleep disorders. A milder form, intermediate DEND syndrome, presents w/less severe DD & w/o epilepsy. Limited info reg DM phenotype exists; severity appears variable. Low birth weight is common. Neonatal DM, DD, sacral agenesis, & imperforate anus. Additional neurologic, skeletal, lung, & urologic congenital anomalies reported in 1 infant w/PNDM & biallelic Neonatal DM presenting at age <2 mos w/normal pancreatic size Low birth weight is common. Neonatal DM presents in 1st few days of life. History of low birth weight is common. Pancreatic exocrine insufficiency Clinical manifestations are milder in persons w/hypomorphic pathogenic variants. Pancreatic hypoplasia/agenesis w/PNDM onset typically age <1 mo Low birth weight is common. Pancreatic hypoplasia w/neonatal DM presenting w/in 1st few days of life Low birth weight is common. Mitchell-Riley syndrome (OMIM PNDM w/hypoplastic or annular pancreas, pancreatic exocrine insufficiency, PNDM is less common than TNDM. History of low birth weight is common. PNDM can respond to high-dose thiamine treatment in some persons. History of low birth weight is common. ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; DEND = Genes are listed in alphabetic order. Results in poor weight gain and loose, foul-smelling stools. No genotype-phenotype correlations for The location of the The severity of PNDM along the spectrum of isolated diabetes mellitus, intermediate DEND syndrome, and DEND syndrome correlates with the genotype [ Of 24 individuals with pathogenic variants at the arginine residue, Arg201, all but three had isolated PNDM. The p.Val59Met variant is associated with intermediate DEND syndrome. The following pathogenic variants associated with DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Cys166Phe, p.Ile296Val [ Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also appears to be genotype dependent: children with the variants p.Val59Met [ Reduced penetrance has been reported in Some individuals with "neonatal" diabetes mellitus may not be diagnosed until age three to six months; therefore it has been suggested that the term "diabetes mellitus of infancy" or "congenital diabetes" should replace the designation "neonatal diabetes mellitus" [ The estimated incidence of neonatal diabetes mellitus ranges from 1:90,000 to 1:260,000 live births, 50% being PNDM [ • Most diagnosed age <3 mos • Most have low birth weight, symptomatic hyperglycemia, & often DKA • Note: PNDM is the most common phenotype; TNDM is also reported. • Most diagnosed age ≤6 mos (median: age 2.4 mos) • DKA at presentation is common. • IUGR • Insulin-requiring DM from 1st day of life • Hyperglycemia in both parents • Low birth weight • Hyperglycemia typically presents shortly after birth. • PNDM severity is variable even among persons w/same pathogenic variant. • Rare cause of PNDM or TNDM presenting w/hyperglycemia at age <6 mos • Pancreatic exocrine insufficiency • Cystic renal disease / renal dysplasia • Median age at diagnosis is 9 wks • Persons present w/DKA or marked hyperglycemia. • Most newborns are small for gestational age. • Most diagnosed age <3 mos • Most have low birth weight, symptomatic hyperglycemia, & often DKA • Treatment w/sulfonylureas corrects hyperglycemia & can prevent/improve neurologic manifestations (see • Note: PNDM is the most common phenotype; TNDM is also reported. • 20%-23% have DEND syndrome. • Neurologic manifestations also incl muscle weakness, ADHD, & sleep disorders. • A milder form, intermediate DEND syndrome, presents w/less severe DD & w/o epilepsy. • Limited info reg DM phenotype exists; severity appears variable. • Low birth weight is common. • Neonatal DM, DD, sacral agenesis, & imperforate anus. • Additional neurologic, skeletal, lung, & urologic congenital anomalies reported in 1 infant w/PNDM & biallelic • Neonatal DM presenting at age <2 mos w/normal pancreatic size • Low birth weight is common. • Neonatal DM presents in 1st few days of life. • History of low birth weight is common. • Pancreatic exocrine insufficiency • Clinical manifestations are milder in persons w/hypomorphic pathogenic variants. • Pancreatic hypoplasia/agenesis w/PNDM onset typically age <1 mo • Low birth weight is common. • Pancreatic hypoplasia w/neonatal DM presenting w/in 1st few days of life • Low birth weight is common. • Mitchell-Riley syndrome (OMIM • PNDM w/hypoplastic or annular pancreas, pancreatic exocrine insufficiency, • PNDM is less common than TNDM. • History of low birth weight is common. • PNDM can respond to high-dose thiamine treatment in some persons. • History of low birth weight is common. • Of 24 individuals with pathogenic variants at the arginine residue, Arg201, all but three had isolated PNDM. • The p.Val59Met variant is associated with intermediate DEND syndrome. • The following pathogenic variants associated with DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Cys166Phe, p.Ile296Val [ • Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also appears to be genotype dependent: children with the variants p.Val59Met [ ## Clinical Description The diabetes mellitus is associated with partial or complete insulin deficiency. Therapy with insulin corrects the hyperglycemia and results in dramatic catch-up growth. Many individuals with Reports of microvascular complications vary among cohorts, with 4%-19% of affected individuals reported to have microalbuminuria and 6% reported to have retinopathy. There was no strong evidence that treatment with sulfonylureas was less effective over time, but there was a trend that later initiation of sulfonylurea treatment was associated with the need for combined treatment with insulin. ## Phenotype Correlations by Gene The course of PNDM is highly variable depending on the causative gene. Additional phenotypic features are associated with pathogenic variants in specific genes (see Permanent Neonatal Diabetes Mellitus: Phenotypes by Gene Most diagnosed age <3 mos Most have low birth weight, symptomatic hyperglycemia, & often DKA Note: PNDM is the most common phenotype; TNDM is also reported. Most diagnosed age ≤6 mos (median: age 2.4 mos) DKA at presentation is common. IUGR Insulin-requiring DM from 1st day of life Hyperglycemia in both parents Low birth weight Hyperglycemia typically presents shortly after birth. PNDM severity is variable even among persons w/same pathogenic variant. Rare cause of PNDM or TNDM presenting w/hyperglycemia at age <6 mos Pancreatic exocrine insufficiency Cystic renal disease / renal dysplasia Median age at diagnosis is 9 wks Persons present w/DKA or marked hyperglycemia. Most newborns are small for gestational age. Most diagnosed age <3 mos Most have low birth weight, symptomatic hyperglycemia, & often DKA Treatment w/sulfonylureas corrects hyperglycemia & can prevent/improve neurologic manifestations (see Note: PNDM is the most common phenotype; TNDM is also reported. 20%-23% have DEND syndrome. Neurologic manifestations also incl muscle weakness, ADHD, & sleep disorders. A milder form, intermediate DEND syndrome, presents w/less severe DD & w/o epilepsy. Limited info reg DM phenotype exists; severity appears variable. Low birth weight is common. Neonatal DM, DD, sacral agenesis, & imperforate anus. Additional neurologic, skeletal, lung, & urologic congenital anomalies reported in 1 infant w/PNDM & biallelic Neonatal DM presenting at age <2 mos w/normal pancreatic size Low birth weight is common. Neonatal DM presents in 1st few days of life. History of low birth weight is common. Pancreatic exocrine insufficiency Clinical manifestations are milder in persons w/hypomorphic pathogenic variants. Pancreatic hypoplasia/agenesis w/PNDM onset typically age <1 mo Low birth weight is common. Pancreatic hypoplasia w/neonatal DM presenting w/in 1st few days of life Low birth weight is common. Mitchell-Riley syndrome (OMIM PNDM w/hypoplastic or annular pancreas, pancreatic exocrine insufficiency, PNDM is less common than TNDM. History of low birth weight is common. PNDM can respond to high-dose thiamine treatment in some persons. History of low birth weight is common. ADHD = attention-deficit/hyperactivity disorder; DD = developmental delay; DEND = Genes are listed in alphabetic order. Results in poor weight gain and loose, foul-smelling stools. • Most diagnosed age <3 mos • Most have low birth weight, symptomatic hyperglycemia, & often DKA • Note: PNDM is the most common phenotype; TNDM is also reported. • Most diagnosed age ≤6 mos (median: age 2.4 mos) • DKA at presentation is common. • IUGR • Insulin-requiring DM from 1st day of life • Hyperglycemia in both parents • Low birth weight • Hyperglycemia typically presents shortly after birth. • PNDM severity is variable even among persons w/same pathogenic variant. • Rare cause of PNDM or TNDM presenting w/hyperglycemia at age <6 mos • Pancreatic exocrine insufficiency • Cystic renal disease / renal dysplasia • Median age at diagnosis is 9 wks • Persons present w/DKA or marked hyperglycemia. • Most newborns are small for gestational age. • Most diagnosed age <3 mos • Most have low birth weight, symptomatic hyperglycemia, & often DKA • Treatment w/sulfonylureas corrects hyperglycemia & can prevent/improve neurologic manifestations (see • Note: PNDM is the most common phenotype; TNDM is also reported. • 20%-23% have DEND syndrome. • Neurologic manifestations also incl muscle weakness, ADHD, & sleep disorders. • A milder form, intermediate DEND syndrome, presents w/less severe DD & w/o epilepsy. • Limited info reg DM phenotype exists; severity appears variable. • Low birth weight is common. • Neonatal DM, DD, sacral agenesis, & imperforate anus. • Additional neurologic, skeletal, lung, & urologic congenital anomalies reported in 1 infant w/PNDM & biallelic • Neonatal DM presenting at age <2 mos w/normal pancreatic size • Low birth weight is common. • Neonatal DM presents in 1st few days of life. • History of low birth weight is common. • Pancreatic exocrine insufficiency • Clinical manifestations are milder in persons w/hypomorphic pathogenic variants. • Pancreatic hypoplasia/agenesis w/PNDM onset typically age <1 mo • Low birth weight is common. • Pancreatic hypoplasia w/neonatal DM presenting w/in 1st few days of life • Low birth weight is common. • Mitchell-Riley syndrome (OMIM • PNDM w/hypoplastic or annular pancreas, pancreatic exocrine insufficiency, • PNDM is less common than TNDM. • History of low birth weight is common. • PNDM can respond to high-dose thiamine treatment in some persons. • History of low birth weight is common. ## Genotype-Phenotype Correlations No genotype-phenotype correlations for The location of the The severity of PNDM along the spectrum of isolated diabetes mellitus, intermediate DEND syndrome, and DEND syndrome correlates with the genotype [ Of 24 individuals with pathogenic variants at the arginine residue, Arg201, all but three had isolated PNDM. The p.Val59Met variant is associated with intermediate DEND syndrome. The following pathogenic variants associated with DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Cys166Phe, p.Ile296Val [ Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also appears to be genotype dependent: children with the variants p.Val59Met [ • Of 24 individuals with pathogenic variants at the arginine residue, Arg201, all but three had isolated PNDM. • The p.Val59Met variant is associated with intermediate DEND syndrome. • The following pathogenic variants associated with DEND syndrome are not found in less severely affected individuals: p.Gln52Arg, p.Val59Gly, p.Cys166Phe, p.Ile296Val [ • Improvement of the neurologic features of DEND syndrome with sulfonylurea treatment also appears to be genotype dependent: children with the variants p.Val59Met [ ## Penetrance Reduced penetrance has been reported in ## Nomenclature Some individuals with "neonatal" diabetes mellitus may not be diagnosed until age three to six months; therefore it has been suggested that the term "diabetes mellitus of infancy" or "congenital diabetes" should replace the designation "neonatal diabetes mellitus" [ ## Prevalence The estimated incidence of neonatal diabetes mellitus ranges from 1:90,000 to 1:260,000 live births, 50% being PNDM [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in permanent neonatal diabetes mellitus-related genes are summarized in Allelic Disorders + = associated phenotype; DM = diabetes mellitus; MODY = maturity-onset diabetes of the young; TNDM = transient neonatal diabetes mellitus See OMIM Data derived from the subscription-based professional view of Human Gene Mutation Database [ ## Differential Diagnosis The most common causes of TNDM are 6q24-related TNDM is caused by overexpression of the imprinted genes at 6q24 ( Activating pathogenic variants in Syndromic Permanent Neonatal Diabetes Mellitus PNDM Pancreatic agenesis Holoprosencephaly Gallbladder agenesis PNDM Lymphoproliferative syndrome Enteropathy Cytopenias Thyroiditis PNDM Transient hepatitis Enteropathy Dermatitis Pancreatic exocrine insufficiency/agenesis Cardiac abnormalities PNDM Congenital hypothyroidism Sepsis PNDM Dysmorphic facies Widespread autoimmunity PNDM Enteropathy Hypothyroidism Hemolytic anemia PNDM IUGR Pancreatic hypoplasia Gall bladder hypoplasia Pancreatic exocrine insufficiency Brain malformations Microcephaly Microphthalmia Leads to early activation of NEUROG3 & premature endocrine activations Critical component of cytokine signaling Optic atrophy DM & diabetes insipidus Deafness AD = autosomal dominant; AR = autosomal recessive; DM = diabetes mellitus; IUGR = intrauterine growth restriction; MOI = mode of inheritance; PNDM = permanent neonatal diabetes mellitus; XL = X-linked Unfolded protein response and endoplasmic reticulum stress [ Neonatal diabetes and beta cell destruction from autoimmunity [ • 6q24-related TNDM is caused by overexpression of the imprinted genes at 6q24 ( • Activating pathogenic variants in • PNDM • Pancreatic agenesis • Holoprosencephaly • Gallbladder agenesis • PNDM • Lymphoproliferative syndrome • Enteropathy • Cytopenias • Thyroiditis • PNDM • Transient hepatitis • Enteropathy • Dermatitis • Pancreatic exocrine insufficiency/agenesis • Cardiac abnormalities • PNDM • Congenital hypothyroidism • Sepsis • PNDM • Dysmorphic facies • Widespread autoimmunity • PNDM • Enteropathy • Hypothyroidism • Hemolytic anemia • PNDM • IUGR • Pancreatic hypoplasia • Gall bladder hypoplasia • Pancreatic exocrine insufficiency • Brain malformations • Microcephaly • Microphthalmia • Leads to early activation of NEUROG3 & premature endocrine activations • Critical component of cytokine signaling • Optic atrophy • DM & diabetes insipidus • Deafness ## Management No clinical practice guidelines for permanent neonatal diabetes mellitus (PNDM) have been published. General guidelines for treatment of neonatal diabetes are available in the ISPAD Clinical Guidelines for Permanent Neonatal Diabetes [ To establish the extent of disease and needs in an individual diagnosed with PNDM, the evaluations summarized in Permanent Neonatal Diabetes Mellitus: Recommended Evaluations Following Initial Diagnosis Developmental eval Neurology eval & EEG in those w/suspected seizures Imaging of pancreas Eval of pancreatic exocrine function (fecal elastase, serum concentrations of fat-soluble vitamins) Community or Social work involvement for parental support Home nursing referral DEND = Medical geneticist, certified genetic counselor, certified advanced genetic nurse Note: Mild beneficial effect of oral sulfonylureas in persons 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 Permanent Neonatal Diabetes Mellitus: Treatment of Manifestations Longer-acting preparations w/no significant peak-of-action effect (e.g., glargine, detemir) may work better in small infants. Some centers recommend continuous subcutaneous insulin infusion for young infants as a safer, more physiologic, & more accurate way of administering insulin. In general, rapid-acting (lispro, aspart) & short-acting preparations should be avoided as they may cause severe hypoglycemic events (except when used as a continuous IV or subcutaneous infusion). Intermediate-acting preparations (neutral protamine hagedorn) tend to have shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. DEND = In 2020 the American Diabetes Association revised the HbA1c target to be individualized for children who are not able to express symptoms of hypoglycemia [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Permanent Neonatal Diabetes Mellitus: Recommended Surveillance Frequent monitoring in hospital immediately following diagnosis Lifelong monitoring (≥4x/day or w/continuous glucose monitor) after stabilization on treatment Urinalysis for microalbuminuria Measurement of cystatin C in blood DEND = In general, rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations should be avoided (except when used as a continuous intravenous or subcutaneous infusion), as they may cause severe hypoglycemic events in young children. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and treatment of hyperglycemia. (Hyperglycemia may be asymptomatic.) Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Screening with HbA1c or fasting or post-prandial glucose levels may be used to assess for abnormalities in glycemic control if the pathogenic variant(s) in the family are not known. Rarely an oral glucose tolerance test is needed. Continuous glucose monitors to track glucose patterns in relatives of individuals with monogenic forms of diabetes have been used. See Pregnant women with PNDM should be managed by an endocrinologist and maternal-fetal medicine specialist. Management should conform to the guidelines for treatment of other forms of diabetes during gestation [ Until recently, insulin was the mainstay of therapy for diabetes during pregnancy. Although there have been reports supporting the safety and efficacy of glyburide in the treatment of diabetes during pregnancy [ Search • Developmental eval • Neurology eval & EEG in those w/suspected seizures • Imaging of pancreas • Eval of pancreatic exocrine function (fecal elastase, serum concentrations of fat-soluble vitamins) • Community or • Social work involvement for parental support • Home nursing referral • Longer-acting preparations w/no significant peak-of-action effect (e.g., glargine, detemir) may work better in small infants. • Some centers recommend continuous subcutaneous insulin infusion for young infants as a safer, more physiologic, & more accurate way of administering insulin. • In general, rapid-acting (lispro, aspart) & short-acting preparations should be avoided as they may cause severe hypoglycemic events (except when used as a continuous IV or subcutaneous infusion). • Intermediate-acting preparations (neutral protamine hagedorn) tend to have shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. • Frequent monitoring in hospital immediately following diagnosis • Lifelong monitoring (≥4x/day or w/continuous glucose monitor) after stabilization on treatment • Urinalysis for microalbuminuria • Measurement of cystatin C in blood • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Screening with HbA1c or fasting or post-prandial glucose levels may be used to assess for abnormalities in glycemic control if the pathogenic variant(s) in the family are not known. Rarely an oral glucose tolerance test is needed. Continuous glucose monitors to track glucose patterns in relatives of individuals with monogenic forms of diabetes have been used. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PNDM, the evaluations summarized in Permanent Neonatal Diabetes Mellitus: Recommended Evaluations Following Initial Diagnosis Developmental eval Neurology eval & EEG in those w/suspected seizures Imaging of pancreas Eval of pancreatic exocrine function (fecal elastase, serum concentrations of fat-soluble vitamins) Community or Social work involvement for parental support Home nursing referral DEND = Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Developmental eval • Neurology eval & EEG in those w/suspected seizures • Imaging of pancreas • Eval of pancreatic exocrine function (fecal elastase, serum concentrations of fat-soluble vitamins) • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Note: Mild beneficial effect of oral sulfonylureas in persons 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 Permanent Neonatal Diabetes Mellitus: Treatment of Manifestations Longer-acting preparations w/no significant peak-of-action effect (e.g., glargine, detemir) may work better in small infants. Some centers recommend continuous subcutaneous insulin infusion for young infants as a safer, more physiologic, & more accurate way of administering insulin. In general, rapid-acting (lispro, aspart) & short-acting preparations should be avoided as they may cause severe hypoglycemic events (except when used as a continuous IV or subcutaneous infusion). Intermediate-acting preparations (neutral protamine hagedorn) tend to have shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. DEND = In 2020 the American Diabetes Association revised the HbA1c target to be individualized for children who are not able to express symptoms of hypoglycemia [ • Longer-acting preparations w/no significant peak-of-action effect (e.g., glargine, detemir) may work better in small infants. • Some centers recommend continuous subcutaneous insulin infusion for young infants as a safer, more physiologic, & more accurate way of administering insulin. • In general, rapid-acting (lispro, aspart) & short-acting preparations should be avoided as they may cause severe hypoglycemic events (except when used as a continuous IV or subcutaneous infusion). • Intermediate-acting preparations (neutral protamine hagedorn) tend to have shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. ## Targeted Therapy Note: Mild beneficial effect of oral sulfonylureas in persons 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 Permanent Neonatal Diabetes Mellitus: Treatment of Manifestations Longer-acting preparations w/no significant peak-of-action effect (e.g., glargine, detemir) may work better in small infants. Some centers recommend continuous subcutaneous insulin infusion for young infants as a safer, more physiologic, & more accurate way of administering insulin. In general, rapid-acting (lispro, aspart) & short-acting preparations should be avoided as they may cause severe hypoglycemic events (except when used as a continuous IV or subcutaneous infusion). Intermediate-acting preparations (neutral protamine hagedorn) tend to have shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. DEND = In 2020 the American Diabetes Association revised the HbA1c target to be individualized for children who are not able to express symptoms of hypoglycemia [ • Longer-acting preparations w/no significant peak-of-action effect (e.g., glargine, detemir) may work better in small infants. • Some centers recommend continuous subcutaneous insulin infusion for young infants as a safer, more physiologic, & more accurate way of administering insulin. • In general, rapid-acting (lispro, aspart) & short-acting preparations should be avoided as they may cause severe hypoglycemic events (except when used as a continuous IV or subcutaneous infusion). • Intermediate-acting preparations (neutral protamine hagedorn) tend to have shorter duration of action in infants, possibly because of smaller dose size or higher subcutaneous blood flow. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Permanent Neonatal Diabetes Mellitus: Recommended Surveillance Frequent monitoring in hospital immediately following diagnosis Lifelong monitoring (≥4x/day or w/continuous glucose monitor) after stabilization on treatment Urinalysis for microalbuminuria Measurement of cystatin C in blood DEND = • Frequent monitoring in hospital immediately following diagnosis • Lifelong monitoring (≥4x/day or w/continuous glucose monitor) after stabilization on treatment • Urinalysis for microalbuminuria • Measurement of cystatin C in blood ## Agents/Circumstances to Avoid In general, rapid-acting insulin preparations (lispro and aspart) as well as short-acting (regular) insulin preparations should be avoided (except when used as a continuous intravenous or subcutaneous infusion), as they may cause severe hypoglycemic events in young children. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance and treatment of hyperglycemia. (Hyperglycemia may be asymptomatic.) Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Screening with HbA1c or fasting or post-prandial glucose levels may be used to assess for abnormalities in glycemic control if the pathogenic variant(s) in the family are not known. Rarely an oral glucose tolerance test is needed. Continuous glucose monitors to track glucose patterns in relatives of individuals with monogenic forms of diabetes have been used. See • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Screening with HbA1c or fasting or post-prandial glucose levels may be used to assess for abnormalities in glycemic control if the pathogenic variant(s) in the family are not known. Rarely an oral glucose tolerance test is needed. Continuous glucose monitors to track glucose patterns in relatives of individuals with monogenic forms of diabetes have been used. ## Pregnancy Management Pregnant women with PNDM should be managed by an endocrinologist and maternal-fetal medicine specialist. Management should conform to the guidelines for treatment of other forms of diabetes during gestation [ Until recently, insulin was the mainstay of therapy for diabetes during pregnancy. Although there have been reports supporting the safety and efficacy of glyburide in the treatment of diabetes during pregnancy [ ## Therapies Under Investigation Search ## Genetic Counseling The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) varies by gene (see Permanent Neonatal Diabetes Mellitus: Mode of Inheritance AD = autosomal dominant; AR = autosomal recessive If an individual has a specific genetic syndrome associated with PNDM (e.g., Wolcott-Rallison syndrome or The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in Most reported individuals with autosomal dominant Approximately 73% of individuals with Some individuals with autosomal dominant PNDM have the disorder as the result of a pathogenic variant inherited from a parent. Children with autosomal dominant Children with autosomal dominant Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. If a molecular diagnosis has been established in the proband, the pathogenic variant found 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. Gonadal mosaicism for a pathogenic variant in Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder in affected family members, reduced penetrance ( If a parent of the proband is affected and/or is known to have the PNDM-related pathogenic variant identified in the proband, the risk to the sibs is 50%. If a molecular diagnosis has been established in the proband and the PNDM-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population 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 appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. The parents of a child with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. Recommendations for the evaluation of parents of a proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus (see In 43% of individuals with Individuals who are heterozygous for a pathogenic variant in If both parents are known to be heterozygous for a PNDM-related pathogenic 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 pathogenic variants. The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. Heterozygotes for pathogenic variants in Heterozygotes for pathogenic variants in 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. Referral to a maternal-fetal medicine specialist should be considered for females with PNDM who are pregnant or considering pregnancy (see Once the PNDM-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate. • The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in • Most reported individuals with autosomal dominant • Approximately 73% of individuals with • Most reported individuals with autosomal dominant • Approximately 73% of individuals with • Some individuals with autosomal dominant PNDM have the disorder as the result of a pathogenic variant inherited from a parent. • Children with autosomal dominant • Children with autosomal dominant • Children with autosomal dominant • Children with autosomal dominant • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. • If a molecular diagnosis has been established in the proband, the pathogenic variant found 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. Gonadal mosaicism for a pathogenic variant in • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Gonadal mosaicism for a pathogenic variant in • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder in affected family members, reduced penetrance ( • Most reported individuals with autosomal dominant • Approximately 73% of individuals with • Children with autosomal dominant • Children with autosomal dominant • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Gonadal mosaicism for a pathogenic variant in • If a parent of the proband is affected and/or is known to have the PNDM-related pathogenic variant identified in the proband, the risk to the sibs is 50%. • If a molecular diagnosis has been established in the proband and the PNDM-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population 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 appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • The parents of a child with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. • Recommendations for the evaluation of parents of a proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. • The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus (see • In 43% of individuals with • Individuals who are heterozygous for a pathogenic variant in • In 43% of individuals with • Individuals who are heterozygous for a pathogenic variant in • In 43% of individuals with • Individuals who are heterozygous for a pathogenic variant in • If both parents are known to be heterozygous for a PNDM-related pathogenic 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 pathogenic variants. • The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for 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 or at risk. • Referral to a maternal-fetal medicine specialist should be considered for females with PNDM who are pregnant or considering pregnancy (see ## Mode of Inheritance The mode of inheritance of permanent neonatal diabetes mellitus (PNDM) varies by gene (see Permanent Neonatal Diabetes Mellitus: Mode of Inheritance AD = autosomal dominant; AR = autosomal recessive If an individual has a specific genetic syndrome associated with PNDM (e.g., Wolcott-Rallison syndrome or ## Autosomal Dominant Inheritance – Risk to Family Members The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in Most reported individuals with autosomal dominant Approximately 73% of individuals with Some individuals with autosomal dominant PNDM have the disorder as the result of a pathogenic variant inherited from a parent. Children with autosomal dominant Children with autosomal dominant Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. If a molecular diagnosis has been established in the proband, the pathogenic variant found 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. Gonadal mosaicism for a pathogenic variant in Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder in affected family members, reduced penetrance ( If a parent of the proband is affected and/or is known to have the PNDM-related pathogenic variant identified in the proband, the risk to the sibs is 50%. If a molecular diagnosis has been established in the proband and the PNDM-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population 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 appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. • The majority of individuals with autosomal dominant PNDM caused by a heterozygous pathogenic variant in • Most reported individuals with autosomal dominant • Approximately 73% of individuals with • Most reported individuals with autosomal dominant • Approximately 73% of individuals with • Some individuals with autosomal dominant PNDM have the disorder as the result of a pathogenic variant inherited from a parent. • Children with autosomal dominant • Children with autosomal dominant • Children with autosomal dominant • Children with autosomal dominant • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. • If a molecular diagnosis has been established in the proband, the pathogenic variant found 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. Gonadal mosaicism for a pathogenic variant in • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Gonadal mosaicism for a pathogenic variant in • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the disorder in affected family members, reduced penetrance ( • Most reported individuals with autosomal dominant • Approximately 73% of individuals with • Children with autosomal dominant • Children with autosomal dominant • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Gonadal mosaicism for a pathogenic variant in • If a parent of the proband is affected and/or is known to have the PNDM-related pathogenic variant identified in the proband, the risk to the sibs is 50%. • If a molecular diagnosis has been established in the proband and the PNDM-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population 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 appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. Recommendations for the evaluation of parents of a proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus (see In 43% of individuals with Individuals who are heterozygous for a pathogenic variant in If both parents are known to be heterozygous for a PNDM-related pathogenic 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 pathogenic variants. The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. Heterozygotes for pathogenic variants in Heterozygotes for pathogenic variants in • The parents of a child with PNDM caused by biallelic pathogenic variants are presumed to be heterozygous for a PNDM-related pathogenic variant. • Recommendations for the evaluation of parents of a proband include molecular genetic testing (if a molecular diagnosis has been established in the proband) and clinical testing for diabetes mellitus including screening HbA1c, blood glucose monitoring, or oral glucose tolerance testing. • The heterozygous parents of a child with autosomal recessive PNDM may or may not have diabetes mellitus (see • In 43% of individuals with • Individuals who are heterozygous for a pathogenic variant in • In 43% of individuals with • Individuals who are heterozygous for a pathogenic variant in • In 43% of individuals with • Individuals who are heterozygous for a pathogenic variant in • If both parents are known to be heterozygous for a PNDM-related pathogenic 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 pathogenic variants. • The heterozygous sibs of a proband with autosomal recessive PNDM may or may not have diabetes mellitus. • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in • Heterozygotes for pathogenic variants in ## 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. Referral to a maternal-fetal medicine specialist should be considered for females with PNDM who are pregnant or considering pregnancy (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. • Referral to a maternal-fetal medicine specialist should be considered for females with PNDM who are pregnant or considering pregnancy (see ## Prenatal Testing and Preimplantation Genetic Testing Once the PNDM-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals consider decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate. ## Resources United Kingdom United Kingdom Monogenic Diabetes at the University of Chicago • • • United Kingdom • • • • • • • United Kingdom • • • Monogenic Diabetes at the University of Chicago • ## Molecular Genetics Permanent Neonatal Diabetes Mellitus: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Permanent Neonatal Diabetes Mellitus ( Pathogenic variants in either Permanent Neonatal Diabetes Mellitus: Mechanism of Disease Causation ER = endoplasmic reticulum; GLUT2 = solute carrier family 2, facilitated glucose transporter member 2 Genes from There are no gene-specific laboratory technical considerations for the other genes listed in • There are no gene-specific laboratory technical considerations for the other genes listed in ## Molecular Pathogenesis Pathogenic variants in either Permanent Neonatal Diabetes Mellitus: Mechanism of Disease Causation ER = endoplasmic reticulum; GLUT2 = solute carrier family 2, facilitated glucose transporter member 2 Genes from There are no gene-specific laboratory technical considerations for the other genes listed in • There are no gene-specific laboratory technical considerations for the other genes listed in ## Chapter Notes Dr Sara Pinney ( Dr Pinney is also interested in hearing from clinicians treating families affected by monogenic diabetes in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Children's Hospital of Philadelphia The authors receive grant support from NIH grants R01DK098517 and R01FD004095 (DDDL); and R37DK056268. Diva D De León, MD (2008-present)Sara E Pinney, MD, MSTR (2024-present)Charles A Stanley, MD; Children's Hospital of Philadelphia (2008-2024) 14 November 2024 (sw) Comprehensive update posted live 29 July 2016 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 5 July 2011 (me) Comprehensive update posted live 8 February 2008 (me) Review posted live 9 August 2007 (cas) Original submission • 14 November 2024 (sw) Comprehensive update posted live • 29 July 2016 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 5 July 2011 (me) Comprehensive update posted live • 8 February 2008 (me) Review posted live • 9 August 2007 (cas) Original submission ## Author Notes Dr Sara Pinney ( Dr Pinney is also interested in hearing from clinicians treating families affected by monogenic diabetes in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Children's Hospital of Philadelphia ## Acknowledgments The authors receive grant support from NIH grants R01DK098517 and R01FD004095 (DDDL); and R37DK056268. ## Author History Diva D De León, MD (2008-present)Sara E Pinney, MD, MSTR (2024-present)Charles A Stanley, MD; Children's Hospital of Philadelphia (2008-2024) ## Revision History 14 November 2024 (sw) Comprehensive update posted live 29 July 2016 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 5 July 2011 (me) Comprehensive update posted live 8 February 2008 (me) Review posted live 9 August 2007 (cas) Original submission • 14 November 2024 (sw) Comprehensive update posted live • 29 July 2016 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 5 July 2011 (me) Comprehensive update posted live • 8 February 2008 (me) Review posted live • 9 August 2007 (cas) Original submission ## Key Sections in This ## References ## Literature Cited
[]
8/2/2008
14/11/2024
4/3/2008
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dmtn
dmtn
[ "6q24-TNDM", "6q24-TNDM", "Not applicable", "Zinc finger protein 57 homolog", "Zinc finger protein PLAGL1", "HYMAI", "PLAGL1", "ZFP57", "Diabetes Mellitus, 6q24-Related Transient Neonatal" ]
Diabetes Mellitus, 6q24-Related Transient Neonatal
Isabel Karen Temple, Deborah JG Mackay
Summary 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) is defined as transient neonatal diabetes mellitus caused by genetic aberrations of the imprinted locus at 6q24. The cardinal features are: severe intrauterine growth restriction, hyperglycemia that begins in the neonatal period in a term infant and resolves by age 18 months, dehydration, and absence of ketoacidosis. Macroglossia and umbilical hernia may be present. 6q24-TNDM associated with a multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Diabetes mellitus usually starts within the first week of life and lasts on average three months but can last longer than a year. Although insulin is usually required initially, the need for insulin gradually declines over time. Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Diabetes mellitus may recur in adolescence or later in adulthood. Women who have had 6q24-TNDM are at risk for relapse during pregnancy. The diagnosis of 6q24-TNDM is established in a proband with transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the 6q24 differentially methylated region (DMR). 6q24-TNDM is caused by overexpression of the imprinted genes at 6q24 ( The risk to sibs and offspring of a proband of having 6q24-TNDM or of developing diabetes later in life depends on the genetic mechanism in the family. Recurrence risk counseling by a genetics professional is strongly recommended. 6q24-TNDM caused by paternal UPD6 is typically a
## Diagnosis Diagnosis of 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) Severe intrauterine growth restriction Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following: Hyperglycemia Dehydration Plasma insulin concentrations that are low in the presence of high serum glucose concentrations Absence of ketoacidosis. Ketones are usually not present in the urine. Absence of islet cell antibodies Presence of a pancreas The diagnosis of 6q24-TNDM Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the Partial or complete paternal uniparental disomy of chromosome 6 Paternal duplication of 6q24 Hypomethylation of the maternal 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 [ The maternal alleles of As an isolated imprinting defect of the As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in Note: In individuals with 6q24 duplication of the paternal allele, the presence of two unmethylated alleles and one methylated allele of the Molecular Genetic Mechanisms for 6q24-Related Transient Neonatal Diabetes Mellitus In unaffected individuals, the maternally derived methylated copy is not expressed. Molecular genetic testing approaches can include Note: DNA methylation analysis is the only technique that will diagnose 6q24-TNDM caused by any genetic mechanism, but it cannot establish the specific mechanism. Tier 2 testing is necessary to differentiate the two different genetic mechanisms that cause expression of an extra copy of the paternal alleles of Tier 3 testing is necessary if tier 2 testing does not identify the genetic mechanism for 6q24 hypomethylation. For an introduction to multigene panels click Molecular Genetic Testing Used in 6q24-Related Transient Neonatal Diabetes Mellitus (TNDM) DMR = differentially methylated region; UPD = uniparental disomy Can establish diagnosis, but will not distinguish genetic mechanism; can be done by Southern blot, methylation-specific multiple ligation-mediated PCR analysis (MS-MLPA), or methylation-specific PCR. Note: Only methylation analysis will detect an imprinting center defect, which is causative in ~30% of individuals. Paternal disomy occurs by postzygotic somatic recombination resulting in isodisomy and can therefore be identified by proband-only SNP array analysis. Use of genetic markers (usually short tandem repeats) to determine parental identity (maternal or paternal) of a chromosome or chromosomal segment in a proband. Note: This testing requires a DNA sample from the proband, mother, and father. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Reported duplications range in size from 200 kb to several megabases [ 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 See • Severe intrauterine growth restriction • Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following: • Hyperglycemia • Dehydration • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations • Absence of ketoacidosis. Ketones are usually not present in the urine. • Absence of islet cell antibodies • Presence of a pancreas • Hyperglycemia • Dehydration • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations • Absence of ketoacidosis. Ketones are usually not present in the urine. • Absence of islet cell antibodies • Presence of a pancreas • Hyperglycemia • Dehydration • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations • Absence of ketoacidosis. Ketones are usually not present in the urine. • Absence of islet cell antibodies • Presence of a pancreas • Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the • Partial or complete paternal uniparental disomy of chromosome 6 • Paternal duplication of 6q24 • Hypomethylation of the maternal • Partial or complete paternal uniparental disomy of chromosome 6 • Paternal duplication of 6q24 • Hypomethylation of the maternal • 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 [ • Partial or complete paternal uniparental disomy of chromosome 6 • Paternal duplication of 6q24 • Hypomethylation of the maternal • As an isolated imprinting defect of the • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in • As an isolated imprinting defect of the • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in • Note: In individuals with 6q24 duplication of the paternal allele, the presence of two unmethylated alleles and one methylated allele of the • As an isolated imprinting defect of the • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in ## Suggestive Findings Diagnosis of 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) Severe intrauterine growth restriction Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following: Hyperglycemia Dehydration Plasma insulin concentrations that are low in the presence of high serum glucose concentrations Absence of ketoacidosis. Ketones are usually not present in the urine. Absence of islet cell antibodies Presence of a pancreas • Severe intrauterine growth restriction • Diabetes mellitus that commences in the first six weeks of life in a term infant and resolves by age 18 months. Presentation includes the following: • Hyperglycemia • Dehydration • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations • Absence of ketoacidosis. Ketones are usually not present in the urine. • Absence of islet cell antibodies • Presence of a pancreas • Hyperglycemia • Dehydration • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations • Absence of ketoacidosis. Ketones are usually not present in the urine. • Absence of islet cell antibodies • Presence of a pancreas • Hyperglycemia • Dehydration • Plasma insulin concentrations that are low in the presence of high serum glucose concentrations • Absence of ketoacidosis. Ketones are usually not present in the urine. • Absence of islet cell antibodies • Presence of a pancreas ## Establishing the Diagnosis The diagnosis of 6q24-TNDM Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the Partial or complete paternal uniparental disomy of chromosome 6 Paternal duplication of 6q24 Hypomethylation of the maternal 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 [ The maternal alleles of As an isolated imprinting defect of the As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in Note: In individuals with 6q24 duplication of the paternal allele, the presence of two unmethylated alleles and one methylated allele of the Molecular Genetic Mechanisms for 6q24-Related Transient Neonatal Diabetes Mellitus In unaffected individuals, the maternally derived methylated copy is not expressed. Molecular genetic testing approaches can include Note: DNA methylation analysis is the only technique that will diagnose 6q24-TNDM caused by any genetic mechanism, but it cannot establish the specific mechanism. Tier 2 testing is necessary to differentiate the two different genetic mechanisms that cause expression of an extra copy of the paternal alleles of Tier 3 testing is necessary if tier 2 testing does not identify the genetic mechanism for 6q24 hypomethylation. For an introduction to multigene panels click Molecular Genetic Testing Used in 6q24-Related Transient Neonatal Diabetes Mellitus (TNDM) DMR = differentially methylated region; UPD = uniparental disomy Can establish diagnosis, but will not distinguish genetic mechanism; can be done by Southern blot, methylation-specific multiple ligation-mediated PCR analysis (MS-MLPA), or methylation-specific PCR. Note: Only methylation analysis will detect an imprinting center defect, which is causative in ~30% of individuals. Paternal disomy occurs by postzygotic somatic recombination resulting in isodisomy and can therefore be identified by proband-only SNP array analysis. Use of genetic markers (usually short tandem repeats) to determine parental identity (maternal or paternal) of a chromosome or chromosomal segment in a proband. Note: This testing requires a DNA sample from the proband, mother, and father. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Reported duplications range in size from 200 kb to several megabases [ 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 See • Transient neonatal diabetes mellitus and DNA methylation analysis demonstrating relative hypomethylation within the • Partial or complete paternal uniparental disomy of chromosome 6 • Paternal duplication of 6q24 • Hypomethylation of the maternal • Partial or complete paternal uniparental disomy of chromosome 6 • Paternal duplication of 6q24 • Hypomethylation of the maternal • 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 [ • Partial or complete paternal uniparental disomy of chromosome 6 • Paternal duplication of 6q24 • Hypomethylation of the maternal • As an isolated imprinting defect of the • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in • As an isolated imprinting defect of the • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in • Note: In individuals with 6q24 duplication of the paternal allele, the presence of two unmethylated alleles and one methylated allele of the • As an isolated imprinting defect of the • As part of a more generalized multilocus imprinting disturbance (MLID) caused by biallelic (homozygous or compound heterozygous) pathogenic variants in ## Tier 1 Testing Note: DNA methylation analysis is the only technique that will diagnose 6q24-TNDM caused by any genetic mechanism, but it cannot establish the specific mechanism. ## Tier 2 Testing Tier 2 testing is necessary to differentiate the two different genetic mechanisms that cause expression of an extra copy of the paternal alleles of ## Tier 3 Testing Tier 3 testing is necessary if tier 2 testing does not identify the genetic mechanism for 6q24 hypomethylation. ## Parallel or Additional Testing Options For an introduction to multigene panels click Molecular Genetic Testing Used in 6q24-Related Transient Neonatal Diabetes Mellitus (TNDM) DMR = differentially methylated region; UPD = uniparental disomy Can establish diagnosis, but will not distinguish genetic mechanism; can be done by Southern blot, methylation-specific multiple ligation-mediated PCR analysis (MS-MLPA), or methylation-specific PCR. Note: Only methylation analysis will detect an imprinting center defect, which is causative in ~30% of individuals. Paternal disomy occurs by postzygotic somatic recombination resulting in isodisomy and can therefore be identified by proband-only SNP array analysis. Use of genetic markers (usually short tandem repeats) to determine parental identity (maternal or paternal) of a chromosome or chromosomal segment in a proband. Note: This testing requires a DNA sample from the proband, mother, and father. Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Reported duplications range in size from 200 kb to several megabases [ 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 See ## Clinical Characteristics Diabetes mellitus lasts on average three months but has been reported to last longer than a year [ Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Few studies have been performed during this period and so the extent of these episodes is not known. Diabetes may recur in very early childhood. The average age of recurrence in the series of Women are at risk for relapse during pregnancy and may present with gestational diabetes mellitus. Permanent diabetes mellitus can occur in up to 50% in some series [ Studies have not been performed to assess the level of diabetes-related complications that can occur in this disorder. One individual with poor compliance with treatment had persistent hyperglycemia from ages 14 to 28 years. He did not develop ketoacidosis but did develop evidence of microangiopathy [ 6q24-TNDM caused by generalized multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Intelligence and growth are usually normal in this condition except in individuals with loss of methylation at multiple loci, who may have developmental delay. However, the long-term outcomes for most individuals are still not known. Non-diabetes manifestations vary by causative genetic mechanism. Congenital anomalies were significantly more frequent in individuals with paternal uniparental disomy of chromosome 6 (UPD6) or MLID than in those with 6q24 duplication or isolated hypomethylation defects [ Reduced penetrance of the 6q24-TNDM has rarely been described, but has been noted in sibs of affected individuals. The sibs reported did not have a history of neonatal diabetes mellitus but were found to have either a paternal duplication of 6q24 or biallelic The incidence of neonatal diabetes is reported to be 1:215,000 to 1:400,000 [ ## Clinical Description Diabetes mellitus lasts on average three months but has been reported to last longer than a year [ Intermittent episodes of hyperglycemia may occur in childhood, particularly during intercurrent illnesses. Few studies have been performed during this period and so the extent of these episodes is not known. Diabetes may recur in very early childhood. The average age of recurrence in the series of Women are at risk for relapse during pregnancy and may present with gestational diabetes mellitus. Permanent diabetes mellitus can occur in up to 50% in some series [ Studies have not been performed to assess the level of diabetes-related complications that can occur in this disorder. One individual with poor compliance with treatment had persistent hyperglycemia from ages 14 to 28 years. He did not develop ketoacidosis but did develop evidence of microangiopathy [ 6q24-TNDM caused by generalized multilocus imprinting disturbance (MLID) can be associated with marked hypotonia, congenital heart disease, deafness, neurologic features including epilepsy, and renal malformations. Intelligence and growth are usually normal in this condition except in individuals with loss of methylation at multiple loci, who may have developmental delay. However, the long-term outcomes for most individuals are still not known. ## Genotype-Phenotype Correlations Non-diabetes manifestations vary by causative genetic mechanism. Congenital anomalies were significantly more frequent in individuals with paternal uniparental disomy of chromosome 6 (UPD6) or MLID than in those with 6q24 duplication or isolated hypomethylation defects [ ## Penetrance Reduced penetrance of the 6q24-TNDM has rarely been described, but has been noted in sibs of affected individuals. The sibs reported did not have a history of neonatal diabetes mellitus but were found to have either a paternal duplication of 6q24 or biallelic ## Prevalence The incidence of neonatal diabetes is reported to be 1:215,000 to 1:400,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Transient neonatal diabetes mellitus (TNDM) accounts for approximately 50% of diabetes mellitus presenting in the neonatal period [ Other genetic causes of neonatal diabetes mellitus (isolated and syndromic, transient and permanent): ## Management To establish the extent of disease and needs in an individual diagnosed with 6q24-related transient neonatal diabetes mellitus (6q24-TNDM), the following evaluations are recommended if they have not already been completed: Birth weight, length, and head circumference and any subsequent growth parameters General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus Neurologic examination and developmental assessment Investigation of the anatomy of the pancreas by ultrasound examination or MRI Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by Brain MRI examination if evidence of developmental delay or hypotonia Serum glucose concentration C peptide measurement Pancreatic beta cell autoantibody measurements Liver function and thyroid function tests Consultation with a pediatric endocrinologist for follow up of diabetes Consultation with a clinical geneticist and/or genetic counselor Individuals with multilocus imprinting disturbance (MLID) should be evaluated for hypotonia and other neurologic features including epilepsy, congenital heart disease, deafness, renal malformations, and pseudohypoparathyroidism with measurement of serum concentrations of calcium and phosphate and parathyroid hormone testing. Rehydration and IV insulin on a sliding scale are usually required. Some infants produce some insulin and can be treated by rehydration alone. Subcutaneous injection of insulin is introduced as soon as possible, often within two weeks. Continuous insulin pump therapy (as opposed to intermittent insulin injections) has been used successfully in a number of cases in the UK and France [JP Shield, personal communication]. Successful treatment with subcutaneous insulin glargine has also been reported [ Blood glucose concentration should be monitored and insulin doses changed accordingly as in the standard treatment for diabetes mellitus. Insulin can be discontinued when blood glucose concentrations stabilize. Once diabetes mellitus is in remission, parents need to be alerted to the possibility of recurrence of the diabetes mellitus, particularly during periods of illness. Symptoms such as excessive thirst, polyuria, and repeated bacterial infections should prompt measurement of blood glucose concentration. If diabetes mellitus recurs, treatment may require diet alone, oral agents, or insulin, although the doses of insulin needed tend to be less than those required in type 1 diabetes mellitus (i.e., some residual endogenous insulin remains). It should be noted that insulin is not always required even in the neonatal period. In several individuals, sulphonylureas or diet alone was adequate to treat relapses [ Note: Macroglossia could potentially cause airway obstruction; macroglossia severe enough to require treatment has not been reported. The main concerns are related to failure to make the diagnosis soon enough. Dehydration secondary to hyperglycemia can cause serious long-term sequelae if not treated promptly. Therefore, rehydration is most important in the early stages of the disease. Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes mellitus in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state. Insulin response to intravenous glucose loading is often normal but suggests future recurrence if abnormal [ Measure growth (height, weight, head circumference) at regular intervals (i.e., at least every 6 months). Developmental assessment to identify any special educational needs is appropriate. Children with MLID need to be monitored for developmental delay and special educational needs. General factors that predispose to late-onset diabetes (e.g., excessive weight gain) or risk factors for cardiovascular disorders should be avoided. It is appropriate to test apparently asymptomatic at-risk relatives for the 6q24-TNDM genetic mechanism identified in the proband in order to identify family members who would benefit from follow up. (Hyperglycemia may be asymptomatic.) Recommendations for follow up vary by underlying genetic mechanism: See There are no specific guidelines on pregnancy management for women with a history of 6q24-TNDM. However, it is important to inform health professionals during the pregnancy of a susceptibility to diabetes. Rarely, some affected women with classic 6q24-TNDM genetic aberrations (e.g., duplication of 6q24, paternal uniparental disomy of chromosome 6, methylation defects) will develop gestational diabetes; therefore, pregnancy is thought to be a risk factor for recurrence of diabetes. If prenatal diagnosis identifies an affected fetus, fetal growth is anticipated to lag during the third trimester. See Search • Birth weight, length, and head circumference and any subsequent growth parameters • General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus • Neurologic examination and developmental assessment • Investigation of the anatomy of the pancreas by ultrasound examination or MRI • Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by • Brain MRI examination if evidence of developmental delay or hypotonia • Serum glucose concentration • C peptide measurement • Pancreatic beta cell autoantibody measurements • Liver function and thyroid function tests • Consultation with a pediatric endocrinologist for follow up of diabetes • 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 6q24-related transient neonatal diabetes mellitus (6q24-TNDM), the following evaluations are recommended if they have not already been completed: Birth weight, length, and head circumference and any subsequent growth parameters General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus Neurologic examination and developmental assessment Investigation of the anatomy of the pancreas by ultrasound examination or MRI Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by Brain MRI examination if evidence of developmental delay or hypotonia Serum glucose concentration C peptide measurement Pancreatic beta cell autoantibody measurements Liver function and thyroid function tests Consultation with a pediatric endocrinologist for follow up of diabetes Consultation with a clinical geneticist and/or genetic counselor Individuals with multilocus imprinting disturbance (MLID) should be evaluated for hypotonia and other neurologic features including epilepsy, congenital heart disease, deafness, renal malformations, and pseudohypoparathyroidism with measurement of serum concentrations of calcium and phosphate and parathyroid hormone testing. • Birth weight, length, and head circumference and any subsequent growth parameters • General dysmorphology examination, preferably by a clinical geneticist, including evaluation of tongue size and umbilicus • Neurologic examination and developmental assessment • Investigation of the anatomy of the pancreas by ultrasound examination or MRI • Echocardiogram and ultrasound examination of the liver and kidneys to help identify those infants likely to have 6q24-TNDM caused by • Brain MRI examination if evidence of developmental delay or hypotonia • Serum glucose concentration • C peptide measurement • Pancreatic beta cell autoantibody measurements • Liver function and thyroid function tests • Consultation with a pediatric endocrinologist for follow up of diabetes • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Rehydration and IV insulin on a sliding scale are usually required. Some infants produce some insulin and can be treated by rehydration alone. Subcutaneous injection of insulin is introduced as soon as possible, often within two weeks. Continuous insulin pump therapy (as opposed to intermittent insulin injections) has been used successfully in a number of cases in the UK and France [JP Shield, personal communication]. Successful treatment with subcutaneous insulin glargine has also been reported [ Blood glucose concentration should be monitored and insulin doses changed accordingly as in the standard treatment for diabetes mellitus. Insulin can be discontinued when blood glucose concentrations stabilize. Once diabetes mellitus is in remission, parents need to be alerted to the possibility of recurrence of the diabetes mellitus, particularly during periods of illness. Symptoms such as excessive thirst, polyuria, and repeated bacterial infections should prompt measurement of blood glucose concentration. If diabetes mellitus recurs, treatment may require diet alone, oral agents, or insulin, although the doses of insulin needed tend to be less than those required in type 1 diabetes mellitus (i.e., some residual endogenous insulin remains). It should be noted that insulin is not always required even in the neonatal period. In several individuals, sulphonylureas or diet alone was adequate to treat relapses [ Note: Macroglossia could potentially cause airway obstruction; macroglossia severe enough to require treatment has not been reported. ## Prevention of Secondary Complications The main concerns are related to failure to make the diagnosis soon enough. Dehydration secondary to hyperglycemia can cause serious long-term sequelae if not treated promptly. Therefore, rehydration is most important in the early stages of the disease. ## Surveillance Periodic glucose tolerance tests can be used to assess insulin secretion. Most children with transient neonatal diabetes mellitus in remission have no evidence of beta cell dysfunction or insulin resistance in the fasting state. Insulin response to intravenous glucose loading is often normal but suggests future recurrence if abnormal [ Measure growth (height, weight, head circumference) at regular intervals (i.e., at least every 6 months). Developmental assessment to identify any special educational needs is appropriate. Children with MLID need to be monitored for developmental delay and special educational needs. ## Agents/Circumstances to Avoid General factors that predispose to late-onset diabetes (e.g., excessive weight gain) or risk factors for cardiovascular disorders should be avoided. ## Evaluation of Relatives at Risk It is appropriate to test apparently asymptomatic at-risk relatives for the 6q24-TNDM genetic mechanism identified in the proband in order to identify family members who would benefit from follow up. (Hyperglycemia may be asymptomatic.) Recommendations for follow up vary by underlying genetic mechanism: See ## Pregnancy Management There are no specific guidelines on pregnancy management for women with a history of 6q24-TNDM. However, it is important to inform health professionals during the pregnancy of a susceptibility to diabetes. Rarely, some affected women with classic 6q24-TNDM genetic aberrations (e.g., duplication of 6q24, paternal uniparental disomy of chromosome 6, methylation defects) will develop gestational diabetes; therefore, pregnancy is thought to be a risk factor for recurrence of diabetes. If prenatal diagnosis identifies an affected fetus, fetal growth is anticipated to lag during the third trimester. See ## Therapies Under Investigation Search ## Genetic Counseling 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) results from overexpression of imprinted genes at 6q24 ( Paternal uniparental disomy of chromosome 6 (41%) Both complete and partial paternal uniparental disomy of chromosome 6 are typically Duplication of 6q24 on the paternal allele (29%) Paternal duplication of 6q24 can occur Hypomethylation of the maternal Maternal Karyotype testing of a proband with paternal uniparental disomy of chromosome 6 (UPD6) is recommended for more accurate determination of recurrence risk. The risk to parents, sibs, and offspring of a proband with 6q24-TNDM caused by paternal UPD6 and a normal karyotype is unlikely to be higher than the risk to the general population, as paternal UPD6 is a If the proband has a chromosome abnormality in addition to paternal UPD6, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband. The father of a proband may have the (submicroscopic or visible) 6q24 duplication identified in the proband and may be at risk of developing diabetes mellitus later in life (or having had a history of early diabetes mellitus) Alternatively, the 6q24 duplication may be a Recommendations for the evaluation of the father of a proband with 6q24-TNDM include routine cytogenetic analysis and molecular genetic testing to identify a 6q24 duplication if present, and to exclude a balanced/unbalanced translocation involving the 6q24 critical region. If the father If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of reduced penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but they are at increased risk of developing diabetes mellitus later in life. If the father has a complex chromosomal rearrangement involving 6q24, the risk to sibs is related to the specific rearrangement. Risks depend on the underlying cause of the hypomethylation. Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to be at increased risk of having 6q24-TNDM or of developing diabetes mellitus. Because the cause of isolated DMR hypomethylation is not understood and it is possible that it is not The parents of an affected child are likely obligate heterozygotes (i.e., carriers of one Parents heterozygous for At conception, assuming both parents of the proband are heterozygous for a If one parent has biallelic In sibs who have inherited two The risk to sibs, offspring, and parents is unknown as recurrence has not been reported in this subgroup. Note: There is an increased incidence of assisted reproductive technology (ART) used by the parents of these probands; whether a causal relationship exists between ART and hypomethylation is not clear [ 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. Consideration of prenatal testing for 6q24-TNDM depends on the genetic mechanism in the family: paternal UPD6 is typically a Paternal duplication of 6q24 requires prior identification of the structural chromosome abnormality in the family. Hypomethylation of the maternal • Paternal uniparental disomy of chromosome 6 (41%) • Both complete and partial paternal uniparental disomy of chromosome 6 are typically • Duplication of 6q24 on the paternal allele (29%) • Paternal duplication of 6q24 can occur • Hypomethylation of the maternal • Maternal • Karyotype testing of a proband with paternal uniparental disomy of chromosome 6 (UPD6) is recommended for more accurate determination of recurrence risk. • The risk to parents, sibs, and offspring of a proband with 6q24-TNDM caused by paternal UPD6 and a normal karyotype is unlikely to be higher than the risk to the general population, as paternal UPD6 is a • If the proband has a chromosome abnormality in addition to paternal UPD6, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband. • The father of a proband may have the (submicroscopic or visible) 6q24 duplication identified in the proband and may be at risk of developing diabetes mellitus later in life (or having had a history of early diabetes mellitus) • Alternatively, the 6q24 duplication may be a • Recommendations for the evaluation of the father of a proband with 6q24-TNDM include routine cytogenetic analysis and molecular genetic testing to identify a 6q24 duplication if present, and to exclude a balanced/unbalanced translocation involving the 6q24 critical region. • If the father • If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of reduced penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but they are at increased risk of developing diabetes mellitus later in life. • If the father has a complex chromosomal rearrangement involving 6q24, the risk to sibs is related to the specific rearrangement. • Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to be at increased risk of having 6q24-TNDM or of developing diabetes mellitus. • Because the cause of isolated DMR hypomethylation is not understood and it is possible that it is not • The parents of an affected child are likely obligate heterozygotes (i.e., carriers of one • Parents heterozygous for • At conception, assuming both parents of the proband are heterozygous for a • If one parent has biallelic • In sibs who have inherited two • 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. • Paternal duplication of 6q24 requires prior identification of the structural chromosome abnormality in the family. • Hypomethylation of the maternal ## Mode of Inheritance 6q24-related transient neonatal diabetes mellitus (6q24-TNDM) results from overexpression of imprinted genes at 6q24 ( Paternal uniparental disomy of chromosome 6 (41%) Both complete and partial paternal uniparental disomy of chromosome 6 are typically Duplication of 6q24 on the paternal allele (29%) Paternal duplication of 6q24 can occur Hypomethylation of the maternal Maternal • Paternal uniparental disomy of chromosome 6 (41%) • Both complete and partial paternal uniparental disomy of chromosome 6 are typically • Duplication of 6q24 on the paternal allele (29%) • Paternal duplication of 6q24 can occur • Hypomethylation of the maternal • Maternal ## Paternal Uniparental Disomy of Chromosome 6 – Risk to Family Members Karyotype testing of a proband with paternal uniparental disomy of chromosome 6 (UPD6) is recommended for more accurate determination of recurrence risk. The risk to parents, sibs, and offspring of a proband with 6q24-TNDM caused by paternal UPD6 and a normal karyotype is unlikely to be higher than the risk to the general population, as paternal UPD6 is a If the proband has a chromosome abnormality in addition to paternal UPD6, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband. • Karyotype testing of a proband with paternal uniparental disomy of chromosome 6 (UPD6) is recommended for more accurate determination of recurrence risk. • The risk to parents, sibs, and offspring of a proband with 6q24-TNDM caused by paternal UPD6 and a normal karyotype is unlikely to be higher than the risk to the general population, as paternal UPD6 is a • If the proband has a chromosome abnormality in addition to paternal UPD6, the risk to parents, sibs, and offspring is related to the specific abnormality identified in the proband. ## Paternal Inherited/Derived Duplication of 6q24 (usually submicroscopic tandem duplication) – Risk to Family Members The father of a proband may have the (submicroscopic or visible) 6q24 duplication identified in the proband and may be at risk of developing diabetes mellitus later in life (or having had a history of early diabetes mellitus) Alternatively, the 6q24 duplication may be a Recommendations for the evaluation of the father of a proband with 6q24-TNDM include routine cytogenetic analysis and molecular genetic testing to identify a 6q24 duplication if present, and to exclude a balanced/unbalanced translocation involving the 6q24 critical region. If the father If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of reduced penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but they are at increased risk of developing diabetes mellitus later in life. If the father has a complex chromosomal rearrangement involving 6q24, the risk to sibs is related to the specific rearrangement. • The father of a proband may have the (submicroscopic or visible) 6q24 duplication identified in the proband and may be at risk of developing diabetes mellitus later in life (or having had a history of early diabetes mellitus) • Alternatively, the 6q24 duplication may be a • Recommendations for the evaluation of the father of a proband with 6q24-TNDM include routine cytogenetic analysis and molecular genetic testing to identify a 6q24 duplication if present, and to exclude a balanced/unbalanced translocation involving the 6q24 critical region. • If the father • If the father has the 6q24 duplication, the risk to each sib of inheriting the duplication is 50%. Because of reduced penetrance, sibs who inherit the paternal 6q24 duplication may not develop TNDM, but they are at increased risk of developing diabetes mellitus later in life. • If the father has a complex chromosomal rearrangement involving 6q24, the risk to sibs is related to the specific rearrangement. ## Hypomethylation of the Maternal Risks depend on the underlying cause of the hypomethylation. Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to be at increased risk of having 6q24-TNDM or of developing diabetes mellitus. Because the cause of isolated DMR hypomethylation is not understood and it is possible that it is not The parents of an affected child are likely obligate heterozygotes (i.e., carriers of one Parents heterozygous for At conception, assuming both parents of the proband are heterozygous for a If one parent has biallelic In sibs who have inherited two The risk to sibs, offspring, and parents is unknown as recurrence has not been reported in this subgroup. Note: There is an increased incidence of assisted reproductive technology (ART) used by the parents of these probands; whether a causal relationship exists between ART and hypomethylation is not clear [ • Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to be at increased risk of having 6q24-TNDM or of developing diabetes mellitus. • Because the cause of isolated DMR hypomethylation is not understood and it is possible that it is not • The parents of an affected child are likely obligate heterozygotes (i.e., carriers of one • Parents heterozygous for • At conception, assuming both parents of the proband are heterozygous for a • If one parent has biallelic • In sibs who have inherited two ## Proband with Isolated Hypomethylation at Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to be at increased risk of having 6q24-TNDM or of developing diabetes mellitus. Because the cause of isolated DMR hypomethylation is not understood and it is possible that it is not • Sibs of a proband with 6q24-TNDM caused by isolated DMR hypomethylation are not reported to be at increased risk of having 6q24-TNDM or of developing diabetes mellitus. • Because the cause of isolated DMR hypomethylation is not understood and it is possible that it is not ## Proband with Multilocus Imprinting Disturbance (MLID) as a Result of Biallelic Pathogenic Variants in The parents of an affected child are likely obligate heterozygotes (i.e., carriers of one Parents heterozygous for At conception, assuming both parents of the proband are heterozygous for a If one parent has biallelic In sibs who have inherited two • The parents of an affected child are likely obligate heterozygotes (i.e., carriers of one • Parents heterozygous for • At conception, assuming both parents of the proband are heterozygous for a • If one parent has biallelic • In sibs who have inherited two ## Proband with Multilocus Imprinting Disturbance (MLID) with No Pathogenic Variants Identified in The risk to sibs, offspring, and parents is unknown as recurrence has not been reported in this subgroup. Note: There is an increased incidence of assisted reproductive technology (ART) used by the parents of these probands; whether a causal relationship exists between ART and hypomethylation is not clear [ ## 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 Consideration of prenatal testing for 6q24-TNDM depends on the genetic mechanism in the family: paternal UPD6 is typically a Paternal duplication of 6q24 requires prior identification of the structural chromosome abnormality in the family. Hypomethylation of the maternal • Paternal duplication of 6q24 requires prior identification of the structural chromosome abnormality in the family. • Hypomethylation of the maternal ## Resources United Kingdom Monogenic Diabetes at the University of Chicago United Kingdom • • • • United Kingdom • • • Monogenic Diabetes at the University of Chicago • • • United Kingdom • ## Molecular Genetics Diabetes Mellitus, 6q24-Related Transient Neonatal: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Diabetes Mellitus, 6q24-Related Transient Neonatal ( The molecular pathogenesis of 6q24-TNDM is not yet understood. The minimal disease-associated region has been refined [ All 6q24-TNDM mechanisms described result in overexpression of The mechanism whereby A mouse model for TNDM [ In keeping with this hypothesis, At the molecular level, the picture is complicated by paternally expressed In fibroblasts from an individual with transient neonatal diabetes mellitus, the monoallelic expression of both ## Molecular Pathogenesis The molecular pathogenesis of 6q24-TNDM is not yet understood. The minimal disease-associated region has been refined [ All 6q24-TNDM mechanisms described result in overexpression of The mechanism whereby A mouse model for TNDM [ In keeping with this hypothesis, At the molecular level, the picture is complicated by paternally expressed In fibroblasts from an individual with transient neonatal diabetes mellitus, the monoallelic expression of both ## Chapter Notes IKT and DJGM are supported by Diabetes UK and MRC for work on 6q24 transient neonatal diabetes. Louise E Docherty, BSc (hons), PhD; Salisbury NHS Foundation Trust (2012-2018)Deborah JG Mackay, MA, PhD (2010-present)Isabel K Temple, MD, MBChB, FRCP (2005-present) 13 September 2018 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 27 September 2012 (me) Comprehensive update posted live 23 December 2010 (cd) Revision: sequence analysis of 4 February 2010 (me) Comprehensive update posted live 10 October 2005 (me) Review posted live 10 February 2005 (ikt) Original submission • 13 September 2018 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 27 September 2012 (me) Comprehensive update posted live • 23 December 2010 (cd) Revision: sequence analysis of • 4 February 2010 (me) Comprehensive update posted live • 10 October 2005 (me) Review posted live • 10 February 2005 (ikt) Original submission ## Acknowledgments IKT and DJGM are supported by Diabetes UK and MRC for work on 6q24 transient neonatal diabetes. ## Author History Louise E Docherty, BSc (hons), PhD; Salisbury NHS Foundation Trust (2012-2018)Deborah JG Mackay, MA, PhD (2010-present)Isabel K Temple, MD, MBChB, FRCP (2005-present) ## Revision History 13 September 2018 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 27 September 2012 (me) Comprehensive update posted live 23 December 2010 (cd) Revision: sequence analysis of 4 February 2010 (me) Comprehensive update posted live 10 October 2005 (me) Review posted live 10 February 2005 (ikt) Original submission • 13 September 2018 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 27 September 2012 (me) Comprehensive update posted live • 23 December 2010 (cd) Revision: sequence analysis of • 4 February 2010 (me) Comprehensive update posted live • 10 October 2005 (me) Review posted live • 10 February 2005 (ikt) Original submission ## References ## Literature Cited Three different genetic mechanisms cause 6q24-TNDM: paternal uniparental disomy of chromosome 6 (UPD6) (41%); duplication of 6q24 on the paternal allele (29%); and hypomethylation of the maternally inherited
[ "T Arima, T Kamikihara, T Hayashida, K Kato, T Inoue, Y Shirayoshi, M Oshimura, H Soejima, T Mukai, N Wake. ZAC, LIT1 (KCNQ1OT1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.. Nucleic Acids Res 2005;33:2650-60", "EI Arthur, J Zlotogora, I Lerer, J Dagan, K Marks, D Abeliovich. Transient neonatal diabetes mellitus in a child with invdup (6)(q22–q23) of paternal origin.. Eur J Hum Genet. 1997;5:417-9", "JV Barone, EM Tillman, RJ Ferry. Treatment of transient neonatal diabetes mellitus with subcutaneous insulin glargine in an extremely low birth weight neonate.. J Pediatr Pharmacol Ther 2011;16:291-7", "SE Boonen, DJ Mackay, JM Hahnemann, L Docherty, K Grønskov, A Lehmann, LG Larsen, AP Haemers, Y Kockaerts, L Dooms, DC Vu, CT Ngoc, PB Nguyen, O Kordonouri, F Sundberg, P Dayanikli, V Puthi, C Acerini, AF Massoud, Z Tümer, IK Temple. Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up.. Diabetes Care. 2013;36:505-12", "SE Boonen, S Pörksen, DJ Mackay, E Oestergaard, B Olsen, K Brondum-Nielsen, IK Temple, JM Hahnemann. Clinical characterisation of the multiple maternal hypomethylation syndrome in siblings.. Eur J Hum Genet. 2008;16:453-61", "H Cavé, M Polak, S Drunat, E Denamur, P. Czernichow. Refinement of the 6q chromosomal region implicated in transient neonatal diabetes.. Diabetes. 2000;49:108-13", "C Diatloff-Zito, A Nicole, G Marcelin, H Labit, E Marquis, C Bellanné-Chantelot, JJ Robert. Genetic and epigenetic defects at the 6q24 imprinted locus in a cohort of 13 patients with transient neonatal diabetes: new hypothesis raised by the finding of a unique case with hemizygotic deletion in the critical region.. J Med Genet 2007;44:31-7", "LE Docherty, S Kabwama, A Lehmann, E Hawke, L Harrison, SE Flanagan, S Ellard, AT Hattersley, JPH Shield, S Ennis, DJ Mackay, IK Temple. 6q24 transient neonatal diabetes mellitus (6q24 TNDM) – clinical presentation and genotype phenotype correlation in an international cohort of cases.. Diabetologia 2013;56:758-62", "LE Docherty, RL Poole, CJ Mattocks, A Lehmann, IK Temple, DJ Mackay. Further refinement of the critical minimal genetic region for the imprinting disorder 6q24 transient neonatal diabetes.. Diabetologia 2010;53:2347-51", "SE Flanagan, A Patch, DJG Mackay, EL Edghill, AL Gloyn, D Robinson, JPH Shield, IK Temple, S Ellard, AT Hattersley. Mutations in KATP channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood.. Diabetes. 2007;56:1930-7", "CT Gürson, M Tahsinoglu, S Yakacikli, T Ertugrul. A case of agenesis of the dorsal pancreas with interventricular septal defect in an infant.. Helv Paediatr Acta. 1970;25:522-6", "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", "D Ma, JP Shield, W Dean, I Leclerc, C Knauf, RR Burcelin, GA Rutter, G Kelsey. Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.. J Clin Invest 2004;114:339-48", "DJ Mackay, JL Callaway, SM Marks, HE White, CL Acerini, SE Boonen, P Dayanikli, HV Firth, JA Goodship, AP Haemers, JM Hahnemann, O Kordonouri, AF Masoud, E Oestergaard, J Storr, S Ellard, AT Hattersley, DO Robinson, IK Temple. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57.. Nat Genet 2008;40:949-51", "DJ Mackay, AM Coupe, JP Shield, JN Storr, IK Temple, DO Robinson. Relaxation of imprinted expression of ZAC and HYMAI in a patient with transient neonatal diabetes mellitus.. Hum Genet 2002;110:139-44", "C Metz, H Cavé, AM Bertrand, C Deffert, B Gueguen-Giroux, P Czernichow, M Polak. Neonatal diabetes mellitus: chromosomal analysis in transient and permanent cases.. J Pediatr 2002;141:483-9", "M Polak, H Cavé. Neonatal diabetes mellitus: a disease linked to multiple mechanisms.. Orphanet J Rare Dis 2007;2:12", "M Polak, J Shield. Neonatal and very-early-onset diabetes mellitus.. Semin Neonatol 2004;9:59-65", "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", "JP Shield, IK Temple, M Sabin, D Mackay, DO Robinson, PR Betts, DJ Carson, H Cave, D Chevenne, M Polak. An assessment of pancreatic endocrine function and insulin sensitivity in patients with transient neonatal diabetes in remission.. Arch Dis Child Fetal Neonatal Ed 2004;89:F341-3", "J Stanik, D Gasperikova, M Paskova, L Barak, J Javorkova, E Jancova, M Ciljakova, P Hlava, J Michalek, SE Flanagan, E Pearson, AT Hattersley, S Ellard, I Klimes. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers.. J Clin Endocrinol Metab 2007;92:1276-82", "IK Temple, RJ Gardner, DJ Mackay, JC Barber, DO Robinson, JP Shield. Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes.. Diabetes 2000;49:1359-66", "IK Temple, RJ Gardner, DO Robinson, MS Kibirige, AW Fergusson, JD Baum, JCK Barber, RS James, JPH Shield. Further evidence for an imprinted gene for neonatal diabetes localised to chromosome 6q22–q23.. Hum Mol Genet. 1996;5:1117-21", "G Valerio, A Franzese, M Salerno, G Muzzi, G Cecere, KI Temple, JP Shield. Beta-cell dysfunction in classic transient neonatal diabetes is characterized by impaired insulin response to glucose but normal response to glucagon.. Diabetes Care 2004;27:2405-8", "EM Valleley, SF Cordery, DT Bonthron. Tissue-specific imprinting of the ZAC/PLAGL1 tumour suppressor gene results from variable utilization of monoallelic and biallelic promoters.. Hum Mol Genet 2007;16:972-81", "A Varrault, B Bilanges, DJ Mackay, E Basyuk, B Ahr, C Fernandez, DO Robinson, J Bockaert, L Journot. Characterization of the methylation-sensitive promoter of the imprinted ZAC gene supports its role in transient neonatal diabetes mellitus.. J Biol Chem 2001;276:18653-6", "A Varrault, C Gueydan, A Delalbre, A Bellmann, S Houssami, C Aknin, D Severac, L Chotard, M Kahli, A Le Digarcher, P Pavlidis, L Journot. Zac1 regulates an imprinted gene network critically involved in the control of embryonic growth.. Dev Cell 2006;11:711-22", "B Wiedemann, E Schober, T Waldhoer, J Koehle, S Flanagan, DJG Mackay, E Steichen, D Meraner, L Zimmerhackl, AT Hattersley, S Ellard, S Hofer. Incidence of neonatal diabetes in Austria – calculation based on the Austrian Diabetes Register.. Pediatr Diabetes 2010;11:18-23", "T Yorifuji, M Matsumara, T Okuno, K Shimizu, T Sonomura, J Muroi, C Kuno, Y Takahashi, T Okuno. Hereditary pancreatic hypoplasia, diabetes mellitus, and congenital heart disease: a new syndrome?. J Med Genet 1994;31:331-3" ]
10/10/2005
13/9/2018
23/12/2010
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dnajc6-pd
dnajc6-pd
[ "PARK-DNAJC6", "PARK-DNAJC6", "DNAJC6 Juvenile Parkinson Disease", "DNAJC6 Type of Early-Onset Parkinson Disease", "Auxilin", "DNAJC6", "DNAJC6 Parkinson Disease" ]
Manju A Kurian, Lucia Abela
Summary The majority of individuals have juvenile onset and develop symptoms before age 21 years. Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features occur in the majority of individuals with juvenile onset and often precede parkinsonism. The onset of parkinsonian features usually occurs toward the end of the first or beginning of the second decade and the disease course is rapidly progressive with loss of ambulation in mid-adolescence in the majority of individuals. Additional features include gastrointestinal manifestations and bulbar dysfunction. A minority of individuals with The diagnosis of
For synonyms and outdated names, see For other genetic causes of these phenotypes, see ## Diagnosis Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade Rapid disease progression and neurologic regression after onset of parkinsonism Loss of ambulation often in mid-adolescence Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa) Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders) Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade Slower disease progression than juvenile-onset presentation Some response to dopaminergic medications 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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, one individual has been reported with a • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade • Rapid disease progression and neurologic regression after onset of parkinsonism • Loss of ambulation often in mid-adolescence • Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa) • Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders) • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade • Slower disease progression than juvenile-onset presentation • Some response to dopaminergic medications • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade Rapid disease progression and neurologic regression after onset of parkinsonism Loss of ambulation often in mid-adolescence Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa) Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders) Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade Slower disease progression than juvenile-onset presentation Some response to dopaminergic medications • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade • Rapid disease progression and neurologic regression after onset of parkinsonism • Loss of ambulation often in mid-adolescence • Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa) • Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders) • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade • Slower disease progression than juvenile-onset presentation • Some response to dopaminergic medications ## Juvenile-onset presentation (onset age <21 years) Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade Rapid disease progression and neurologic regression after onset of parkinsonism Loss of ambulation often in mid-adolescence Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa) Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders) • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) usually at the end of the first or beginning of the second decade • Rapid disease progression and neurologic regression after onset of parkinsonism • Loss of ambulation often in mid-adolescence • Parkinsonian symptoms often difficult to treat with common medications used for Parkinson disease (e.g., levodopa) • Additional features that often precede the parkinsonian features: developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features (anxiety, psychosis, behavior disorders, sleep disorders) ## Early-onset presentation (onset age 21- 44 years) Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade Slower disease progression than juvenile-onset presentation Some response to dopaminergic medications • Onset of parkinsonism (bradykinesia, resting tremor, rigidity, postural instability) in the third to fourth decade • Slower disease progression than juvenile-onset presentation • Some response to dopaminergic medications ## 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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, one individual has been reported with a • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics The following description of the phenotypic features associated with this condition is based on reports of the 20 individuals with biallelic – = not reported in this group One person, age seven years, with seizures, developmental delay, obesity, and no signs of a movement disorder, had a homozygous Parkinsonism is the predominant motor phenotype in individuals with The majority of individuals reported to date (14/21) developed symptoms before age 21 years [ Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features are observed in the majority of individuals with juvenile onset and often precede the movement disorder [ Detailed developmental history was available for six individuals with juvenile-onset parkinsonism. They showed delay in motor and language development but ultimately reached independent walking and achieved spoken language between ages three and four years. These individuals had slow developmental progress over time and manifested learning difficulties requiring special educational support. Three individuals suffered cognitive decline; of these, two became nonverbal in the second decade of life in tandem with progression of the movement disorder. The remaining three individuals were reported to have mild-to-moderate intellectual disability (IQ range 40-63). Seizures were classified as generalized (5/7) and/or atypical absences (4/7), when specified [ Additional movement disorders often occurred as the disease progressed, with dystonia being the most frequent feature, followed by spasticity and myoclonus. Dystonia and spasticity also increased the risk of secondary complications such as limb contractures, hip dislocation, and kyphoscoliosis. To date, eye movement abnormalities have only been reported in one individual, who had hypometric saccades [ Neuropsychiatric features included anxiety disorder, behavior disorders (e.g., emotional lability, aggressive behavior, perseveration behavior, attention-deficit disorder), and psychosis. Behavioral features and psychosis emerged after levodopa therapy in two individuals. Disrupted sleep pattern in tandem with neuropsychiatric features was observed in three individuals. Systemic features, in particular gastrointestinal (neonatal/infantile feeding difficulties, recurrent vomiting, sialorrhea) and bulbar dysfunction (dysphagia, dysarthria, drooling), were associated with a more severe disease course [ CSF neurotransmitter analysis showed low CSF homovanillic acid (HVA) in three individuals and borderline CSF HVA in one individual. A reduced CSF HVA:5-HIAA ratio was identified in four individuals with juvenile-onset parkinsonism. Other CSF neurotransmitter metabolites (pterins species, 5-methyltetrahydrofolate) were normal in these four individuals [ Treatment with levodopa showed a moderate-to-good response in six of fourteen individuals – although in two individuals, levodopa had to be discontinued due to intolerable motor and neuropsychiatric side effects. Scoliosis (1 individual) Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded. Six individuals from four families have been reported with symptom onset in the third to fourth decade. The median age of onset was 32 years (range 21-44 years). Additional neurologic features were not observed in this group, although psychosis was described in one individual. In this group, there appears to be slower disease progression [ Fourteen individuals had a normal brain MRI. Mild-to-moderate generalized cerebral atrophy was reported in five individuals with juvenile-onset disease, and two of these five individuals also had cerebellar atrophy [ F-DOPA-PET performed in two individuals with early-onset parkinsonism showed striatonigral abnormalities [ Five individuals with Parkinson disease (representing both simplex and multiplex cases) have been reported with heterozygous Though data are limited, there is some evidence of a genotype-phenotype correlation. Other terms used to refer to PARK- "Autosomal recessive juvenile-onset Parkinson's disease" [ The prevalence of • Scoliosis (1 individual) • Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded. • PARK- • "Autosomal recessive juvenile-onset Parkinson's disease" [ ## Clinical Description The following description of the phenotypic features associated with this condition is based on reports of the 20 individuals with biallelic – = not reported in this group One person, age seven years, with seizures, developmental delay, obesity, and no signs of a movement disorder, had a homozygous Parkinsonism is the predominant motor phenotype in individuals with The majority of individuals reported to date (14/21) developed symptoms before age 21 years [ Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features are observed in the majority of individuals with juvenile onset and often precede the movement disorder [ Detailed developmental history was available for six individuals with juvenile-onset parkinsonism. They showed delay in motor and language development but ultimately reached independent walking and achieved spoken language between ages three and four years. These individuals had slow developmental progress over time and manifested learning difficulties requiring special educational support. Three individuals suffered cognitive decline; of these, two became nonverbal in the second decade of life in tandem with progression of the movement disorder. The remaining three individuals were reported to have mild-to-moderate intellectual disability (IQ range 40-63). Seizures were classified as generalized (5/7) and/or atypical absences (4/7), when specified [ Additional movement disorders often occurred as the disease progressed, with dystonia being the most frequent feature, followed by spasticity and myoclonus. Dystonia and spasticity also increased the risk of secondary complications such as limb contractures, hip dislocation, and kyphoscoliosis. To date, eye movement abnormalities have only been reported in one individual, who had hypometric saccades [ Neuropsychiatric features included anxiety disorder, behavior disorders (e.g., emotional lability, aggressive behavior, perseveration behavior, attention-deficit disorder), and psychosis. Behavioral features and psychosis emerged after levodopa therapy in two individuals. Disrupted sleep pattern in tandem with neuropsychiatric features was observed in three individuals. Systemic features, in particular gastrointestinal (neonatal/infantile feeding difficulties, recurrent vomiting, sialorrhea) and bulbar dysfunction (dysphagia, dysarthria, drooling), were associated with a more severe disease course [ CSF neurotransmitter analysis showed low CSF homovanillic acid (HVA) in three individuals and borderline CSF HVA in one individual. A reduced CSF HVA:5-HIAA ratio was identified in four individuals with juvenile-onset parkinsonism. Other CSF neurotransmitter metabolites (pterins species, 5-methyltetrahydrofolate) were normal in these four individuals [ Treatment with levodopa showed a moderate-to-good response in six of fourteen individuals – although in two individuals, levodopa had to be discontinued due to intolerable motor and neuropsychiatric side effects. Scoliosis (1 individual) Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded. Six individuals from four families have been reported with symptom onset in the third to fourth decade. The median age of onset was 32 years (range 21-44 years). Additional neurologic features were not observed in this group, although psychosis was described in one individual. In this group, there appears to be slower disease progression [ Fourteen individuals had a normal brain MRI. Mild-to-moderate generalized cerebral atrophy was reported in five individuals with juvenile-onset disease, and two of these five individuals also had cerebellar atrophy [ F-DOPA-PET performed in two individuals with early-onset parkinsonism showed striatonigral abnormalities [ Five individuals with Parkinson disease (representing both simplex and multiplex cases) have been reported with heterozygous • Scoliosis (1 individual) • Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded. ## Juvenile-Onset Parkinsonism The majority of individuals reported to date (14/21) developed symptoms before age 21 years [ Developmental delay, intellectual disability, seizures, other movement disorders (e.g., dystonia, spasticity, myoclonus), and neuropsychiatric features are observed in the majority of individuals with juvenile onset and often precede the movement disorder [ Detailed developmental history was available for six individuals with juvenile-onset parkinsonism. They showed delay in motor and language development but ultimately reached independent walking and achieved spoken language between ages three and four years. These individuals had slow developmental progress over time and manifested learning difficulties requiring special educational support. Three individuals suffered cognitive decline; of these, two became nonverbal in the second decade of life in tandem with progression of the movement disorder. The remaining three individuals were reported to have mild-to-moderate intellectual disability (IQ range 40-63). Seizures were classified as generalized (5/7) and/or atypical absences (4/7), when specified [ Additional movement disorders often occurred as the disease progressed, with dystonia being the most frequent feature, followed by spasticity and myoclonus. Dystonia and spasticity also increased the risk of secondary complications such as limb contractures, hip dislocation, and kyphoscoliosis. To date, eye movement abnormalities have only been reported in one individual, who had hypometric saccades [ Neuropsychiatric features included anxiety disorder, behavior disorders (e.g., emotional lability, aggressive behavior, perseveration behavior, attention-deficit disorder), and psychosis. Behavioral features and psychosis emerged after levodopa therapy in two individuals. Disrupted sleep pattern in tandem with neuropsychiatric features was observed in three individuals. Systemic features, in particular gastrointestinal (neonatal/infantile feeding difficulties, recurrent vomiting, sialorrhea) and bulbar dysfunction (dysphagia, dysarthria, drooling), were associated with a more severe disease course [ CSF neurotransmitter analysis showed low CSF homovanillic acid (HVA) in three individuals and borderline CSF HVA in one individual. A reduced CSF HVA:5-HIAA ratio was identified in four individuals with juvenile-onset parkinsonism. Other CSF neurotransmitter metabolites (pterins species, 5-methyltetrahydrofolate) were normal in these four individuals [ Treatment with levodopa showed a moderate-to-good response in six of fourteen individuals – although in two individuals, levodopa had to be discontinued due to intolerable motor and neuropsychiatric side effects. Scoliosis (1 individual) Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded. • Scoliosis (1 individual) • Primary non-progressive microcephaly (3 sibs from a consanguineous family); the possibility of a second condition causing microcephaly cannot be fully excluded. ## Early-Onset Parkinsonism Six individuals from four families have been reported with symptom onset in the third to fourth decade. The median age of onset was 32 years (range 21-44 years). Additional neurologic features were not observed in this group, although psychosis was described in one individual. In this group, there appears to be slower disease progression [ ## Neuroradiographic Features Fourteen individuals had a normal brain MRI. Mild-to-moderate generalized cerebral atrophy was reported in five individuals with juvenile-onset disease, and two of these five individuals also had cerebellar atrophy [ F-DOPA-PET performed in two individuals with early-onset parkinsonism showed striatonigral abnormalities [ ## Heterozygotes Five individuals with Parkinson disease (representing both simplex and multiplex cases) have been reported with heterozygous ## Genotype-Phenotype Correlations Though data are limited, there is some evidence of a genotype-phenotype correlation. ## Nomenclature Other terms used to refer to PARK- "Autosomal recessive juvenile-onset Parkinson's disease" [ • PARK- • "Autosomal recessive juvenile-onset Parkinson's disease" [ ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes Associated with Early-Onset Autosomal Recessive Parkinson Disease and Parkinsonism in the Differential Diagnosis of DD = developmental delay; EOPD = early-onset Parkinson disease; ID = intellectual disability; PD = Parkinson disease Nomenclature based on Data from Based on persons with clinical information reported in the literature PARK- Other features of this disorder typically manifest before the onset of parkinsonism. For individuals with juvenile-onset parkinsonism, especially those with prominent dystonia, dystonia-parkinsonism phenotypes should be considered (see Genes Associated with Dystonia-Parkinsonism in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; BIA = brain iron accumulation; DD = developmental delay; DYT = dystonia; HSP = hereditary spastic paraplegia; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; PARK = parkinsonism; XL = X-linked Movement disorder nomenclature is based on OMIM OMIM OMIM OMIM Mitochondrial dysfunction can be associated with infantile-onset parkinsonism, pyramidal signs, and axonal neuropathy and should be considered in the differential diagnosis of any progressive multisystem disorder. Many nuclear and mitochondrial genes are known to be associated with respiratory chain defects; see Most affected individuals have some, but not all, of the features of a given phenotype. Associated phenotypes are: Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum, myoclonic epilepsy myopathy sensory ataxia, ataxia neuropathy spectrum, autosomal recessive progressive external ophthalmoplegia, and autosomal dominant progressive external ophthalmoplegia. See also ## Early-Onset Parkinson Disease Genes Associated with Early-Onset Autosomal Recessive Parkinson Disease and Parkinsonism in the Differential Diagnosis of DD = developmental delay; EOPD = early-onset Parkinson disease; ID = intellectual disability; PD = Parkinson disease Nomenclature based on Data from Based on persons with clinical information reported in the literature PARK- Other features of this disorder typically manifest before the onset of parkinsonism. ## Juvenile-Onset Parkinsonism with Prominent Dystonia For individuals with juvenile-onset parkinsonism, especially those with prominent dystonia, dystonia-parkinsonism phenotypes should be considered (see Genes Associated with Dystonia-Parkinsonism in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; BIA = brain iron accumulation; DD = developmental delay; DYT = dystonia; HSP = hereditary spastic paraplegia; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; PARK = parkinsonism; XL = X-linked Movement disorder nomenclature is based on OMIM OMIM OMIM OMIM Mitochondrial dysfunction can be associated with infantile-onset parkinsonism, pyramidal signs, and axonal neuropathy and should be considered in the differential diagnosis of any progressive multisystem disorder. Many nuclear and mitochondrial genes are known to be associated with respiratory chain defects; see Most affected individuals have some, but not all, of the features of a given phenotype. Associated phenotypes are: Alpers-Huttenlocher syndrome, childhood myocerebrohepatopathy spectrum, myoclonic epilepsy myopathy sensory ataxia, ataxia neuropathy spectrum, autosomal recessive progressive external ophthalmoplegia, and autosomal dominant progressive external ophthalmoplegia. See also ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Detailed developmental assessment in those w/juvenile onset Formal IQ testing w/psychologist Nutritional eval by dietician to monitor & ensure adequate caloric intake Speech-language therapist to assess safety of feeding Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Levodopa, started at low dosage, & cautiously titrated & adjusted, esp in those w/juvenile onset If levodopa is not effective, other agents incl dopaminergic agonists or anticholinergics may be used. Oral medications: dopamine-related medications (levodopa, dopaminergic agonists), anticholinergics, benzodiazepines, gabapentin, baclofen, clonidine Surgical interventions: Deep brain stimulation, pallidotomy Oral medications: baclofen, benzodiazepines, dantrolene, local botulinum toxin PT & OT Surgical interventions: tenotomy Multidisciplinary mgmt per PT, OT, speech & language therapy Special education services as indicated Supportive feeding measures (e.g., gastrostomy) if needed for ↓ oral intake or aspiration risk Treatment of constipation (laxatives, diet) Sialorrhea therapy w/hyoscine patches, glycopyrronium bromide, or (if severe) botulinum toxin or surgical approaches Treatment of reflux w/proton pump inhibitors Supportive rehab devices & equipment Surgical interventions may be needed for hip dislocation or kyphoscoliosis. Low vision therapy Glasses Surgical intervention for strabismus if needed DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; OT = occupational therapist/therapy; PT = physical therapist/therapy Recommended Surveillance for Individuals with Who are nonambulatory at age >2 yrs W/signs/symptoms concerning for spinal deformity OT = occupational therapy; PT = physical therapy Though there are no data available to date, dopamine antagonists and vesicular monoamine transporter 2 (VMAT2) inhibitors should be avoided as they could aggravate dopamine deficiency. VMAT2 inhibitors prevent reuptake and storage of neurotransmitters into synaptic vesicles and thus could theoretically cause further depletion of presynaptic dopamine. See Search • Detailed developmental assessment in those w/juvenile onset • Formal IQ testing w/psychologist • Nutritional eval by dietician to monitor & ensure adequate caloric intake • Speech-language therapist to assess safety of feeding • Community or • Social work involvement for parental support; • Home nursing referral. • Levodopa, started at low dosage, & cautiously titrated & adjusted, esp in those w/juvenile onset • If levodopa is not effective, other agents incl dopaminergic agonists or anticholinergics may be used. • Oral medications: dopamine-related medications (levodopa, dopaminergic agonists), anticholinergics, benzodiazepines, gabapentin, baclofen, clonidine • Surgical interventions: Deep brain stimulation, pallidotomy • Oral medications: baclofen, benzodiazepines, dantrolene, local botulinum toxin • PT & OT • Surgical interventions: tenotomy • Multidisciplinary mgmt per PT, OT, speech & language therapy • Special education services as indicated • Supportive feeding measures (e.g., gastrostomy) if needed for ↓ oral intake or aspiration risk • Treatment of constipation (laxatives, diet) • Sialorrhea therapy w/hyoscine patches, glycopyrronium bromide, or (if severe) botulinum toxin or surgical approaches • Treatment of reflux w/proton pump inhibitors • Supportive rehab devices & equipment • Surgical interventions may be needed for hip dislocation or kyphoscoliosis. • Low vision therapy • Glasses • Surgical intervention for strabismus if needed • Who are nonambulatory at age >2 yrs • W/signs/symptoms concerning for spinal deformity ## 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 Detailed developmental assessment in those w/juvenile onset Formal IQ testing w/psychologist Nutritional eval by dietician to monitor & ensure adequate caloric intake Speech-language therapist to assess safety of feeding Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Detailed developmental assessment in those w/juvenile onset • Formal IQ testing w/psychologist • Nutritional eval by dietician to monitor & ensure adequate caloric intake • Speech-language therapist to assess safety of feeding • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Levodopa, started at low dosage, & cautiously titrated & adjusted, esp in those w/juvenile onset If levodopa is not effective, other agents incl dopaminergic agonists or anticholinergics may be used. Oral medications: dopamine-related medications (levodopa, dopaminergic agonists), anticholinergics, benzodiazepines, gabapentin, baclofen, clonidine Surgical interventions: Deep brain stimulation, pallidotomy Oral medications: baclofen, benzodiazepines, dantrolene, local botulinum toxin PT & OT Surgical interventions: tenotomy Multidisciplinary mgmt per PT, OT, speech & language therapy Special education services as indicated Supportive feeding measures (e.g., gastrostomy) if needed for ↓ oral intake or aspiration risk Treatment of constipation (laxatives, diet) Sialorrhea therapy w/hyoscine patches, glycopyrronium bromide, or (if severe) botulinum toxin or surgical approaches Treatment of reflux w/proton pump inhibitors Supportive rehab devices & equipment Surgical interventions may be needed for hip dislocation or kyphoscoliosis. Low vision therapy Glasses Surgical intervention for strabismus if needed DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; OT = occupational therapist/therapy; PT = physical therapist/therapy • Levodopa, started at low dosage, & cautiously titrated & adjusted, esp in those w/juvenile onset • If levodopa is not effective, other agents incl dopaminergic agonists or anticholinergics may be used. • Oral medications: dopamine-related medications (levodopa, dopaminergic agonists), anticholinergics, benzodiazepines, gabapentin, baclofen, clonidine • Surgical interventions: Deep brain stimulation, pallidotomy • Oral medications: baclofen, benzodiazepines, dantrolene, local botulinum toxin • PT & OT • Surgical interventions: tenotomy • Multidisciplinary mgmt per PT, OT, speech & language therapy • Special education services as indicated • Supportive feeding measures (e.g., gastrostomy) if needed for ↓ oral intake or aspiration risk • Treatment of constipation (laxatives, diet) • Sialorrhea therapy w/hyoscine patches, glycopyrronium bromide, or (if severe) botulinum toxin or surgical approaches • Treatment of reflux w/proton pump inhibitors • Supportive rehab devices & equipment • Surgical interventions may be needed for hip dislocation or kyphoscoliosis. • Low vision therapy • Glasses • Surgical intervention for strabismus if needed ## Surveillance Recommended Surveillance for Individuals with Who are nonambulatory at age >2 yrs W/signs/symptoms concerning for spinal deformity OT = occupational therapy; PT = physical therapy • Who are nonambulatory at age >2 yrs • W/signs/symptoms concerning for spinal deformity ## Agents/Circumstances to Avoid Though there are no data available to date, dopamine antagonists and vesicular monoamine transporter 2 (VMAT2) inhibitors should be avoided as they could aggravate dopamine deficiency. VMAT2 inhibitors prevent reuptake and storage of neurotransmitters into synaptic vesicles and thus could theoretically cause further depletion of presynaptic dopamine. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Note: The identification of heterozygous 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. The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, If both parents are known to be heterozygous for a In sibs who inherit biallelic Onset between ages seven and 14 years in juvenile-onset disease [ Onset between ages 21 and 44 years in early-onset disease [ The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, Heterozygote testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or are at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider 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. • The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, • 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 • In sibs who inherit biallelic • Onset between ages seven and 14 years in juvenile-onset disease [ • Onset between ages 21 and 44 years in early-onset disease [ • Onset between ages seven and 14 years in juvenile-onset disease [ • Onset between ages 21 and 44 years in early-onset disease [ • The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, • Onset between ages seven and 14 years in juvenile-onset disease [ • Onset between ages 21 and 44 years in early-onset disease [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance Note: The identification of heterozygous ## Risk to Family Members (Autosomal Recessive Inheritance) 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. The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, If both parents are known to be heterozygous for a In sibs who inherit biallelic Onset between ages seven and 14 years in juvenile-onset disease [ Onset between ages 21 and 44 years in early-onset disease [ The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, • 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. • The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, • 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 • In sibs who inherit biallelic • Onset between ages seven and 14 years in juvenile-onset disease [ • Onset between ages 21 and 44 years in early-onset disease [ • Onset between ages seven and 14 years in juvenile-onset disease [ • Onset between ages 21 and 44 years in early-onset disease [ • The risk to heterozygotes of developing manifestations is not yet determined (see Clinical Characteristics, • Onset between ages seven and 14 years in juvenile-onset disease [ • Onset between ages 21 and 44 years in early-onset disease [ ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • • • • • United Kingdom • • • ## Molecular Genetics DNAJC6 Parkinson Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DNAJC6 Parkinson Disease ( Auxilin deficiency has been investigated in several animal models. The auxilin knockout mouse model demonstrated increased early postnatal mortality and a significantly reduced body weight in one-week old mice [ Altogether, these findings suggest that auxilin deficiency leads to impaired synaptic vesicle endocytosis, which in turn negatively impacts synaptic neurotransmission, synaptic homeostasis, and signaling. However, the exact pathogenic mechanisms by which auxilin deficiency leads to dopaminergic neurodegeneration and a complex neurologic phenotype still remain to be fully elucidated. Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. Predicted to introduce an aberrant spice acceptor site ## Molecular Pathogenesis Auxilin deficiency has been investigated in several animal models. The auxilin knockout mouse model demonstrated increased early postnatal mortality and a significantly reduced body weight in one-week old mice [ Altogether, these findings suggest that auxilin deficiency leads to impaired synaptic vesicle endocytosis, which in turn negatively impacts synaptic neurotransmission, synaptic homeostasis, and signaling. However, the exact pathogenic mechanisms by which auxilin deficiency leads to dopaminergic neurodegeneration and a complex neurologic phenotype still remain to be fully elucidated. Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions. Predicted to introduce an aberrant spice acceptor site ## Chapter Notes Dr Lucia AbelaDevelopmental NeurosciencesZayed Centre for Research into Rare Diseases in ChildrenUCL Great Ormond Street-Institute of Child Health, London Dr Abela is a senior resident in pediatric neurology and currently a research fellow in Dr Kurian’s research group with a special interest in childhood movement disorders. Professor Manju Ann KurianDevelopmental NeurosciencesZayed Centre for Research into Rare Diseases in ChildrenUCL Great Ormond Street-Institute of Child Health, London Prof Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders. 13 May 2021 (sw) Review posted live 10 September 2020 (mak) Original submission • 13 May 2021 (sw) Review posted live • 10 September 2020 (mak) Original submission ## Author Notes Dr Lucia AbelaDevelopmental NeurosciencesZayed Centre for Research into Rare Diseases in ChildrenUCL Great Ormond Street-Institute of Child Health, London Dr Abela is a senior resident in pediatric neurology and currently a research fellow in Dr Kurian’s research group with a special interest in childhood movement disorders. Professor Manju Ann KurianDevelopmental NeurosciencesZayed Centre for Research into Rare Diseases in ChildrenUCL Great Ormond Street-Institute of Child Health, London Prof Kurian is a pediatric neurologist and clinician-scientist with a clinical and research interest in childhood movement disorders. ## Revision History 13 May 2021 (sw) Review posted live 10 September 2020 (mak) Original submission • 13 May 2021 (sw) Review posted live • 10 September 2020 (mak) Original submission ## References ## Literature Cited
[]
13/5/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dnmt1-ddsn
dnmt1-ddsn
[ "Hereditary Sensory and Autonomic Neuropathy Type 1E (HSAN1E)", "Autosomal Dominant Cerebellar Ataxia, Deafness, and Narcolepsy (ADCA-DN)", "DNA (cytosine-5)-methyltransferase 1", "DNMT1", "DNMT1-Related Disorder" ]
Christopher J Klein
Summary The diagnosis of Each child of an individual with
Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) For synonyms and outdated names see For other genetic causes of these phenotypes see • Hereditary sensory and autonomic neuropathy type 1E (HSAN1E) • Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) ## Diagnosis The phenotype of Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing, and thermoregulatory sweat testing can help to identify postganglionic sudomotor abnormalities that spare cardiovagal and adrenergic autonomic functions. Special quantitative sensory testing and histopathologic preparations can assist in studying the sensory fibers implicated in autonomic involvement. The pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers. Length-dependent sensory axonal loss including both small fiber loss (drC and Aσ) and large fiber proprioceptive Aβ loss; Absent or reduced sensory nerve action potentials with normal motor nerve conduction velocities. 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 sensory neuropathy, and/or hearing loss, If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – 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 such variants have not been identified as a cause 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. • Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing, and thermoregulatory sweat testing can help to identify postganglionic sudomotor abnormalities that spare cardiovagal and adrenergic autonomic functions. • Special quantitative sensory testing and histopathologic preparations can assist in studying the sensory fibers implicated in autonomic involvement. The pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers. • Length-dependent sensory axonal loss including both small fiber loss (drC and Aσ) and large fiber proprioceptive Aβ loss; • Absent or reduced sensory nerve action potentials with normal motor nerve conduction velocities. • For an introduction to multigene panels click ## Suggestive Findings Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing, and thermoregulatory sweat testing can help to identify postganglionic sudomotor abnormalities that spare cardiovagal and adrenergic autonomic functions. Special quantitative sensory testing and histopathologic preparations can assist in studying the sensory fibers implicated in autonomic involvement. The pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers. Length-dependent sensory axonal loss including both small fiber loss (drC and Aσ) and large fiber proprioceptive Aβ loss; Absent or reduced sensory nerve action potentials with normal motor nerve conduction velocities. • Laboratory-based tests such as tilt table testing for postural hypotension, quantitative sudomotor axon reflex testing, and thermoregulatory sweat testing can help to identify postganglionic sudomotor abnormalities that spare cardiovagal and adrenergic autonomic functions. • Special quantitative sensory testing and histopathologic preparations can assist in studying the sensory fibers implicated in autonomic involvement. The pan sensory neuropathy affects large proprioceptive and vibratory sensing fibers as well as small heat-, pain-, and temperature-sensing fibers. • Length-dependent sensory axonal loss including both small fiber loss (drC and Aσ) and large fiber proprioceptive Aβ loss; • Absent or reduced sensory nerve action potentials with normal motor nerve conduction velocities. ## 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 sensory neuropathy, and/or hearing loss, If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – 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 such variants have not been identified as a cause 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click ## Option 1 When the phenotypic and 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 sensory neuropathy, and/or hearing loss, If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance – 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 such variants have not been identified as a cause 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics In a cohort of 45 affected individuals, the average age of onset was estimated to be 37.7 years; the most common initial manifestation was hearing loss (36%), followed by sensory loss, ulcerations and/or arthropathy (33%), cognitive decline (7%), and gait imbalance (7%). It is likely that the range of phenotypes will expand as more affected individuals are identified [ All pathogenic variants that cause Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain [ Variants that cause autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus of the TS domain [ The penetrance of This Hereditary sensory and autonomic neuropathy type IE (HSAN1E) is considered a sensory-predominant neuropathy. To date, a total of 21 families with • Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain [ • Variants that cause autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus of the TS domain [ ## Clinical Description In a cohort of 45 affected individuals, the average age of onset was estimated to be 37.7 years; the most common initial manifestation was hearing loss (36%), followed by sensory loss, ulcerations and/or arthropathy (33%), cognitive decline (7%), and gait imbalance (7%). It is likely that the range of phenotypes will expand as more affected individuals are identified [ ## Genotype-Phenotype Correlations All pathogenic variants that cause Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain [ Variants that cause autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus of the TS domain [ • Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain [ • Variants that cause autosomal dominant cerebellar ataxia, deafness and narcolepsy are located in the C-terminus of the TS domain [ ## Penetrance The penetrance of ## Nomenclature This Hereditary sensory and autonomic neuropathy type IE (HSAN1E) is considered a sensory-predominant neuropathy. ## Prevalence To date, a total of 21 families with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Autosomal dominant hereditary sensory and autonomic neuropathies are genetically heterogeneous, but hereditary sensory and autonomic neuropathy type IE (HSAN1E) that includes dementia and hearing loss represents a unique phenotype. The combination of neuropathy with hearing loss can be confused with some forms of See ## Management To establish the extent of disease and needs of an individual diagnosed with Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulceration Past medical history to determine extent of autonomic involvement Evaluation of central nervous system involvement, using tests of cognitive function and brain imaging Audiologic examination to determine if hearing loss is present and, if present, its type and severity Consultation with a clinical geneticist and/or genetic counselor No cure for The emphasis of management is to help parents and affected individuals understand the sudomotor defect and injury prevention when sensory impairment is significant. To prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water. Because hearing loss may be severe, initial use of hearing aids and/or assistive communication methods may be needed. See also Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations associated with dementia. Because behavioral changes and the loss of insight and judgment in individuals often present a considerable burden for partners or other caregivers, information about the disease and psychological support for partners or other caregivers are essential. Observation of behavior Use of tools such as the Mini Mental State Exam (MMSE) Avoid sharp objects and hot water, which may damage skin. See Search • Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulceration • Past medical history to determine extent of autonomic involvement • Evaluation of central nervous system involvement, using tests of cognitive function and brain imaging • Audiologic examination to determine if hearing loss is present and, if present, its type and severity • Consultation with a clinical geneticist and/or genetic counselor • Observation of behavior • Use of tools such as the Mini Mental State Exam (MMSE) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulceration Past medical history to determine extent of autonomic involvement Evaluation of central nervous system involvement, using tests of cognitive function and brain imaging Audiologic examination to determine if hearing loss is present and, if present, its type and severity Consultation with a clinical geneticist and/or genetic counselor • Neurologic examination to determine the extent of sensory involvement, including sensory testing and observation for skin ulceration • Past medical history to determine extent of autonomic involvement • Evaluation of central nervous system involvement, using tests of cognitive function and brain imaging • Audiologic examination to determine if hearing loss is present and, if present, its type and severity • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations No cure for The emphasis of management is to help parents and affected individuals understand the sudomotor defect and injury prevention when sensory impairment is significant. To prevent injury to extremities with decreased sensation, protect the skin with appropriate socks and shoes and avoid exposure of feet to hot water. Because hearing loss may be severe, initial use of hearing aids and/or assistive communication methods may be needed. See also Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations associated with dementia. Because behavioral changes and the loss of insight and judgment in individuals often present a considerable burden for partners or other caregivers, information about the disease and psychological support for partners or other caregivers are essential. ## Surveillance Observation of behavior Use of tools such as the Mini Mental State Exam (MMSE) • Observation of behavior • Use of tools such as the Mini Mental State Exam (MMSE) ## Agents/Circumstances to Avoid Avoid sharp objects and hot water, which may damage skin. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most individuals diagnosed with A proband with Clinical evaluation and 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 If a parent of the proband is affected and/or is known to have the If the Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, 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 • Clinical evaluation and 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 • If a parent of the proband is affected and/or is known to have the • If the • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Most individuals diagnosed with A proband with Clinical evaluation and 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 If a parent of the proband is affected and/or is known to have the If the • Most individuals diagnosed with • A proband with • Clinical evaluation and 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 • If a parent of the proband is affected and/or is known to have the • If the ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, 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 • • ## Molecular Genetics DNMT1-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DNMT1-Related Disorder ( DNMT1 is the sole maintenance methyltransferase and an essential component of cellular epigenetic regulation that keeps the fidelity of methylation inheritance starting from embryogenesis and throughout life. The proper allosteric folding of N-terminal regulatory region is required for enzymatic function. The targeting sequence (TS) domain, where all the pathogenic variants reside to date, is in the N-terminal regulatory region and regulates DNMT1 binding to hemimethylated DNA during S and binding to heterochromatin during G2 phases. Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain. Variants that cause autosomal dominant cerebellar ataxia, deafness, and narcolepsy are located in the C-terminus of the TS domain. • Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain. • Variants that cause autosomal dominant cerebellar ataxia, deafness, and narcolepsy are located in the C-terminus of the TS domain. ## Molecular Pathogenesis DNMT1 is the sole maintenance methyltransferase and an essential component of cellular epigenetic regulation that keeps the fidelity of methylation inheritance starting from embryogenesis and throughout life. The proper allosteric folding of N-terminal regulatory region is required for enzymatic function. The targeting sequence (TS) domain, where all the pathogenic variants reside to date, is in the N-terminal regulatory region and regulates DNMT1 binding to hemimethylated DNA during S and binding to heterochromatin during G2 phases. Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain. Variants that cause autosomal dominant cerebellar ataxia, deafness, and narcolepsy are located in the C-terminus of the TS domain. • Variants resulting in the HSAN1E phenotype (a predominantly sensory neuropathy) are in the N-terminus or middle part of the TS domain. • Variants that cause autosomal dominant cerebellar ataxia, deafness, and narcolepsy are located in the C-terminus of the TS domain. ## Chapter Notes 31 January 2019 (bp) Comprehensive update posted live 17 May 2012 (cd) Revision: sequence analysis of 8 March 2012 (cd) Revision: four families with mutations in 16 February 2012 (me) Review posted live 24 October 2011 (cjk) Original submission • 31 January 2019 (bp) Comprehensive update posted live • 17 May 2012 (cd) Revision: sequence analysis of • 8 March 2012 (cd) Revision: four families with mutations in • 16 February 2012 (me) Review posted live • 24 October 2011 (cjk) Original submission ## Revision History 31 January 2019 (bp) Comprehensive update posted live 17 May 2012 (cd) Revision: sequence analysis of 8 March 2012 (cd) Revision: four families with mutations in 16 February 2012 (me) Review posted live 24 October 2011 (cjk) Original submission • 31 January 2019 (bp) Comprehensive update posted live • 17 May 2012 (cd) Revision: sequence analysis of • 8 March 2012 (cd) Revision: four families with mutations in • 16 February 2012 (me) Review posted live • 24 October 2011 (cjk) Original submission ## References ## Literature Cited
[ "J Baets, X Duan, Y Wu, G Smith, WW Seeley, I Mademan, NM McGrath, NC Beadell, J Khoury, MV Botuyan, G Mer, GA Worrell, K Hojo, J DeLeon, M Laura, YT Liu, J Senderek, J Weis, P Van den Bergh, SL Merrill, MM Reilly, H Houlden, M Grossman, SS Scherer, P De Jonghe, PJ Dyck, CJ Klein. Defects of mutant DNMT1 are linked to a spectrum of neurological disorders.. Brain. 2015;138:845-61", "K Hojo, T Imamura, M Takanashi, K Ishii, M Sasaki, S Imura, R Ozono, Y Takatsuki, S Takauchi, E Mori. Hereditary sensory neuropathy with deafness and dementia: a clinical and neuroimaging study.. Eur J Neurol. 1999;6:357-61", "CJ Klein, MV Botuyan, Y Wu, CJ Ward, GA Nicholson, S Hammans, K Hojo, H Yamanishi, AR Karpf, DC Wallace, M Simon, C Lander, LA Boardman, JM Cunningham, GE Smith, WJ Litchy, B Boes, EJ Atkinson, S Middha, PJB Dyck, JE Parisi, G Mer, DI Smith, PJ Dyck. Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss.. Nat Genet. 2011;43:595-600", "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", "Z Sun, Y Wu, T Ordog, S Baheti, J Nie, X Duan, K Hojo, JP Kocher, PJ Dyck, CJ Klein. Aberrant signature methylome by DNMT1 hot spot mutation in hereditary sensory and autonomic neuropathy 1E.. Epigenetics. 2014;9:1184-93", "J Winkelmann, L Lin, B Schormair, BR Kornum, J Faraco, G Plazzi, A Melberg, F Cornelio, AE Urban, F Pizza, F Poli, F Grubert, T Wieland, E Graf, J Hallmayer, TM Strom, E Mignot. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy.. Hum Mol Genet. 2012;21:2205-10", "A Wright, PJ Dyck. Hereditary sensory neuropathy with sensorineural deafness and early-onset dementia.. Neurology. 1995;45:560-2" ]
16/2/2012
31/1/2019
17/5/2012
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
donnai
donnai
[ "DBS/FOAR Syndrome", "Faciooculoacousticorenal Syndrome", "FOAR Syndrome", "FOAR Syndrome", "DBS/FOAR Syndrome", "Low-density lipoprotein receptor-related protein 2", "LRP2", "Donnai-Barrow Syndrome" ]
Donnai-Barrow Syndrome
Mauro Longoni, Sibel Kantarci, Dian Donnai, Barbara R Pober
Summary Donnai-Barrow syndrome (DBS) is characterized by typical craniofacial features (large anterior fontanelle, wide metopic suture, widow's peak, markedly widely spaced eyes, enlarged globes, downslanted palpebral fissures, posteriorly rotated ears, depressed nasal bridge, and short nose. Ocular complications include high myopia, retinal detachment, retinal dystrophy, and progressive vision loss. Additional common features include agenesis of the corpus callosum, sensorineural hearing loss, intellectual disability, and congenital diaphragmatic hernia and/or omphalocele. Both inter- and intrafamilial phenotypic variability are observed. The diagnosis of DBS is established in a proband with: the characteristic clinical features and a distinctive pattern of low-molecular-weight proteinuria; and/or biallelic pathogenic variants in DBS is inherited in an autosomal recessive manner. In general, the parents of an affected child are obligate heterozygotes with each carrying one pathogenic variant; one instance of uniparental disomy has been reported. When both parents are known to be carriers of a pathogenic variant, 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. If the pathogenic variants in the family are known, carrier testing for at-risk relatives and prenatal testing of a pregnancy at increased risk are possible.
## Diagnosis Donnai-Barrow syndrome (DBS) Large anterior fontanelle in infants and young children Wide metopic suture in infants and young children Widow's peak Widely spaced eyes, typically marked Enlarged globes leading to the appearance of prominent eyes Downslanted palpebral fissures Posteriorly rotated ears Depressed nasal bridge Short nose with broad or bifid tip The diagnosis of Donnai-Barrow syndrome (DBS) 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 [ Absent or abnormally functioning megalin, the protein encoded by Retinol-binding protein (RBP) Vitamin D-binding protein (VDBP) * Note: The use of a "dipstick" is not an adequate substitute to protein electrophoresis to identify megalin ligands in the urine of individuals with DBS. Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of DBS, molecular genetic testing approaches can include Note: As For an introduction to multigene panels click When the diagnosis of DBS is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Donnai-Barrow 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 One affected individual was homozygous for an Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Large anterior fontanelle in infants and young children • Wide metopic suture in infants and young children • Widow's peak • Widely spaced eyes, typically marked • Enlarged globes leading to the appearance of prominent eyes • Downslanted palpebral fissures • Posteriorly rotated ears • Depressed nasal bridge • Short nose with broad or bifid tip • Large anterior fontanelle in infants and young children • Wide metopic suture in infants and young children • Widow's peak • Widely spaced eyes, typically marked • Enlarged globes leading to the appearance of prominent eyes • Downslanted palpebral fissures • Posteriorly rotated ears • Depressed nasal bridge • Short nose with broad or bifid tip • Large anterior fontanelle in infants and young children • Wide metopic suture in infants and young children • Widow's peak • Widely spaced eyes, typically marked • Enlarged globes leading to the appearance of prominent eyes • Downslanted palpebral fissures • Posteriorly rotated ears • Depressed nasal bridge • Short nose with broad or bifid tip • Retinol-binding protein (RBP) • Vitamin D-binding protein (VDBP) • Note: As • For an introduction to multigene panels click ## Suggestive Findings Donnai-Barrow syndrome (DBS) Large anterior fontanelle in infants and young children Wide metopic suture in infants and young children Widow's peak Widely spaced eyes, typically marked Enlarged globes leading to the appearance of prominent eyes Downslanted palpebral fissures Posteriorly rotated ears Depressed nasal bridge Short nose with broad or bifid tip • Large anterior fontanelle in infants and young children • Wide metopic suture in infants and young children • Widow's peak • Widely spaced eyes, typically marked • Enlarged globes leading to the appearance of prominent eyes • Downslanted palpebral fissures • Posteriorly rotated ears • Depressed nasal bridge • Short nose with broad or bifid tip • Large anterior fontanelle in infants and young children • Wide metopic suture in infants and young children • Widow's peak • Widely spaced eyes, typically marked • Enlarged globes leading to the appearance of prominent eyes • Downslanted palpebral fissures • Posteriorly rotated ears • Depressed nasal bridge • Short nose with broad or bifid tip • Large anterior fontanelle in infants and young children • Wide metopic suture in infants and young children • Widow's peak • Widely spaced eyes, typically marked • Enlarged globes leading to the appearance of prominent eyes • Downslanted palpebral fissures • Posteriorly rotated ears • Depressed nasal bridge • Short nose with broad or bifid tip ## Establishing the Diagnosis The diagnosis of Donnai-Barrow syndrome (DBS) 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 [ Absent or abnormally functioning megalin, the protein encoded by Retinol-binding protein (RBP) Vitamin D-binding protein (VDBP) * Note: The use of a "dipstick" is not an adequate substitute to protein electrophoresis to identify megalin ligands in the urine of individuals with DBS. Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of DBS, molecular genetic testing approaches can include Note: As For an introduction to multigene panels click When the diagnosis of DBS is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Donnai-Barrow 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 One affected individual was homozygous for an Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Retinol-binding protein (RBP) • Vitamin D-binding protein (VDBP) • Note: As • For an introduction to multigene panels click ## Biochemical Testing Absent or abnormally functioning megalin, the protein encoded by Retinol-binding protein (RBP) Vitamin D-binding protein (VDBP) * Note: The use of a "dipstick" is not an adequate substitute to protein electrophoresis to identify megalin ligands in the urine of individuals with DBS. • Retinol-binding protein (RBP) • Vitamin D-binding protein (VDBP) ## Molecular Genetic Testing Molecular genetic testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of DBS, molecular genetic testing approaches can include Note: As For an introduction to multigene panels click • Note: As • For an introduction to multigene panels click ## Option 2 When the diagnosis of DBS is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Donnai-Barrow 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 One affected individual was homozygous for an Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 following information is based on case reports reviewed in No clinically relevant genotype-phenotype correlations are known. Donnai-Barrow syndrome (DBS) [ The following terms should no longer be used when referring to DBS: Syndrome of ocular and facial anomalies, telecanthus, and deafness Holmes-Schepens syndrome Diaphragmatic hernia-exomphalos-hypertelorism syndrome Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome No population-based incidence or prevalence data are available. Only 49 individuals with sufficient clinical and/or molecular data to establish the diagnosis of DBS have been reported in the medical literature. Many of these individuals are members of a few large consanguineous families. DBS has been reported in different ethnic groups, including northern and central European, Middle Eastern, American of European origin, and African American. No one ethnic group predominates. • Syndrome of ocular and facial anomalies, telecanthus, and deafness • Holmes-Schepens syndrome • Diaphragmatic hernia-exomphalos-hypertelorism syndrome • Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome ## Clinical Description The following information is based on case reports reviewed in ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations are known. ## Nomenclature Donnai-Barrow syndrome (DBS) [ The following terms should no longer be used when referring to DBS: Syndrome of ocular and facial anomalies, telecanthus, and deafness Holmes-Schepens syndrome Diaphragmatic hernia-exomphalos-hypertelorism syndrome Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome • Syndrome of ocular and facial anomalies, telecanthus, and deafness • Holmes-Schepens syndrome • Diaphragmatic hernia-exomphalos-hypertelorism syndrome • Diaphragmatic hernia-hypertelorism-myopia-deafness syndrome ## Prevalence No population-based incidence or prevalence data are available. Only 49 individuals with sufficient clinical and/or molecular data to establish the diagnosis of DBS have been reported in the medical literature. Many of these individuals are members of a few large consanguineous families. DBS has been reported in different ethnic groups, including northern and central European, Middle Eastern, American of European origin, and African American. No one ethnic group predominates. ## Genetically Related (Allelic) Disorders No phenotypes other than Donnai-Barrow syndrome are currently known to be associated with pathogenic variants in ## Differential Diagnosis Donnai-Barrow syndrome (DBS) is associated with congenital diaphragmatic hernia (CDH). Disorders to Consider in the Differential Diagnosis of Donnai-Barrow Syndrome Diaphragmatic hernia Relatively high birth weight Widely spaced eyes Marked hypotonia More severe DD in some Skin w/hypo- & hyperpigmented streaks Coarse facial features Sparse hair Diaphragmatic defects Occasionally agenesis of corpus callosum Widely spaced eyes Abnormal fingers & toes: brachytelephalangy &/or underdeveloped nails Characteristic craniofacial dysmorphisms Orofacial clefting Polyhydramnios Sensorineural hearing loss Partial agenesis of corpus callosum Hydrocephalus &/or ventriculomegaly Cortical dysplasia &/or subcortical gray matter heterotopia Usually normal psychomotor development Widely spaced eyes Absence of corpus callosum Macrocephaly Large anterior fontanelle Hypercalciuria, nephrocalcinosis, & nephrolithiasis Rickets Congenital or acquired cataracts, & glaucoma Congenital diaphragmatic hernia Widely spaced eyes Agenesis of corpus callosum Craniofacial asymmetry, craniosynostosis, brachycephaly (more severe in females) Clefting of nasal tip Anomalies of joints & digits (e.g., grooved nails) High myopia & occasional retinal detachment Hearing loss Pierre Robin sequence Midface hypoplasia Joint problems (hypermobility, arthritis) AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; NA = not applicable; XL = X-linked Clinical and biochemical overlap has been proposed between these conditions and DBS Heterozygous pathogenic variants in • Diaphragmatic hernia • Relatively high birth weight • Widely spaced eyes • Marked hypotonia • More severe DD in some • Skin w/hypo- & hyperpigmented streaks • Coarse facial features • Sparse hair • Diaphragmatic defects • Occasionally agenesis of corpus callosum • Widely spaced eyes • Abnormal fingers & toes: brachytelephalangy &/or underdeveloped nails • Characteristic craniofacial dysmorphisms • Orofacial clefting • Polyhydramnios • Sensorineural hearing loss • Partial agenesis of corpus callosum • Hydrocephalus &/or ventriculomegaly • Cortical dysplasia &/or subcortical gray matter heterotopia • Usually normal psychomotor development • Widely spaced eyes • Absence of corpus callosum • Macrocephaly • Large anterior fontanelle • Hypercalciuria, nephrocalcinosis, & nephrolithiasis • Rickets • Congenital or acquired cataracts, & glaucoma • Congenital diaphragmatic hernia • Widely spaced eyes • Agenesis of corpus callosum • Craniofacial asymmetry, craniosynostosis, brachycephaly (more severe in females) • Clefting of nasal tip • Anomalies of joints & digits (e.g., grooved nails) • High myopia & occasional retinal detachment • Hearing loss • Pierre Robin sequence • Midface hypoplasia • Joint problems (hypermobility, arthritis) ## Management To establish the extent of disease and needs in an individual diagnosed with Donnai-Barrow syndrome (DBS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Donnai-Barrow Syndrome Treatment of Manifestations in Individuals with Donnai-Barrow Syndrome ASM = anti-seizure medication; ENT = ear, nose, and throat (specialist) Surgical repair of omphalocele and/or diaphragmatic hernia appears to pose no greater risk than repair of these defects in children with other genetic syndromes. 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. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention deficit hyperactivity disorder, when necessary. Repetitive self-injurious behavior has been reported in a single individual [ Recommended Surveillance for Individuals with DBS See Search • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Donnai-Barrow syndrome (DBS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Donnai-Barrow Syndrome ## Treatment of Manifestations Treatment of Manifestations in Individuals with Donnai-Barrow Syndrome ASM = anti-seizure medication; ENT = ear, nose, and throat (specialist) Surgical repair of omphalocele and/or diaphragmatic hernia appears to pose no greater risk than repair of these defects in children with other genetic syndromes. 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. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention deficit hyperactivity disorder, when necessary. Repetitive self-injurious behavior has been reported in a single individual [ • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Developmental Delay / Intellectual Disability Management Issues 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. ## Social/Behavioral Concerns Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavioral management strategies or providing prescription medications, such as medication used to treat attention deficit hyperactivity disorder, when necessary. Repetitive self-injurious behavior has been reported in a single individual [ ## Surveillance Recommended Surveillance for Individuals with DBS ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Donnai-Barrow syndrome (DBS) is inherited in an autosomal recessive manner. The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one Paternal uniparental isodisomy for chromosome 2 accounted for homozygous Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. When both parents are carriers of an Given the variability among affected sibs of the occurrence of major structural birth defects (i.e., omphalocele or CDH), the presence of one of the defects in one sib does not predict the presence of either or both in another sib. In the case of uniparental isodisomy (see Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. 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. • The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one • Paternal uniparental isodisomy for chromosome 2 accounted for homozygous • Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. • When both parents are carriers of an • Given the variability among affected sibs of the occurrence of major structural birth defects (i.e., omphalocele or CDH), the presence of one of the defects in one sib does not predict the presence of either or both in another sib. • In the case of uniparental isodisomy (see • Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. • 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 Donnai-Barrow syndrome (DBS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one Paternal uniparental isodisomy for chromosome 2 accounted for homozygous Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. When both parents are carriers of an Given the variability among affected sibs of the occurrence of major structural birth defects (i.e., omphalocele or CDH), the presence of one of the defects in one sib does not predict the presence of either or both in another sib. In the case of uniparental isodisomy (see Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. • The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one • Paternal uniparental isodisomy for chromosome 2 accounted for homozygous • Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. • When both parents are carriers of an • Given the variability among affected sibs of the occurrence of major structural birth defects (i.e., omphalocele or CDH), the presence of one of the defects in one sib does not predict the presence of either or both in another sib. • In the case of uniparental isodisomy (see • Heterozygotes (carriers) are asymptomatic in that they do not manifest structural birth defects, craniofacial dysmorphology, or kidney dysfunction. ## 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 ## Resources • • • • • • • • • • ## Molecular Genetics Donnai-Barrow Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Donnai-Barrow Syndrome ( Donnai-Barrow syndrome (DBS) is caused by loss-of-function pathogenic variants in Many features of DBS are recapitulated in animal models of megalin deficiency; for example: Forebrain anomalies, including agenesis of corpus callosum and mild holoprosencephaly (not reported in individuals with DBS) [ Enlarged and exophthalmic eyes (buphthalmos) [ Glaucoma or glaucomatous changes in some but not every model [ Defects of cardiovascular development, specifically of the outflow tract and the atrioventricular canal [ Megalin is required for endocytosis [ 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 ( The homozygous pathogenic variant caused by paternal uniparental isodisomy for chromosome 2 in an affected individual with DBS/FOAR [ • Forebrain anomalies, including agenesis of corpus callosum and mild holoprosencephaly (not reported in individuals with DBS) [ • Enlarged and exophthalmic eyes (buphthalmos) [ • Glaucoma or glaucomatous changes in some but not every model [ • Defects of cardiovascular development, specifically of the outflow tract and the atrioventricular canal [ ## Molecular Pathogenesis Donnai-Barrow syndrome (DBS) is caused by loss-of-function pathogenic variants in Many features of DBS are recapitulated in animal models of megalin deficiency; for example: Forebrain anomalies, including agenesis of corpus callosum and mild holoprosencephaly (not reported in individuals with DBS) [ Enlarged and exophthalmic eyes (buphthalmos) [ Glaucoma or glaucomatous changes in some but not every model [ Defects of cardiovascular development, specifically of the outflow tract and the atrioventricular canal [ Megalin is required for endocytosis [ 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 ( The homozygous pathogenic variant caused by paternal uniparental isodisomy for chromosome 2 in an affected individual with DBS/FOAR [ • Forebrain anomalies, including agenesis of corpus callosum and mild holoprosencephaly (not reported in individuals with DBS) [ • Enlarged and exophthalmic eyes (buphthalmos) [ • Glaucoma or glaucomatous changes in some but not every model [ • Defects of cardiovascular development, specifically of the outflow tract and the atrioventricular canal [ ## Chapter Notes We thank Dr Patricia K Donahoe for her leadership and continuous support. We also thank the many physicians who referred patients with DBS/FOAR to us. Finally, we gratefully thank all families who have participated in our study, through which we were able to find the gene responsible for DBS/FOAR. Dian Donnai, MD (2008-present)Sibel Kantarci, PhD, FACMG (2008-present)Mauro Longoni, MD (2018-present)Kristin M Noonan, MD; Medical College of Wisconsin (2008-2018)Barbara R Pober, MD (2008-present) 21 November 2018 (sw) Comprehensive update posted live 28 June 2011 (me) Comprehensive update posted live 28 August 2008 (me) Review posted live 28 April 2008 (brp) Original submission • 21 November 2018 (sw) Comprehensive update posted live • 28 June 2011 (me) Comprehensive update posted live • 28 August 2008 (me) Review posted live • 28 April 2008 (brp) Original submission ## Acknowledgments We thank Dr Patricia K Donahoe for her leadership and continuous support. We also thank the many physicians who referred patients with DBS/FOAR to us. Finally, we gratefully thank all families who have participated in our study, through which we were able to find the gene responsible for DBS/FOAR. ## Author History Dian Donnai, MD (2008-present)Sibel Kantarci, PhD, FACMG (2008-present)Mauro Longoni, MD (2018-present)Kristin M Noonan, MD; Medical College of Wisconsin (2008-2018)Barbara R Pober, MD (2008-present) ## Revision History 21 November 2018 (sw) Comprehensive update posted live 28 June 2011 (me) Comprehensive update posted live 28 August 2008 (me) Review posted live 28 April 2008 (brp) Original submission • 21 November 2018 (sw) Comprehensive update posted live • 28 June 2011 (me) Comprehensive update posted live • 28 August 2008 (me) Review posted live • 28 April 2008 (brp) Original submission ## References ## Literature Cited Facial characteristics over time in the same male with Donnai-Barrow syndrome A. At age six months; broad forehead, markedly widely spaced eyes, left iris coloboma, and short nose B. At age 2.5 years; same features are apparent. Note the hearing aids. C. & D. At ages 8 and 19 years, respectively; slight coarsening of facial features, persistent hypertelorism, and progressive visual loss in the right eye MRI in a female age three years demonstrates numerous abnormalities including hypogenesis of the corpus callosum (most notably involving the rostrum and splenium) (long white arrow), partially empty sella turcica (S), and small pons (P).
[]
28/8/2008
21/11/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
drd
drd
[ "Autosomal Dominant Dopa-Responsive Dystonia", "Autosomal Dominant Segawa Syndrome", "DYT5a", "Hereditary Progressive Dystonia with Marked Diurnal Fluctuation", "Hereditary Progressive Dystonia with Marked Diurnal Fluctuation", "Autosomal Dominant Segawa Syndrome", "Autosomal Dominant Dopa-Responsive Dystonia", "DYT5a", "GTP cyclohydrolase 1", "GCH1", "GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia" ]
GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia
Yoshiaki Furukawa
Summary GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is characterized by childhood-onset dystonia and a dramatic and sustained response to low doses of oral administration of levodopa. This disorder typically presents with gait disturbance caused by foot dystonia, later development of parkinsonism, and diurnal fluctuation of symptoms (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). Initial symptoms are often gait difficulties attributable to flexion-inversion (equinovarus posture) of the foot. Occasionally, initial symptoms are arm dystonia, postural tremor of the hand, or slowness of movements. Brisk deep-tendon reflexes in the legs, ankle clonus, and/or the striatal toe (dystonic extension of the big toe) are present in many affected individuals. In general, gradual progression to generalized dystonia is observed. Intellectual, cerebellar, sensory, and autonomic disturbances generally do not occur. The diagnosis of GTPCH1-deficient DRD is established in a proband by identification of a heterozygous pathogenic variant in Children age <6 years: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses Children age ≥6 years: 25-50 mg levodopa/DCI 1-3x daily Adults: 50 mg levodopa/DCI 1-3x daily For all, dose should be changed slowly and by small increments as needed. Motor benefit occurs immediately or within a few days of starting levodopa; full benefit occurs within several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. Although dyskinesias may appear at the beginning of levodopa therapy, they subside following dose reduction and do not reappear when the dose is gradually increased. Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. GTPCH1-deficient DRD is inherited in an autosomal dominant manner. Affected individuals often have an affected parent with typical GTPCH1-deficient DRD or adult-onset parkinsonism caused by a
## Diagnosis GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) Onset typically in childhood following normal early motor development Onset of dystonia in a limb, typically foot dystonia (equinovarus posture) resulting in gait disturbance Later development of parkinsonism (tremor is mainly postural) Presence of brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe, which may be misinterpreted as a Babinski response) in many individuals In general, normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). The degree of diurnal fluctuation is variable. Gradual progression to generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course Frequent attenuation in the magnitude of diurnal fluctuation with age and disease progression A dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of orally administered levodopa. Maximum benefit is generally achieved by less than 300-400 mg/day of levodopa with a decarboxylase inhibitor (DCI) or 20-30 mg/kg/day of levodopa without a DCI. Typically, absence of adverse motor effects of long-term levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) under optimal doses of levodopa Female predominance among clinically affected individuals The diagnosis of GTPCH1-deficient DRD In individuals with a suspected diagnosis of GTPCH1-deficient DRD and no identifiable 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 GTPCH1-deficient DRD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of GTPCH1-deficient DRD, molecular genetic testing approaches can include Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click When the diagnosis of GTPCH1-deficient DRD is not considered because an individual has atypical phenotypic 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 GTPCH1-Deficient DRD 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. If molecular testing does not identify a pathogenic variant, biochemical testing should be performed. • Onset typically in childhood following normal early motor development • Onset of dystonia in a limb, typically foot dystonia (equinovarus posture) resulting in gait disturbance • Later development of parkinsonism (tremor is mainly postural) • Presence of brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe, which may be misinterpreted as a Babinski response) in many individuals • In general, normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances • Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). The degree of diurnal fluctuation is variable. • Gradual progression to generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course • Frequent attenuation in the magnitude of diurnal fluctuation with age and disease progression • A dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of orally administered levodopa. Maximum benefit is generally achieved by less than 300-400 mg/day of levodopa with a decarboxylase inhibitor (DCI) or 20-30 mg/kg/day of levodopa without a DCI. • Typically, absence of adverse motor effects of long-term levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) under optimal doses of levodopa • Female predominance among clinically affected individuals • Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Suggestive Findings GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) Onset typically in childhood following normal early motor development Onset of dystonia in a limb, typically foot dystonia (equinovarus posture) resulting in gait disturbance Later development of parkinsonism (tremor is mainly postural) Presence of brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe, which may be misinterpreted as a Babinski response) in many individuals In general, normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). The degree of diurnal fluctuation is variable. Gradual progression to generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course Frequent attenuation in the magnitude of diurnal fluctuation with age and disease progression A dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of orally administered levodopa. Maximum benefit is generally achieved by less than 300-400 mg/day of levodopa with a decarboxylase inhibitor (DCI) or 20-30 mg/kg/day of levodopa without a DCI. Typically, absence of adverse motor effects of long-term levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) under optimal doses of levodopa Female predominance among clinically affected individuals • Onset typically in childhood following normal early motor development • Onset of dystonia in a limb, typically foot dystonia (equinovarus posture) resulting in gait disturbance • Later development of parkinsonism (tremor is mainly postural) • Presence of brisk deep-tendon reflexes in the legs, ankle clonus, and/or striatal toe (dystonic extension of the big toe, which may be misinterpreted as a Babinski response) in many individuals • In general, normal intellectual and cognitive function and absence of cerebellar, sensory, and autonomic disturbances • Diurnal fluctuation (aggravation of symptoms toward the evening and alleviation of symptoms in the morning after sleep). The degree of diurnal fluctuation is variable. • Gradual progression to generalized dystonia, typically more pronounced dystonia in the legs throughout the disease course • Frequent attenuation in the magnitude of diurnal fluctuation with age and disease progression • A dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of orally administered levodopa. Maximum benefit is generally achieved by less than 300-400 mg/day of levodopa with a decarboxylase inhibitor (DCI) or 20-30 mg/kg/day of levodopa without a DCI. • Typically, absence of adverse motor effects of long-term levodopa therapy (wearing-off and on-off phenomena and dopa-induced dyskinesias) under optimal doses of levodopa • Female predominance among clinically affected individuals ## Establishing the Diagnosis The diagnosis of GTPCH1-deficient DRD In individuals with a suspected diagnosis of GTPCH1-deficient DRD and no identifiable 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 GTPCH1-deficient DRD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of GTPCH1-deficient DRD, molecular genetic testing approaches can include Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click When the diagnosis of GTPCH1-deficient DRD is not considered because an individual has atypical phenotypic 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 GTPCH1-Deficient DRD 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. • Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of GTPCH1-deficient DRD, molecular genetic testing approaches can include Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click • Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 2 When the diagnosis of GTPCH1-deficient DRD is not considered because an individual has atypical phenotypic 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 GTPCH1-Deficient DRD 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. ## Biochemical Testing If molecular testing does not identify a pathogenic variant, biochemical testing should be performed. ## Clinical Characteristics GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the major form of DRD, is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of levodopa. The perinatal and postnatal periods are normal, as is early motor development. A variable degree of rigidity and slowness of movements are recognized in the affected limbs. Tremor is usually postural, especially in the early course of illness. Rapid fatiguing of effort with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed. Some clinical findings suggestive of pyramidal signs in the lower extremities (brisk deep-tendon reflexes, spasticity, ankle clonus, and/or intermittent extensor plantar responses) are detected in many affected individuals. However, normal efferent cortical spinal activity with magneto-electrical stimulation of the motor cortex suggests a non-pyramidal basis for these findings. In fact, after starting levodopa therapy, severe hyperreflexia and spasticity resolve and an extensor plantar response often disappears in individuals with GTPCH1-deficient DRD. Dystonic extension of the big toe (the striatal toe) may be misinterpreted as an extensor plantar response. In general, intellectual and cognitive function is normal and there is no evidence of cerebellar, sensory, and autonomic disturbances in individuals with GTPCH1-deficient DRD. Symptoms in individuals with adolescent onset are usually milder than in those with childhood onset and disease progression is slower. Individuals with adolescent-onset GTPCH1-deficient DRD seldom develop severe generalized dystonia. Such individuals may become more symptomatic in mid-adulthood because of development of overt parkinsonism. At the initiation of levodopa therapy, some individuals with GTPCH1-deficient DRD develop dyskinesias, which subside following dose reduction and do not reappear when the dose is slowly increased later; note that these transient dyskinesias are different from those with motor response fluctuations observed in persons with early-onset parkinsonism and Parkinson disease during chronic levodopa therapy. Under optimal doses, individuals with typical GTPCH1-deficient DRD on long-term levodopa treatment do not develop either motor response fluctuations or dopa-induced dyskinesias. The clinical phenotypic spectrum has been extended to include adult-onset "benign" parkinsonism, various types of focal dystonia, DRD-simulating cerebral palsy or spastic paraplegia, and spontaneous remission of dystonia and/or parkinsonism (sometimes with a relapse in the later course of illness) [ Individuals with adult-onset "benign" parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. These individuals respond markedly to low doses of levodopa and, when treated with optimal doses of levodopa, remain functionally normal for a long period of time without developing motor response fluctuations or dopa-induced dyskinesias. PET and SPECT studies using presynaptic dopaminergic markers have demonstrated normal results in "benign" parkinsonism [ "Neurodegenerative" parkinsonism, including Parkinson disease associated with In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [ Six of the 23 individuals with GTPCH1-deficient DRD described by Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies using presynaptic dopaminergic markers have demonstrated normal results in the striatum of DRD and "benign" parkinsonism due to Network analysis of [ At autopsy, biopterin (BP) and neopterin (NP) levels in the putamen were substantially lower in two affected individuals (mean: -84% and -62%) than in age-matched normal controls. The caudal portion of the putamen was the striatal subdivision most affected by dopamine loss (-88%). Striatal levels of dopa decarboxylase protein, dopamine transporter, and vesicular monoamine transporter were normal, but tyrosine hydroxylase (TH) protein levels were markedly decreased in the putamen (> -97%). These biochemical findings suggest that striatal dopamine reduction in GTPCH1-deficient DRD is caused by both decreased TH activity resulting from a low cofactor (BH In an asymptomatic individual with a No correlations between specific clinical features and types of pathogenic variants in Penetrance in individuals with GTPCH1-deficient DRD has been reported to be higher in females than in males: 87% vs 38% [ The term "DRD" is now used to delineate the following disease entities: GTPCH1-deficient DRD (DYT-GCH1, DYT5a; the major form of DRD) Dopa-responsive dystonia (DRD) is observed worldwide, and prevalence of DRD (of any cause) in both England and Japan has been estimated at 0.5 per million [ • Individuals with adult-onset "benign" parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. These individuals respond markedly to low doses of levodopa and, when treated with optimal doses of levodopa, remain functionally normal for a long period of time without developing motor response fluctuations or dopa-induced dyskinesias. PET and SPECT studies using presynaptic dopaminergic markers have demonstrated normal results in "benign" parkinsonism [ • "Neurodegenerative" parkinsonism, including Parkinson disease associated with • In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [ • Six of the 23 individuals with GTPCH1-deficient DRD described by • GTPCH1-deficient DRD (DYT-GCH1, DYT5a; the major form of DRD) ## Clinical Description GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the major form of DRD, is a clinical syndrome characterized by childhood-onset dystonia and a dramatic and sustained response (complete or near-complete responsiveness of symptoms) to relatively low doses of levodopa. The perinatal and postnatal periods are normal, as is early motor development. A variable degree of rigidity and slowness of movements are recognized in the affected limbs. Tremor is usually postural, especially in the early course of illness. Rapid fatiguing of effort with repetitive motor tasks (e.g., finger tapping or foot tapping) is often observed. Some clinical findings suggestive of pyramidal signs in the lower extremities (brisk deep-tendon reflexes, spasticity, ankle clonus, and/or intermittent extensor plantar responses) are detected in many affected individuals. However, normal efferent cortical spinal activity with magneto-electrical stimulation of the motor cortex suggests a non-pyramidal basis for these findings. In fact, after starting levodopa therapy, severe hyperreflexia and spasticity resolve and an extensor plantar response often disappears in individuals with GTPCH1-deficient DRD. Dystonic extension of the big toe (the striatal toe) may be misinterpreted as an extensor plantar response. In general, intellectual and cognitive function is normal and there is no evidence of cerebellar, sensory, and autonomic disturbances in individuals with GTPCH1-deficient DRD. Symptoms in individuals with adolescent onset are usually milder than in those with childhood onset and disease progression is slower. Individuals with adolescent-onset GTPCH1-deficient DRD seldom develop severe generalized dystonia. Such individuals may become more symptomatic in mid-adulthood because of development of overt parkinsonism. At the initiation of levodopa therapy, some individuals with GTPCH1-deficient DRD develop dyskinesias, which subside following dose reduction and do not reappear when the dose is slowly increased later; note that these transient dyskinesias are different from those with motor response fluctuations observed in persons with early-onset parkinsonism and Parkinson disease during chronic levodopa therapy. Under optimal doses, individuals with typical GTPCH1-deficient DRD on long-term levodopa treatment do not develop either motor response fluctuations or dopa-induced dyskinesias. The clinical phenotypic spectrum has been extended to include adult-onset "benign" parkinsonism, various types of focal dystonia, DRD-simulating cerebral palsy or spastic paraplegia, and spontaneous remission of dystonia and/or parkinsonism (sometimes with a relapse in the later course of illness) [ Individuals with adult-onset "benign" parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. These individuals respond markedly to low doses of levodopa and, when treated with optimal doses of levodopa, remain functionally normal for a long period of time without developing motor response fluctuations or dopa-induced dyskinesias. PET and SPECT studies using presynaptic dopaminergic markers have demonstrated normal results in "benign" parkinsonism [ "Neurodegenerative" parkinsonism, including Parkinson disease associated with In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [ Six of the 23 individuals with GTPCH1-deficient DRD described by Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies using presynaptic dopaminergic markers have demonstrated normal results in the striatum of DRD and "benign" parkinsonism due to Network analysis of [ At autopsy, biopterin (BP) and neopterin (NP) levels in the putamen were substantially lower in two affected individuals (mean: -84% and -62%) than in age-matched normal controls. The caudal portion of the putamen was the striatal subdivision most affected by dopamine loss (-88%). Striatal levels of dopa decarboxylase protein, dopamine transporter, and vesicular monoamine transporter were normal, but tyrosine hydroxylase (TH) protein levels were markedly decreased in the putamen (> -97%). These biochemical findings suggest that striatal dopamine reduction in GTPCH1-deficient DRD is caused by both decreased TH activity resulting from a low cofactor (BH In an asymptomatic individual with a • Individuals with adult-onset "benign" parkinsonism manifest no dystonia prior to the onset of parkinsonism in mid- or late adulthood. These individuals respond markedly to low doses of levodopa and, when treated with optimal doses of levodopa, remain functionally normal for a long period of time without developing motor response fluctuations or dopa-induced dyskinesias. PET and SPECT studies using presynaptic dopaminergic markers have demonstrated normal results in "benign" parkinsonism [ • "Neurodegenerative" parkinsonism, including Parkinson disease associated with • In rare instances, anxiety, depression, obsessive-compulsive disorder, and/or sleep disturbances have been reported [ • Six of the 23 individuals with GTPCH1-deficient DRD described by ## Genotype-Phenotype Correlations No correlations between specific clinical features and types of pathogenic variants in ## Penetrance Penetrance in individuals with GTPCH1-deficient DRD has been reported to be higher in females than in males: 87% vs 38% [ ## Nomenclature The term "DRD" is now used to delineate the following disease entities: GTPCH1-deficient DRD (DYT-GCH1, DYT5a; the major form of DRD) • GTPCH1-deficient DRD (DYT-GCH1, DYT5a; the major form of DRD) ## Prevalence Dopa-responsive dystonia (DRD) is observed worldwide, and prevalence of DRD (of any cause) in both England and Japan has been estimated at 0.5 per million [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis A dramatic and sustained response to low doses of levodopa in dopa-responsive dystonia (DRD) distinguishes this disorder from cerebral palsy, spastic paraplegia, and all other forms of dystonia, including early-onset primary dystonia (DYT1). (For a differential diagnosis of dystonia, see The major differential diagnoses of GTPCH1-deficient DRD are summarized in Disorders to Consider in the Differential Diagnosis of GTPCH1-Deficient DRD Persons w/mild form of TH deficiency can develop DRD. Complete responsiveness of symptoms to levodopa Onset of symptoms generally age 12 mos - 6 yrs Initial symptoms typically lower-limb dystonia &/or difficulty walking No delay in psychomotor development 1 family reported w/strikingly mild sepiapterin reductase deficiency phenotype (DRD w/o motor & cognitive delay) Sepiapterin reductase deficiency w/mild findings may mimic GTPCH1-deficient DRD. Remarkable response to levodopa Diurnal fluctuation of symptoms ↑ concentration of BP is assoc w/nl concentration of NP in CSF. Manifestations of DYT-SPR typically begin earlier than those in GTPCH1-deficient DRD. In the early course, the clinical differentiation between early-onset Parkinson disease w/dystonia & GTPCH1-deficient DRD is difficult. Persons w/early-onset Parkinson disease (esp those w/onset age <20 yrs) often develop gait disturbance (attributable to foot dystonia) as the initial symptom. ↓ concentration of BP is assoc w/nl concentration of NP in CSF of Parkinson disease (incl parkin type of early-onset Parkinson disease). PINK1 type of early-onset Parkinson disease often presents w/abnl behavior &/or psychiatric manifestations. The most reliable clinical distinction between early-onset Parkinson disease (especially parkin-type) & GTPCH1-deficient DRD is the subsequent occurrence of adverse motor effects of chronic levodopa therapy (wearing-off & on-off phenomena & dopa-induced dyskinesias) in early-onset Parkinson disease. AD = autosomal dominant; AR = autosomal recessive; BP = total biopterin; CSF = cerebrospinal fluid; DiffDx = differential diagnosis; DRD = dopa-responsive dystonia; MOI = mode of inheritance; nl = normal; NP = total neopterin; XL = X-linked Analyses of both Both total biopterin (BP) and total neopterin (NP) are reduced in GTPCH1-deficient DRD [ Sepiapterin reductase deficiency is a rare cause of dopa-responsive dystonia. Sepiapterin reductase deficiency is usually associated with more severe symptoms [ Pathogenic variants in Pathogenic variants in • Persons w/mild form of TH deficiency can develop DRD. • Complete responsiveness of symptoms to levodopa • Onset of symptoms generally age 12 mos - 6 yrs • Initial symptoms typically lower-limb dystonia &/or difficulty walking • No delay in psychomotor development • 1 family reported w/strikingly mild sepiapterin reductase deficiency phenotype (DRD w/o motor & cognitive delay) • Sepiapterin reductase deficiency w/mild findings may mimic GTPCH1-deficient DRD. • Remarkable response to levodopa • Diurnal fluctuation of symptoms • ↑ concentration of BP is assoc w/nl concentration of NP in CSF. • Manifestations of DYT-SPR typically begin earlier than those in GTPCH1-deficient DRD. • In the early course, the clinical differentiation between early-onset Parkinson disease w/dystonia & GTPCH1-deficient DRD is difficult. • Persons w/early-onset Parkinson disease (esp those w/onset age <20 yrs) often develop gait disturbance (attributable to foot dystonia) as the initial symptom. • ↓ concentration of BP is assoc w/nl concentration of NP in CSF of Parkinson disease (incl parkin type of early-onset Parkinson disease). • PINK1 type of early-onset Parkinson disease often presents w/abnl behavior &/or psychiatric manifestations. • The most reliable clinical distinction between early-onset Parkinson disease (especially parkin-type) & GTPCH1-deficient DRD is the subsequent occurrence of adverse motor effects of chronic levodopa therapy (wearing-off & on-off phenomena & dopa-induced dyskinesias) in early-onset Parkinson disease. ## Management To establish the extent of disease and needs in an individual diagnosed with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with GTPCH1-Deficient DRD Treatment of Manifestations in Individuals with GTPCH1-Deficient DRD Initial suggested dose Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day Adults: 50 mg levodopa/DCI 1-3x/day Changing the dose slowly & by small increments is recommended. Motor benefit can be recognized immediately or w/in a few days of starting levodopa therapy; full benefit occurs w/in several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. Transient dyskinesias do not reappear w/later gradual increment in dose. Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. DCI = decarboxylase inhibitor Early diagnosis and therapy (with low doses of levodopa) may prevent transient dyskinesias at initiation of levodopa treatment. Examination by a movement disorder specialist at least several times yearly is recommended. Discontinuation of levodopa treatment usually results in return of symptoms. 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. Note: Molecular genetic testing cannot be used to predict the occurrence of symptoms (see See In 20 pregnancies reported in 12 affected individuals, levodopa was continued without adverse effect in most. Two women experienced remission resulting in a reduction or cessation of therapy. Two women reported mild deterioration of dystonia; an increase in dose was required in one. No fetal abnormalities were identified [ See Search • Initial suggested dose • Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses • Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day • Adults: 50 mg levodopa/DCI 1-3x/day • Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses • Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day • Adults: 50 mg levodopa/DCI 1-3x/day • Changing the dose slowly & by small increments is recommended. • Motor benefit can be recognized immediately or w/in a few days of starting levodopa therapy; full benefit occurs w/in several days to a few months. • Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. • Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses • Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day • Adults: 50 mg levodopa/DCI 1-3x/day • Transient dyskinesias do not reappear w/later gradual increment in dose. • Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with GTPCH1-Deficient DRD ## Treatment of Manifestations Treatment of Manifestations in Individuals with GTPCH1-Deficient DRD Initial suggested dose Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day Adults: 50 mg levodopa/DCI 1-3x/day Changing the dose slowly & by small increments is recommended. Motor benefit can be recognized immediately or w/in a few days of starting levodopa therapy; full benefit occurs w/in several days to a few months. Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. Transient dyskinesias do not reappear w/later gradual increment in dose. Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. DCI = decarboxylase inhibitor • Initial suggested dose • Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses • Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day • Adults: 50 mg levodopa/DCI 1-3x/day • Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses • Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day • Adults: 50 mg levodopa/DCI 1-3x/day • Changing the dose slowly & by small increments is recommended. • Motor benefit can be recognized immediately or w/in a few days of starting levodopa therapy; full benefit occurs w/in several days to a few months. • Maximum benefit (complete or near-complete responsiveness of symptoms) is generally achieved by <300-400 mg/day of levodopa/DCI. • Children ˂6 yrs: 1-10 mg/kg levodopa/DCI daily, administered in multiple doses • Children ≥6 years: 25-50 mg levodopa/DCI 1-3x/day • Adults: 50 mg levodopa/DCI 1-3x/day • Transient dyskinesias do not reappear w/later gradual increment in dose. • Typically, adverse motor effects of chronic levodopa therapy (motor response fluctuations and dopa-induced dyskinesias) do not occur. ## Prevention of Secondary Complications Early diagnosis and therapy (with low doses of levodopa) may prevent transient dyskinesias at initiation of levodopa treatment. ## Surveillance Examination by a movement disorder specialist at least several times yearly is recommended. ## Agents/Circumstances to Avoid Discontinuation of levodopa treatment usually results in return of symptoms. ## 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. Note: Molecular genetic testing cannot be used to predict the occurrence of symptoms (see See ## Pregnancy Management In 20 pregnancies reported in 12 affected individuals, levodopa was continued without adverse effect in most. Two women experienced remission resulting in a reduction or cessation of therapy. Two women reported mild deterioration of dystonia; an increase in dose was required in one. No fetal abnormalities were identified [ See ## Therapies Under Investigation Search ## Genetic Counseling GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is inherited in an autosomal dominant manner. Many individuals diagnosed with GTPCH1-deficient DRD have a parent with GTPCH1-deficient DRD or adult-onset parkinsonism caused by a Some individuals diagnosed with GTPCH1-deficient DRD have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with GTPCH1-deficient DRD may appear to be negative because of failure to recognize the disorder in family members, sex-related incomplete penetrance (i.e., higher penetrance in women than in men), phenotypic variability, early death of the parent before the onset of symptoms, or late onset of the disease in the heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and molecular genetic testing has been performed on the parents of the proband. If a parent of the proband is heterozygous for the If the parents have been tested for the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the 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. • Many individuals diagnosed with GTPCH1-deficient DRD have a parent with GTPCH1-deficient DRD or adult-onset parkinsonism caused by a • Some individuals diagnosed with GTPCH1-deficient DRD have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with GTPCH1-deficient DRD may appear to be negative because of failure to recognize the disorder in family members, sex-related incomplete penetrance (i.e., higher penetrance in women than in men), phenotypic variability, early death of the parent before the onset of symptoms, or late onset of the disease in the heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and molecular genetic testing has been performed on the parents of the proband. • If a parent of the proband is heterozygous for the • If the parents have been tested for the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD) is inherited in an autosomal dominant manner. ## Risk to Family Members Many individuals diagnosed with GTPCH1-deficient DRD have a parent with GTPCH1-deficient DRD or adult-onset parkinsonism caused by a Some individuals diagnosed with GTPCH1-deficient DRD have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with GTPCH1-deficient DRD may appear to be negative because of failure to recognize the disorder in family members, sex-related incomplete penetrance (i.e., higher penetrance in women than in men), phenotypic variability, early death of the parent before the onset of symptoms, or late onset of the disease in the heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and molecular genetic testing has been performed on the parents of the proband. If a parent of the proband is heterozygous for the If the parents have been tested for the If the parents have not been tested for the • Many individuals diagnosed with GTPCH1-deficient DRD have a parent with GTPCH1-deficient DRD or adult-onset parkinsonism caused by a • Some individuals diagnosed with GTPCH1-deficient DRD have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with GTPCH1-deficient DRD may appear to be negative because of failure to recognize the disorder in family members, sex-related incomplete penetrance (i.e., higher penetrance in women than in men), phenotypic variability, early death of the parent before the onset of symptoms, or late onset of the disease in the heterozygous parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and molecular genetic testing has been performed on the parents of the proband. • If a parent of the proband is heterozygous for the • If the parents have been tested for the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the 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 • • • ## Molecular Genetics GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia ( Human and animal data indicate that striatal dopamine reduction in GTPCH1-deficient DRD is caused not only by decreased TH activity resulting from low biopterin content but also by actual loss of TH protein without nerve terminal loss [ The same degrees of biopterin reduction associated with the different degrees of TH protein and dopamine reduction in the putamen of symptomatic and asymptomatic individuals with GTPCH1-deficient DRD suggest that there are additional genetic and/or environmental factors modulating the regulatory effect of BH ## References ## Literature Cited ## Chapter Notes 24 January 2019 (ha) Comprehensive update posted live 5 March 2015 (me) Comprehensive update posted live 3 May 2012 (yf) Revision: information about autosomal recessive sepiapterin reductase (SR)-deficient DRD added 6 October 2011 (me) Comprehensive update posted live 4 August 2009 (me) Comprehensive update posted live 15 February 2007 (me) Comprehensive update posted live. Change in scope of Dopa-Responsive Dystonia chapter: GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia (i.e., this chapter) and 15 June 2004 (me) Comprehensive update posted live 5 March 2004 (me) Comprehensive update posted live 21 February 2002 (me) Review posted live 30 June 2001 (yf) Original submission • 24 January 2019 (ha) Comprehensive update posted live • 5 March 2015 (me) Comprehensive update posted live • 3 May 2012 (yf) Revision: information about autosomal recessive sepiapterin reductase (SR)-deficient DRD added • 6 October 2011 (me) Comprehensive update posted live • 4 August 2009 (me) Comprehensive update posted live • 15 February 2007 (me) Comprehensive update posted live. Change in scope of Dopa-Responsive Dystonia chapter: GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia (i.e., this chapter) and • 15 June 2004 (me) Comprehensive update posted live • 5 March 2004 (me) Comprehensive update posted live • 21 February 2002 (me) Review posted live • 30 June 2001 (yf) Original submission ## Revision History 24 January 2019 (ha) Comprehensive update posted live 5 March 2015 (me) Comprehensive update posted live 3 May 2012 (yf) Revision: information about autosomal recessive sepiapterin reductase (SR)-deficient DRD added 6 October 2011 (me) Comprehensive update posted live 4 August 2009 (me) Comprehensive update posted live 15 February 2007 (me) Comprehensive update posted live. Change in scope of Dopa-Responsive Dystonia chapter: GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia (i.e., this chapter) and 15 June 2004 (me) Comprehensive update posted live 5 March 2004 (me) Comprehensive update posted live 21 February 2002 (me) Review posted live 30 June 2001 (yf) Original submission • 24 January 2019 (ha) Comprehensive update posted live • 5 March 2015 (me) Comprehensive update posted live • 3 May 2012 (yf) Revision: information about autosomal recessive sepiapterin reductase (SR)-deficient DRD added • 6 October 2011 (me) Comprehensive update posted live • 4 August 2009 (me) Comprehensive update posted live • 15 February 2007 (me) Comprehensive update posted live. Change in scope of Dopa-Responsive Dystonia chapter: GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia (i.e., this chapter) and • 15 June 2004 (me) Comprehensive update posted live • 5 March 2004 (me) Comprehensive update posted live • 21 February 2002 (me) Review posted live • 30 June 2001 (yf) Original submission
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21/2/2002
24/1/2019
3/5/2012
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
drpla
drpla
[ "Dentatorubral-Pallidoluysian Atrophy", "Dentatorubral-Pallidoluysian Atrophy", "Atrophin-1", "ATN1", "DRPLA" ]
DRPLA
Silvia Prades, Claudio Melo de Gusmao, Silvia Grimaldi, Yael Shiloh-Malawsky, Thomas Felton, Henry Houlden
Summary DRPLA (dentatorubral-pallidoluysian atrophy) is a progressive neurologic disorder characterized by five cardinal features (irrespective of the age of onset): ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations. Onset ranges from infancy to late adulthood (range: age 0-72 years; mean: age 31.5 years). The clinical presentation varies by age of onset: individuals with juvenile onset (before age 20 years) have myoclonus, epilepsy, and progressive intellectual deterioration, whereas individuals with adult onset (after age 20 years) have ataxia, choreoathetosis, and dementia or neuropsychiatric changes. Disease duration is on average eight years (range: 0-35 years) and age at death is on average 49 years (range: age 18-80 years). The diagnosis of DRPLA is established in a proband with suggestive clinical findings and a heterozygous pathogenic CAG trinucleotide expansion in DRPLA is inherited in an autosomal dominant manner. The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent. Once an abnormal CAG repeat expansion in
## Diagnosis No consensus clinical diagnostic criteria for DRPLA (dentatorubral-pallidoluysian atrophy) have been published. DRPLA The diagnosis of DRPLA Note: Pathogenic CAG repeat expansions in Molecular Genetic Testing Used in DRPLA See See Note: To date, standard sequence-based multigene panels and exome sequencing cannot reliably detect pathogenic CAG repeat expansions in this gene. ## Suggestive Findings DRPLA ## Establishing the Diagnosis The diagnosis of DRPLA Note: Pathogenic CAG repeat expansions in Molecular Genetic Testing Used in DRPLA See See Note: To date, standard sequence-based multigene panels and exome sequencing cannot reliably detect pathogenic CAG repeat expansions in this gene. ## Clinical Characteristics DRPLA (dentatorubral-pallidoluysian atrophy) is a progressive neurologic disorder characterized by five cardinal features (irrespective of the age of onset): ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations [ Onset ranges from infancy to late adulthood (range: age 0-72 years; mean: age 31.5 years). Juvenile onset (before age 20 years) is characterized by myoclonus, epilepsy, and progressive intellectual deterioration, whereas adult onset (after age 20 years) is characterized by ataxia, choreoathetosis, and dementia or neuropsychiatric changes. Disease duration is on average eight years (range: 0-35 years) and age at death is on average 49 years (range: age 18-80 years) [ Juvenile-onset (also referred to as childhood- or early-onset) DRPLA is generally associated with ≥65 CAG repeats. Juvenile onset is typically characterized by developmental delay, progressive intellectual disability, myoclonus, and epilepsy, often referred to as a progressive myoclonic epilepsy (PME) phenotype [ Developmental delay and intellectual disability are the most common initial manifestations, with a mean age of onset of 7.1 ± 4.8 (range: 2-18) years [ Seizure types vary and are frequently resistant to anti-seizure medication [ Ataxia may occur early in the disease course or develop later. Eventually, chorea and psychiatric manifestations may also develop [ Adult-onset (also referred to as late-onset) DRPLA is generally associated with <65 CAG repeats. In one series, the mean age of onset was 48 years [ Behavioral impairment is characterized by delusions, hallucinations, depressed mood, apathy, loss of inhibitory control, poor judgment, impulsivity, irritability, and aggression [ Rarely, seizures may be present in individuals with disease onset between ages 20 and 40 years. Older individuals (especially those older than age 60 years in one series) may present with isolated ataxia and/or ataxia combined with dementia [ The severity and frequency of sleep disturbances in DRPLA are probably underestimated. Insomnia, excessive daytime sleepiness, and circadian rhythm disturbance can occur. In a case report by Other clinical manifestations that may be present in adult-onset DRPLA irrespective of the actual age of onset include choreoathetosis, dystonia, myoclonus, oculomotor impairments, postural instability, corneal endothelial degeneration, and optic atrophy [ Dysphagia is frequently seen in the late stages of disease [ Other clinical manifestations rarely reported include parkinsonism, tremors, hyperreflexia, and posterior column sensory loss [ Cerebellar white matter lesions are also described in individuals with late adult-onset and elderly-onset disease, often in the paravermal areas (medial part of the cerebellar hemispheres adjacent to the vermis) and present as high-intensity signals in MRI FLAIR images. Although paravermal lesions are considered typical of DRPLA and lacking in other autosomal dominant spinocerebellar ataxias, they are not specific to DRPLA and can be present in adult-onset neuronal intranuclear inclusion disease and Diffuse high-intensity areas deep in the white matter are often observed on T Using Histologically, as in other polyglutamine diseases, neurons show intranuclear inclusions [ Note: Correlation between Age at Onset and Size of Adapted from Because juvenile onset (before age 20 years) is associated with the progressive myoclonus epilepsy (PME) phenotype and adult onset (after age 20 years) with the non-PME phenotype, the clinical presentation is strongly correlated with the size of expanded CAG repeats. The frequency of signs and symptoms in affected individuals with <65 CAG repeats and those with ≥65 CAG repeats were summarized by Severe infantile onset with an extreme An individual with relatively small biallelic expanded An individual of Japanese ancestry homozygous for a 57-CAG repeat expansion was born to consanguineous parents. Early onset (around age 18 years) and more severe manifestations were observed [ Pathogenic (full-penetrance) CAG repeats (i.e., 48-93 CAG repeats) are fully penetrant, except for one individual with 51 CAG repeats who was asymptomatic at age 81 years [ The marked expansion of the DRPLA may also be referred to as: Naito-Oyanagi disease [ Haw River syndrome [ DRPLA is more prevalent in populations of Japanese ancestry, where it affects 0.2-0.7 in 100,000 people [ DRPLA is thought to occur at much lower rates in non-Japanese populations; however, it has also been reported in North America, South America, Europe, and Australia (for a summary of all cases reported see Brazil: 0.2%-0.92% [ China: 1% [ France: 0.25% [ Italy: 1% [ Korea: 3.4% [ Portugal: 2%-11.2% [ Singapore: 3.4% [ South Wales: 11.4% [ Spain: 1.4%-3.3% [ Venezuela: 3.1% [ • An individual with relatively small biallelic expanded • An individual of Japanese ancestry homozygous for a 57-CAG repeat expansion was born to consanguineous parents. Early onset (around age 18 years) and more severe manifestations were observed [ • Naito-Oyanagi disease [ • Haw River syndrome [ • Brazil: 0.2%-0.92% [ • China: 1% [ • France: 0.25% [ • Italy: 1% [ • Korea: 3.4% [ • Portugal: 2%-11.2% [ • Singapore: 3.4% [ • South Wales: 11.4% [ • Spain: 1.4%-3.3% [ • Venezuela: 3.1% [ ## Clinical Description DRPLA (dentatorubral-pallidoluysian atrophy) is a progressive neurologic disorder characterized by five cardinal features (irrespective of the age of onset): ataxia, cognitive decline, myoclonus, chorea, epilepsy, and psychiatric manifestations [ Onset ranges from infancy to late adulthood (range: age 0-72 years; mean: age 31.5 years). Juvenile onset (before age 20 years) is characterized by myoclonus, epilepsy, and progressive intellectual deterioration, whereas adult onset (after age 20 years) is characterized by ataxia, choreoathetosis, and dementia or neuropsychiatric changes. Disease duration is on average eight years (range: 0-35 years) and age at death is on average 49 years (range: age 18-80 years) [ Juvenile-onset (also referred to as childhood- or early-onset) DRPLA is generally associated with ≥65 CAG repeats. Juvenile onset is typically characterized by developmental delay, progressive intellectual disability, myoclonus, and epilepsy, often referred to as a progressive myoclonic epilepsy (PME) phenotype [ Developmental delay and intellectual disability are the most common initial manifestations, with a mean age of onset of 7.1 ± 4.8 (range: 2-18) years [ Seizure types vary and are frequently resistant to anti-seizure medication [ Ataxia may occur early in the disease course or develop later. Eventually, chorea and psychiatric manifestations may also develop [ Adult-onset (also referred to as late-onset) DRPLA is generally associated with <65 CAG repeats. In one series, the mean age of onset was 48 years [ Behavioral impairment is characterized by delusions, hallucinations, depressed mood, apathy, loss of inhibitory control, poor judgment, impulsivity, irritability, and aggression [ Rarely, seizures may be present in individuals with disease onset between ages 20 and 40 years. Older individuals (especially those older than age 60 years in one series) may present with isolated ataxia and/or ataxia combined with dementia [ The severity and frequency of sleep disturbances in DRPLA are probably underestimated. Insomnia, excessive daytime sleepiness, and circadian rhythm disturbance can occur. In a case report by Other clinical manifestations that may be present in adult-onset DRPLA irrespective of the actual age of onset include choreoathetosis, dystonia, myoclonus, oculomotor impairments, postural instability, corneal endothelial degeneration, and optic atrophy [ Dysphagia is frequently seen in the late stages of disease [ Other clinical manifestations rarely reported include parkinsonism, tremors, hyperreflexia, and posterior column sensory loss [ Cerebellar white matter lesions are also described in individuals with late adult-onset and elderly-onset disease, often in the paravermal areas (medial part of the cerebellar hemispheres adjacent to the vermis) and present as high-intensity signals in MRI FLAIR images. Although paravermal lesions are considered typical of DRPLA and lacking in other autosomal dominant spinocerebellar ataxias, they are not specific to DRPLA and can be present in adult-onset neuronal intranuclear inclusion disease and Diffuse high-intensity areas deep in the white matter are often observed on T Using Histologically, as in other polyglutamine diseases, neurons show intranuclear inclusions [ ## Juvenile Onset (Before Age 20 Years) Juvenile-onset (also referred to as childhood- or early-onset) DRPLA is generally associated with ≥65 CAG repeats. Juvenile onset is typically characterized by developmental delay, progressive intellectual disability, myoclonus, and epilepsy, often referred to as a progressive myoclonic epilepsy (PME) phenotype [ Developmental delay and intellectual disability are the most common initial manifestations, with a mean age of onset of 7.1 ± 4.8 (range: 2-18) years [ Seizure types vary and are frequently resistant to anti-seizure medication [ Ataxia may occur early in the disease course or develop later. Eventually, chorea and psychiatric manifestations may also develop [ ## Adult Onset (After Age 20 Years) Adult-onset (also referred to as late-onset) DRPLA is generally associated with <65 CAG repeats. In one series, the mean age of onset was 48 years [ Behavioral impairment is characterized by delusions, hallucinations, depressed mood, apathy, loss of inhibitory control, poor judgment, impulsivity, irritability, and aggression [ Rarely, seizures may be present in individuals with disease onset between ages 20 and 40 years. Older individuals (especially those older than age 60 years in one series) may present with isolated ataxia and/or ataxia combined with dementia [ The severity and frequency of sleep disturbances in DRPLA are probably underestimated. Insomnia, excessive daytime sleepiness, and circadian rhythm disturbance can occur. In a case report by Other clinical manifestations that may be present in adult-onset DRPLA irrespective of the actual age of onset include choreoathetosis, dystonia, myoclonus, oculomotor impairments, postural instability, corneal endothelial degeneration, and optic atrophy [ Dysphagia is frequently seen in the late stages of disease [ Other clinical manifestations rarely reported include parkinsonism, tremors, hyperreflexia, and posterior column sensory loss [ ## All Ages Cerebellar white matter lesions are also described in individuals with late adult-onset and elderly-onset disease, often in the paravermal areas (medial part of the cerebellar hemispheres adjacent to the vermis) and present as high-intensity signals in MRI FLAIR images. Although paravermal lesions are considered typical of DRPLA and lacking in other autosomal dominant spinocerebellar ataxias, they are not specific to DRPLA and can be present in adult-onset neuronal intranuclear inclusion disease and Diffuse high-intensity areas deep in the white matter are often observed on T Using Histologically, as in other polyglutamine diseases, neurons show intranuclear inclusions [ ## Genotype-Phenotype Correlations Note: Correlation between Age at Onset and Size of Adapted from Because juvenile onset (before age 20 years) is associated with the progressive myoclonus epilepsy (PME) phenotype and adult onset (after age 20 years) with the non-PME phenotype, the clinical presentation is strongly correlated with the size of expanded CAG repeats. The frequency of signs and symptoms in affected individuals with <65 CAG repeats and those with ≥65 CAG repeats were summarized by Severe infantile onset with an extreme An individual with relatively small biallelic expanded An individual of Japanese ancestry homozygous for a 57-CAG repeat expansion was born to consanguineous parents. Early onset (around age 18 years) and more severe manifestations were observed [ • An individual with relatively small biallelic expanded • An individual of Japanese ancestry homozygous for a 57-CAG repeat expansion was born to consanguineous parents. Early onset (around age 18 years) and more severe manifestations were observed [ ## Penetrance Pathogenic (full-penetrance) CAG repeats (i.e., 48-93 CAG repeats) are fully penetrant, except for one individual with 51 CAG repeats who was asymptomatic at age 81 years [ ## Anticipation The marked expansion of the ## Nomenclature DRPLA may also be referred to as: Naito-Oyanagi disease [ Haw River syndrome [ • Naito-Oyanagi disease [ • Haw River syndrome [ ## Prevalence DRPLA is more prevalent in populations of Japanese ancestry, where it affects 0.2-0.7 in 100,000 people [ DRPLA is thought to occur at much lower rates in non-Japanese populations; however, it has also been reported in North America, South America, Europe, and Australia (for a summary of all cases reported see Brazil: 0.2%-0.92% [ China: 1% [ France: 0.25% [ Italy: 1% [ Korea: 3.4% [ Portugal: 2%-11.2% [ Singapore: 3.4% [ South Wales: 11.4% [ Spain: 1.4%-3.3% [ Venezuela: 3.1% [ • Brazil: 0.2%-0.92% [ • China: 1% [ • France: 0.25% [ • Italy: 1% [ • Korea: 3.4% [ • Portugal: 2%-11.2% [ • Singapore: 3.4% [ • South Wales: 11.4% [ • Spain: 1.4%-3.3% [ • Venezuela: 3.1% [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Selected Genes in the Differential Diagnosis of Adult-Onset DRPLA Selected Genes in the Differential Diagnosis of Early-Onset DRPLA AD = autosomal dominant; AR = autosomal recessive; EPM = epilepsy, progressive myoclonic; Mat = maternal; MOI = mode of inheritance Neuronal ceroid lipofuscinosis (NCL) is inherited in an autosomal recessive manner with the exception of ## Management No clinical practice guidelines for DRPLA (dentatorubral-pallidoluysian atrophy) have been published. To establish the extent of disease and needs in an individual diagnosed with DRPLA, the evaluations summarized in DRPLA: Recommended Evaluations Following Initial Diagnosis by Age of Onset To incl motor, adaptive, & cognitive Eval for IEP Rare after age 40 years EEG Refer to psychiatrist, psychologist, &/or neuropsychologist as needed. Use neuropsychological tests to establish baseline for cognitive decline. Consider that behavioral impairment & affective disturbances are often reported by caregiver. Community or Social work involvement for parental support for children; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ASM = anti-seizure medication; BARS = Brief Ataxia Rating Scale; ICARS = International Cooperative Ataxia Rating Scale; IEP = individualized education program; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; MOI = mode of inheritance; SARA = Scale for the Assessment and Rating of Ataxia; SLP = speech-language pathologist; UMRS = Unified Myoclonus Rating Scale Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for DRPLA. Few publications regarding symptomatic treatment for DRPLA are available in the literature. Thus, many manifestations of DRPLA are treated in a standard way in clinical practice. The supportive care for individuals with juvenile-onset (before age 20 years) DRPLA is summarized in Juvenile-Onset DRPLA: Treatment of Manifestations Carbamazepine, phenytoin Levetiracetam All standard drugs Generalized seizures: sodium valproate, perampanel, zonisamide Standard medications 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). Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. Weight control to avoid obesity Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. 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) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy Adult-Onset DRPLA: Treatment of Manifestations PT & OT 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) Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. Weight control to avoid obesity Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Use standard treatments for psychiatric manifestations. Quetiapine may be beneficial for psychosis. Ensure appropriate social work involvement to connect families or care providers w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist 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. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Juvenile-Onset DRPLA: Recommended Surveillance Monitor BMI Consult nutritionist High-calorie supplementation ADL = activities of daily living; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist; UMRS = Unified Myoclonus Rating Scale Adult-Onset DRPLA: Recommended Surveillance Monitor BMI. Consult nutritionist re need for high-calorie supplementation. BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; SLP = speech-language pathologist General anesthesia can increase the risk of intra- and postoperative seizures [ See In general, women with epilepsy from any cause are at greater risk for mortality during pregnancy than pregnant women without epilepsy; use of anti-seizure medications (ASMs) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ The medications carbamazepine, phenytoin, and levetiracetam, discussed in There is little to no human data on potential adverse fetal effects when piracetam, brivaracetam, or perampanel is taken during pregnancy. Limited data about the use of N-acetylcysteine during human pregnancy has been reassuring, without an appreciable increased risk of fetal malformations. The use of riluzole during pregnancy has not been well studied in humans. One woman took riluzole throughout her pregnancy and delivered a healthy term infant, whereas another woman delivered an infant with growth restriction [ See Search • To incl motor, adaptive, & cognitive • Eval for IEP • Rare after age 40 years • EEG • Refer to psychiatrist, psychologist, &/or neuropsychologist as needed. • Use neuropsychological tests to establish baseline for cognitive decline. • Consider that behavioral impairment & affective disturbances are often reported by caregiver. • Community or • Social work involvement for parental support for children; • Home nursing referral. • Carbamazepine, phenytoin • Levetiracetam • All standard drugs • Generalized seizures: sodium valproate, perampanel, zonisamide • Standard medications • 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). • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. • Weight control to avoid obesity • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. • 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) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • PT & OT • 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) • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. • Weight control to avoid obesity • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Use standard treatments for psychiatric manifestations. • Quetiapine may be beneficial for psychosis. • Ensure appropriate social work involvement to connect families or care providers w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • 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. • Monitor BMI • Consult nutritionist • High-calorie supplementation • Monitor BMI. • Consult nutritionist re need for high-calorie supplementation. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DRPLA, the evaluations summarized in DRPLA: Recommended Evaluations Following Initial Diagnosis by Age of Onset To incl motor, adaptive, & cognitive Eval for IEP Rare after age 40 years EEG Refer to psychiatrist, psychologist, &/or neuropsychologist as needed. Use neuropsychological tests to establish baseline for cognitive decline. Consider that behavioral impairment & affective disturbances are often reported by caregiver. Community or Social work involvement for parental support for children; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ASM = anti-seizure medication; BARS = Brief Ataxia Rating Scale; ICARS = International Cooperative Ataxia Rating Scale; IEP = individualized education program; MDS-UPDRS = Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale; MOI = mode of inheritance; SARA = Scale for the Assessment and Rating of Ataxia; SLP = speech-language pathologist; UMRS = Unified Myoclonus Rating Scale Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, & cognitive • Eval for IEP • Rare after age 40 years • EEG • Refer to psychiatrist, psychologist, &/or neuropsychologist as needed. • Use neuropsychological tests to establish baseline for cognitive decline. • Consider that behavioral impairment & affective disturbances are often reported by caregiver. • Community or • Social work involvement for parental support for children; • Home nursing referral. ## Treatment of Manifestations There is no cure for DRPLA. Few publications regarding symptomatic treatment for DRPLA are available in the literature. Thus, many manifestations of DRPLA are treated in a standard way in clinical practice. The supportive care for individuals with juvenile-onset (before age 20 years) DRPLA is summarized in Juvenile-Onset DRPLA: Treatment of Manifestations Carbamazepine, phenytoin Levetiracetam All standard drugs Generalized seizures: sodium valproate, perampanel, zonisamide Standard medications 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). Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. Weight control to avoid obesity Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. 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) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy Adult-Onset DRPLA: Treatment of Manifestations PT & OT 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) Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. Weight control to avoid obesity Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Use standard treatments for psychiatric manifestations. Quetiapine may be beneficial for psychosis. Ensure appropriate social work involvement to connect families or care providers w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathologist 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. • Carbamazepine, phenytoin • Levetiracetam • All standard drugs • Generalized seizures: sodium valproate, perampanel, zonisamide • Standard medications • 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). • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. • Weight control to avoid obesity • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. • 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) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • PT & OT • 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) • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in affected persons w/degenerative ataxias. • Weight control to avoid obesity • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected persons should maintain activity. • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Use standard treatments for psychiatric manifestations. • Quetiapine may be beneficial for psychosis. • Ensure appropriate social work involvement to connect families or care providers w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • 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. ## 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 To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Juvenile-Onset DRPLA: Recommended Surveillance Monitor BMI Consult nutritionist High-calorie supplementation ADL = activities of daily living; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist; UMRS = Unified Myoclonus Rating Scale Adult-Onset DRPLA: Recommended Surveillance Monitor BMI. Consult nutritionist re need for high-calorie supplementation. BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; SLP = speech-language pathologist • Monitor BMI • Consult nutritionist • High-calorie supplementation • Monitor BMI. • Consult nutritionist re need for high-calorie supplementation. ## Agents/Circumstances to Avoid General anesthesia can increase the risk of intra- and postoperative seizures [ ## Evaluation of Relatives at Risk See ## Pregnancy Management In general, women with epilepsy from any cause are at greater risk for mortality during pregnancy than pregnant women without epilepsy; use of anti-seizure medications (ASMs) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ The medications carbamazepine, phenytoin, and levetiracetam, discussed in There is little to no human data on potential adverse fetal effects when piracetam, brivaracetam, or perampanel is taken during pregnancy. Limited data about the use of N-acetylcysteine during human pregnancy has been reassuring, without an appreciable increased risk of fetal malformations. The use of riluzole during pregnancy has not been well studied in humans. One woman took riluzole throughout her pregnancy and delivered a healthy term infant, whereas another woman delivered an infant with growth restriction [ See ## Therapies Under Investigation Search ## Genetic Counseling DRPLA (dentatorubral-pallidoluysian atrophy) is inherited in an autosomal dominant manner. Most individuals diagnosed with DRPLA have an affected parent. In some families, an asymptomatic father of an affected individual has a mildly expanded CAG repeat and paternal transmission results in intergenerational increase in the size of the expanded CAG repeats. Examples include: A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ If neither of the parents of the proband is known to have DRPLA, recommendations for the evaluation of parents include physical examination and consideration of targeted analysis for an The family history of some individuals diagnosed with DRPLA may also appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for an expanded If a parent of the proband has an abnormal The marked expansion of the In general, an inverse correlation exists between the age at onset and the size of the expanded The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent. DRPLA exhibits significant anticipation, particularly when transmitted paternally (see The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Testing of at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. 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 of minors for disorders for which early treatment would have no beneficial effect on disease morbidity and mortality 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 It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of DRPLA. Once an abnormal CAG repeat expansion in 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 DRPLA have an affected parent. • In some families, an asymptomatic father of an affected individual has a mildly expanded CAG repeat and paternal transmission results in intergenerational increase in the size of the expanded CAG repeats. Examples include: • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ • If neither of the parents of the proband is known to have DRPLA, recommendations for the evaluation of parents include physical examination and consideration of targeted analysis for an • The family history of some individuals diagnosed with DRPLA may also appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for an expanded • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ • If a parent of the proband has an abnormal • The marked expansion of the • In general, an inverse correlation exists between the age at onset and the size of the expanded • The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent. • DRPLA exhibits significant anticipation, particularly when transmitted paternally (see • The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Testing of at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. • 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 of minors for disorders for which early treatment would have no beneficial effect on disease morbidity and mortality 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 DRPLA (dentatorubral-pallidoluysian atrophy) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with DRPLA have an affected parent. In some families, an asymptomatic father of an affected individual has a mildly expanded CAG repeat and paternal transmission results in intergenerational increase in the size of the expanded CAG repeats. Examples include: A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ If neither of the parents of the proband is known to have DRPLA, recommendations for the evaluation of parents include physical examination and consideration of targeted analysis for an The family history of some individuals diagnosed with DRPLA may also appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for an expanded If a parent of the proband has an abnormal The marked expansion of the In general, an inverse correlation exists between the age at onset and the size of the expanded The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent. DRPLA exhibits significant anticipation, particularly when transmitted paternally (see • Most individuals diagnosed with DRPLA have an affected parent. • In some families, an asymptomatic father of an affected individual has a mildly expanded CAG repeat and paternal transmission results in intergenerational increase in the size of the expanded CAG repeats. Examples include: • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ • If neither of the parents of the proband is known to have DRPLA, recommendations for the evaluation of parents include physical examination and consideration of targeted analysis for an • The family history of some individuals diagnosed with DRPLA may also appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for an expanded • A proband with no family history of DRPLA whose father had 59 CAG repeats and was asymptomatic at age 65 years [ • A proband with no family history of DRPLA whose father had 51 CAG repeats and was asymptomatic at 81 years [ • If a parent of the proband has an abnormal • The marked expansion of the • In general, an inverse correlation exists between the age at onset and the size of the expanded • The risk to the children of an affected individual of inheriting an expanded CAG repeat is 50%. The size of the repeat transmitted to the offspring depends on the size of the parent's repeat and the sex of the transmitting parent. • DRPLA exhibits significant anticipation, particularly when transmitted paternally (see ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Testing of at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. 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 of minors for disorders for which early treatment would have no beneficial effect on disease morbidity and mortality 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 It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of DRPLA. • The optimal time for determination of genetic risk and availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Testing of at-risk adults for DRPLA in the presence of nonspecific or equivocal symptoms is predictive testing, not diagnostic testing. • 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 of minors for disorders for which early treatment would have no beneficial effect on disease morbidity and mortality 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 an abnormal CAG repeat expansion in 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 Spain Sanford Research • • • • United Kingdom • • • United Kingdom • • • • • • • Spain • • • Sanford Research • • • ## Molecular Genetics DRPLA: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DRPLA ( Expression of truncated proteins encoded by As in other polyglutamine disorders, the disease-causing CAG expansion in Molecular genetic testing approaches have until recently involved Genome sequencing-based tools have been developed for the detection of triplet repeat expansions [ Variants detectable by sequencing have not been associated with DRPLA, but are associated with Variants listed in the table have been provided by the authors. • Molecular genetic testing approaches have until recently involved • Genome sequencing-based tools have been developed for the detection of triplet repeat expansions [ • Variants detectable by sequencing have not been associated with DRPLA, but are associated with ## Molecular Pathogenesis Expression of truncated proteins encoded by As in other polyglutamine disorders, the disease-causing CAG expansion in Molecular genetic testing approaches have until recently involved Genome sequencing-based tools have been developed for the detection of triplet repeat expansions [ Variants detectable by sequencing have not been associated with DRPLA, but are associated with Variants listed in the table have been provided by the authors. • Molecular genetic testing approaches have until recently involved • Genome sequencing-based tools have been developed for the detection of triplet repeat expansions [ • Variants detectable by sequencing have not been associated with DRPLA, but are associated with ## Chapter Notes Silvia Prades, PhD, is actively involved in managing research projects regarding individuals with DRPLA and peer support groups. She would be happy to communicate with persons who have any questions regarding diagnosis of DRPLA or other considerations. Thomas Felton, MS, CGC (2023-present)Marina Frontali, MD; Italian National Research Council (2016-2023) Silvia Grimaldi, MD (2023-present)Henry Houlden, MD, PhD (2023-present)Claudio Melo de Gusmao, MD (2023-present)Silvia Prades, PhD (2023-present)Yael Shiloh-Malawsky, MD (2023-present)Shoji Tsuji, MD, PhD; University of Tokyo Graduate School of Medicine (1999-2016)Liana Veneziano, PhD; Italian National Research Council (2016-2023) 21 September 2023 (bp) Comprehensive update posted live 9 June 2016 (ma) Comprehensive update posted live 1 June 2010 (me) Comprehensive update posted live 22 December 2006 (me) Comprehensive update posted live 15 June 2004 (me) Comprehensive update posted live 24 May 2002 (me) Comprehensive update posted live 6 August 1999 (pb) Review posted live 15 February 1999 (st) Original submission • 21 September 2023 (bp) Comprehensive update posted live • 9 June 2016 (ma) Comprehensive update posted live • 1 June 2010 (me) Comprehensive update posted live • 22 December 2006 (me) Comprehensive update posted live • 15 June 2004 (me) Comprehensive update posted live • 24 May 2002 (me) Comprehensive update posted live • 6 August 1999 (pb) Review posted live • 15 February 1999 (st) Original submission ## Author Notes Silvia Prades, PhD, is actively involved in managing research projects regarding individuals with DRPLA and peer support groups. She would be happy to communicate with persons who have any questions regarding diagnosis of DRPLA or other considerations. ## Author History Thomas Felton, MS, CGC (2023-present)Marina Frontali, MD; Italian National Research Council (2016-2023) Silvia Grimaldi, MD (2023-present)Henry Houlden, MD, PhD (2023-present)Claudio Melo de Gusmao, MD (2023-present)Silvia Prades, PhD (2023-present)Yael Shiloh-Malawsky, MD (2023-present)Shoji Tsuji, MD, PhD; University of Tokyo Graduate School of Medicine (1999-2016)Liana Veneziano, PhD; Italian National Research Council (2016-2023) ## Revision History 21 September 2023 (bp) Comprehensive update posted live 9 June 2016 (ma) Comprehensive update posted live 1 June 2010 (me) Comprehensive update posted live 22 December 2006 (me) Comprehensive update posted live 15 June 2004 (me) Comprehensive update posted live 24 May 2002 (me) Comprehensive update posted live 6 August 1999 (pb) Review posted live 15 February 1999 (st) Original submission • 21 September 2023 (bp) Comprehensive update posted live • 9 June 2016 (ma) Comprehensive update posted live • 1 June 2010 (me) Comprehensive update posted live • 22 December 2006 (me) Comprehensive update posted live • 15 June 2004 (me) Comprehensive update posted live • 24 May 2002 (me) Comprehensive update posted live • 6 August 1999 (pb) Review posted live • 15 February 1999 (st) Original submission ## References ## Literature Cited
[]
6/8/1999
21/9/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
drrs
drrs
[ "Duane-Radial Ray Syndrome (DRRS) / Okihiro Syndrome", "Acro-Renal-Ocular Syndrome (AROS)", "SALL4-Related Holt-Oram Syndrome (HOS)", "Sal-like protein 4", "SALL4", "SALL4-Related Disorders" ]
Jürgen Kohlhase
Summary DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in The diagnosis of a
Duane-radial ray syndrome (DRRS) / Okihiro syndrome Acro-renal-ocular syndrome (AROS) For synonyms and outdated names see • Duane-radial ray syndrome (DRRS) / Okihiro syndrome • Acro-renal-ocular syndrome (AROS) ## Diagnosis Radial ray malformations Renal abnormalities: mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, and bladder diverticula Ocular abnormalities: ocular coloboma and Duane anomaly Upper-extremity malformations: radial, thenar, and/or carpal bones, including preaxial polydactyly Congenital heart malformations: ventricular septal defects, atrial septal defects, and tetralogy of Fallot Cardiac conduction defects (less common than in Note: HOS is a heterogeneous phenotype in which 70% of affected individuals have pathogenic variants in The diagnosis of a Note: Identification of a heterozygous Molecular genetic testing approaches can include single-gene testing (see When the phenotypic findings suggest the diagnosis of a Sequence analysis of If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. When the phenotype falls outside of the typical spectrum of 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. • Radial ray malformations • Renal abnormalities: mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, and bladder diverticula • Ocular abnormalities: ocular coloboma and Duane anomaly • Upper-extremity malformations: radial, thenar, and/or carpal bones, including preaxial polydactyly • Congenital heart malformations: ventricular septal defects, atrial septal defects, and tetralogy of Fallot • Cardiac conduction defects (less common than in • Note: HOS is a heterogeneous phenotype in which 70% of affected individuals have pathogenic variants in • Sequence analysis of • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. ## Suggestive Findings Radial ray malformations Renal abnormalities: mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, and bladder diverticula Ocular abnormalities: ocular coloboma and Duane anomaly Upper-extremity malformations: radial, thenar, and/or carpal bones, including preaxial polydactyly Congenital heart malformations: ventricular septal defects, atrial septal defects, and tetralogy of Fallot Cardiac conduction defects (less common than in Note: HOS is a heterogeneous phenotype in which 70% of affected individuals have pathogenic variants in • Radial ray malformations • Renal abnormalities: mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, and bladder diverticula • Ocular abnormalities: ocular coloboma and Duane anomaly • Upper-extremity malformations: radial, thenar, and/or carpal bones, including preaxial polydactyly • Congenital heart malformations: ventricular septal defects, atrial septal defects, and tetralogy of Fallot • Cardiac conduction defects (less common than in • Note: HOS is a heterogeneous phenotype in which 70% of affected individuals have pathogenic variants in ## Establishing the Diagnosis The diagnosis of a Note: Identification of a heterozygous Molecular genetic testing approaches can include single-gene testing (see When the phenotypic findings suggest the diagnosis of a Sequence analysis of If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. When the phenotype falls outside of the typical spectrum of 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. • Sequence analysis of • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. ## Option 1 When the phenotypic findings suggest the diagnosis of a Sequence analysis of If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • Sequence analysis of • If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. ## Option 2 When the phenotype falls outside of the typical spectrum of 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. ## Clinical Characteristics DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in Of 69 affected individuals from 23 families with a J Kohlhase, unpublished data Most The only clearly pathogenic missense variant identified to date in an individual with malformations ( The only truncating pathogenic variant predicted to escape nonsense-mediated mRNA decay is associated with extensive clinical variability and severe hemifacial microsomia in one affected member of the reported family [ Some pathogenic missense variants have been reported to result in a gain of function, and those variants have been reported to cause premature ovarian failure alone, without developmental disorder (see Penetrance is approximately 95% but may be lower for certain pathogenic variants. Of 69 family members known in 2004 to have a One of the earliest reports of Duane anomaly occurring together with radial ray defects is that of The term "acro-renal-ocular syndrome" was used in 1984 to describe a family with autosomal dominant inheritance of thumb abnormalities, renal malformations, and ocular coloboma, ptosis, and Duane anomaly [ Holt-Oram syndrome has also been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures. The prevalence is unknown, partly because in many countries • DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). • AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. • Rarely, pathogenic variants in ## Clinical Description DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. Rarely, pathogenic variants in Of 69 affected individuals from 23 families with a J Kohlhase, unpublished data • DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs, hypoplasia or aplasia of the radii, shortening and radial deviation of the forearms, triphalangeal thumbs, and duplication of the thumb (preaxial polydactyly). • AROS is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. • Rarely, pathogenic variants in ## Genotype-Phenotype Correlations Most The only clearly pathogenic missense variant identified to date in an individual with malformations ( The only truncating pathogenic variant predicted to escape nonsense-mediated mRNA decay is associated with extensive clinical variability and severe hemifacial microsomia in one affected member of the reported family [ Some pathogenic missense variants have been reported to result in a gain of function, and those variants have been reported to cause premature ovarian failure alone, without developmental disorder (see ## Penetrance Penetrance is approximately 95% but may be lower for certain pathogenic variants. Of 69 family members known in 2004 to have a ## Nomenclature One of the earliest reports of Duane anomaly occurring together with radial ray defects is that of The term "acro-renal-ocular syndrome" was used in 1984 to describe a family with autosomal dominant inheritance of thumb abnormalities, renal malformations, and ocular coloboma, ptosis, and Duane anomaly [ Holt-Oram syndrome has also been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures. ## Prevalence The prevalence is unknown, partly because in many countries ## Genetically Related (Allelic) Disorders Persons with DRRS and developmental delay are likely to have a larger deletion including ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; ASD = atrial septal defect; CHD = congenital heart defect; DD = developmental delay; ID = intellectual delay; MOI = mode of inheritance; Genes are ordered by relevance to the differential diagnosis of Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner ( ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Recommended Evaluations Following Initial Diagnosis in Individuals with Clinical assessment for upper- & lower-extremity anomalies X-rays if needed by orthopedist Renal ultrasound exam Assess renal function w/serum electrolyte concentrations, BUN, & creatinine. Eval by cardiologist Echocardiogram EKG Assess for growth deficiency &/or growth hormone deficiency. Assess for signs/symptoms of pituitary hypoplasia. BUN = blood urea nitrogen; CBC = complete blood count; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Cardiac surgery, if required for congenital heart defect, is standard. Cardiologist can assist in determining need for antiarrhythmic medications & surgery. Persons w/severe heart block may require pacemaker implantation. Recommended Surveillance for Individuals with Every 6-12 mos in 1st yrs of life If renal function remains normal, screening intervals may be extended. Repeat if renal position anomalies could cause obstruction. Frequency depends on clinical situation. EKG Consider Holter monitor. CBC = complete blood count Data are sparse on the natural history of thrombocytopenia in individuals with Drugs affecting renal clearance or the inner ear should be avoided in individuals with impaired renal function and/or hearing impairment. Certain medications may be contraindicated in individuals with arrhythmias. Children of affected persons who are themselves not obviously affected should be tested for the pathogenic variant present in the family because individuals with a See Search • Clinical assessment for upper- & lower-extremity anomalies • X-rays if needed by orthopedist • Renal ultrasound exam • Assess renal function w/serum electrolyte concentrations, BUN, & creatinine. • Eval by cardiologist • Echocardiogram • EKG • Assess for growth deficiency &/or growth hormone deficiency. • Assess for signs/symptoms of pituitary hypoplasia. • Cardiac surgery, if required for congenital heart defect, is standard. • Cardiologist can assist in determining need for antiarrhythmic medications & surgery. • Persons w/severe heart block may require pacemaker implantation. • Every 6-12 mos in 1st yrs of life • If renal function remains normal, screening intervals may be extended. • Repeat if renal position anomalies could cause obstruction. • Frequency depends on clinical situation. • EKG • Consider Holter monitor. ## 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 Clinical assessment for upper- & lower-extremity anomalies X-rays if needed by orthopedist Renal ultrasound exam Assess renal function w/serum electrolyte concentrations, BUN, & creatinine. Eval by cardiologist Echocardiogram EKG Assess for growth deficiency &/or growth hormone deficiency. Assess for signs/symptoms of pituitary hypoplasia. BUN = blood urea nitrogen; CBC = complete blood count; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Clinical assessment for upper- & lower-extremity anomalies • X-rays if needed by orthopedist • Renal ultrasound exam • Assess renal function w/serum electrolyte concentrations, BUN, & creatinine. • Eval by cardiologist • Echocardiogram • EKG • Assess for growth deficiency &/or growth hormone deficiency. • Assess for signs/symptoms of pituitary hypoplasia. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Cardiac surgery, if required for congenital heart defect, is standard. Cardiologist can assist in determining need for antiarrhythmic medications & surgery. Persons w/severe heart block may require pacemaker implantation. • Cardiac surgery, if required for congenital heart defect, is standard. • Cardiologist can assist in determining need for antiarrhythmic medications & surgery. • Persons w/severe heart block may require pacemaker implantation. ## Surveillance Recommended Surveillance for Individuals with Every 6-12 mos in 1st yrs of life If renal function remains normal, screening intervals may be extended. Repeat if renal position anomalies could cause obstruction. Frequency depends on clinical situation. EKG Consider Holter monitor. CBC = complete blood count Data are sparse on the natural history of thrombocytopenia in individuals with • Every 6-12 mos in 1st yrs of life • If renal function remains normal, screening intervals may be extended. • Repeat if renal position anomalies could cause obstruction. • Frequency depends on clinical situation. • EKG • Consider Holter monitor. ## Agents/Circumstances to Avoid Drugs affecting renal clearance or the inner ear should be avoided in individuals with impaired renal function and/or hearing impairment. Certain medications may be contraindicated in individuals with arrhythmias. ## Evaluation of Relatives at Risk Children of affected persons who are themselves not obviously affected should be tested for the pathogenic variant present in the family because individuals with a See ## Therapies Under Investigation Search ## Genetic Counseling Many individuals diagnosed with a A proband with a Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include 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 a If a parent of the proband is affected and/or has a If the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. 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. • Many individuals diagnosed with a • A proband with a • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include 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 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. • If a parent of the proband is affected and/or has a • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Many individuals diagnosed with a A proband with a Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include 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 a If a parent of the proband is affected and/or has a If the If the parents have not been tested for the • Many individuals diagnosed with a • A proband with a • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include 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 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. • If a parent of the proband is affected and/or has a • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing 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 SALL4-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SALL4-Related Disorders ( Apart from its role in embryonic and stem cell development, Sall4 is involved in malignant transformation. More than 1,000 putative One pathogenic variant, Another pathogenic variant, Missense variants reported to be causative for premature ovarian insufficiency have been reported to result in a gain of function [ Notable Variants listed in the table have been provided by the author. ## Molecular Pathogenesis Apart from its role in embryonic and stem cell development, Sall4 is involved in malignant transformation. More than 1,000 putative One pathogenic variant, Another pathogenic variant, Missense variants reported to be causative for premature ovarian insufficiency have been reported to result in a gain of function [ Notable Variants listed in the table have been provided by the author. ## Chapter Notes The author's research has received funding from the Wilhelm-Sander-Stiftung of Germany, a nonprofit organization funding medical research, and from the Deutsche Forschungsgemeinschaft. SYNLAB Center for 17 March 2022 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis 19 January 2007 (me) Comprehensive update posted live 16 August 2004 (ca) Review posted live 1 March 2004 (jk) Original submission • 17 March 2022 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis • 19 January 2007 (me) Comprehensive update posted live • 16 August 2004 (ca) Review posted live • 1 March 2004 (jk) Original submission ## Acknowledgments The author's research has received funding from the Wilhelm-Sander-Stiftung of Germany, a nonprofit organization funding medical research, and from the Deutsche Forschungsgemeinschaft. ## Author Notes SYNLAB Center for ## Revision History 17 March 2022 (sw) Comprehensive update posted live 15 January 2015 (me) Comprehensive update posted live 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis 19 January 2007 (me) Comprehensive update posted live 16 August 2004 (ca) Review posted live 1 March 2004 (jk) Original submission • 17 March 2022 (sw) Comprehensive update posted live • 15 January 2015 (me) Comprehensive update posted live • 12 March 2008 (cd) Revision: FISH analysis available on a clinical basis • 19 January 2007 (me) Comprehensive update posted live • 16 August 2004 (ca) Review posted live • 1 March 2004 (jk) Original submission ## References ## Literature Cited
[ "R Al-Baradie, K Yamada, C St Hilaire, WM Chan, C Andrews, N McIntosh, M Nakano, EJ Martonyi, WR Raymond, S Okumura, MM Okihiro, EC Engle. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family.. Am J Hum Genet 2002;71:1195-9", "W Borozdin, D Boehm, M Leipoldt, C Wilhem, W Reardon, J Clayton-Smith, K Becker, H Muhlendyck, R Winter, O Giray, F Silan, J Kohlhase. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenetic mechanism.. J Med Genet 2004a;41", "W Borozdin, JM Graham, D Boehm, MJ Bamshad, S Spranger, L Burke, M Leipoldt, J Kohlhase. Multigene deletions on chromosome 20q13.13-q13.2 including SALL4 result in an expanded phenotype of Okihiro syndrome plus developmental delay.. Hum Mutat 2007;28:830", "W Borozdin, MJ Wright, RC Hennekam, MC Hannibal, YJ Crow, TE Neumann, J Kohlhase. Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum.. J Med Genet 2004b;41", "RL Ferrell, B Jones, RV Lucas. Simultaneous occurrence of the Holt-Oram and the Duane syndromes.. J Pediatr 1966;69:630-4", "C Gao, T Dimitrov, KJ Yong, H Tatetsu, HW Jeong, HR Luo, JE Bradner, DG Tenen, L Chai. Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex.. Blood. 2013;121:1413-21", "F Halal, M Homsy, G Perreault. Acro-renal-ocular syndrome: autosomal dominant thumb hypoplasia, renal ectopia, and eye defect.. Am J Med Genet 1984;17:753-62", "A Hayes, T Costa, RC Polomeno. The Okihiro syndrome of Duane anomaly, radial ray abnormalities, and deafness.. Am J Med Genet 1985;22:273-80", "HW Jeong, W Cui, Y Yang, J Lu, J He, A Li, D Song, Y Guo, BH Liu, L Chai. SALL4, a stem cell factor, affects the side population by regulation of the ATP-binding cassette drug transport genes.. PLoS One. 2011;6", "J Kohlhase, D Chitayat, D Kotzot, S Ceylaner, UG Froster, S Fuchs, T Montgomery, B Rosler. SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders.. Hum Mutat 2005;26:176-83", "J Kohlhase, M Heinrich, L Schubert, M Liebers, A Kispert, F Laccone, P Turnpenny, RM Winter, W Reardon. Okihiro syndrome is caused by SALL4 mutations.. Hum Mol Genet 2002;11:2979-87", "J Kohlhase, L Schubert, M Liebers, A Rauch, K Becker, SN Mohammed, R Newbury-Ecob, W Reardon. Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy.. J Med Genet 2003;40:473-8", "E McCann, AE Fryer, W Newman, RE Appleton, J Kohlhase. A family with Duane anomaly and distal limb abnormalities: a further family with the arthrogryposis-ophthalmoplegia syndrome.. Am J Med Genet A. 2005;139A:123-6", "J Miertus, W Borozdin, V Frecer, G Tonini, S Bertok, A Amoroso, S Miertus, J Kohlhase. A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome.. Hum Genet 2006;119:154-61", "MM Okihiro, T Tasaki, KK Nakano, BK Bennett. Duane syndrome and congenital upper-limb anomalies. A familial occurrence.. Arch Neurol 1977;34:174-9", "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", "SA Temtamy, AS Shoukry, I Ghaly, R El-Meligy, SY Boulos. The Duane radial dysplasia syndrome: an autosomal dominant disorder.. Birth Defects Orig Art Ser 1975;XI:344-5", "P Terhal, B Rosler, J Kohlhase. A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation.. Am J Med Genet A 2006;140:222-6", "R van de Putte, GC Dworschak, E Brosens, HM Reutter, CLM Marcelis, R Acuna-Hidalgo, NE Kurtas, M Steehouwer, SL Dunwoodie, E Schmiedeke, S Märzheuser, N Schwarzer, AS Brooks, A de Klein, CEJ Sloots, D Tibboel, G Brisighelli, A Morandi, MF Bedeschi, MD Bates, MA Levitt, A Peña, I de Blaauw, N Roeleveld, HG Brunner, IALM van Rooij, A Hoischen. A genetics-first approach revealed monogenic disorders in patients with ARM and VACTERL anomalies.. Front Pediatr. 2020;8:310", "C Vanlerberghe, AS Jourdain, J Ghoumid, F Frenois, A Mezel, G Vaksmann, B Lenne, B Delobel, N Porchet, V Cormier-Daire, T Smol, F Escande, S Manouvrier-Hanu, F Petit. Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants.. Eur J Hum Genet. 2019;27:360-8", "B Wang, L Li, X Xie, J Wang, J Yan, Y Mu, X. Ma. Genetic variation of SAL-Like 4 (SALL4) in ventricular septal defect.. Int J Cardiol. 2010;145:224-6", "Q Wang, D Li, B Cai, Q Chen, C Li, Y Wu, L Jin, X Wang, X Zhang, F. Zhang. Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype-phenotype correlations.. Hum Genet. 2019;138:83-92", "Q Wu, X Chen, J Zhang, YH Loh, TY Low, W Zhang, W Zhang, SK Sze, B Lim, HH Ng. Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells.. J Biol Chem 2006;281:24090-4", "J Yang, L Chai, C Gao, TC Fowles, Z Alipio, H Dang, D Xu, LM Fink, DC Ward, Y Ma. SALL4 is a key regulator of survival and apoptosis in human leukemic cells.. Blood. 2008;112:805-13", "KJ Yong, C Gao, JS Lim, B Yan, H Yang, T Dimitrov, A Kawasaki, CW Ong, KF Wong, S Lee, S Ravikumar, S Srivastava, X Tian, RT Poon, ST Fan, JM Luk, YY Dan, M Salto-Tellez, L Chai, DG Tenen. Oncofetal gene SALL4 in aggressive hepatocellular carcinoma.. N Engl J Med. 2013;368:2266-76" ]
16/8/2004
17/3/2022
12/3/2008
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
duane
duane
[ "Duane Anomaly, Isolated", "Duane Retraction Syndrome", "Stilling-Turk-Duane Syndrome", "Duane Retraction Syndrome", "Stilling-Turk-Duane Syndrome", "Duane Anomaly, Isolated", "N-chimaerin", "Sal-like protein 4", "Transcription factor MafB", "CHN1", "MAFB", "SALL4", "Duane Syndrome" ]
Duane Syndrome
Brenda J Barry, Mary C Whitman, David G Hunter, Elizabeth C Engle
Summary Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly results from failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle; globe retraction occurs as a result of abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Many individuals with Duane syndrome have strabismus in primary gaze but can use a compensatory head turn to align the eyes, and thus can preserve binocular vision and avoid diplopia. Individuals with Duane syndrome who lack binocular vision are at risk for amblyopia. The majority of affected individuals with Duane syndrome have isolated Duane syndrome (i.e., they do not have other detected congenital anomalies). Other individuals with Duane syndrome fall into well-defined syndromic diagnoses. However, many individuals with Duane syndrome have non-ocular findings that do not fit a known syndrome; these individuals are included as part of the discussion of nonsyndromic Duane syndrome. The diagnosis of Duane syndrome is usually made by an ophthalmologist based on clinical findings. More than 98% of individuals with isolated Duane syndrome and no family history lack an identified genetic etiology. Molecular genetic testing for a pathogenic variant in The majority of individuals with isolated Duane syndrome represent simplex cases (i.e., a single occurrence in a family), with a positive family history apparent for only approximately 10% of affected individuals. Duane syndrome resulting from a
## Diagnosis Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The diagnosis of Duane syndrome is based on clinical findings and classified into three types (see Most affected individuals with Duane syndrome have isolated Duane syndrome (i.e., they do not have other detected congenital anomalies). Other individuals fall into well-defined syndromic diagnoses (see The vast majority of individuals with isolated Duane syndrome represent simplex cases (i.e., a single occurrence in a family). A positive family history showing autosomal dominant inheritance is apparent for approximately 10% of affected individuals [ Duane syndrome, a congenital, non-progressive eye movement disorder, Congenital limited horizontal eye movement with impairment of abduction and/or adduction Globe retraction (co-contraction) accompanied by narrowing of the palpebral fissure (i.e., reduced distance between the upper and lower eyelids) on adduction. Note: Adduction is movement of the globe toward the midline (the nose); abduction is movement of the globe toward the ear, away ("abducted") from the midline. Clinical Findings: Comparison of Duane Syndrome Types I-III Note: An alternative simpler classification is to note the deviation in primary gaze (esotropic or exotropic Duane syndrome) and specify whether there is limitation of adduction, abduction, or both. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [ A positive family history of Duane syndrome. After finding a Due to variable expressivity, individuals with a Bilateral Duane syndrome. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [ Duane syndrome type I or type III or a combination of those types. Duane syndrome type II has not been observed in those with a positive family history or in individuals with pathogenic variants in the identified genes, suggesting a distinct etiology [ Molecular genetic testing approaches can include Note: (1) If serial gene analysis is to be performed for isolated Duane syndrome, sequence analysis 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 Duane 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. Probands with familial Duane syndrome described in: Probands with a family history negative for Duane syndrome described in No data on detection rate of gene-targeted deletion/duplication analysis are available; however, since Three of 77 individuals with familial Duane syndrome had a pathogenic variant in Isolated Duane syndrome was observed in one of eight and one of four affected individuals in two families with a pathogenic variant in Note: The testing recommendations in this section are for individuals with Duane syndrome, either isolated or with one or more non-ocular anomalies that do not constitute an established or recognizable syndrome. If an individual presents with Duane syndrome plus significant anomalies that suggest the possibility of a chromosome abnormality, testing with chromosome microarray analysis (CMA) can be considered. • Congenital limited horizontal eye movement with impairment of abduction and/or adduction • Globe retraction (co-contraction) accompanied by narrowing of the palpebral fissure (i.e., reduced distance between the upper and lower eyelids) on adduction. • A positive family history of Duane syndrome. • After finding a • Due to variable expressivity, individuals with a • After finding a • Due to variable expressivity, individuals with a • Bilateral Duane syndrome. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [ • Duane syndrome type I or type III or a combination of those types. Duane syndrome type II has not been observed in those with a positive family history or in individuals with pathogenic variants in the identified genes, suggesting a distinct etiology [ • After finding a • Due to variable expressivity, individuals with a • Note: (1) If serial gene analysis is to be performed for isolated Duane syndrome, sequence analysis • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click ## Suggestive Findings Duane syndrome, a congenital, non-progressive eye movement disorder, Congenital limited horizontal eye movement with impairment of abduction and/or adduction Globe retraction (co-contraction) accompanied by narrowing of the palpebral fissure (i.e., reduced distance between the upper and lower eyelids) on adduction. Note: Adduction is movement of the globe toward the midline (the nose); abduction is movement of the globe toward the ear, away ("abducted") from the midline. • Congenital limited horizontal eye movement with impairment of abduction and/or adduction • Globe retraction (co-contraction) accompanied by narrowing of the palpebral fissure (i.e., reduced distance between the upper and lower eyelids) on adduction. ## Establishing the Diagnosis Clinical Findings: Comparison of Duane Syndrome Types I-III Note: An alternative simpler classification is to note the deviation in primary gaze (esotropic or exotropic Duane syndrome) and specify whether there is limitation of adduction, abduction, or both. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [ A positive family history of Duane syndrome. After finding a Due to variable expressivity, individuals with a Bilateral Duane syndrome. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [ Duane syndrome type I or type III or a combination of those types. Duane syndrome type II has not been observed in those with a positive family history or in individuals with pathogenic variants in the identified genes, suggesting a distinct etiology [ Molecular genetic testing approaches can include Note: (1) If serial gene analysis is to be performed for isolated Duane syndrome, sequence analysis 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 Duane 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. Probands with familial Duane syndrome described in: Probands with a family history negative for Duane syndrome described in No data on detection rate of gene-targeted deletion/duplication analysis are available; however, since Three of 77 individuals with familial Duane syndrome had a pathogenic variant in Isolated Duane syndrome was observed in one of eight and one of four affected individuals in two families with a pathogenic variant in Note: The testing recommendations in this section are for individuals with Duane syndrome, either isolated or with one or more non-ocular anomalies that do not constitute an established or recognizable syndrome. If an individual presents with Duane syndrome plus significant anomalies that suggest the possibility of a chromosome abnormality, testing with chromosome microarray analysis (CMA) can be considered. • A positive family history of Duane syndrome. • After finding a • Due to variable expressivity, individuals with a • After finding a • Due to variable expressivity, individuals with a • Bilateral Duane syndrome. The eye findings are more likely to be bilateral in familial cases and in those in whom a pathogenic variant is identified in one of the known associated genes [ • Duane syndrome type I or type III or a combination of those types. Duane syndrome type II has not been observed in those with a positive family history or in individuals with pathogenic variants in the identified genes, suggesting a distinct etiology [ • After finding a • Due to variable expressivity, individuals with a • Note: (1) If serial gene analysis is to be performed for isolated Duane syndrome, sequence analysis • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly is due to failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle, with globe retraction occurring due to abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Affected individuals may also have upshoot or downshoot of the affected eye on attempted adduction. For reasons yet to be determined, the left side is more commonly affected; this is supported by the authors' internal data showing that the left side is affected in 70% of unilateral cases [ Duane syndrome is often reported as more common in females than in males, particularly in unilateral and simplex cases [ Restriction in vertical movement of the eyes may also be found in some individuals with Duane syndrome, depending on the associated gene (see Although esotropia is more common in most studies, a recent report found that nearly a third of individuals with Duane syndrome seen at a tertiary care center in south India had exotropia [ While movement of the affected eye is impaired, when the contralateral eye is able to move freely, it allows individuals with strabismus in primary gaze to use a compensatory head turn in order to align the eyes, thus avoiding diplopia and preserving single binocular vision. Infraduction of the affected eye in attempted lateral gaze; this occurs in the majority of cases [ Marcus Gunn jaw-winking phenomenon (upper eyelid movement/fluttering each time the jaw opens and closes) [ An exaggerated oculo-auricular phenomenon (coactivation of external ear muscles during lateral gaze) [ Crocodile tears (tearing with chewing due to aberrant facial salivary fibers innervating the lacrimal gland) [ Magnetic resonance imaging (MRI) in simplex cases (without a pathogenic variant identified in any known gene) has verified the absence or severe hypoplasia of the abducens nerve, often with normal appearance of the lateral rectus muscle [ It is generally believed that Duane syndrome results from maldevelopment of motor neurons in the abducens nucleus and aberrant innervation of the lateral rectus muscle [ The decreased superior oblique muscle volume observed on MRI, supporting trochlear nerve hypoplasia, leads to the suggestion that Duane syndrome resulting from pathogenic variants in Animal models of both Most affected individuals with Duane syndrome have isolated Duane syndrome without other congenital anomalies. Published estimates of individuals with other systemic findings range from lows of under 10% [ From the authors' unpublished data, 26.7% of individuals with Duane syndrome who do not have a pathogenic variant in any of the currently known associated genes have non-ocular findings, ranging from minor anomalies such as preauricular tags to more severe conditions such as Hirschsprung disease. Families with Duane syndrome in whom a There has been no evidence of reduced penetrance in the limited number of families with isolated Duane syndrome identified with Duane syndrome is named for the ophthalmologist Alexander Duane (1858-1926). Historically, Duane syndrome was initially proposed to be myogenic in origin. Electromyography of the extraocular muscles, postmortem examinations, and MRI, however, now support a neurogenic etiology [ Duane syndrome accounts for 1%-5% of all cases of strabismus. Isolated Duane syndrome in familial and simplex cases has been identified worldwide. The prevalence of Duane syndrome is estimated at between 1:1,000 and 1:10,000 in the general population [ • Although esotropia is more common in most studies, a recent report found that nearly a third of individuals with Duane syndrome seen at a tertiary care center in south India had exotropia [ • While movement of the affected eye is impaired, when the contralateral eye is able to move freely, it allows individuals with strabismus in primary gaze to use a compensatory head turn in order to align the eyes, thus avoiding diplopia and preserving single binocular vision. • Infraduction of the affected eye in attempted lateral gaze; this occurs in the majority of cases [ • Marcus Gunn jaw-winking phenomenon (upper eyelid movement/fluttering each time the jaw opens and closes) [ • An exaggerated oculo-auricular phenomenon (coactivation of external ear muscles during lateral gaze) [ • Crocodile tears (tearing with chewing due to aberrant facial salivary fibers innervating the lacrimal gland) [ ## Clinical Description Duane syndrome is a strabismus condition clinically characterized by congenital non-progressive limited horizontal eye movement accompanied by globe retraction which results in narrowing of the palpebral fissure. The lateral movement anomaly is due to failure of the abducens nucleus and nerve (cranial nerve VI) to fully innervate the lateral rectus muscle, with globe retraction occurring due to abnormal innervation of the lateral rectus muscle by the oculomotor nerve (cranial nerve III). At birth, affected infants have restricted ability to move the affected eye(s) outward (abduction) and/or inward (adduction), though the limitations may not be recognized in early infancy. In addition, the globe retracts into the orbit with attempted adduction, accompanied by narrowing of the palpebral fissure. Affected individuals may also have upshoot or downshoot of the affected eye on attempted adduction. For reasons yet to be determined, the left side is more commonly affected; this is supported by the authors' internal data showing that the left side is affected in 70% of unilateral cases [ Duane syndrome is often reported as more common in females than in males, particularly in unilateral and simplex cases [ Restriction in vertical movement of the eyes may also be found in some individuals with Duane syndrome, depending on the associated gene (see Although esotropia is more common in most studies, a recent report found that nearly a third of individuals with Duane syndrome seen at a tertiary care center in south India had exotropia [ While movement of the affected eye is impaired, when the contralateral eye is able to move freely, it allows individuals with strabismus in primary gaze to use a compensatory head turn in order to align the eyes, thus avoiding diplopia and preserving single binocular vision. Infraduction of the affected eye in attempted lateral gaze; this occurs in the majority of cases [ Marcus Gunn jaw-winking phenomenon (upper eyelid movement/fluttering each time the jaw opens and closes) [ An exaggerated oculo-auricular phenomenon (coactivation of external ear muscles during lateral gaze) [ Crocodile tears (tearing with chewing due to aberrant facial salivary fibers innervating the lacrimal gland) [ Magnetic resonance imaging (MRI) in simplex cases (without a pathogenic variant identified in any known gene) has verified the absence or severe hypoplasia of the abducens nerve, often with normal appearance of the lateral rectus muscle [ • Although esotropia is more common in most studies, a recent report found that nearly a third of individuals with Duane syndrome seen at a tertiary care center in south India had exotropia [ • While movement of the affected eye is impaired, when the contralateral eye is able to move freely, it allows individuals with strabismus in primary gaze to use a compensatory head turn in order to align the eyes, thus avoiding diplopia and preserving single binocular vision. • Infraduction of the affected eye in attempted lateral gaze; this occurs in the majority of cases [ • Marcus Gunn jaw-winking phenomenon (upper eyelid movement/fluttering each time the jaw opens and closes) [ • An exaggerated oculo-auricular phenomenon (coactivation of external ear muscles during lateral gaze) [ • Crocodile tears (tearing with chewing due to aberrant facial salivary fibers innervating the lacrimal gland) [ ## Pathophysiology It is generally believed that Duane syndrome results from maldevelopment of motor neurons in the abducens nucleus and aberrant innervation of the lateral rectus muscle [ The decreased superior oblique muscle volume observed on MRI, supporting trochlear nerve hypoplasia, leads to the suggestion that Duane syndrome resulting from pathogenic variants in Animal models of both ## Other Anomalies Most affected individuals with Duane syndrome have isolated Duane syndrome without other congenital anomalies. Published estimates of individuals with other systemic findings range from lows of under 10% [ From the authors' unpublished data, 26.7% of individuals with Duane syndrome who do not have a pathogenic variant in any of the currently known associated genes have non-ocular findings, ranging from minor anomalies such as preauricular tags to more severe conditions such as Hirschsprung disease. ## Genotype-Phenotype Correlations ## Penetrance Families with Duane syndrome in whom a There has been no evidence of reduced penetrance in the limited number of families with isolated Duane syndrome identified with ## Nomenclature Duane syndrome is named for the ophthalmologist Alexander Duane (1858-1926). Historically, Duane syndrome was initially proposed to be myogenic in origin. Electromyography of the extraocular muscles, postmortem examinations, and MRI, however, now support a neurogenic etiology [ ## Prevalence Duane syndrome accounts for 1%-5% of all cases of strabismus. Isolated Duane syndrome in familial and simplex cases has been identified worldwide. The prevalence of Duane syndrome is estimated at between 1:1,000 and 1:10,000 in the general population [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Duane Syndrome with Associated Congenital Anomalies Anal, ear, limb & renal anomalies Additional ophthalmic findings: coloboma, ptosis, epibulbar dermoid, & crocodile tears Note: Ocular findings are usually Duane syndrome type III or horizontal gaze palsy Bilateral sensorineural hearing loss caused by absent cochlea & rudimentary inner-ear development Subsets of individuals manifest ID, autism, moderate-to-severe central hypoventilation, facial weakness, swallowing difficulties, vocal cord paresis, conotruncal heart defects, & skull & craniofacial abnormalities Deafness Klippel-Feil anomaly (fused cervical vertebrae) AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; ID = intellectual disability; MOI = mode of inheritance; NA = not applicable Most Wildervanck syndrome is sporadic and limited to females. A case report describes a male with Wildervanck syndrome and a 3-kb deletion at Xq26.3 encompassing one gene, Several individuals with Duane syndrome have been reported to have chromosome 8 anomalies: anomalies of the 8q13 DURS1 locus (OMIM Other chromosome aberrations associated with Duane syndrome have been reported to involve 2q13, 4q27-31, 6p25, 7, 10q24.2q26.3, 12q24.31, 19q13.4, 20q13.12, and 22pter-q13.31. Duane syndrome has been described in one individual with 48,XXYY syndrome and another with atypical Silver-Russell syndrome, Duane syndrome, and maternal uniparental disomy of chromosome 7. Individuals with Duane syndrome and associated congenital defects should be evaluated further for possible underlying chromosomal rearrangements. Duane syndrome is the most common of the CCDDs. Other ocular CCDDs include those in Other Congenital Cranial Dysinnervation Disorders to Consider in the Differential Diagnosis of Duane Syndrome AR AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least seven genetically defined syndromes: CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, and Tukel syndrome. Strabismus-Associated Disorders to Consider in the Differential Diagnosis of Duane Syndrome • Anal, ear, limb & renal anomalies • Additional ophthalmic findings: coloboma, ptosis, epibulbar dermoid, & crocodile tears • Note: Ocular findings are usually Duane syndrome type III or horizontal gaze palsy • Bilateral sensorineural hearing loss caused by absent cochlea & rudimentary inner-ear development • Subsets of individuals manifest ID, autism, moderate-to-severe central hypoventilation, facial weakness, swallowing difficulties, vocal cord paresis, conotruncal heart defects, & skull & craniofacial abnormalities • Deafness • Klippel-Feil anomaly (fused cervical vertebrae) ## Management To establish the extent of disease and needs in an individual diagnosed with Duane syndrome, the following evaluations are recommended if they have not already been completed: Family history Ophthalmologic examination Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. Optional forced duction testing and/or force generation testing in cooperative individuals Photographic documentation to identify changes in the condition and for future review If surgery is planned, consideration of brain and orbital MRI to determine brain stem and orbital anatomy (muscles and nerves) General physical examination to look for systemic anomalies that can be found in individuals with Duane syndrome Hearing evaluation Consultation with a clinical geneticist and/or genetic counselor Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem. Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the 1st years of life) maximizes the likelihood of a good response to treatment. Prism glasses may improve the compensatory head position in mild cases. They are more likely to be tolerated by older persons. Correction of hypermetropic refractive error in children may reduce the angle of strabismus and thus decrease the angle of head turn. Surgical intervention is usually pursued when any of the following criteria are met: Symptomatic compensatory head posture Deviation in primary gaze sufficient to provoke diplopia or amblyopia Disfiguring upshoot or downshoot in adduction Note: Surgery does not generally improve abduction of the affected eye, though transposition procedures may provide partial improvement. Tightness of the medial rectus muscle can add to the technical difficulty of the surgical procedure. Postoperative overcorrection in side gaze, a common occurrence, can create new-onset diplopia. In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. Surveillance is important for prevention of amblyopia, and to treat amblyopia if it occurs. Routine ophthalmologic visits every three to six months during the first years of life Annual or biannual examinations in affected individuals once the presence of binocular vision and reduced risk for amblyopia is confirmed, and in all individuals older than age seven to 12 No surveillance in adulthood beyond public health guidelines Ophthalmologic examination within the first year of life is appropriate in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. See Search • Family history • Ophthalmologic examination • Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the • Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. • Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the • Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. • Optional forced duction testing and/or force generation testing in cooperative individuals • Photographic documentation to identify changes in the condition and for future review • If surgery is planned, consideration of brain and orbital MRI to determine brain stem and orbital anatomy (muscles and nerves) • General physical examination to look for systemic anomalies that can be found in individuals with Duane syndrome • Hearing evaluation • Consultation with a clinical geneticist and/or genetic counselor • Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the • Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. • Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem. • Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the 1st years of life) maximizes the likelihood of a good response to treatment. • Prism glasses may improve the compensatory head position in mild cases. They are more likely to be tolerated by older persons. • Correction of hypermetropic refractive error in children may reduce the angle of strabismus and thus decrease the angle of head turn. • Surgical intervention is usually pursued when any of the following criteria are met: • Symptomatic compensatory head posture • Deviation in primary gaze sufficient to provoke diplopia or amblyopia • Disfiguring upshoot or downshoot in adduction • Note: Surgery does not generally improve abduction of the affected eye, though transposition procedures may provide partial improvement. • Symptomatic compensatory head posture • Deviation in primary gaze sufficient to provoke diplopia or amblyopia • Disfiguring upshoot or downshoot in adduction • Tightness of the medial rectus muscle can add to the technical difficulty of the surgical procedure. • Postoperative overcorrection in side gaze, a common occurrence, can create new-onset diplopia. • In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. • In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. • In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. • In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. • Symptomatic compensatory head posture • Deviation in primary gaze sufficient to provoke diplopia or amblyopia • Disfiguring upshoot or downshoot in adduction • In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. • In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. • Routine ophthalmologic visits every three to six months during the first years of life • Annual or biannual examinations in affected individuals once the presence of binocular vision and reduced risk for amblyopia is confirmed, and in all individuals older than age seven to 12 • No surveillance in adulthood beyond public health guidelines ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Duane syndrome, the following evaluations are recommended if they have not already been completed: Family history Ophthalmologic examination Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. Optional forced duction testing and/or force generation testing in cooperative individuals Photographic documentation to identify changes in the condition and for future review If surgery is planned, consideration of brain and orbital MRI to determine brain stem and orbital anatomy (muscles and nerves) General physical examination to look for systemic anomalies that can be found in individuals with Duane syndrome Hearing evaluation Consultation with a clinical geneticist and/or genetic counselor • Family history • Ophthalmologic examination • Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the • Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. • Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the • Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. • Optional forced duction testing and/or force generation testing in cooperative individuals • Photographic documentation to identify changes in the condition and for future review • If surgery is planned, consideration of brain and orbital MRI to determine brain stem and orbital anatomy (muscles and nerves) • General physical examination to look for systemic anomalies that can be found in individuals with Duane syndrome • Hearing evaluation • Consultation with a clinical geneticist and/or genetic counselor • Determination of deviation in primary gaze, anomalous head position, and horizontal and vertical gaze restrictions • Evaluation for aberrant movements. Globe retraction with narrowing of the palpebral fissure in adduction is the • Full ophthalmologic exam to assess for refractive errors, amblyopia, or amblyopia risk factors. ## Treatment of Manifestations Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem. Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the 1st years of life) maximizes the likelihood of a good response to treatment. Prism glasses may improve the compensatory head position in mild cases. They are more likely to be tolerated by older persons. Correction of hypermetropic refractive error in children may reduce the angle of strabismus and thus decrease the angle of head turn. Surgical intervention is usually pursued when any of the following criteria are met: Symptomatic compensatory head posture Deviation in primary gaze sufficient to provoke diplopia or amblyopia Disfiguring upshoot or downshoot in adduction Note: Surgery does not generally improve abduction of the affected eye, though transposition procedures may provide partial improvement. Tightness of the medial rectus muscle can add to the technical difficulty of the surgical procedure. Postoperative overcorrection in side gaze, a common occurrence, can create new-onset diplopia. In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. • Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem. • Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the 1st years of life) maximizes the likelihood of a good response to treatment. • Prism glasses may improve the compensatory head position in mild cases. They are more likely to be tolerated by older persons. • Correction of hypermetropic refractive error in children may reduce the angle of strabismus and thus decrease the angle of head turn. • Surgical intervention is usually pursued when any of the following criteria are met: • Symptomatic compensatory head posture • Deviation in primary gaze sufficient to provoke diplopia or amblyopia • Disfiguring upshoot or downshoot in adduction • Note: Surgery does not generally improve abduction of the affected eye, though transposition procedures may provide partial improvement. • Symptomatic compensatory head posture • Deviation in primary gaze sufficient to provoke diplopia or amblyopia • Disfiguring upshoot or downshoot in adduction • Tightness of the medial rectus muscle can add to the technical difficulty of the surgical procedure. • Postoperative overcorrection in side gaze, a common occurrence, can create new-onset diplopia. • In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. • In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. • In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. • In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. • Symptomatic compensatory head posture • Deviation in primary gaze sufficient to provoke diplopia or amblyopia • Disfiguring upshoot or downshoot in adduction • In esotropic Duane syndrome, diplopia occurs due to exotropia in gaze away from the affected side. • In exotropic Duane syndrome, diplopia occurs due to an increase in esotropia in gaze toward the affected side. ## Surveillance Surveillance is important for prevention of amblyopia, and to treat amblyopia if it occurs. Routine ophthalmologic visits every three to six months during the first years of life Annual or biannual examinations in affected individuals once the presence of binocular vision and reduced risk for amblyopia is confirmed, and in all individuals older than age seven to 12 No surveillance in adulthood beyond public health guidelines • Routine ophthalmologic visits every three to six months during the first years of life • Annual or biannual examinations in affected individuals once the presence of binocular vision and reduced risk for amblyopia is confirmed, and in all individuals older than age seven to 12 • No surveillance in adulthood beyond public health guidelines ## Evaluation of Relatives at Risk Ophthalmologic examination within the first year of life is appropriate in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. See ## Therapies Under Investigation Search ## Genetic Counseling Typically, Duane syndrome occurs in a single affected family member and the molecular basis of the condition is unknown. Familial Duane syndrome represents about 10% of all Duane syndrome [ Duane syndrome resulting from a heterozygous pathogenic variant in Most individuals with isolated Rarely, an individual 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 leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with Duane syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (see 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%. There may be phenotypic variability within families regarding unilateral vs bilateral involvement or, in If the proband has a known Duane syndrome-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 Duane syndrome-related pathogenic variant 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 an increased risk for Duane syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic 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 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Duane syndrome are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals with isolated • Rarely, an individual 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 leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with Duane syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (see • 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%. There may be phenotypic variability within families regarding unilateral vs bilateral involvement or, in • If the proband has a known Duane syndrome-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 Duane syndrome-related pathogenic variant 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 an increased risk for Duane syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic 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 Typically, Duane syndrome occurs in a single affected family member and the molecular basis of the condition is unknown. Familial Duane syndrome represents about 10% of all Duane syndrome [ Duane syndrome resulting from a heterozygous pathogenic variant in ## Risk to Family Members (Autosomal Dominant Inheritance) Most individuals with isolated Rarely, an individual 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 leukocyte DNA of either parent, possible explanations include a The family history of some individuals diagnosed with Duane syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (see 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%. There may be phenotypic variability within families regarding unilateral vs bilateral involvement or, in If the proband has a known Duane syndrome-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 Duane syndrome-related pathogenic variant 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 an increased risk for Duane syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Most individuals with isolated • Rarely, an individual 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 leukocyte DNA of either parent, possible explanations include a • The family history of some individuals diagnosed with Duane syndrome may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (see • 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%. There may be phenotypic variability within families regarding unilateral vs bilateral involvement or, in • If the proband has a known Duane syndrome-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 Duane syndrome-related pathogenic variant 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 an increased risk for Duane syndrome because of the possibility of reduced penetrance in a heterozygous parent or the theoretic 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 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Duane syndrome 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 211 West Wacker Drive Suite 1700 Chicago IL 60606 • • • • • • 211 West Wacker Drive • Suite 1700 • Chicago IL 60606 • ## Molecular Genetics Duane Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Duane Syndrome ( N-terminal SH2 domain C-terminal RhoGAP domain Central C1 domain similar to protein kinase C No pathogenic variants have been identified in the N-terminal SH2 domain. The longest isoform Extended homology region (EHR) Basic region (BR) required for DNA binding LZ domain required for dimerization N-chimaerin: A chick in vivo system was used to demonstrate that N-chimaerin overactivity results in axons terminated prematurely adjacent to the dorsal rectus muscle [ Knock-in mice with the p.Leu20Phe Homozygous Heterozygous Homozygous Heterozygous These allelic series in mice indicate that different tissues have different sensitivity to loss of Duane Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from • N-terminal SH2 domain • C-terminal RhoGAP domain • Central C1 domain similar to protein kinase C • Extended homology region (EHR) • Basic region (BR) required for DNA binding • LZ domain required for dimerization • A chick in vivo system was used to demonstrate that N-chimaerin overactivity results in axons terminated prematurely adjacent to the dorsal rectus muscle [ • Knock-in mice with the p.Leu20Phe • Homozygous • Heterozygous • Homozygous • Heterozygous ## Molecular Pathogenesis N-terminal SH2 domain C-terminal RhoGAP domain Central C1 domain similar to protein kinase C No pathogenic variants have been identified in the N-terminal SH2 domain. The longest isoform Extended homology region (EHR) Basic region (BR) required for DNA binding LZ domain required for dimerization N-chimaerin: A chick in vivo system was used to demonstrate that N-chimaerin overactivity results in axons terminated prematurely adjacent to the dorsal rectus muscle [ Knock-in mice with the p.Leu20Phe Homozygous Heterozygous Homozygous Heterozygous These allelic series in mice indicate that different tissues have different sensitivity to loss of Duane Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from • N-terminal SH2 domain • C-terminal RhoGAP domain • Central C1 domain similar to protein kinase C • Extended homology region (EHR) • Basic region (BR) required for DNA binding • LZ domain required for dimerization • A chick in vivo system was used to demonstrate that N-chimaerin overactivity results in axons terminated prematurely adjacent to the dorsal rectus muscle [ • Knock-in mice with the p.Leu20Phe • Homozygous • Heterozygous • Homozygous • Heterozygous ## Chapter Notes Boston Children's HospitalIntellectual and Developmental Disabilities Research Center (IDDRC) Department of Neurology, Howard Hughes Medical InstituteEngle Laboratory Caroline V Andrews, MSc; Harvard Medical School (2007-2019)Brenda J Barry, MS (2019-present)Elizabeth C Engle, MD (2007-present)David G Hunter, MD, PhD (2007-present)Mary C Whitman, MD, PhD (2019-present) 29 August 2019 (ha) Comprehensive update posted live 19 March 2015 (me) Comprehensive update posted live 5 July 2012 (me) Comprehensive update posted live 18 February 2010 (me) Comprehensive update posted live 25 May 2007 (me) Review posted live 23 February 2007 (ee) Original submission • 29 August 2019 (ha) Comprehensive update posted live • 19 March 2015 (me) Comprehensive update posted live • 5 July 2012 (me) Comprehensive update posted live • 18 February 2010 (me) Comprehensive update posted live • 25 May 2007 (me) Review posted live • 23 February 2007 (ee) Original submission ## Author Notes Boston Children's HospitalIntellectual and Developmental Disabilities Research Center (IDDRC) Department of Neurology, Howard Hughes Medical InstituteEngle Laboratory ## Author History Caroline V Andrews, MSc; Harvard Medical School (2007-2019)Brenda J Barry, MS (2019-present)Elizabeth C Engle, MD (2007-present)David G Hunter, MD, PhD (2007-present)Mary C Whitman, MD, PhD (2019-present) ## Revision History 29 August 2019 (ha) Comprehensive update posted live 19 March 2015 (me) Comprehensive update posted live 5 July 2012 (me) Comprehensive update posted live 18 February 2010 (me) Comprehensive update posted live 25 May 2007 (me) Review posted live 23 February 2007 (ee) Original submission • 29 August 2019 (ha) Comprehensive update posted live • 19 March 2015 (me) Comprehensive update posted live • 5 July 2012 (me) Comprehensive update posted live • 18 February 2010 (me) Comprehensive update posted live • 25 May 2007 (me) Review posted live • 23 February 2007 (ee) Original submission ## References ## Literature Cited
[]
25/5/2007
29/8/2019
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
duarte-gal
duarte-gal
[ "Duarte Galactosemia", "Duarte Galactosemia", "Galactose-1-phosphate uridylyltransferase", "GALT", "Duarte Variant Galactosemia" ]
Duarte Variant Galactosemia
Judith L Fridovich-Keil, Michael J Gambello, Rani H Singh, J Daniel Sharer
Summary Infants with Duarte variant galactosemia who receive breast milk or a high galactose-containing formula (dairy milk-based formula) are typically asymptomatic and show the same prevalence of acute issues seen in the general newborn population. For decades it has been unclear whether Duarte variant galactosemia results in long-term developmental problems either with or without dietary intervention. However, a recent study of 350 children ages six to 12 years reported no detectable differences in developmental outcomes tested between children with Duarte variant galactosemia and controls, or among children with Duarte variant galactosemia as a function of galactose exposure in infancy. Premature ovarian insufficiency, which is common in classic galactosemia, also has not been reported for girls or women with Duarte variant galactosemia. Duarte variant galactosemia is diagnosed by a combination of biochemical and genetic testing. Specifically, erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity is typically about 25% of control activity, and Duarte variant galactosemia is inherited in an autosomal recessive manner. When one parent is heterozygous for the
## Diagnosis Duarte variant galactosemia is defined by a combination of the following: One Erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity that is typically about 25% of control activity Duarte variant galactosemia, caused by a partial deficiency in erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme, NBS for classic galactosemia and its variants (including Duarte variant galactosemia) is primarily based on quantification of erythrocyte GALT enzyme activity on dried blood spots. Note: While all states in the US now include screening for classic galactosemia in their NBS panel, some states have set their newborn screening GALT enzyme activity cutoff level to ensure the detection of classic and clinical variant galactosemia while minimizing false positives and the detection of infants with Duarte variant galactosemia [ GALT enzyme activity below the cutoff defined by the screening program is considered positive and requires follow-up diagnostic testing (see Note: GALT is a labile enzyme; exposure of the sample to heat and/or humidity in storage or transit (as sometimes occurs in hot climates especially during the summer months) can result in artifactual loss of activity and higher false positive rates. Note: Dairy milk products contain lactose, which is metabolized to glucose and galactose by normal digestion. Therefore, any product that contains dairy milk and/or lactose also contains galactose. Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ Click The diagnosis of Duarte variant galactosemia Of primary importance is a 4-bp deletion in the If the D Molecular Genetic Testing Used in Duarte Variant Galactosemia 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. Deletion/duplication analysis will not identify the D Exon and multiexon • One • Erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme activity that is typically about 25% of control activity • NBS for classic galactosemia and its variants (including Duarte variant galactosemia) is primarily based on quantification of erythrocyte GALT enzyme activity on dried blood spots. • Note: While all states in the US now include screening for classic galactosemia in their NBS panel, some states have set their newborn screening GALT enzyme activity cutoff level to ensure the detection of classic and clinical variant galactosemia while minimizing false positives and the detection of infants with Duarte variant galactosemia [ • GALT enzyme activity below the cutoff defined by the screening program is considered positive and requires follow-up diagnostic testing (see • Note: GALT is a labile enzyme; exposure of the sample to heat and/or humidity in storage or transit (as sometimes occurs in hot climates especially during the summer months) can result in artifactual loss of activity and higher false positive rates. • Note: Dairy milk products contain lactose, which is metabolized to glucose and galactose by normal digestion. Therefore, any product that contains dairy milk and/or lactose also contains galactose. • Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ • Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ • Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ • Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ • The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ • Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ • The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ • Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ • Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ • Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ • The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ • Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ • If the D ## Suggestive Findings Duarte variant galactosemia, caused by a partial deficiency in erythrocyte galactose-1-phosphate uridylyltransferase (GALT) enzyme, NBS for classic galactosemia and its variants (including Duarte variant galactosemia) is primarily based on quantification of erythrocyte GALT enzyme activity on dried blood spots. Note: While all states in the US now include screening for classic galactosemia in their NBS panel, some states have set their newborn screening GALT enzyme activity cutoff level to ensure the detection of classic and clinical variant galactosemia while minimizing false positives and the detection of infants with Duarte variant galactosemia [ GALT enzyme activity below the cutoff defined by the screening program is considered positive and requires follow-up diagnostic testing (see Note: GALT is a labile enzyme; exposure of the sample to heat and/or humidity in storage or transit (as sometimes occurs in hot climates especially during the summer months) can result in artifactual loss of activity and higher false positive rates. Note: Dairy milk products contain lactose, which is metabolized to glucose and galactose by normal digestion. Therefore, any product that contains dairy milk and/or lactose also contains galactose. Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ Click • NBS for classic galactosemia and its variants (including Duarte variant galactosemia) is primarily based on quantification of erythrocyte GALT enzyme activity on dried blood spots. • Note: While all states in the US now include screening for classic galactosemia in their NBS panel, some states have set their newborn screening GALT enzyme activity cutoff level to ensure the detection of classic and clinical variant galactosemia while minimizing false positives and the detection of infants with Duarte variant galactosemia [ • GALT enzyme activity below the cutoff defined by the screening program is considered positive and requires follow-up diagnostic testing (see • Note: GALT is a labile enzyme; exposure of the sample to heat and/or humidity in storage or transit (as sometimes occurs in hot climates especially during the summer months) can result in artifactual loss of activity and higher false positive rates. • Note: Dairy milk products contain lactose, which is metabolized to glucose and galactose by normal digestion. Therefore, any product that contains dairy milk and/or lactose also contains galactose. • Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ • Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ • Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ • Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ • The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ • Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ • The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ • Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ • Erythrocyte galactose-1-phosphate concentrations may exceed 30 mg/dL within the first few weeks of life; however, even in infants with Duarte variant galactosemia who are not treated with a galactose-restricted diet the concentration tends to normalize (<1.0 mg/dL) within the first year [ • Erythrocyte galactose-1-phosphate concentration in infants placed on a galactose-restricted diet normalizes rapidly, decreasing to an almost undetectable level within one month [ • The mean urinary galactitol level in a cohort of young children with Duarte variant galactosemia on unrestricted (regular) diet at age one year was 46±14 mmol/mol creatinine [ • Mean urinary galactitol in controls (<1 year of age) was reported to range from 2-78 mmol/mol creatinine, and mean urinary galactitol in infants (<1 year) with classic galactosemia was 466±166 mmol/mol [ ## Establishing the Diagnosis The diagnosis of Duarte variant galactosemia Of primary importance is a 4-bp deletion in the If the D Molecular Genetic Testing Used in Duarte Variant Galactosemia 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. Deletion/duplication analysis will not identify the D Exon and multiexon • If the D ## Clinical Characteristics Note: Resolution of acute symptoms over time following removal of breast milk or dairy milk-based formula from the diet does No significant difference in prevalence of complications was seen between affected individuals and controls for any of the outcomes tested. No significant difference was seen comparing developmental outcomes of children with Duarte variant galactosemia who consumed breast milk or dairy milk-based formula versus low-galactose formula in the first year of life. Combined, these results strongly support the assertion that Duarte variant galactosemia does not cause developmental complications in children with or without dietary restriction of galactose. Note: The developmental outcomes of school-age children with Duarte variant galactosemia has been a point of controversy for some time, in part because a study by No significant genotype-phenotype relationships for Duarte variant galactosemia with regard to different pathogenic Duarte variant galactosemia may also be called Duarte galactosemia, DG, or biochemical variant galactosemia. Sometimes, Duarte variant galactosemia is simply called variant galactosemia; however, this term is better reserved for individuals now said to have " The prevalence of Duarte variant galactosemia is difficult to confirm due to incomplete ascertainment. Duarte variant galactosemia is detected in as many as 1:3,500 screened births in some states and essentially zero in others, largely reflecting differences in NBS protocols [ The true prevalence of Duarte variant galactosemia in the US newborn population is estimated to be approximately tenfold the prevalence of classic galactosemia [ Among newborns diagnosed with Duarte variant galactosemia some patterns implicating differential prevalence by race are evident [ • No significant difference in prevalence of complications was seen between affected individuals and controls for any of the outcomes tested. • No significant difference was seen comparing developmental outcomes of children with Duarte variant galactosemia who consumed breast milk or dairy milk-based formula versus low-galactose formula in the first year of life. • Combined, these results strongly support the assertion that Duarte variant galactosemia does not cause developmental complications in children with or without dietary restriction of galactose. ## Clinical Description Note: Resolution of acute symptoms over time following removal of breast milk or dairy milk-based formula from the diet does No significant difference in prevalence of complications was seen between affected individuals and controls for any of the outcomes tested. No significant difference was seen comparing developmental outcomes of children with Duarte variant galactosemia who consumed breast milk or dairy milk-based formula versus low-galactose formula in the first year of life. Combined, these results strongly support the assertion that Duarte variant galactosemia does not cause developmental complications in children with or without dietary restriction of galactose. Note: The developmental outcomes of school-age children with Duarte variant galactosemia has been a point of controversy for some time, in part because a study by • No significant difference in prevalence of complications was seen between affected individuals and controls for any of the outcomes tested. • No significant difference was seen comparing developmental outcomes of children with Duarte variant galactosemia who consumed breast milk or dairy milk-based formula versus low-galactose formula in the first year of life. • Combined, these results strongly support the assertion that Duarte variant galactosemia does not cause developmental complications in children with or without dietary restriction of galactose. ## Genotype-Phenotype Correlations No significant genotype-phenotype relationships for Duarte variant galactosemia with regard to different pathogenic ## Nomenclature Duarte variant galactosemia may also be called Duarte galactosemia, DG, or biochemical variant galactosemia. Sometimes, Duarte variant galactosemia is simply called variant galactosemia; however, this term is better reserved for individuals now said to have " ## Prevalence The prevalence of Duarte variant galactosemia is difficult to confirm due to incomplete ascertainment. Duarte variant galactosemia is detected in as many as 1:3,500 screened births in some states and essentially zero in others, largely reflecting differences in NBS protocols [ The true prevalence of Duarte variant galactosemia in the US newborn population is estimated to be approximately tenfold the prevalence of classic galactosemia [ Among newborns diagnosed with Duarte variant galactosemia some patterns implicating differential prevalence by race are evident [ ## Genetically Related (Allelic) Disorders The Los Angeles (LA) variant (D ## Differential Diagnosis Most infants with Duarte variant galactosemia are diagnosed because of a positive NBS result for galactosemia. The differential diagnosis of a positive NBS for galactosemia is: Duarte variant galactosemia GALK (galactokinase) deficiency (OMIM GALM deficiency galactosemia (OMIM Compromised galactose utilization not caused by a Leloir enzyme deficiency (e.g., Fanconi-Bickel syndrome [OMIM A false positive result that includes: Heterozygotes (carriers) for a Other combinations of partially impaired Individuals with completely normal Disorders to Consider Given a Newborn Screening Result Suggestive of Galactosemia Compared with the erythrocyte GALT enzyme activity of controls See • • Duarte variant galactosemia • • GALK (galactokinase) deficiency (OMIM • GALM deficiency galactosemia (OMIM • Compromised galactose utilization not caused by a Leloir enzyme deficiency (e.g., Fanconi-Bickel syndrome [OMIM • A false positive result that includes: • Heterozygotes (carriers) for a • Other combinations of partially impaired • Individuals with completely normal • Heterozygotes (carriers) for a • Other combinations of partially impaired • Individuals with completely normal • Heterozygotes (carriers) for a • Other combinations of partially impaired • Individuals with completely normal ## Management An infant who is symptomatic should be seen by a metabolic specialist for evaluation for other possible conditions. To assist the family with understanding the genetic implications of a diagnosis of Duarte variant galactosemia for the child and family, a genetic counseling consultation is recommended. Current data suggest that infants and children with Duarte variant galactosemia are not at increased risk for acute or long-term developmental [ Immediate dietary galactose restriction for infants with erythrocyte galactose-1-phosphate >10 mg/dL Full dietary restriction of galactose by feeding low-galactose formula, through age one year, at which time a galactose challenge is performed A compromise approach in which parents wishing to breastfeed alternate breast milk with a low-galactose formula Obtain a baseline erythrocyte galactose-1-phosphate level at diagnosis and again around age six months (i.e., after the introduction of solid foods). At age 12 months, gradually liberalize the dietary intake of galactose, and obtain an erythrocyte galactose-1-phosphate level one month later. If the erythrocyte galactose-1-phosphate level is within the normal range (<1.0 mg/dL) despite dairy milk ingestion, dietary restriction of galactose is not resumed. Most individuals diagnosed with Duarte variant galactosemia as infants who are followed by a genetics or metabolic specialist are discharged from follow up after a successful galactose challenge at age one year (see Among children with Duarte variant galactosemia who have been restricted for dietary galactose as infants, if the erythrocyte galactose-1-phosphate level is >1.0 mg/dL following a galactose challenge at age one year, galactose restriction may be resumed, and the galactose challenge and measurement of erythrocyte galactose-1-phosphate level repeated every four to six months until the level stabilizes at <1.0 mg/dL. Some health care providers recommend avoiding all high galactose foods (e.g., dairy milk products) until age one year; other health care providers argue that this precaution is neither warranted nor desirable [ See Search • Immediate dietary galactose restriction for infants with erythrocyte galactose-1-phosphate >10 mg/dL • Full dietary restriction of galactose by feeding low-galactose formula, through age one year, at which time a galactose challenge is performed • A compromise approach in which parents wishing to breastfeed alternate breast milk with a low-galactose formula • Obtain a baseline erythrocyte galactose-1-phosphate level at diagnosis and again around age six months (i.e., after the introduction of solid foods). • At age 12 months, gradually liberalize the dietary intake of galactose, and obtain an erythrocyte galactose-1-phosphate level one month later. • If the erythrocyte galactose-1-phosphate level is within the normal range (<1.0 mg/dL) despite dairy milk ingestion, dietary restriction of galactose is not resumed. ## Evaluations Following Initial Diagnosis An infant who is symptomatic should be seen by a metabolic specialist for evaluation for other possible conditions. To assist the family with understanding the genetic implications of a diagnosis of Duarte variant galactosemia for the child and family, a genetic counseling consultation is recommended. ## Treatment of Manifestations Current data suggest that infants and children with Duarte variant galactosemia are not at increased risk for acute or long-term developmental [ Immediate dietary galactose restriction for infants with erythrocyte galactose-1-phosphate >10 mg/dL Full dietary restriction of galactose by feeding low-galactose formula, through age one year, at which time a galactose challenge is performed A compromise approach in which parents wishing to breastfeed alternate breast milk with a low-galactose formula Obtain a baseline erythrocyte galactose-1-phosphate level at diagnosis and again around age six months (i.e., after the introduction of solid foods). At age 12 months, gradually liberalize the dietary intake of galactose, and obtain an erythrocyte galactose-1-phosphate level one month later. If the erythrocyte galactose-1-phosphate level is within the normal range (<1.0 mg/dL) despite dairy milk ingestion, dietary restriction of galactose is not resumed. • Immediate dietary galactose restriction for infants with erythrocyte galactose-1-phosphate >10 mg/dL • Full dietary restriction of galactose by feeding low-galactose formula, through age one year, at which time a galactose challenge is performed • A compromise approach in which parents wishing to breastfeed alternate breast milk with a low-galactose formula • Obtain a baseline erythrocyte galactose-1-phosphate level at diagnosis and again around age six months (i.e., after the introduction of solid foods). • At age 12 months, gradually liberalize the dietary intake of galactose, and obtain an erythrocyte galactose-1-phosphate level one month later. • If the erythrocyte galactose-1-phosphate level is within the normal range (<1.0 mg/dL) despite dairy milk ingestion, dietary restriction of galactose is not resumed. ## Surveillance Most individuals diagnosed with Duarte variant galactosemia as infants who are followed by a genetics or metabolic specialist are discharged from follow up after a successful galactose challenge at age one year (see Among children with Duarte variant galactosemia who have been restricted for dietary galactose as infants, if the erythrocyte galactose-1-phosphate level is >1.0 mg/dL following a galactose challenge at age one year, galactose restriction may be resumed, and the galactose challenge and measurement of erythrocyte galactose-1-phosphate level repeated every four to six months until the level stabilizes at <1.0 mg/dL. ## Agents/Circumstances to Avoid Some health care providers recommend avoiding all high galactose foods (e.g., dairy milk products) until age one year; other health care providers argue that this precaution is neither warranted nor desirable [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Duarte variant galactosemia is inherited in an autosomal recessive manner. Individuals with Duarte variant galactosemia have at least one Duarte (D Molecular genetic testing is needed to clarify the genetic status of parents. Typically, one parent of a child with Duarte variant galactosemia carries the Duarte (D Rarely, a parent may have Duarte variant galactosemia or another genotype that includes the D Heterozygotes (carriers) of a single If one parent is heterozygous for the D A 25% chance of having Duarte variant galactosemia; A 25% chance of being an asymptomatic carrier of the D A 25% chance of being an asymptomatic carrier of a A 25% chance of being unaffected and not a carrier of either variant. In some families, it is possible for the sibs of a proband with Duarte variant galactosemia to have A 25% chance of having Duarte variant galactosemia; A 25% chance of having classic galactosemia or clinical variant galactosemia; A 25% chance of being an asymptomatic carrier of the D A 25% chance of being an asymptomatic carrier of a Risks to sibs are different for other parental genotypes. Referral for genetic counseling is indicated for such families. Heterozygotes (carriers) of (1) a single The offspring of an individual with Duarte variant galactosemia are typically heterozygotes (carriers) of a Accurate determination of the risk to offspring is only possible after molecular genetic testing of the proband's reproductive partner. 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 available prenatal testing options is before pregnancy. Although current research indicates that individuals with Duarte variant galactosemia are typically asymptomatic [ 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. • Molecular genetic testing is needed to clarify the genetic status of parents. • Typically, one parent of a child with Duarte variant galactosemia carries the Duarte (D • Rarely, a parent may have Duarte variant galactosemia or another genotype that includes the D • Heterozygotes (carriers) of a single • If one parent is heterozygous for the D • A 25% chance of having Duarte variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of being unaffected and not a carrier of either variant. • A 25% chance of having Duarte variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of being unaffected and not a carrier of either variant. • In some families, it is possible for the sibs of a proband with Duarte variant galactosemia to have • A 25% chance of having Duarte variant galactosemia; • A 25% chance of having classic galactosemia or clinical variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of having Duarte variant galactosemia; • A 25% chance of having classic galactosemia or clinical variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • Risks to sibs are different for other parental genotypes. Referral for genetic counseling is indicated for such families. • Heterozygotes (carriers) of (1) a single • A 25% chance of having Duarte variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of being unaffected and not a carrier of either variant. • A 25% chance of having Duarte variant galactosemia; • A 25% chance of having classic galactosemia or clinical variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • The offspring of an individual with Duarte variant galactosemia are typically heterozygotes (carriers) of a • Accurate determination of the risk to offspring is only possible after molecular genetic testing of the proband's reproductive partner. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of available prenatal testing options is before pregnancy. • Although current research indicates that individuals with Duarte variant galactosemia are typically asymptomatic [ ## Mode of Inheritance Duarte variant galactosemia is inherited in an autosomal recessive manner. Individuals with Duarte variant galactosemia have at least one Duarte (D ## Risk to Family Members Molecular genetic testing is needed to clarify the genetic status of parents. Typically, one parent of a child with Duarte variant galactosemia carries the Duarte (D Rarely, a parent may have Duarte variant galactosemia or another genotype that includes the D Heterozygotes (carriers) of a single If one parent is heterozygous for the D A 25% chance of having Duarte variant galactosemia; A 25% chance of being an asymptomatic carrier of the D A 25% chance of being an asymptomatic carrier of a A 25% chance of being unaffected and not a carrier of either variant. In some families, it is possible for the sibs of a proband with Duarte variant galactosemia to have A 25% chance of having Duarte variant galactosemia; A 25% chance of having classic galactosemia or clinical variant galactosemia; A 25% chance of being an asymptomatic carrier of the D A 25% chance of being an asymptomatic carrier of a Risks to sibs are different for other parental genotypes. Referral for genetic counseling is indicated for such families. Heterozygotes (carriers) of (1) a single The offspring of an individual with Duarte variant galactosemia are typically heterozygotes (carriers) of a Accurate determination of the risk to offspring is only possible after molecular genetic testing of the proband's reproductive partner. • Molecular genetic testing is needed to clarify the genetic status of parents. • Typically, one parent of a child with Duarte variant galactosemia carries the Duarte (D • Rarely, a parent may have Duarte variant galactosemia or another genotype that includes the D • Heterozygotes (carriers) of a single • If one parent is heterozygous for the D • A 25% chance of having Duarte variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of being unaffected and not a carrier of either variant. • A 25% chance of having Duarte variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of being unaffected and not a carrier of either variant. • In some families, it is possible for the sibs of a proband with Duarte variant galactosemia to have • A 25% chance of having Duarte variant galactosemia; • A 25% chance of having classic galactosemia or clinical variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of having Duarte variant galactosemia; • A 25% chance of having classic galactosemia or clinical variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • Risks to sibs are different for other parental genotypes. Referral for genetic counseling is indicated for such families. • Heterozygotes (carriers) of (1) a single • A 25% chance of having Duarte variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • A 25% chance of being unaffected and not a carrier of either variant. • A 25% chance of having Duarte variant galactosemia; • A 25% chance of having classic galactosemia or clinical variant galactosemia; • A 25% chance of being an asymptomatic carrier of the D • A 25% chance of being an asymptomatic carrier of a • The offspring of an individual with Duarte variant galactosemia are typically heterozygotes (carriers) of a • Accurate determination of the risk to offspring is only possible after molecular genetic testing of the proband's reproductive partner. ## 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 available prenatal testing options is before pregnancy. Although current research indicates that individuals with Duarte variant galactosemia are typically asymptomatic [ • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of available prenatal testing options is before pregnancy. • Although current research indicates that individuals with Duarte variant galactosemia are typically asymptomatic [ ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Health Resources & Services Administration • • • • Health Resources & Services Administration • ## Molecular Genetics Duarte Variant Galactosemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Duarte Variant Galactosemia ( The mechanism of pathogenesis of the The mechanism of pathogenesis of different Four are noncoding nucleotide variants that are unique to the D Of primary importance is a 4-bp deletion in the The three remaining variants unique to D The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Reduces promoter function (reviewed in Also, rarely, some individuals with classic galactosemia (who by definition have biallelic Therefore, demonstrating the presence of the D Of note, the parents of a child with an identified D If each parent carries one variant found in the child, the D If one parent carries both the D A • Four are noncoding nucleotide variants that are unique to the D • Of primary importance is a 4-bp deletion in the • The three remaining variants unique to D • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D • Four are noncoding nucleotide variants that are unique to the D • Of primary importance is a 4-bp deletion in the • The three remaining variants unique to D • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D • Four are noncoding nucleotide variants that are unique to the D • Of primary importance is a 4-bp deletion in the • The three remaining variants unique to D • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D • If each parent carries one variant found in the child, the D • If one parent carries both the D ## Molecular Pathogenesis The mechanism of pathogenesis of the The mechanism of pathogenesis of different Four are noncoding nucleotide variants that are unique to the D Of primary importance is a 4-bp deletion in the The three remaining variants unique to D The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Reduces promoter function (reviewed in Also, rarely, some individuals with classic galactosemia (who by definition have biallelic Therefore, demonstrating the presence of the D Of note, the parents of a child with an identified D If each parent carries one variant found in the child, the D If one parent carries both the D A • Four are noncoding nucleotide variants that are unique to the D • Of primary importance is a 4-bp deletion in the • The three remaining variants unique to D • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D • Four are noncoding nucleotide variants that are unique to the D • Of primary importance is a 4-bp deletion in the • The three remaining variants unique to D • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D • Four are noncoding nucleotide variants that are unique to the D • Of primary importance is a 4-bp deletion in the • The three remaining variants unique to D • The fifth sequence change is the missense variant c.940A>G (p.Asn314Asp, also called N314D); while always on the D • If each parent carries one variant found in the child, the D • If one parent carries both the D ## Chapter Notes The authors are grateful to their colleagues and to the many families affected by Duarte variant galactosemia who participate in research studies. 25 June 2020 (AA) Revision: added GALM deficiency and associated references 23 May 2019 (ma) Comprehensive update posted live 4 December 2014 (me) Review posted live 20 May 2014 (jfk) Original submission • 25 June 2020 (AA) Revision: added GALM deficiency and associated references • 23 May 2019 (ma) Comprehensive update posted live • 4 December 2014 (me) Review posted live • 20 May 2014 (jfk) Original submission ## Acknowledgments The authors are grateful to their colleagues and to the many families affected by Duarte variant galactosemia who participate in research studies. ## Revision History 25 June 2020 (AA) Revision: added GALM deficiency and associated references 23 May 2019 (ma) Comprehensive update posted live 4 December 2014 (me) Review posted live 20 May 2014 (jfk) Original submission • 25 June 2020 (AA) Revision: added GALM deficiency and associated references • 23 May 2019 (ma) Comprehensive update posted live • 4 December 2014 (me) Review posted live • 20 May 2014 (jfk) Original submission ## References ## Literature Cited
[]
4/12/2014
23/5/2019
25/6/2020
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dup15q
dup15q
[ "Maternal Interstitial 15q11.2-q13.1 Duplication or Triplication", "Maternal Isodicentric 15q11.2-q13.1 Supernumerary Chromosome [idic(15)]", "Not applicable", "Not applicable", "Maternal 15q Duplication Syndrome" ]
Maternal 15q Duplication Syndrome
Laina Lusk, Vanessa Vogel-Farley, Charlotte DiStefano, Shafali Jeste
Summary Maternal 15q duplication syndrome (maternal dup15q) is characterized by hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms. Rarely, maternal dup15q may also be associated with psychosis or sudden unexplained death. Those with a maternal isodicentric 15q11.2-q13.1 supernumerary chromosome are typically more severely affected than those with an interstitial duplication. The diagnosis of maternal dup15q is established by detection of at least one extra maternally derived copy of the Prader-Willi/Angelman critical region, a region approximately 5 Mb long within chromosome region 15q11.2-q13.1. The extra copy or copies most commonly arise by one of two mechanisms: A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – typically comprising two extra copies of 15q11.2-q13.1 and resulting in tetrasomy for 15q11.2-q13.1 (~60-80%); A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20-40%). Maternal dup15q caused by: Prenatal testing or preimplantation genetic testing using chromosomal microarray (CMA) will detect the 15q interstitial duplication; however, prenatal test results cannot reliably predict the severity of the phenotype even in a pregnancy known to be at increased risk for maternal dup15q.
Maternal isodicentric 15q11.2-q13.1 supernumerary chromosome [idic(15)] resulting in tetrasomy or hexasomy for 15q11.2-q13.1 Maternal interstitial 15q11.2-q13.1 duplication or triplication For synonyms and outdated terms see • Maternal isodicentric 15q11.2-q13.1 supernumerary chromosome [idic(15)] resulting in tetrasomy or hexasomy for 15q11.2-q13.1 • Maternal interstitial 15q11.2-q13.1 duplication or triplication ## Diagnosis Maternal 15q duplication syndrome (maternal dup15q) Moderate-to-severe hypotonia in infancy and early delays in reaching motor milestones Developmental delay that includes not only motor but also language Intellectual disability (ID) Autism spectrum disorder (ASD) Seizures, particularly infantile spasms Dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures [ Behavioral difficulties including hyperactivity, anxiety, or emotional lability [ A characteristic EEG biomarker involving excessive beta oscillations (12–30 Hz) [ The diagnosis of maternal dup15q The proximal 15q region includes five regions of segmental duplications or low copy repeats (designated by breakpoints [BPs]), which result in increased susceptibility to genomic rearrangements [ The extra copy or copies of the PWACR most commonly arise by one of two mechanisms ( A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60-80%) OR A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20-40%) For this Although several genes of interest (e.g., Note: (1) Most individuals with maternal dup15q are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) FISH or a cytogenetic study is required to determine whether the duplication is supernumerary or interstitial and to determine whether there is evidence for mosaicism. Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 15q11.2-q13.1 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. Genotyping or methylation analysis, including PCR-based methylation analysis [ Identification of a 15q11.2-q13.1 interstitial duplication in a maternal sample Genomic Testing used in Maternal 15q Duplication Syndrome PWACR = Prader-Willi/Angelman critical region See Standardized clinical annotation and interpretation for genomic variants from the Class 1 duplication, approximately 6 Mb, extending from BP1 to BP3 Class 2 duplication, approximately 5 Mb, extending from BP2 to BP3 Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 15q11.2-q13.1 region. Note: Maternal 15q duplication may not have been detectable by older oligonucleotide or BAC platforms. FISH or cytogenetic analysis (e.g., G-banded chromosome study) should be completed as a follow up to CMA in most instances in order to determine whether the duplication is interstitial or contained within a supernumerary chromosome. Although CMA results may indicate whether the duplication is interstitial, this is not common. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for diagnosis of an individual in whom the 15q11.2-q13.1 duplication was not detected by CMA designed to target this region. • Moderate-to-severe hypotonia in infancy and early delays in reaching motor milestones • Developmental delay that includes not only motor but also language • Intellectual disability (ID) • Autism spectrum disorder (ASD) • Seizures, particularly infantile spasms • Dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures [ • Behavioral difficulties including hyperactivity, anxiety, or emotional lability [ • A characteristic EEG biomarker involving excessive beta oscillations (12–30 Hz) [ • A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60-80%) • OR • A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20-40%) • Genotyping or methylation analysis, including PCR-based methylation analysis [ • Identification of a 15q11.2-q13.1 interstitial duplication in a maternal sample ## Suggestive Findings Maternal 15q duplication syndrome (maternal dup15q) Moderate-to-severe hypotonia in infancy and early delays in reaching motor milestones Developmental delay that includes not only motor but also language Intellectual disability (ID) Autism spectrum disorder (ASD) Seizures, particularly infantile spasms Dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures [ Behavioral difficulties including hyperactivity, anxiety, or emotional lability [ A characteristic EEG biomarker involving excessive beta oscillations (12–30 Hz) [ • Moderate-to-severe hypotonia in infancy and early delays in reaching motor milestones • Developmental delay that includes not only motor but also language • Intellectual disability (ID) • Autism spectrum disorder (ASD) • Seizures, particularly infantile spasms • Dysmorphic features including upturned nose, epicanthal folds, and downslanting palpebral fissures [ • Behavioral difficulties including hyperactivity, anxiety, or emotional lability [ • A characteristic EEG biomarker involving excessive beta oscillations (12–30 Hz) [ ## Establishing the Diagnosis The diagnosis of maternal dup15q The proximal 15q region includes five regions of segmental duplications or low copy repeats (designated by breakpoints [BPs]), which result in increased susceptibility to genomic rearrangements [ The extra copy or copies of the PWACR most commonly arise by one of two mechanisms ( A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60-80%) OR A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20-40%) For this Although several genes of interest (e.g., Note: (1) Most individuals with maternal dup15q are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, or autism spectrum disorder. (2) FISH or a cytogenetic study is required to determine whether the duplication is supernumerary or interstitial and to determine whether there is evidence for mosaicism. Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 15q11.2-q13.1 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. Genotyping or methylation analysis, including PCR-based methylation analysis [ Identification of a 15q11.2-q13.1 interstitial duplication in a maternal sample Genomic Testing used in Maternal 15q Duplication Syndrome PWACR = Prader-Willi/Angelman critical region See Standardized clinical annotation and interpretation for genomic variants from the Class 1 duplication, approximately 6 Mb, extending from BP1 to BP3 Class 2 duplication, approximately 5 Mb, extending from BP2 to BP3 Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 15q11.2-q13.1 region. Note: Maternal 15q duplication may not have been detectable by older oligonucleotide or BAC platforms. FISH or cytogenetic analysis (e.g., G-banded chromosome study) should be completed as a follow up to CMA in most instances in order to determine whether the duplication is interstitial or contained within a supernumerary chromosome. Although CMA results may indicate whether the duplication is interstitial, this is not common. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for diagnosis of an individual in whom the 15q11.2-q13.1 duplication was not detected by CMA designed to target this region. • A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60-80%) • OR • A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20-40%) • Genotyping or methylation analysis, including PCR-based methylation analysis [ • Identification of a 15q11.2-q13.1 interstitial duplication in a maternal sample ## Clinical Characteristics Maternal 15q duplication syndrome (maternal dup15q) is characterized by hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms. These clinical findings differ significantly between people with a maternal interstitial duplication and those with a maternal isodicentric supernumerary chromosome, or idic(15) ( Maternal 15q Interstitial Duplication and Idic(15): Comparison of Clinical Features Although childhood hypotonia impairs motor development, most children achieve independent walking after age two to three years (younger in children with an interstitial duplication) [ A wide-based or ataxic gait is common [ In addition to motor delays, speech and language development is particularly affected, with universal delays ranging from moderate to severe [ Most children and adults with maternal dup15q function in the moderate-to-severe range of intellectual disability; however, there is some variability, with a higher range of cognitive abilities seen in those with an interstitial duplication [ Individuals with maternal dup15q who have a diagnosis of epilepsy have lower verbal, daily living, socialization, fine motor, and gross motor skills compared to individuals with maternal dup15q who do not have epilepsy [ Compared to children with nonsyndromic ASD, children with maternal dup15q-ASD demonstrate a distinctive behavioral profile, including preserved responsive social smile and directed facial expressions towards others – features that may inform behavioral interventions [ Maternal dup15q is one of the most common known causes of infantile spasms [ Intractable epilepsy in individuals with maternal dup15q may result in disabling secondary effects, including falls or developmental regression. This occurs in more than half of individuals with frequent, uncontrolled seizures or nonconvulsive status epilepticus [ Children with epilepsy have been found to have lower cognitive and adaptive function than those without epilepsy [ The mechanism underlying SUDEP is not well understood; however, available evidence suggests that in most instances a tonic-clonic seizure is followed by a shutdown of brain function and cardio-respiratory arrest. SUDEP occurs in 9% of individuals with epilepsy; the incidence of SUDEP in individuals with maternal dup15q is unknown. In maternal idic(15) penetrance is 100%. In maternal interstitial 15q11.2-q13.1 duplication penetrance appears to be complete, although some individuals may have mild features and appear unaffected. Penetrance is the same for males and females. Terms used to refer to maternal 15q duplication syndrome and related disorders: 15q11.2-q13.1 duplication syndrome Dup15q syndrome Inverted duplication 15 (inv dup15) Partial trisomy 15 Isodicentric chromosome 15 syndrome [Idic(15)] Supernumerary marker chromosome 15 (SMC15) Partial tetrasomy 15q Maternal dup15q is one of the most common cytogenetic anomalies in persons with ASD, occurring in approximately 1:522 persons with ASD [ • 15q11.2-q13.1 duplication syndrome • Dup15q syndrome • Inverted duplication 15 (inv dup15) • Partial trisomy 15 • Isodicentric chromosome 15 syndrome [Idic(15)] • Supernumerary marker chromosome 15 (SMC15) • Partial tetrasomy 15q ## Clinical Description Maternal 15q duplication syndrome (maternal dup15q) is characterized by hypotonia and motor delays, intellectual disability, autism spectrum disorder (ASD), and epilepsy including infantile spasms. These clinical findings differ significantly between people with a maternal interstitial duplication and those with a maternal isodicentric supernumerary chromosome, or idic(15) ( Maternal 15q Interstitial Duplication and Idic(15): Comparison of Clinical Features Although childhood hypotonia impairs motor development, most children achieve independent walking after age two to three years (younger in children with an interstitial duplication) [ A wide-based or ataxic gait is common [ In addition to motor delays, speech and language development is particularly affected, with universal delays ranging from moderate to severe [ Most children and adults with maternal dup15q function in the moderate-to-severe range of intellectual disability; however, there is some variability, with a higher range of cognitive abilities seen in those with an interstitial duplication [ Individuals with maternal dup15q who have a diagnosis of epilepsy have lower verbal, daily living, socialization, fine motor, and gross motor skills compared to individuals with maternal dup15q who do not have epilepsy [ Compared to children with nonsyndromic ASD, children with maternal dup15q-ASD demonstrate a distinctive behavioral profile, including preserved responsive social smile and directed facial expressions towards others – features that may inform behavioral interventions [ Maternal dup15q is one of the most common known causes of infantile spasms [ Intractable epilepsy in individuals with maternal dup15q may result in disabling secondary effects, including falls or developmental regression. This occurs in more than half of individuals with frequent, uncontrolled seizures or nonconvulsive status epilepticus [ Children with epilepsy have been found to have lower cognitive and adaptive function than those without epilepsy [ The mechanism underlying SUDEP is not well understood; however, available evidence suggests that in most instances a tonic-clonic seizure is followed by a shutdown of brain function and cardio-respiratory arrest. SUDEP occurs in 9% of individuals with epilepsy; the incidence of SUDEP in individuals with maternal dup15q is unknown. ## Penetrance In maternal idic(15) penetrance is 100%. In maternal interstitial 15q11.2-q13.1 duplication penetrance appears to be complete, although some individuals may have mild features and appear unaffected. Penetrance is the same for males and females. ## Nomenclature Terms used to refer to maternal 15q duplication syndrome and related disorders: 15q11.2-q13.1 duplication syndrome Dup15q syndrome Inverted duplication 15 (inv dup15) Partial trisomy 15 Isodicentric chromosome 15 syndrome [Idic(15)] Supernumerary marker chromosome 15 (SMC15) Partial tetrasomy 15q • 15q11.2-q13.1 duplication syndrome • Dup15q syndrome • Inverted duplication 15 (inv dup15) • Partial trisomy 15 • Isodicentric chromosome 15 syndrome [Idic(15)] • Supernumerary marker chromosome 15 (SMC15) • Partial tetrasomy 15q ## Prevalence Maternal dup15q is one of the most common cytogenetic anomalies in persons with ASD, occurring in approximately 1:522 persons with ASD [ ## Genetically Related Disorders Genetically Related Disorders Variable phenotype that may incl DD, dysmorphic features, ↑ risk for epilepsy, ASD, & sleep concerns such as parasomnia (abnormal or unusual behavior during sleep). Clinical findings, esp autistic features, may be present in ≤50% of those w/a paternal interstitial duplication of 15q11.2-q13.1. Due to overlap in phenotypic features of maternal & paternal duplications, parent-of-origin testing should be performed to determine whether a proband has maternal dup15q or a paternal interstitial duplication. ASD = autism spectrum disorder; maternal dup15q = maternal 15q duplication syndrome; DD = developmental delay; ID = intellectual disability; PWACR = Prader-Willi/Angelman critical region; UPD = uniparental disomy • Variable phenotype that may incl DD, dysmorphic features, ↑ risk for epilepsy, ASD, & sleep concerns such as parasomnia (abnormal or unusual behavior during sleep). Clinical findings, esp autistic features, may be present in ≤50% of those w/a paternal interstitial duplication of 15q11.2-q13.1. • Due to overlap in phenotypic features of maternal & paternal duplications, parent-of-origin testing should be performed to determine whether a proband has maternal dup15q or a paternal interstitial duplication. ## Differential Diagnosis Phenotypic features associated with maternal 15q duplication syndrome (maternal dup15q) are not sufficient for diagnosis. All chromosome anomalies and genes known to be associated with intellectual disability (ID) should be included in the differential diagnosis of maternal dup15q. See ## Management To establish the extent of disease and needs in an individual diagnosed with maternal 15q duplication syndrome (maternal dup15q), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Maternal 15q Duplication Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake 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 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 A multidisciplinary team evaluation is recommended beginning in early infancy to evaluate motor and speech development and later to assist in referrals for appropriate educational programs. Treatment of Manifestations in Individuals with Maternal 15q Duplication Syndrome Standardized treatment w/ASM, vagus nerve stimulators, &/or ketogenic diets by experienced neurologist 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; DD/ID = developmental delay / intellectual disability; FTT = failure to thrive; 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 Approximately half of seizure-related deaths are not due to SUDEP, but to other causes including status epilepticus, drowning, falls, and accidents. Many of these are preventable. For example, status epilepticus may be prevented with the use of rescue medications such as rectal diazepam or nasal midazolam. Some evidence suggests that prompt identification of a seizure and basic care (e.g., repositioning a person on the side instead of face down) after a seizure may help prevent SUDEP [ The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary by country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Maternal 15q Duplication Syndrome 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. OT = occupational therapy; PT = physical therapy Seizure triggers (e.g., sleep deprivation, stress, and failure to follow medication regimen) should be avoided. Consider genetic testing of sibs of a proband who is known to have an inherited maternal interstitial 15q11.2-q13.1 duplication in order to refer sibs with an interstitial duplication promptly for developmental evaluation and early intervention services. Note: Recurrence is extremely rare in the sibs of probands with a maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15). See Search • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • 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 • Community or • Social work involvement for parental support; • Home nursing referral. • Standardized treatment w/ASM, vagus nerve stimulators, &/or ketogenic diets by experienced neurologist • 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. • 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. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with maternal 15q duplication syndrome (maternal dup15q), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Maternal 15q Duplication Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake 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 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 • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • 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 • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations A multidisciplinary team evaluation is recommended beginning in early infancy to evaluate motor and speech development and later to assist in referrals for appropriate educational programs. Treatment of Manifestations in Individuals with Maternal 15q Duplication Syndrome Standardized treatment w/ASM, vagus nerve stimulators, &/or ketogenic diets by experienced neurologist 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; DD/ID = developmental delay / intellectual disability; FTT = failure to thrive; 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 Approximately half of seizure-related deaths are not due to SUDEP, but to other causes including status epilepticus, drowning, falls, and accidents. Many of these are preventable. For example, status epilepticus may be prevented with the use of rescue medications such as rectal diazepam or nasal midazolam. Some evidence suggests that prompt identification of a seizure and basic care (e.g., repositioning a person on the side instead of face down) after a seizure may help prevent SUDEP [ The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary by country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Standardized treatment w/ASM, vagus nerve stimulators, &/or ketogenic diets by experienced neurologist • 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. ## 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. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Maternal 15q Duplication Syndrome 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. OT = occupational therapy; PT = physical therapy • 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. ## Agents/Circumstances to Avoid Seizure triggers (e.g., sleep deprivation, stress, and failure to follow medication regimen) should be avoided. ## Evaluation of Relatives at Risk Consider genetic testing of sibs of a proband who is known to have an inherited maternal interstitial 15q11.2-q13.1 duplication in order to refer sibs with an interstitial duplication promptly for developmental evaluation and early intervention services. Note: Recurrence is extremely rare in the sibs of probands with a maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15). See ## Therapies Under Investigation Search ## Genetic Counseling Maternal 15q duplication syndrome (maternal dup15q) is an autosomal dominant disorder typically caused by a All probands reported to date with maternal dup15q caused by idic(15) whose parents have undergone genomic testing have had the disorder as the result of a Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling. Note: Maternal transmission of supernumerary partial trisomy of the region has been reported in one instance [ The risk to sibs is presumed to be low as the idic(15) has occurred as a If the idic(15) identified in the proband is not identified in a parent, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the idic(15). Approximately 85% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication have a Approximately 15% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication inherited the genetic alteration from the mother. If the mother of a proband inherited a 15q interstitial duplication from her father (i.e., the maternal grandfather of the proband), the mother will not have maternal dup15q syndrome. Instead, she may appear to be unaffected or have features associated with paternal duplications, which – although distinct from those of the proband – may share some similarities (see Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling If the maternal 15q interstitial duplication found in the proband cannot be detected in maternal leukocyte DNA, the most likely explanation is a If the mother of the proband has the 15q interstitial duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the severity of the phenotype in sibs who inherit a maternal interstitial 15q11.2-q13.1 duplication (see If the maternal 15q interstitial duplication identified in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the duplication. If the proband is female, offspring who inherit a 15q interstitial duplication are at risk for maternal dup15q. If the proband is male, offspring who inherit a 15q interstitial duplication are at risk for features associated with paternal interstitial duplications of 15q11.2-q13.1 (see See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with maternal dup15q. Note: Prenatal test results cannot reliably predict the severity of the phenotype (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. • All probands reported to date with maternal dup15q caused by idic(15) whose parents have undergone genomic testing have had the disorder as the result of a • Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling. Note: Maternal transmission of supernumerary partial trisomy of the region has been reported in one instance [ • The risk to sibs is presumed to be low as the idic(15) has occurred as a • If the idic(15) identified in the proband is not identified in a parent, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the idic(15). • Approximately 85% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication have a • Approximately 15% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication inherited the genetic alteration from the mother. • If the mother of a proband inherited a 15q interstitial duplication from her father (i.e., the maternal grandfather of the proband), the mother will not have maternal dup15q syndrome. Instead, she may appear to be unaffected or have features associated with paternal duplications, which – although distinct from those of the proband – may share some similarities (see • Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling • If the maternal 15q interstitial duplication found in the proband cannot be detected in maternal leukocyte DNA, the most likely explanation is a • If the mother of the proband has the 15q interstitial duplication, the risk to each sib of inheriting the duplication is 50%. • It is not possible to reliably predict the severity of the phenotype in sibs who inherit a maternal interstitial 15q11.2-q13.1 duplication (see • If the maternal 15q interstitial duplication identified in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the duplication. • If the proband is female, offspring who inherit a 15q interstitial duplication are at risk for maternal dup15q. • If the proband is male, offspring who inherit a 15q interstitial duplication are at risk for features associated with paternal interstitial duplications of 15q11.2-q13.1 (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with maternal dup15q. ## Mode of Inheritance Maternal 15q duplication syndrome (maternal dup15q) is an autosomal dominant disorder typically caused by a ## Risk to Family Members All probands reported to date with maternal dup15q caused by idic(15) whose parents have undergone genomic testing have had the disorder as the result of a Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling. Note: Maternal transmission of supernumerary partial trisomy of the region has been reported in one instance [ The risk to sibs is presumed to be low as the idic(15) has occurred as a If the idic(15) identified in the proband is not identified in a parent, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the idic(15). Approximately 85% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication have a Approximately 15% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication inherited the genetic alteration from the mother. If the mother of a proband inherited a 15q interstitial duplication from her father (i.e., the maternal grandfather of the proband), the mother will not have maternal dup15q syndrome. Instead, she may appear to be unaffected or have features associated with paternal duplications, which – although distinct from those of the proband – may share some similarities (see Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling If the maternal 15q interstitial duplication found in the proband cannot be detected in maternal leukocyte DNA, the most likely explanation is a If the mother of the proband has the 15q interstitial duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the severity of the phenotype in sibs who inherit a maternal interstitial 15q11.2-q13.1 duplication (see If the maternal 15q interstitial duplication identified in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the duplication. If the proband is female, offspring who inherit a 15q interstitial duplication are at risk for maternal dup15q. If the proband is male, offspring who inherit a 15q interstitial duplication are at risk for features associated with paternal interstitial duplications of 15q11.2-q13.1 (see • All probands reported to date with maternal dup15q caused by idic(15) whose parents have undergone genomic testing have had the disorder as the result of a • Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling. Note: Maternal transmission of supernumerary partial trisomy of the region has been reported in one instance [ • The risk to sibs is presumed to be low as the idic(15) has occurred as a • If the idic(15) identified in the proband is not identified in a parent, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the idic(15). • Approximately 85% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication have a • Approximately 15% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication inherited the genetic alteration from the mother. • If the mother of a proband inherited a 15q interstitial duplication from her father (i.e., the maternal grandfather of the proband), the mother will not have maternal dup15q syndrome. Instead, she may appear to be unaffected or have features associated with paternal duplications, which – although distinct from those of the proband – may share some similarities (see • Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling • If the maternal 15q interstitial duplication found in the proband cannot be detected in maternal leukocyte DNA, the most likely explanation is a • If the mother of the proband has the 15q interstitial duplication, the risk to each sib of inheriting the duplication is 50%. • It is not possible to reliably predict the severity of the phenotype in sibs who inherit a maternal interstitial 15q11.2-q13.1 duplication (see • If the maternal 15q interstitial duplication identified in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the duplication. • If the proband is female, offspring who inherit a 15q interstitial duplication are at risk for maternal dup15q. • If the proband is male, offspring who inherit a 15q interstitial duplication are at risk for features associated with paternal interstitial duplications of 15q11.2-q13.1 (see ## Maternal Isodicentric 15q11.2-q13.1 Supernumerary Chromosome – Idic(15) All probands reported to date with maternal dup15q caused by idic(15) whose parents have undergone genomic testing have had the disorder as the result of a Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling. Note: Maternal transmission of supernumerary partial trisomy of the region has been reported in one instance [ The risk to sibs is presumed to be low as the idic(15) has occurred as a If the idic(15) identified in the proband is not identified in a parent, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the idic(15). • All probands reported to date with maternal dup15q caused by idic(15) whose parents have undergone genomic testing have had the disorder as the result of a • Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling. Note: Maternal transmission of supernumerary partial trisomy of the region has been reported in one instance [ • The risk to sibs is presumed to be low as the idic(15) has occurred as a • If the idic(15) identified in the proband is not identified in a parent, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the idic(15). ## Maternal 15q Interstitial Duplication Approximately 85% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication have a Approximately 15% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication inherited the genetic alteration from the mother. If the mother of a proband inherited a 15q interstitial duplication from her father (i.e., the maternal grandfather of the proband), the mother will not have maternal dup15q syndrome. Instead, she may appear to be unaffected or have features associated with paternal duplications, which – although distinct from those of the proband – may share some similarities (see Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling If the maternal 15q interstitial duplication found in the proband cannot be detected in maternal leukocyte DNA, the most likely explanation is a If the mother of the proband has the 15q interstitial duplication, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the severity of the phenotype in sibs who inherit a maternal interstitial 15q11.2-q13.1 duplication (see If the maternal 15q interstitial duplication identified in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the duplication. If the proband is female, offspring who inherit a 15q interstitial duplication are at risk for maternal dup15q. If the proband is male, offspring who inherit a 15q interstitial duplication are at risk for features associated with paternal interstitial duplications of 15q11.2-q13.1 (see • Approximately 85% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication have a • Approximately 15% of individuals with maternal dup15q caused by a maternal interstitial 15q11.2-q13.1 duplication inherited the genetic alteration from the mother. • If the mother of a proband inherited a 15q interstitial duplication from her father (i.e., the maternal grandfather of the proband), the mother will not have maternal dup15q syndrome. Instead, she may appear to be unaffected or have features associated with paternal duplications, which – although distinct from those of the proband – may share some similarities (see • Evaluation of the mother by genomic testing to determine if she has the genetic alteration present in the proband is recommended to confirm her genetic status and to allow reliable recurrence risk counseling • If the maternal 15q interstitial duplication found in the proband cannot be detected in maternal leukocyte DNA, the most likely explanation is a • If the mother of the proband has the 15q interstitial duplication, the risk to each sib of inheriting the duplication is 50%. • It is not possible to reliably predict the severity of the phenotype in sibs who inherit a maternal interstitial 15q11.2-q13.1 duplication (see • If the maternal 15q interstitial duplication identified in the proband cannot be detected in maternal leukocyte DNA, the risk to sibs is presumed to be marginally greater than in the general population because of the theoretic possibility of maternal germline mosaicism for the duplication. • If the proband is female, offspring who inherit a 15q interstitial duplication are at risk for maternal dup15q. • If the proband is male, offspring who inherit a 15q interstitial duplication are at risk for features associated with paternal interstitial duplications of 15q11.2-q13.1 (see ## 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. Similarly, decisions about testing to determine the genetic status of at-risk family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with maternal dup15q. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with maternal dup15q. ## Prenatal Testing and Preimplantation Genetic Testing Note: Prenatal test results cannot reliably predict the severity of the phenotype (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 PO Box 674 Fayetteville NY 13066 United Kingdom • • PO Box 674 • Fayetteville NY 13066 • • • United Kingdom • • • ## Molecular Genetics Maternal 15q Duplication Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Maternal 15q Duplication Syndrome ( The extra copy or copies of the PWACR most commonly arise by one of two mechanisms ( A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60%-80%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) OR A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20%-40%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) The proximal 15q region includes five regions of segmental duplications or low copy repeats (designated by breakpoints [BPs]), which result in increased susceptibility to genomic rearrangements [ The maternal isodicentric 15q11.2-q13.1 – or idic(15) – is typically a bisatellited chromosome thought to arise from U-type exchange during meiosis. Idic(15), which typically includes two mirrored copies of 15pter-q13.1 (p arm of chromosome 15, centromere, and 15q11.2-q13.1) [ Interstitial duplications leading to maternal dup15q arise by nonallelic homologous recombination (NAHR) between two different breakpoint regions (e.g., BP1 and BP3). The distal breakpoint for maternal interstitial duplications is typically BP3 (approximate position [hg38] chr15:28300000), and the proximal breakpoint is typically either BP1 or BP2 (approximate positions [hg38] chr15:22300000 or [hg38] chr15:23300000, respectively). Interstitial duplications usually result in trisomy for 15q11.2-q13.1. Variations of these primary mechanisms include the following: Interstitial 15q11.2-q13.1 triplication, which results in tetrasomy of 15q11.2-q13.1. This phenotype tends to be more severe than that of maternal interstitial 15q11.2-q13.1 duplication and more like that of maternal isodicentric 15q11.2-q13.1 supernumerary chromosome [ Isodicentric 15q hexasomy. The phenotype is severe, including profound intellectual disability, intractable epilepsy, and more prominent dysmorphic features (myopathic facies and low-set ears) [ Asymmetric isodicentric or interstitial maternal triplications, which typically result in tetrasomy for 15q11.2-q13.2 and trisomy for 15q13.2-13.3. These asymmetric copy number variations are observed in approximately 10%-15% of isodicentric and interstitial chromosomes (Dup15q Alliance International Registry, 3-14-14) (see Ring chromosome 15. Rarely, supernumerary ring chromosomes that include the PWACR have been seen. These are typically mosaic, indicating the unstable nature of ring chromosomes [ • A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60%-80%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) • OR • A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20%-40%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) • Interstitial 15q11.2-q13.1 triplication, which results in tetrasomy of 15q11.2-q13.1. This phenotype tends to be more severe than that of maternal interstitial 15q11.2-q13.1 duplication and more like that of maternal isodicentric 15q11.2-q13.1 supernumerary chromosome [ • Isodicentric 15q hexasomy. The phenotype is severe, including profound intellectual disability, intractable epilepsy, and more prominent dysmorphic features (myopathic facies and low-set ears) [ • Asymmetric isodicentric or interstitial maternal triplications, which typically result in tetrasomy for 15q11.2-q13.2 and trisomy for 15q13.2-13.3. These asymmetric copy number variations are observed in approximately 10%-15% of isodicentric and interstitial chromosomes (Dup15q Alliance International Registry, 3-14-14) (see • Ring chromosome 15. Rarely, supernumerary ring chromosomes that include the PWACR have been seen. These are typically mosaic, indicating the unstable nature of ring chromosomes [ ## Molecular Pathogenesis The extra copy or copies of the PWACR most commonly arise by one of two mechanisms ( A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60%-80%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) OR A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20%-40%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) The proximal 15q region includes five regions of segmental duplications or low copy repeats (designated by breakpoints [BPs]), which result in increased susceptibility to genomic rearrangements [ The maternal isodicentric 15q11.2-q13.1 – or idic(15) – is typically a bisatellited chromosome thought to arise from U-type exchange during meiosis. Idic(15), which typically includes two mirrored copies of 15pter-q13.1 (p arm of chromosome 15, centromere, and 15q11.2-q13.1) [ Interstitial duplications leading to maternal dup15q arise by nonallelic homologous recombination (NAHR) between two different breakpoint regions (e.g., BP1 and BP3). The distal breakpoint for maternal interstitial duplications is typically BP3 (approximate position [hg38] chr15:28300000), and the proximal breakpoint is typically either BP1 or BP2 (approximate positions [hg38] chr15:22300000 or [hg38] chr15:23300000, respectively). Interstitial duplications usually result in trisomy for 15q11.2-q13.1. Variations of these primary mechanisms include the following: Interstitial 15q11.2-q13.1 triplication, which results in tetrasomy of 15q11.2-q13.1. This phenotype tends to be more severe than that of maternal interstitial 15q11.2-q13.1 duplication and more like that of maternal isodicentric 15q11.2-q13.1 supernumerary chromosome [ Isodicentric 15q hexasomy. The phenotype is severe, including profound intellectual disability, intractable epilepsy, and more prominent dysmorphic features (myopathic facies and low-set ears) [ Asymmetric isodicentric or interstitial maternal triplications, which typically result in tetrasomy for 15q11.2-q13.2 and trisomy for 15q13.2-13.3. These asymmetric copy number variations are observed in approximately 10%-15% of isodicentric and interstitial chromosomes (Dup15q Alliance International Registry, 3-14-14) (see Ring chromosome 15. Rarely, supernumerary ring chromosomes that include the PWACR have been seen. These are typically mosaic, indicating the unstable nature of ring chromosomes [ • A maternal isodicentric 15q11.2-q13.1 supernumerary chromosome – idic(15) – that typically comprises two extra copies of 15q11.2-q13.1, resulting in tetrasomy for 15q11.2-q13.1 (~60%-80%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) • OR • A maternal interstitial 15q11.2-q13.1 duplication that typically includes one extra copy of 15q11.2-q13.1 within chromosome 15, resulting in trisomy for 15q11.2-q13.1 (~20%-40%) (Dup15q Alliance International Registry, 3-8-21 and 3-14-14) • Interstitial 15q11.2-q13.1 triplication, which results in tetrasomy of 15q11.2-q13.1. This phenotype tends to be more severe than that of maternal interstitial 15q11.2-q13.1 duplication and more like that of maternal isodicentric 15q11.2-q13.1 supernumerary chromosome [ • Isodicentric 15q hexasomy. The phenotype is severe, including profound intellectual disability, intractable epilepsy, and more prominent dysmorphic features (myopathic facies and low-set ears) [ • Asymmetric isodicentric or interstitial maternal triplications, which typically result in tetrasomy for 15q11.2-q13.2 and trisomy for 15q13.2-13.3. These asymmetric copy number variations are observed in approximately 10%-15% of isodicentric and interstitial chromosomes (Dup15q Alliance International Registry, 3-14-14) (see • Ring chromosome 15. Rarely, supernumerary ring chromosomes that include the PWACR have been seen. These are typically mosaic, indicating the unstable nature of ring chromosomes [ ## Chapter Notes The authors are indebted to the Dup15q Alliance for its efforts to advance research into maternal dup15q. Many thanks go to Christa L Martin, PhD, Geisinger Health System, for technical assistance in the preparation of this review. Dimitrios Arkilo, MD; Minnesota Epilepsy Group (2016-2021)Guy Calvert, DPhil; Dup15q Alliance (2016-2021)Stormy Chamberlain, PhD; University of Connecticut Health Center (2016-2021)Edwin H Cook, MD; University of Illinois at Chicago (2016-2021)Orrin Devinsky, MD; New York University Langone Medical Center (2016-2021)Scott Dindot, PhD; Texas A&M University (2016-2021)Charlotte DiStefano, PhD (2021-present)Brenda M Finucane, MS, LGC; Geisinger Health System (2016-2021)Shafali Jeste, MD (2016-present)Janine M LaSalle, PhD; University of California Davis School of Medicine (2016-2021)Kadi Luchsinger, BS, PT; Dup15q Alliance (2016-2021)Laina Lusk, MMSc, CGC (2016-present)Lawrence T Reiter, PhD; University of Tennessee Health Science Center (2016-2021)N Carolyn Schanen, MD, PhD; Dup15q Alliance (2016-2021)Sarah J Spence, MD, PhD; Children's Hospital Boston (2016-2021)Ronald L Thibert, DO, MSPH; Massachusetts General Hospital (2016-2021)Vanessa Vogel-Farley, BA (2021-present) 15 July 2021 (sw) Comprehensive update posted live 16 June 2016 (bp) Review posted live 23 September 2015 (ll) Original submission • 15 July 2021 (sw) Comprehensive update posted live • 16 June 2016 (bp) Review posted live • 23 September 2015 (ll) Original submission ## Acknowledgments The authors are indebted to the Dup15q Alliance for its efforts to advance research into maternal dup15q. Many thanks go to Christa L Martin, PhD, Geisinger Health System, for technical assistance in the preparation of this review. ## Author History Dimitrios Arkilo, MD; Minnesota Epilepsy Group (2016-2021)Guy Calvert, DPhil; Dup15q Alliance (2016-2021)Stormy Chamberlain, PhD; University of Connecticut Health Center (2016-2021)Edwin H Cook, MD; University of Illinois at Chicago (2016-2021)Orrin Devinsky, MD; New York University Langone Medical Center (2016-2021)Scott Dindot, PhD; Texas A&M University (2016-2021)Charlotte DiStefano, PhD (2021-present)Brenda M Finucane, MS, LGC; Geisinger Health System (2016-2021)Shafali Jeste, MD (2016-present)Janine M LaSalle, PhD; University of California Davis School of Medicine (2016-2021)Kadi Luchsinger, BS, PT; Dup15q Alliance (2016-2021)Laina Lusk, MMSc, CGC (2016-present)Lawrence T Reiter, PhD; University of Tennessee Health Science Center (2016-2021)N Carolyn Schanen, MD, PhD; Dup15q Alliance (2016-2021)Sarah J Spence, MD, PhD; Children's Hospital Boston (2016-2021)Ronald L Thibert, DO, MSPH; Massachusetts General Hospital (2016-2021)Vanessa Vogel-Farley, BA (2021-present) ## Revision History 15 July 2021 (sw) Comprehensive update posted live 16 June 2016 (bp) Review posted live 23 September 2015 (ll) Original submission • 15 July 2021 (sw) Comprehensive update posted live • 16 June 2016 (bp) Review posted live • 23 September 2015 (ll) Original submission ## References ## Literature Cited A. Schematic of the normal paternal and maternal chromosome 15 B. & C. The most common causes of maternal dup15q: — B. Interstitial duplication of 15q11.2-13.1 — C. Isodicentric triplication of 15q11.2-13.1 Note: Light blue denotes breakpoint 1(BP1) to breakpoint 2 (BP2), red denotes BP2 to BP3 (PWACR), and green denotes BP3 to BP5. Asymmetry in dup15q, as seen in: A. Interstitial triplication of 15q11.2-13.1; and B. Isodicentric triplication of 15q11.2-13.1. Note: Light blue denotes BP1 to BP2, red denotes BP2 to BP3 (PWACR), and green denotes BP3 to BP5. Uncommon variations in copy number seen in dup15q A. Interstitial triplication of 15q11.2-13.1 B. Supernumerary hexasomy of 15q11.2-13.1, manifest as two isodicentric chromosomes C. A larger isodicentric chromosome Note: Light blue denotes BP1 to BP2, red denotes BP2 to BP3 (PWACR), and green denotes BP3 to BP5.
[]
16/6/2016
15/7/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dup17q12
dup17q12
[ "Not applicable", "Not applicable", "17q12 Recurrent Duplication" ]
17q12 Recurrent Duplication
Heather Mefford
Summary The 17q12 recurrent duplication is characterized by intellectual abilities ranging from normal to severe disability and other variable clinical manifestations. Speech delay is common, and most affected individuals have some degree of hypotonia and gross motor delay. Behavioral and psychiatric conditions reported in some affected individuals include autism spectrum disorder, schizophrenia, and behavioral abnormalities (aggression and self-injury). Seizures are present in 36%. Additional common findings include microcephaly, ocular abnormalities, and endocrine abnormalities. Short stature and renal and cardiac abnormalities are also reported in some individuals. Penetrance is reduced and clinical findings are variable. The diagnosis is established in a proband by detection of the 1.4-megabase heterozygous recurrent duplication at chromosome 17q12 by chromosomal microarray testing or other genomic methods. The 17q12 recurrent duplication is inherited in an autosomal dominant manner, with approximately 10% of duplications occurring
## Diagnosis The 17q12 recurrent duplication Intellectual disability Developmental delays Seizures Ocular anomalies and/or vision problems Cardiac malformations Renal malformations Gastrointestinal abnormalities (e.g., duodenal obstruction) The diagnosis of the 17q12 recurrent duplication For this Note: The phenotype of significantly larger or smaller duplications or deletions within this region may be clinically distinct from the 17q12 recurrent duplication (see For information on the 15 known genes within the 17q12 region see Note: The 17q12 recurrent duplication is Note: (1) Most individuals with the 17q12 recurrent duplication are identified by CMA performed in the context of developmental delay, intellectual disability, and/or autism spectrum disorders. (2) Prior to 2008, many CMA platforms did not include coverage for this region and thus may not have detected this duplication. Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. Genomic Testing Used in the 17q12 Recurrent Duplication NA = not applicable See Standardized clinical annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 17q12 region. Note: The 17q12 recurrent duplication may not have been detectable by older oligonucleotide or BAC platforms. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. Targeted duplication analysis may be used to test at-risk relatives of a proband known to have the 17q12 recurrent duplication. • Intellectual disability • Developmental delays • Seizures • Ocular anomalies and/or vision problems • Cardiac malformations • Renal malformations • Gastrointestinal abnormalities (e.g., duodenal obstruction) • Note: (1) Most individuals with the 17q12 recurrent duplication are identified by CMA performed in the context of developmental delay, intellectual disability, and/or autism spectrum disorders. (2) Prior to 2008, many CMA platforms did not include coverage for this region and thus may not have detected this duplication. • Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. ## Suggestive Findings The 17q12 recurrent duplication Intellectual disability Developmental delays Seizures Ocular anomalies and/or vision problems Cardiac malformations Renal malformations Gastrointestinal abnormalities (e.g., duodenal obstruction) • Intellectual disability • Developmental delays • Seizures • Ocular anomalies and/or vision problems • Cardiac malformations • Renal malformations • Gastrointestinal abnormalities (e.g., duodenal obstruction) ## Establishing the Diagnosis The diagnosis of the 17q12 recurrent duplication For this Note: The phenotype of significantly larger or smaller duplications or deletions within this region may be clinically distinct from the 17q12 recurrent duplication (see For information on the 15 known genes within the 17q12 region see Note: The 17q12 recurrent duplication is Note: (1) Most individuals with the 17q12 recurrent duplication are identified by CMA performed in the context of developmental delay, intellectual disability, and/or autism spectrum disorders. (2) Prior to 2008, many CMA platforms did not include coverage for this region and thus may not have detected this duplication. Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. Genomic Testing Used in the 17q12 Recurrent Duplication NA = not applicable See Standardized clinical annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays. CMA designs in current clinical use target the 17q12 region. Note: The 17q12 recurrent duplication may not have been detectable by older oligonucleotide or BAC platforms. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Targeted duplication analysis is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. Targeted duplication analysis may be used to test at-risk relatives of a proband known to have the 17q12 recurrent duplication. • Note: (1) Most individuals with the 17q12 recurrent duplication are identified by CMA performed in the context of developmental delay, intellectual disability, and/or autism spectrum disorders. (2) Prior to 2008, many CMA platforms did not include coverage for this region and thus may not have detected this duplication. • Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 17q12 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. ## Clinical Characteristics To date, published reports include 86 individuals with the 17q12 recurrent duplication, along with some phenotypic data [ Frequency of Phenotypic Features in 86 Reported Individuals with 17q12 Recurrent Duplication Based on Tracheoesophageal fistula has been reported in three individuals. Duodenal atresia has been reported in three individuals. The penetrance of the 17q12 recurrent duplication has not been established. Although an estimated penetrance of approximately 21% has been proposed [ In four studies of apparently unaffected controls, the 17q12 recurrent duplication was present in 1:2443 individuals [ In two different studies of individuals with intellectual disability, developmental delay or autism, the 17q12 recurrent duplication was reported in 5:2,034 (0.25%) individuals [ In a cohort of individuals with schizophrenia, the 17q12 recurrent duplication was identified in 4:4,719 (0.08%) individuals [ • Tracheoesophageal fistula has been reported in three individuals. • Duodenal atresia has been reported in three individuals. ## Clinical Description To date, published reports include 86 individuals with the 17q12 recurrent duplication, along with some phenotypic data [ Frequency of Phenotypic Features in 86 Reported Individuals with 17q12 Recurrent Duplication Based on Tracheoesophageal fistula has been reported in three individuals. Duodenal atresia has been reported in three individuals. • Tracheoesophageal fistula has been reported in three individuals. • Duodenal atresia has been reported in three individuals. ## Penetrance The penetrance of the 17q12 recurrent duplication has not been established. Although an estimated penetrance of approximately 21% has been proposed [ ## Prevalence In four studies of apparently unaffected controls, the 17q12 recurrent duplication was present in 1:2443 individuals [ In two different studies of individuals with intellectual disability, developmental delay or autism, the 17q12 recurrent duplication was reported in 5:2,034 (0.25%) individuals [ In a cohort of individuals with schizophrenia, the 17q12 recurrent duplication was identified in 4:4,719 (0.08%) individuals [ ## Genetically Related Disorders ## Differential Diagnosis The differential diagnosis of the 17q12 recurrent duplication is broad due to the clinical variability and the presence of relatively common abnormal phenotypes that occur in affected individuals including developmental delay, intellectual disability (ID), epilepsy, behavioral abnormalities, and microcephaly. All chromosome anomalies and genes known to be associated with ID (see ## Management To establish the extent of disease and needs in an individual diagnosed with the 17q12 recurrent duplication, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with 17q12 Recurrent Duplication 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. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with 17q12 Recurrent Duplication 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; DD/ID = developmental delay / intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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 17q12 Recurrent Duplication Assess for new seizures. Monitor those w/seizures as clinically indicated. Measurement of growth parameters Eval of nutritional status & safety of oral intake Consider genomic testing of sibs of a proband who is known to have the 17q12 recurrent duplication in order to refer sibs with a duplication promptly for close assessment/monitoring of developmental milestones in childhood and psychological issues through adulthood. 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. • 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Assess for new seizures. • Monitor those w/seizures as clinically indicated. • 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 the 17q12 recurrent duplication, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with 17q12 Recurrent Duplication 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. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GI = gastrointestinal; 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 • To incl brain MRI • Consider EEG if seizures are a concern. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with 17q12 Recurrent Duplication 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; DD/ID = developmental delay / intellectual disability Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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 consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. ## 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 ## 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 17q12 Recurrent Duplication Assess for new seizures. Monitor those w/seizures as clinically indicated. Measurement of growth parameters Eval of nutritional status & safety of oral intake • Assess for new seizures. • Monitor those w/seizures as clinically indicated. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Evaluation of Relatives at Risk Consider genomic testing of sibs of a proband who is known to have the 17q12 recurrent duplication in order to refer sibs with a duplication promptly for close assessment/monitoring of developmental milestones in childhood and psychological issues through adulthood. See ## Therapies Under Investigation Search ## Genetic Counseling The 17q12 recurrent duplication is inherited in an autosomal dominant manner. About 90% of individuals with a 17q12 recurrent duplication inherited the genetic alteration from a parent. In many instances, the parent with the 17q12 recurrent duplication is phenotypically normal or minimally affected; in parents with features associated with the 17q12 recurrent duplication, reported manifestations range from mild cognitive impairment to learning difficulties, seizures, and mental illness. The 17q12 recurrent duplication is Genomic testing that will detect the 17q12 recurrent duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the 17q12 recurrent duplication identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered: The proband has a The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. If one of the parents has the 17q12 recurrent duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to predict the phenotype in sibs who inherit a 17q12 recurrent duplication because a wide spectrum of manifestations may be observed in family members with the duplication, ranging from no or mild cognitive impairment to learning difficulties, seizures, and mental illness. If the 17q12 recurrent duplication identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic 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 at risk of having a child with a 17q12 recurrent duplication. Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 17q12 recurrent duplication, the prenatal finding of a 17q12 recurrent duplication cannot be used to predict the phenotype. 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 90% of individuals with a 17q12 recurrent duplication inherited the genetic alteration from a parent. In many instances, the parent with the 17q12 recurrent duplication is phenotypically normal or minimally affected; in parents with features associated with the 17q12 recurrent duplication, reported manifestations range from mild cognitive impairment to learning difficulties, seizures, and mental illness. • The 17q12 recurrent duplication is • Genomic testing that will detect the 17q12 recurrent duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the 17q12 recurrent duplication identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered: • The proband has a • The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If one of the parents has the 17q12 recurrent duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to predict the phenotype in sibs who inherit a 17q12 recurrent duplication because a wide spectrum of manifestations may be observed in family members with the duplication, ranging from no or mild cognitive impairment to learning difficulties, seizures, and mental illness. • If the 17q12 recurrent duplication identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic 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 at risk of having a child with a 17q12 recurrent duplication. ## Mode of Inheritance The 17q12 recurrent duplication is inherited in an autosomal dominant manner. ## Risk to Family Members About 90% of individuals with a 17q12 recurrent duplication inherited the genetic alteration from a parent. In many instances, the parent with the 17q12 recurrent duplication is phenotypically normal or minimally affected; in parents with features associated with the 17q12 recurrent duplication, reported manifestations range from mild cognitive impairment to learning difficulties, seizures, and mental illness. The 17q12 recurrent duplication is Genomic testing that will detect the 17q12 recurrent duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the 17q12 recurrent duplication identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered: The proband has a The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. If one of the parents has the 17q12 recurrent duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to predict the phenotype in sibs who inherit a 17q12 recurrent duplication because a wide spectrum of manifestations may be observed in family members with the duplication, ranging from no or mild cognitive impairment to learning difficulties, seizures, and mental illness. If the 17q12 recurrent duplication identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism. • About 90% of individuals with a 17q12 recurrent duplication inherited the genetic alteration from a parent. In many instances, the parent with the 17q12 recurrent duplication is phenotypically normal or minimally affected; in parents with features associated with the 17q12 recurrent duplication, reported manifestations range from mild cognitive impairment to learning difficulties, seizures, and mental illness. • The 17q12 recurrent duplication is • Genomic testing that will detect the 17q12 recurrent duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the 17q12 recurrent duplication identified in the proband is not identified in either confirmed biological parent, the following possibilities should be considered: • The proband has a • The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If one of the parents has the 17q12 recurrent duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to predict the phenotype in sibs who inherit a 17q12 recurrent duplication because a wide spectrum of manifestations may be observed in family members with the duplication, ranging from no or mild cognitive impairment to learning difficulties, seizures, and mental illness. • If the 17q12 recurrent duplication identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low (<1%) but greater than that of the general population because of the theoretic 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 at risk of having a child with a 17q12 recurrent duplication. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with a 17q12 recurrent duplication. ## Prenatal Testing and Preimplantation Genetic Testing Note: Regardless of whether a pregnancy is known or not known to be at increased risk for the 17q12 recurrent duplication, the prenatal finding of a 17q12 recurrent duplication cannot be used to predict the phenotype. 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 17q12 Recurrent Duplication: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for 17q12 Recurrent Duplication ( Pathogenic variants in (or deletion of) ## Molecular Pathogenesis Pathogenic variants in (or deletion of) ## Chapter Notes Heather C Mefford, MD, PhD (2016-present)Elyse Mitchell, MS, CGC; Mayo Clinic (2016-2021)Jennelle Hodge, PhD; Cedars-Sinai Medical Center (2016-2021) 13 January 2022 (aa) Revision: percentage of probands with duplications occurring 29 April 2021 (sw) Comprehensive update posted live 25 February 2016 (bp) Review posted live 5 October 2015 (jh) Original submission • 13 January 2022 (aa) Revision: percentage of probands with duplications occurring • 29 April 2021 (sw) Comprehensive update posted live • 25 February 2016 (bp) Review posted live • 5 October 2015 (jh) Original submission ## Author History Heather C Mefford, MD, PhD (2016-present)Elyse Mitchell, MS, CGC; Mayo Clinic (2016-2021)Jennelle Hodge, PhD; Cedars-Sinai Medical Center (2016-2021) ## Revision History 13 January 2022 (aa) Revision: percentage of probands with duplications occurring 29 April 2021 (sw) Comprehensive update posted live 25 February 2016 (bp) Review posted live 5 October 2015 (jh) Original submission • 13 January 2022 (aa) Revision: percentage of probands with duplications occurring • 29 April 2021 (sw) Comprehensive update posted live • 25 February 2016 (bp) Review posted live • 5 October 2015 (jh) Original submission ## References ## Literature Cited
[]
25/2/2016
29/4/2021
13/1/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dup7q11_23
dup7q11_23
[ "Not applicable", "Not applicable", "7q11.23 Duplication Syndrome" ]
7q11.23 Duplication Syndrome
Carolyn B Mervis, Colleen A Morris, Bonita P Klein-Tasman, Shelley L Velleman, Lucy R Osborne
Summary 7q11.23 duplication syndrome is characterized by delayed motor, speech, and social skills in early childhood; neurologic abnormalities (hypotonia, adventitious movements, and abnormal gait and station); speech sound disorders including motor speech disorders (childhood apraxia of speech and/or dysarthria) and phonologic disorders; behavior issues including anxiety disorders (especially social anxiety disorder [social phobia]), selective mutism, attention-deficit/hyperactivity disorder, oppositional disorders, physical aggression, and autism spectrum disorder; and intellectual disability in some individuals. Distinctive facial features are common. Cardiovascular disease includes dilatation of the ascending aorta. Approximately 30% of individuals have one or more congenital anomalies. The diagnosis of 7q11.23 duplication syndrome is established by detection of a recurrent 1.5- to 1.8-Mb heterozygous duplication of the Williams-Beuren syndrome critical region. 7q11.23 duplication syndrome is transmitted in an autosomal dominant manner. About 27% of individuals diagnosed with 7q11.23 duplication syndrome have an affected parent; about 73% of individuals have the disorder as the result of a
## Diagnosis 7q11.23 duplication syndrome Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. The diagnosis of 7q11.23 duplication syndrome For this Note: (1) Since these duplications are recurrent and mediated by segmental duplications, the unique genetic sequence that is duplicated is the same in all individuals with each duplication; however, the reported size of the duplication: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see Note: (1) Most individuals with a 7q11.23 recurrent duplication are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder. (2) This duplication can be detected by BAC arrays. Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 7q11.23 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. Genomic Testing Used in 7q11.23 Duplication Syndrome See Standardized clinical annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 7q11.23 region. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Not applicable. Targeted duplication analysis is not appropriate for an individual in whom the 7q11.23 duplication was not detected by CMA designed to target this region. Targeted duplication analysis may be used to test at-risk relatives of a proband who is known to have the 7q11.23 duplication. • Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children • Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. • Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. • Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children • Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. • Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. • Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children • Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. • Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. • Note: (1) Most individuals with a 7q11.23 recurrent duplication are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder. (2) This duplication can be detected by BAC arrays. • Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 7q11.23 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. ## Suggestive Findings 7q11.23 duplication syndrome Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. • Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children • Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. • Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. • Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children • Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. • Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. • Motor. Hypotonia, adventitious movements, abnormalities of gait and station, developmental coordination disorder in children • Language. Speech delay, childhood apraxia of speech, dysarthria. Expressive language is usually more delayed than receptive language. • Cognitive. About 20% have borderline intellectual ability, approximately 18% have intellectual disability. The majority of school-age children have intellectual ability in the low average-to-average range. ## Establishing the Diagnosis The diagnosis of 7q11.23 duplication syndrome For this Note: (1) Since these duplications are recurrent and mediated by segmental duplications, the unique genetic sequence that is duplicated is the same in all individuals with each duplication; however, the reported size of the duplication: (a) may be larger if adjacent segmental duplications are included in the size; and (b) may vary based on the design of the microarray used to detect it (see Note: (1) Most individuals with a 7q11.23 recurrent duplication are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder. (2) This duplication can be detected by BAC arrays. Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 7q11.23 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. Genomic Testing Used in 7q11.23 Duplication Syndrome See Standardized clinical annotation and interpretation for genomic variants from the Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 7q11.23 region. Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA) as well as other targeted quantitative methods. Not applicable. Targeted duplication analysis is not appropriate for an individual in whom the 7q11.23 duplication was not detected by CMA designed to target this region. Targeted duplication analysis may be used to test at-risk relatives of a proband who is known to have the 7q11.23 duplication. • Note: (1) Most individuals with a 7q11.23 recurrent duplication are identified by CMA performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder. (2) This duplication can be detected by BAC arrays. • Note: (1) Targeted duplication testing is not appropriate for an individual in whom the 7q11.23 recurrent duplication was not detected by CMA designed to target this region. (2) It is not possible to size the duplication routinely by use of targeted methods. ## Clinical Characteristics Among probands with 7q11.23 duplication syndrome, the most common reasons for evaluation were developmental delay and autism spectrum disorder (ASD) [ To date, more than 150 individuals with a 7q11.23 recurrent duplication have been identified [ 7q11.23 Duplication Syndrome: Frequency of Select Features ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; GI = gastrointestinal; GU = genitourinary; ID = intellectual disability All individuals reported have had some subset of the listed craniofacial features. However, the overall facial gestalt is not as striking as in DSM-V speech sound disorder, present in 83%, includes motor speech disorders (such as childhood apraxia of speech), phonologic disorders (cognitive-linguistic disorders reflecting inaccurate or incomplete phonologic representations or inappropriate phonologic rules), and articulation disorders (persistent distortions of certain sounds). The incidence and severity of speech disorders decrease with age [ The most common speech sound disorder in children with 7q11.23 duplication is childhood apraxia of speech (a neurologic speech disorder not due to muscle weakness or muscle tone differences but rather due to problems of planning and coordinating the muscle movements needed to pronounce words) or manifestations of this disorder. Childhood dysarthria or its manifestations (usually resulting from low muscle tone) are also common [ On omnibus tests of language abilities (including receptive and expressive modalities and vocabulary and grammar) overall performance is most commonly in the range of mild-to-moderate language disorder but can range from severe language disorder to average language ability. For most children vocabulary abilities are stronger than grammatical abilities [ School-age children who received consistent speech-language therapy from late infancy or early toddlerhood had considerably stronger language and literacy skills than children who had not. Children who were taught to read using a systematic phonics approach had better reading skills than children taught with other approaches [ Thirty-three percent screened positive for a possible autism spectrum disorder [ The prevalence of aortic dilatation is 46% [ Based on the limited number of affected individuals identified, there is currently no indication of phenotypic difference between those with the 1.5-Mb duplication and those with the slightly larger 1.8-Mb duplication [ Penetrance is complete in both males and females. Prevalence has been estimated at 1:7,500-1:20,000 [ ## Clinical Description Among probands with 7q11.23 duplication syndrome, the most common reasons for evaluation were developmental delay and autism spectrum disorder (ASD) [ To date, more than 150 individuals with a 7q11.23 recurrent duplication have been identified [ 7q11.23 Duplication Syndrome: Frequency of Select Features ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; GI = gastrointestinal; GU = genitourinary; ID = intellectual disability All individuals reported have had some subset of the listed craniofacial features. However, the overall facial gestalt is not as striking as in DSM-V speech sound disorder, present in 83%, includes motor speech disorders (such as childhood apraxia of speech), phonologic disorders (cognitive-linguistic disorders reflecting inaccurate or incomplete phonologic representations or inappropriate phonologic rules), and articulation disorders (persistent distortions of certain sounds). The incidence and severity of speech disorders decrease with age [ The most common speech sound disorder in children with 7q11.23 duplication is childhood apraxia of speech (a neurologic speech disorder not due to muscle weakness or muscle tone differences but rather due to problems of planning and coordinating the muscle movements needed to pronounce words) or manifestations of this disorder. Childhood dysarthria or its manifestations (usually resulting from low muscle tone) are also common [ On omnibus tests of language abilities (including receptive and expressive modalities and vocabulary and grammar) overall performance is most commonly in the range of mild-to-moderate language disorder but can range from severe language disorder to average language ability. For most children vocabulary abilities are stronger than grammatical abilities [ School-age children who received consistent speech-language therapy from late infancy or early toddlerhood had considerably stronger language and literacy skills than children who had not. Children who were taught to read using a systematic phonics approach had better reading skills than children taught with other approaches [ Thirty-three percent screened positive for a possible autism spectrum disorder [ The prevalence of aortic dilatation is 46% [ ## Genotype/Phenotype Correlations Based on the limited number of affected individuals identified, there is currently no indication of phenotypic difference between those with the 1.5-Mb duplication and those with the slightly larger 1.8-Mb duplication [ ## Penetrance Penetrance is complete in both males and females. ## Prevalence Prevalence has been estimated at 1:7,500-1:20,000 [ ## Genetically Related (Allelic) Disorders WS is characterized by cardiovascular disease (elastin arteriopathy, peripheral pulmonary stenosis, supravalvar aortic stenosis, hypertension), distinctive facies, connective tissue abnormalities, intellectual disability (usually mild), a specific cognitive profile, unique personality characteristics, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism, and early puberty). Behaviorally, WS is characterized by overfriendliness, social disinhibition, attention issues, and non-social anxiety, including non-social specific phobias. WS is also associated with difficulty with sensory modulation and emotional regulation. A child age 38 months with a 7q11.23 triplication including almost all of the genes in the WBSCR has been reported [ A child who has a triplication of four genes in the WBSCR plus a duplication of the remaining genes in the WBSCR has been reported [ A large family including 11 individuals in three generations who had a triplication of • A child age 38 months with a 7q11.23 triplication including almost all of the genes in the WBSCR has been reported [ • A child who has a triplication of four genes in the WBSCR plus a duplication of the remaining genes in the WBSCR has been reported [ • A large family including 11 individuals in three generations who had a triplication of ## Differential Diagnosis 7q11.23 duplication syndrome should be distinguished from other syndromes that include developmental delay, macrocephaly, hypotonia, distinctive craniofacial features, and behavior issues. Examples include fragile X syndrome (see 7q11.23 duplication syndrome should be added to the list of syndromes that are associated with aortic dilatation: ## Management Suggestions for evaluation, health surveillance, and treatment have been published [ To establish the extent of disease and needs in an individual diagnosed with 7q11.23 duplication syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with 7q11.23 Duplication Syndrome Speech-language eval preferably by examiner experienced in evaluating childhood apraxia of speech PT eval OT eval (incl assessment for sensory integration difficulties) Eval for early intervention / special education, incl learning disability services Consider EEG if seizures are a concern. Consider brain MRI in those w/macrocephaly &/or abnormal neurologic exam to evaluate for ventriculomegaly/hydrocephalus, cerebellar vermis hypoplasia, &/or white matter abnormalities. Anxiety (e.g., social anxiety disorder, selective mutism, separation anxiety, generalized anxiety disorder) Attention issues ASD. If indicated, refer for gold-standard autism assessment (ADOS-2 and ADI-R, + clinical judgment) Oppositional behavior/aggression. If indicated, refer for functional behavioral assessment, preferably by board-certified behavior analyst. To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Males: physical exam for cryptorchidism Females w/unilateral renal agenesis: eval of müllerian structures 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) Community or online Social work involvement for parental support; Home nursing or respite care referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ADI-R = Autism Diagnostic Interview Schedule – Revised; ADOS = Autism Diagnostic Observation Schedule; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Because sedation is likely to be necessary for brain MRI, this should be weighed carefully and may not be necessary in every individual. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with 7q11.23 Duplication Syndrome Early intervention programs, special education programs, vocational training Speech-language therapy, PT, OT Cognitive-behavioral intervention for anxiety (preferably by licensed clinical psychologist) Psychotropic medication if indicated Behavioral modifications in home & school settings Psychotropic medication if indicated Applied behavior analysis intervention Psychotropic medication if indicated Behavioral interventions w/emphasis on reinforcing positive behaviors Psychotropic medication if indicated 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. Standard treatment of otitis Hearing aids may be helpful per ENT. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; DD = developmental delay; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Recommended Surveillance for Individuals with 7q11.23 Duplication Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake Assess for new-onset seizures. Monitor those w/seizures as clinically indicated. Behavior assessment (e.g., attention, anxiety, opposition, aggression) Educators should be made aware of signs/symptoms of social anxiety disorder & selective mutism, & of appropriate educational interventions & support for children w/these disorders. Cardiologic eval Echocardiogram to measure aortic root & ascending aorta w/calculation of z scores to monitor for progressive aortic dilatation Annually Significant dilatation may require more frequent monitoring &/or CT angiography or MR angiography. Based on GI = gastrointestinal; OT = occupational therapy; PT = physical therapy See Search • Speech-language eval preferably by examiner experienced in evaluating childhood apraxia of speech • PT eval • OT eval (incl assessment for sensory integration difficulties) • Eval for early intervention / special education, incl learning disability services • Consider EEG if seizures are a concern. • Consider brain MRI in those w/macrocephaly &/or abnormal neurologic exam to evaluate for ventriculomegaly/hydrocephalus, cerebellar vermis hypoplasia, &/or white matter abnormalities. • Anxiety (e.g., social anxiety disorder, selective mutism, separation anxiety, generalized anxiety disorder) • Attention issues • ASD. If indicated, refer for gold-standard autism assessment (ADOS-2 and ADI-R, + clinical judgment) • Oppositional behavior/aggression. If indicated, refer for functional behavioral assessment, preferably by board-certified behavior analyst. • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Males: physical exam for cryptorchidism • Females w/unilateral renal agenesis: eval of müllerian structures • 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) • Community or online • Social work involvement for parental support; • Home nursing or respite care referral. • Early intervention programs, special education programs, vocational training • Speech-language therapy, PT, OT • Cognitive-behavioral intervention for anxiety (preferably by licensed clinical psychologist) • Psychotropic medication if indicated • Behavioral modifications in home & school settings • Psychotropic medication if indicated • Applied behavior analysis intervention • Psychotropic medication if indicated • Behavioral interventions w/emphasis on reinforcing positive behaviors • Psychotropic medication if indicated • 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. • Standard treatment of otitis • Hearing aids may be helpful per ENT. • 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 • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assess for new-onset seizures. • Monitor those w/seizures as clinically indicated. • Behavior assessment (e.g., attention, anxiety, opposition, aggression) • Educators should be made aware of signs/symptoms of social anxiety disorder & selective mutism, & of appropriate educational interventions & support for children w/these disorders. • Cardiologic eval • Echocardiogram to measure aortic root & ascending aorta w/calculation of z scores to monitor for progressive aortic dilatation • Annually • Significant dilatation may require more frequent monitoring &/or CT angiography or MR angiography. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with 7q11.23 duplication syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with 7q11.23 Duplication Syndrome Speech-language eval preferably by examiner experienced in evaluating childhood apraxia of speech PT eval OT eval (incl assessment for sensory integration difficulties) Eval for early intervention / special education, incl learning disability services Consider EEG if seizures are a concern. Consider brain MRI in those w/macrocephaly &/or abnormal neurologic exam to evaluate for ventriculomegaly/hydrocephalus, cerebellar vermis hypoplasia, &/or white matter abnormalities. Anxiety (e.g., social anxiety disorder, selective mutism, separation anxiety, generalized anxiety disorder) Attention issues ASD. If indicated, refer for gold-standard autism assessment (ADOS-2 and ADI-R, + clinical judgment) Oppositional behavior/aggression. If indicated, refer for functional behavioral assessment, preferably by board-certified behavior analyst. To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Males: physical exam for cryptorchidism Females w/unilateral renal agenesis: eval of müllerian structures 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) Community or online Social work involvement for parental support; Home nursing or respite care referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ADI-R = Autism Diagnostic Interview Schedule – Revised; ADOS = Autism Diagnostic Observation Schedule; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Because sedation is likely to be necessary for brain MRI, this should be weighed carefully and may not be necessary in every individual. Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Speech-language eval preferably by examiner experienced in evaluating childhood apraxia of speech • PT eval • OT eval (incl assessment for sensory integration difficulties) • Eval for early intervention / special education, incl learning disability services • Consider EEG if seizures are a concern. • Consider brain MRI in those w/macrocephaly &/or abnormal neurologic exam to evaluate for ventriculomegaly/hydrocephalus, cerebellar vermis hypoplasia, &/or white matter abnormalities. • Anxiety (e.g., social anxiety disorder, selective mutism, separation anxiety, generalized anxiety disorder) • Attention issues • ASD. If indicated, refer for gold-standard autism assessment (ADOS-2 and ADI-R, + clinical judgment) • Oppositional behavior/aggression. If indicated, refer for functional behavioral assessment, preferably by board-certified behavior analyst. • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Males: physical exam for cryptorchidism • Females w/unilateral renal agenesis: eval of müllerian structures • 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) • Community or online • Social work involvement for parental support; • Home nursing or respite care referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with 7q11.23 Duplication Syndrome Early intervention programs, special education programs, vocational training Speech-language therapy, PT, OT Cognitive-behavioral intervention for anxiety (preferably by licensed clinical psychologist) Psychotropic medication if indicated Behavioral modifications in home & school settings Psychotropic medication if indicated Applied behavior analysis intervention Psychotropic medication if indicated Behavioral interventions w/emphasis on reinforcing positive behaviors Psychotropic medication if indicated 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. Standard treatment of otitis Hearing aids may be helpful per ENT. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ASM = anti-seizure medication; DD = developmental delay; 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 • Early intervention programs, special education programs, vocational training • Speech-language therapy, PT, OT • Cognitive-behavioral intervention for anxiety (preferably by licensed clinical psychologist) • Psychotropic medication if indicated • Behavioral modifications in home & school settings • Psychotropic medication if indicated • Applied behavior analysis intervention • Psychotropic medication if indicated • Behavioral interventions w/emphasis on reinforcing positive behaviors • Psychotropic medication if indicated • 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. • Standard treatment of otitis • Hearing aids may be helpful per ENT. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or ## Surveillance Recommended Surveillance for Individuals with 7q11.23 Duplication Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake Assess for new-onset seizures. Monitor those w/seizures as clinically indicated. Behavior assessment (e.g., attention, anxiety, opposition, aggression) Educators should be made aware of signs/symptoms of social anxiety disorder & selective mutism, & of appropriate educational interventions & support for children w/these disorders. Cardiologic eval Echocardiogram to measure aortic root & ascending aorta w/calculation of z scores to monitor for progressive aortic dilatation Annually Significant dilatation may require more frequent monitoring &/or CT angiography or MR angiography. Based on GI = gastrointestinal; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assess for new-onset seizures. • Monitor those w/seizures as clinically indicated. • Behavior assessment (e.g., attention, anxiety, opposition, aggression) • Educators should be made aware of signs/symptoms of social anxiety disorder & selective mutism, & of appropriate educational interventions & support for children w/these disorders. • Cardiologic eval • Echocardiogram to measure aortic root & ascending aorta w/calculation of z scores to monitor for progressive aortic dilatation • Annually • Significant dilatation may require more frequent monitoring &/or CT angiography or MR angiography. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling 7q11.23 duplication syndrome is transmitted in an autosomal dominant manner. About 27% of individuals diagnosed with 7q11.23 duplication syndrome have an affected parent [ About 73% of individuals diagnosed with 7q11.23 duplication syndrome have the disorder as the result of a Genomic testing that will detect the 7q11.23 duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Testing for a balanced chromosome rearrangement in the parents is also recommended. If the 7q11.23 duplication identified in the proband is not identified in either confirmed biological parent and neither parent has a balanced chromosome rearrangement, the following possibilities should be considered: The proband has a The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Parental mosaicism has been reported in one family [ If one of the parents has the 7q11.23 duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype in sibs who inherit a 7q11.23 duplication because manifestations of 7q11.23 duplication syndrome may vary in affected family members. If the 7q11.23 duplication identified in the proband cannot be detected in parental leukocyte DNA and neither parent has a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism. If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 7q11.23 duplication is increased and depends on the specific chromosome rearrangement and the possibility of other variables. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 7q11.23 duplication syndrome. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements. Note: The manifestations of 7q11.23 duplication syndrome cannot be reliably predicted on the basis of prenatal test results or family history. 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 27% of individuals diagnosed with 7q11.23 duplication syndrome have an affected parent [ • About 73% of individuals diagnosed with 7q11.23 duplication syndrome have the disorder as the result of a • Genomic testing that will detect the 7q11.23 duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Testing for a balanced chromosome rearrangement in the parents is also recommended. • If the 7q11.23 duplication identified in the proband is not identified in either confirmed biological parent and neither parent has a balanced chromosome rearrangement, the following possibilities should be considered: • The proband has a • The proband inherited a duplication 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 duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in one family [ • The proband has a • The proband inherited a duplication 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 one of the parents has the 7q11.23 duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype in sibs who inherit a 7q11.23 duplication because manifestations of 7q11.23 duplication syndrome may vary in affected family members. • If the 7q11.23 duplication identified in the proband cannot be detected in parental leukocyte DNA and neither parent has a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism. • If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 7q11.23 duplication is increased and depends on the specific chromosome rearrangement and the possibility of other variables. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 7q11.23 duplication syndrome. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements. ## Mode of Inheritance 7q11.23 duplication syndrome is transmitted in an autosomal dominant manner. ## Risk to Family Members About 27% of individuals diagnosed with 7q11.23 duplication syndrome have an affected parent [ About 73% of individuals diagnosed with 7q11.23 duplication syndrome have the disorder as the result of a Genomic testing that will detect the 7q11.23 duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Testing for a balanced chromosome rearrangement in the parents is also recommended. If the 7q11.23 duplication identified in the proband is not identified in either confirmed biological parent and neither parent has a balanced chromosome rearrangement, the following possibilities should be considered: The proband has a The proband inherited a duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. Parental mosaicism has been reported in one family [ If one of the parents has the 7q11.23 duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype in sibs who inherit a 7q11.23 duplication because manifestations of 7q11.23 duplication syndrome may vary in affected family members. If the 7q11.23 duplication identified in the proband cannot be detected in parental leukocyte DNA and neither parent has a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism. If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 7q11.23 duplication is increased and depends on the specific chromosome rearrangement and the possibility of other variables. • About 27% of individuals diagnosed with 7q11.23 duplication syndrome have an affected parent [ • About 73% of individuals diagnosed with 7q11.23 duplication syndrome have the disorder as the result of a • Genomic testing that will detect the 7q11.23 duplication present in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. Testing for a balanced chromosome rearrangement in the parents is also recommended. • If the 7q11.23 duplication identified in the proband is not identified in either confirmed biological parent and neither parent has a balanced chromosome rearrangement, the following possibilities should be considered: • The proband has a • The proband inherited a duplication 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 duplication from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • Parental mosaicism has been reported in one family [ • The proband has a • The proband inherited a duplication 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 one of the parents has the 7q11.23 duplication identified in the proband, the risk to each sib of inheriting the duplication is 50%. It is not possible to reliably predict the phenotype in sibs who inherit a 7q11.23 duplication because manifestations of 7q11.23 duplication syndrome may vary in affected family members. • If the 7q11.23 duplication identified in the proband cannot be detected in parental leukocyte DNA and neither parent has a balanced chromosome rearrangement, the recurrence risk to sibs is low (presumed to be <1%) but greater than that of the general population because of the possibility of parental germline mosaicism. • If one of the parents has a balanced chromosome rearrangement, the risk to sibs of having the 7q11.23 duplication is increased and depends on the specific chromosome rearrangement and the possibility of other variables. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 7q11.23 duplication syndrome. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with 7q11.23 duplication syndrome. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements. ## Prenatal Testing and Preimplantation Genetic Testing Note: The manifestations of 7q11.23 duplication syndrome cannot be reliably predicted on the basis of prenatal test results or family history. 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 7q11.23 Duplication Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for 7q11.23 Duplication Syndrome ( An inversion polymorphism at 7q11.23 in one parent has been detected in 20% of children with a classic The contribution of the remaining genes within the 7q11.23 duplicated region to the phenotype is unknown. Note: Genes marked with an ## Molecular Pathogenesis An inversion polymorphism at 7q11.23 in one parent has been detected in 20% of children with a classic The contribution of the remaining genes within the 7q11.23 duplicated region to the phenotype is unknown. Note: Genes marked with an ## Chapter Notes The authors' research was supported by grant SFARI 328896 from the Simons Foundation, grant R01 NS35102 from the National Institute of Neurological Disorders and Stroke, grant R37 HD29957 from the National Institute of Child Health and Human Development, and the Las Vegas Pediatric Research Fund of the University of Nevada School of Medicine. We are very grateful to the individuals with 7q11.23 duplication syndrome and their families who have participated in our research for their commitment to the research and for giving so generously of their time. 25 March 2021 (sw) Comprehensive updated posted live 25 November 2015 (me) Review posted live 10 July 2015 (cbm) Original submission • 25 March 2021 (sw) Comprehensive updated posted live • 25 November 2015 (me) Review posted live • 10 July 2015 (cbm) Original submission ## Acknowledgments The authors' research was supported by grant SFARI 328896 from the Simons Foundation, grant R01 NS35102 from the National Institute of Neurological Disorders and Stroke, grant R37 HD29957 from the National Institute of Child Health and Human Development, and the Las Vegas Pediatric Research Fund of the University of Nevada School of Medicine. We are very grateful to the individuals with 7q11.23 duplication syndrome and their families who have participated in our research for their commitment to the research and for giving so generously of their time. ## Revision History 25 March 2021 (sw) Comprehensive updated posted live 25 November 2015 (me) Review posted live 10 July 2015 (cbm) Original submission • 25 March 2021 (sw) Comprehensive updated posted live • 25 November 2015 (me) Review posted live • 10 July 2015 (cbm) Original submission ## References ## Literature Cited Children with characteristic facial features of 7q11.23 duplication syndrome Top row: Age 1 year, age 2 years, age 2 years, age 2 years, age 4 years Bottom row: Age 4 years (front and profile), age 7 years, age 7 years, age 8 years Note the brachycephaly, broad forehead, straight eyebrows, deeply set eyes, long eyelashes, broad nasal tip, low insertion of the columella, short philtrum, thin vermilion of the upper lip, and minor ear anomalies (overfolded helix, protruding ears). Adolescents and adults with 7q11.23 duplication syndrome Top row: Age 12 years (front and profile), age 14 years, age 21 years Bottom row: Age 18 years (front and profile), age 39 years (front and profile) In addition to the facial features noted in children (
[]
25/11/2015
25/3/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dupl22q11
dupl22q11
[ "22q11.2 Microduplication Syndrome", "Microduplication 22q11.2", "Not applicable", "Not applicable", "22q11.2 Duplication" ]
22q11.2 Duplication – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Helen V Firth
Summary 22q11.2 duplication is defined for this The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds alone. 22q11.2 duplication is not detectable by routine G-banded karyotyping. Most individuals with 22q11.2 duplication are identified by a chromosomal microarray. 22q11.2 duplication may be inherited in an autosomal dominant manner or occur as a
## Diagnosis 22q11.2 duplication is a recently described condition, with the first report appearing in 2003 [ Because chromosomal microarray testing is commonly performed as part of the evaluation of developmental delay or intellectual disability, this significant ascertainment bias makes the phenotype associated with 22q11.2 duplication difficult to establish. The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds alone. Duplication 22q11.2 may be confirmed by molecular genetic testing. Note: (1) For this Molecular Genetic Testing Used in 22q11.2 Duplication See Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; for this disorder genomic chromosomal microarrays (CMA) are used (e.g., aCGH, SNP array) Other deletion/duplication methods focused on the 22q11.2 region may be employed for reflex testing to confirm the duplication, determine the size of the duplication and also for testing relatives of the proband the presence of the duplication (e.g., Interphase FISH, multiplex ligation-dependent probe amplification, quantitative PCR). ## Clinical Diagnosis 22q11.2 duplication is a recently described condition, with the first report appearing in 2003 [ Because chromosomal microarray testing is commonly performed as part of the evaluation of developmental delay or intellectual disability, this significant ascertainment bias makes the phenotype associated with 22q11.2 duplication difficult to establish. The phenotype is not sufficiently distinct to be specifically suspected on clinical grounds alone. Duplication 22q11.2 may be confirmed by molecular genetic testing. Note: (1) For this ## Molecular Genetic Testing Molecular Genetic Testing Used in 22q11.2 Duplication See Testing that identifies exon or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; for this disorder genomic chromosomal microarrays (CMA) are used (e.g., aCGH, SNP array) Other deletion/duplication methods focused on the 22q11.2 region may be employed for reflex testing to confirm the duplication, determine the size of the duplication and also for testing relatives of the proband the presence of the duplication (e.g., Interphase FISH, multiplex ligation-dependent probe amplification, quantitative PCR). ## Testing Strategy ## Clinical Characteristics Findings in individuals with 22q11.2 duplication range from apparently normal to intellectual disability / learning disability, delayed psychomotor development, growth retardation, and/or hypotonia. The most common findings in symptomatic individuals with 22q11.2 duplication are [ Intellectual disability / learning disability (97%), but note Delayed psychomotor development (67%) Growth retardation (63%) Muscular hypotonia (43%) In a study of nine individuals with duplication of 22q11.2, the phenotypes observed were generally mild and highly variable [ The high frequency with which the 22q11.2 duplication is found in an apparently normal parent of a proband suggests that many individuals can harbor a duplication of 22q11.2 with no discernible phenotypic effect. Eichler et al found that the incidence of 22q11.2 tandem duplication in a cohort of individuals with diverse developmental disorders was 0.31% i.e., fivefold higher than the incidence of 0.06% in a control group of persons without any known developmental disorder (p=1.26x10 Given the limited data and difficulties in establishing whether and to what extent a 22q11.2 duplication modifies phenotype, it is not possible to determine whether there is a predictable difference between the larger recurrent duplication (3 Mb) and the smaller recurrent duplication (1.5 Mb). An individual with the smaller duplication is described in In probands in whom 22q11.2 tandem duplication is identified, caution is needed in attributing the observed clinical features to this finding. Duplication 22q11.2 has been observed in normal people as well as in people who were studied because they had developmental delay, intellectual disability, or other clinical features suggestive of a chromosomal abnormality. Tandem duplication of 22q11.2 is often inherited. A study by In a study of 7,000 individuals referred for genomic microarray analysis for the investigation of developmental delay/intellectual disability, 3-Mb duplications of 22q11.2 were identified in ten individuals, giving a prevalence of approximately 1:700 in this referral population [ A more recent study [E Eicher, unpublished data May 2011; referenced in • Intellectual disability / learning disability (97%), but note • Delayed psychomotor development (67%) • Growth retardation (63%) • Muscular hypotonia (43%) ## Clinical Description Findings in individuals with 22q11.2 duplication range from apparently normal to intellectual disability / learning disability, delayed psychomotor development, growth retardation, and/or hypotonia. The most common findings in symptomatic individuals with 22q11.2 duplication are [ Intellectual disability / learning disability (97%), but note Delayed psychomotor development (67%) Growth retardation (63%) Muscular hypotonia (43%) In a study of nine individuals with duplication of 22q11.2, the phenotypes observed were generally mild and highly variable [ The high frequency with which the 22q11.2 duplication is found in an apparently normal parent of a proband suggests that many individuals can harbor a duplication of 22q11.2 with no discernible phenotypic effect. Eichler et al found that the incidence of 22q11.2 tandem duplication in a cohort of individuals with diverse developmental disorders was 0.31% i.e., fivefold higher than the incidence of 0.06% in a control group of persons without any known developmental disorder (p=1.26x10 • Intellectual disability / learning disability (97%), but note • Delayed psychomotor development (67%) • Growth retardation (63%) • Muscular hypotonia (43%) ## Genotype-Phenotype Correlations Given the limited data and difficulties in establishing whether and to what extent a 22q11.2 duplication modifies phenotype, it is not possible to determine whether there is a predictable difference between the larger recurrent duplication (3 Mb) and the smaller recurrent duplication (1.5 Mb). An individual with the smaller duplication is described in ## Penetrance In probands in whom 22q11.2 tandem duplication is identified, caution is needed in attributing the observed clinical features to this finding. Duplication 22q11.2 has been observed in normal people as well as in people who were studied because they had developmental delay, intellectual disability, or other clinical features suggestive of a chromosomal abnormality. Tandem duplication of 22q11.2 is often inherited. A study by ## Prevalence In a study of 7,000 individuals referred for genomic microarray analysis for the investigation of developmental delay/intellectual disability, 3-Mb duplications of 22q11.2 were identified in ten individuals, giving a prevalence of approximately 1:700 in this referral population [ A more recent study [E Eicher, unpublished data May 2011; referenced in ## Genetically Related (Allelic) Disorders ## Differential Diagnosis The most common findings in duplication 22q11.2 – intellectual disability / learning disability, delayed psychomotor development, growth retardation, and muscular hypotonia – are common and relatively nonspecific indications for cytogenetic analysis; the extent to which duplication 22q11.2 is a cause for this group of findings in any individual is currently unknown. There is a growing appreciation that some children have more than one genetic diagnosis as the cause of their developmental problems. If a child with severe developmental problems and/or multiple congenital anomalies is diagnosed with a tandem 22q11.2 microduplication, it may be appropriate to consider further investigations (e.g., higher resolution array and/or exome analysis) to determine whether additional genetic diagnoses are contributing to the phenotype. ## Management To establish the extent of disease and needs in an individual diagnosed with 22q11.2 duplication, the following are recommended: Clinical examination Developmental assessment Consultation with a clinical geneticist and/or genetic counselor Educational program should be tailored to individual needs. Periodic developmental assessment to assure that educational needs are being met is appropriate. See Search • Clinical examination • Developmental assessment • 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 22q11.2 duplication, the following are recommended: Clinical examination Developmental assessment Consultation with a clinical geneticist and/or genetic counselor • Clinical examination • Developmental assessment • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Educational program should be tailored to individual needs. ## Surveillance Periodic developmental assessment to assure that educational needs are being met is appropriate. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling 22q11.2 duplication may be inherited in an autosomal dominant manner or occur Most individuals diagnosed with a 22q11.2 duplication have inherited the duplication from a parent [ 63 individuals from 35 families have been described with duplication 22q11.2 by A parent who has the duplication 22q11.2 may have a normal or near-normal phenotype (i.e., no physical findings of the 22q11.2 duplication), while the child with an apparently identical genomic alteration has obvious clinical features. Because the penetrance of 22q11.2 duplication is incomplete, both parents should be tested to distinguish inherited from The risk to the sibs of the proband depends on the genetic status of the proband’s parents. If the parents of an individual with the 22q11.2 duplication have normal interphase FISH/MLPA/array studies, the risk to sibs is low but greater than that of the general population because one parent may have germline mosaicism or low-level somatic mosaicism that also includes the gonads. If a parent also has the 22q11.2 duplication, the risk to each sib of inheriting the duplication is 50%. However, it is not possible to predict the phenotype reliably from a laboratory finding of the 22q11.2 duplication, and many people who have this genomic alteration are clinically normal. In one report [ The risk to other family members depends on the status of the proband's parents. If a parent has the 22q11.2 duplication, his or her family members may also have the duplication. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have the 22q11.2 duplication or are at risk of having it. Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using interphase FISH in the manner described in However, it is not possible to reliably predict the phenotype from a laboratory finding of 22q11.2 duplication. Whether prenatal testing for 22q11.2 duplication is clinically appropriate (given the difficulty in predicting the phenotype accurately in this nebulous disorder) is uncertain. With the current state of knowledge, such a request would merit careful thought and discussion and review of the current literature. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. • Most individuals diagnosed with a 22q11.2 duplication have inherited the duplication from a parent [ • 63 individuals from 35 families have been described with duplication 22q11.2 by • A parent who has the duplication 22q11.2 may have a normal or near-normal phenotype (i.e., no physical findings of the 22q11.2 duplication), while the child with an apparently identical genomic alteration has obvious clinical features. • Because the penetrance of 22q11.2 duplication is incomplete, both parents should be tested to distinguish inherited from • The risk to the sibs of the proband depends on the genetic status of the proband’s parents. • If the parents of an individual with the 22q11.2 duplication have normal interphase FISH/MLPA/array studies, the risk to sibs is low but greater than that of the general population because one parent may have germline mosaicism or low-level somatic mosaicism that also includes the gonads. • If a parent also has the 22q11.2 duplication, the risk to each sib of inheriting the duplication is 50%. However, it is not possible to predict the phenotype reliably from a laboratory finding of the 22q11.2 duplication, and many people who have this genomic alteration are clinically normal. • In one report [ • The risk to other family members depends on the status of the proband's parents. • If a parent has the 22q11.2 duplication, his or her family members may also have the duplication. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have the 22q11.2 duplication or are at risk of having it. ## Mode of Inheritance 22q11.2 duplication may be inherited in an autosomal dominant manner or occur ## Risk to Family Members Most individuals diagnosed with a 22q11.2 duplication have inherited the duplication from a parent [ 63 individuals from 35 families have been described with duplication 22q11.2 by A parent who has the duplication 22q11.2 may have a normal or near-normal phenotype (i.e., no physical findings of the 22q11.2 duplication), while the child with an apparently identical genomic alteration has obvious clinical features. Because the penetrance of 22q11.2 duplication is incomplete, both parents should be tested to distinguish inherited from The risk to the sibs of the proband depends on the genetic status of the proband’s parents. If the parents of an individual with the 22q11.2 duplication have normal interphase FISH/MLPA/array studies, the risk to sibs is low but greater than that of the general population because one parent may have germline mosaicism or low-level somatic mosaicism that also includes the gonads. If a parent also has the 22q11.2 duplication, the risk to each sib of inheriting the duplication is 50%. However, it is not possible to predict the phenotype reliably from a laboratory finding of the 22q11.2 duplication, and many people who have this genomic alteration are clinically normal. In one report [ The risk to other family members depends on the status of the proband's parents. If a parent has the 22q11.2 duplication, his or her family members may also have the duplication. • Most individuals diagnosed with a 22q11.2 duplication have inherited the duplication from a parent [ • 63 individuals from 35 families have been described with duplication 22q11.2 by • A parent who has the duplication 22q11.2 may have a normal or near-normal phenotype (i.e., no physical findings of the 22q11.2 duplication), while the child with an apparently identical genomic alteration has obvious clinical features. • Because the penetrance of 22q11.2 duplication is incomplete, both parents should be tested to distinguish inherited from • The risk to the sibs of the proband depends on the genetic status of the proband’s parents. • If the parents of an individual with the 22q11.2 duplication have normal interphase FISH/MLPA/array studies, the risk to sibs is low but greater than that of the general population because one parent may have germline mosaicism or low-level somatic mosaicism that also includes the gonads. • If a parent also has the 22q11.2 duplication, the risk to each sib of inheriting the duplication is 50%. However, it is not possible to predict the phenotype reliably from a laboratory finding of the 22q11.2 duplication, and many people who have this genomic alteration are clinically normal. • In one report [ • The risk to other family members depends on the status of the proband's parents. • If a parent has the 22q11.2 duplication, his or her family members may also have the duplication. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have the 22q11.2 duplication or are at risk of having it. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have the 22q11.2 duplication or are at risk of having it. ## Prenatal Testing Prenatal testing is technically feasible. Chromosome preparations from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or CVS at approximately ten to 12 weeks' gestation can be analyzed using interphase FISH in the manner described in However, it is not possible to reliably predict the phenotype from a laboratory finding of 22q11.2 duplication. Whether prenatal testing for 22q11.2 duplication is clinically appropriate (given the difficulty in predicting the phenotype accurately in this nebulous disorder) is uncertain. With the current state of knowledge, such a request would merit careful thought and discussion and review of the current literature. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. ## Resources c/o Murney Rinholm 7108 Partinwood Drive Fuquay-Varina NC 27526 PO Box 724 Boca Raton FL 33429-0724 Wellcome Trust Genome Campus Hinxton Cambridgeshire CB10 1SA United Kingdom G1 The Stables Station Road West Oxted Surrey RH8 9EE United Kingdom • • c/o Murney Rinholm • 7108 Partinwood Drive • Fuquay-Varina NC 27526 • • • PO Box 724 • Boca Raton FL 33429-0724 • • • Wellcome Trust Genome Campus • Hinxton Cambridgeshire CB10 1SA • United Kingdom • • • G1 The Stables • Station Road West • Oxted Surrey RH8 9EE • United Kingdom • ## Molecular Genetics 22q11.2 Duplication: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for 22q11.2 Duplication ( The low-copy repeat sequences on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in microdeletions and microduplications. This region of the genome is highly dynamic, and in at least one family, expansion of a duplication of 22q11.2 to a triplication has been observed [ Duplications of 22q11.2 vary in size and thereby in gene content. They include: The typical common 3-Mb tandem duplication, thought to arise by nonallelic homologous recombination (NAHR) between one set of LCRs; A 1.5-Mb tandem duplication consistent with NAHR between other distinct LCRs [ These duplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region [ Smaller duplications may also occur within this highly dynamic region, with frequent rearrangements using alternative LCRs (LCR22s) as recombination substrates within and distal to the DiGeorge/velocardiofacial syndrome region. • The typical common 3-Mb tandem duplication, thought to arise by nonallelic homologous recombination (NAHR) between one set of LCRs; • A 1.5-Mb tandem duplication consistent with NAHR between other distinct LCRs [ ## Molecular Pathogenesis The low-copy repeat sequences on chromosome 22q11.2 (LCR22s) mediate chromosomal rearrangements resulting in microdeletions and microduplications. This region of the genome is highly dynamic, and in at least one family, expansion of a duplication of 22q11.2 to a triplication has been observed [ Duplications of 22q11.2 vary in size and thereby in gene content. They include: The typical common 3-Mb tandem duplication, thought to arise by nonallelic homologous recombination (NAHR) between one set of LCRs; A 1.5-Mb tandem duplication consistent with NAHR between other distinct LCRs [ These duplications likely represent the predicted reciprocal rearrangements to the microdeletions characterized in the 22q11.2 region [ Smaller duplications may also occur within this highly dynamic region, with frequent rearrangements using alternative LCRs (LCR22s) as recombination substrates within and distal to the DiGeorge/velocardiofacial syndrome region. • The typical common 3-Mb tandem duplication, thought to arise by nonallelic homologous recombination (NAHR) between one set of LCRs; • A 1.5-Mb tandem duplication consistent with NAHR between other distinct LCRs [ ## References ## Literature Cited ## Chapter Notes DECIPHER 30 January 2020 (ma) Chapter retired: phenotype is too broad 21 November 2013 (me) Comprehensive update posted live 17 February 2009 (cg) Review posted live 5 September 2008 (hvf) Original submission • 30 January 2020 (ma) Chapter retired: phenotype is too broad • 21 November 2013 (me) Comprehensive update posted live • 17 February 2009 (cg) Review posted live • 5 September 2008 (hvf) Original submission ## Author Notes DECIPHER ## Revision History 30 January 2020 (ma) Chapter retired: phenotype is too broad 21 November 2013 (me) Comprehensive update posted live 17 February 2009 (cg) Review posted live 5 September 2008 (hvf) Original submission • 30 January 2020 (ma) Chapter retired: phenotype is too broad • 21 November 2013 (me) Comprehensive update posted live • 17 February 2009 (cg) Review posted live • 5 September 2008 (hvf) Original submission
[ "A Alberti, C Romano, M Falco, F Calì, P Schinocca, O Galesi, A Spalletta, D Di Benedetto, M. Fichera. 1.5 Mb de novo 22q11.21 microduplication in a patient with cognitive deficits and dysmorphic facial features.. Clin Genet. 2007;71:177-82", "W Courtens, I Schramme, A. Laridon. Microduplication 22q11.2: a benign polymorphism or a syndrome with a very large clinical variability and reduced penetrance?--Report of two families.. Am J Med Genet A. 2008;146A:758-63", "RE Ensenauer, A Adeyinka, HC Flynn, VV Michels, NM Lindor, DB Dawson, EC Thorland, CP Lorentz, JL Goldstein, MT McDonald, WE Smith, E Simon-Fayard, AA Alexander, AS Kulharya, RP Ketterling, RD Clark, SM Jalal. Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients.. Am J Hum Genet. 2003;73:1027-40", "SJ Hassed, D Hopcus-Niccum, L Zhang, S Li, JJ Mulvihill. A new genomic duplication syndrome complementary to the velocardiofacial (22q11 deletion) syndrome.. Clin Genet. 2004;65:400-4", "JR Lupski. Structural variation in the human genome.. N Engl J Med. 2007;356:1169-71", "Z Ou, JS Berg, H Yonath, VB Enciso, DT Miller, J Picker, T Lenzi, CE Keegan, VR Sutton, J Belmont, AC Chinault, JR Lupski, SW Cheung, E Roeder, A Patel. Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes.. Genet Med. 2008;10:267-77", "AC Stachon, B Baskin, AC Smith, A Shugar, C Cytrynbaum, L Fishman, R Mendoza-Londono, R Klatt, A Teebi, PN Ray, R Weksberg. Molecular diagnosis of 22q11.2 deletion and duplication by multiplex ligation dependent probe amplification.. Am J Med Genet A. 2007;143A:2924-30", "S Van Campenhout, K Devriendt, J Breckpot, JP Frijns, H Peeters, G Van Buggenhout, H Van Esch, B Maes, A Swillen. Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood.. Genet Couns. 2012;23:135-48", "C Wentzel, M Fernström, Y Ohrner, G Annerén, AC Thuresson. Clinical variability of the 22q11.2 duplication syndrome.. Eur J Med Genet. 2008;51:501-10", "TM Yobb, MJ Somerville, L Willatt, HV Firth, K Harrison, J MacKenzie, N Gallo, BE Morrow, LG Shaffer, M Babcock, J Chernos, F Bernier, K Sprysak, J Christiansen, S Haase, B Elyas, M Lilley, S Bamforth, HE McDermid. Microduplication and triplication of 22q11.2: a highly variable syndrome.. Am J Hum Genet. 2005;76:865-76", "S Yu, K Cox, K Friend, S Smith, R Buchheim, S Bain, J Liebelt, E Thompson, D. Bratkovic. Familial 22q11.2 duplication: a three-generation family with a 3-Mb duplication and a familial 1.5-Mb duplication.. Clin Genet. 2008;73:160-4" ]
17/2/2009
21/11/2013
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dync1h1-dis
dync1h1-dis
[ "DYNC1H1-Related Neuromuscular Disorder (DYNC1H1-NMD)", "DYNC1H1-Related Neurodevelopmental Disorder (DYNC1H1-NDD)", "Cytoplasmic dynein 1 heavy chain 1", "DYNC1H1", "DYNC1H1-Related Disorders" ]
Birk Möller, Antonietta Coppola, Heinz Jungbluth, Hormos Salimi Dafsari
Summary The diagnosis of a
Motor axonal neuropathy ± delayed motor milestones Developmental delay / intellectual disability Epilepsy Neurobehavioral/psychiatric manifestations Movement disorders ± malformations of cortical development CNS = central nervous system; PNS = peripheral nervous system Based on • Motor axonal neuropathy • ± delayed motor milestones • Developmental delay / intellectual disability • Epilepsy • Neurobehavioral/psychiatric manifestations • Movement disorders • ± malformations of cortical development ## Diagnosis A Muscle weakness and reduced-to-absent reflexes that can manifest: Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. Note that in individuals with primarily central nervous system involvement the signs of axonal neuropathy may be mild or masked and thus may only be detected on electrophysiologic evaluation. Secondary skeletal involvement due to progressive muscle weakness that can manifest: In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; In older individuals due to spastic quadri- or paraparesis. Spastic paraparesis first involves the lower limbs, manifesting as gait abnormalities and ataxia progressing to spastic quadriparesis and akinesia. Upper limb involvement is less pronounced at disease onset but may progress (over ten to 20 years) during adolescence or adulthood. Nerve conduction studies (NCS) may reveal low/decreased motor amplitude [ Electromyography (EMG) may reveal chronic, axonal neurogenic changes comprising denervation and faulty reinnervation, large-amplitude and long-duration motor unit potentials, positive sharp waves, giant potentials during slight contraction, and neurogenic recruitment patterns [ NCS and EMG may be consistent with sensory neuropathy [ In addition to axonal neuropathy described above, all individuals with DYNC1H1-NDD have Additionally, some individuals manifest the following: Malformations of cortical development including pachygyria, lissencephaly, polymicrogyria, and other types of cortical dysgyria Dysgenesis or agenesis of the corpus callosum Enlarged ventricles Gray matter heterotopia Pontocerebellar hypoplasia White matter abnormalities (less common) Because 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. Reference to "pathogenic variants" in this 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, splice site variants and small 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. • Muscle weakness and reduced-to-absent reflexes that can manifest: • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • Note that in individuals with primarily central nervous system involvement the signs of axonal neuropathy may be mild or masked and thus may only be detected on electrophysiologic evaluation. • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • Secondary skeletal involvement due to progressive muscle weakness that can manifest: • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • Spastic paraparesis first involves the lower limbs, manifesting as gait abnormalities and ataxia progressing to spastic quadriparesis and akinesia. Upper limb involvement is less pronounced at disease onset but may progress (over ten to 20 years) during adolescence or adulthood. • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • Nerve conduction studies (NCS) may reveal low/decreased motor amplitude [ • Electromyography (EMG) may reveal chronic, axonal neurogenic changes comprising denervation and faulty reinnervation, large-amplitude and long-duration motor unit potentials, positive sharp waves, giant potentials during slight contraction, and neurogenic recruitment patterns [ • NCS and EMG may be consistent with sensory neuropathy [ • Malformations of cortical development including pachygyria, lissencephaly, polymicrogyria, and other types of cortical dysgyria • Dysgenesis or agenesis of the corpus callosum • Enlarged ventricles • Gray matter heterotopia • Pontocerebellar hypoplasia • White matter abnormalities (less common) ## Suggestive Findings A Muscle weakness and reduced-to-absent reflexes that can manifest: Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. Note that in individuals with primarily central nervous system involvement the signs of axonal neuropathy may be mild or masked and thus may only be detected on electrophysiologic evaluation. Secondary skeletal involvement due to progressive muscle weakness that can manifest: In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; In older individuals due to spastic quadri- or paraparesis. Spastic paraparesis first involves the lower limbs, manifesting as gait abnormalities and ataxia progressing to spastic quadriparesis and akinesia. Upper limb involvement is less pronounced at disease onset but may progress (over ten to 20 years) during adolescence or adulthood. Nerve conduction studies (NCS) may reveal low/decreased motor amplitude [ Electromyography (EMG) may reveal chronic, axonal neurogenic changes comprising denervation and faulty reinnervation, large-amplitude and long-duration motor unit potentials, positive sharp waves, giant potentials during slight contraction, and neurogenic recruitment patterns [ NCS and EMG may be consistent with sensory neuropathy [ In addition to axonal neuropathy described above, all individuals with DYNC1H1-NDD have Additionally, some individuals manifest the following: Malformations of cortical development including pachygyria, lissencephaly, polymicrogyria, and other types of cortical dysgyria Dysgenesis or agenesis of the corpus callosum Enlarged ventricles Gray matter heterotopia Pontocerebellar hypoplasia White matter abnormalities (less common) Because • Muscle weakness and reduced-to-absent reflexes that can manifest: • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • Note that in individuals with primarily central nervous system involvement the signs of axonal neuropathy may be mild or masked and thus may only be detected on electrophysiologic evaluation. • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • Secondary skeletal involvement due to progressive muscle weakness that can manifest: • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • Spastic paraparesis first involves the lower limbs, manifesting as gait abnormalities and ataxia progressing to spastic quadriparesis and akinesia. Upper limb involvement is less pronounced at disease onset but may progress (over ten to 20 years) during adolescence or adulthood. • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • Nerve conduction studies (NCS) may reveal low/decreased motor amplitude [ • Electromyography (EMG) may reveal chronic, axonal neurogenic changes comprising denervation and faulty reinnervation, large-amplitude and long-duration motor unit potentials, positive sharp waves, giant potentials during slight contraction, and neurogenic recruitment patterns [ • NCS and EMG may be consistent with sensory neuropathy [ • Malformations of cortical development including pachygyria, lissencephaly, polymicrogyria, and other types of cortical dysgyria • Dysgenesis or agenesis of the corpus callosum • Enlarged ventricles • Gray matter heterotopia • Pontocerebellar hypoplasia • White matter abnormalities (less common) Muscle weakness and reduced-to-absent reflexes that can manifest: Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. Note that in individuals with primarily central nervous system involvement the signs of axonal neuropathy may be mild or masked and thus may only be detected on electrophysiologic evaluation. Secondary skeletal involvement due to progressive muscle weakness that can manifest: In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; In older individuals due to spastic quadri- or paraparesis. Spastic paraparesis first involves the lower limbs, manifesting as gait abnormalities and ataxia progressing to spastic quadriparesis and akinesia. Upper limb involvement is less pronounced at disease onset but may progress (over ten to 20 years) during adolescence or adulthood. Nerve conduction studies (NCS) may reveal low/decreased motor amplitude [ Electromyography (EMG) may reveal chronic, axonal neurogenic changes comprising denervation and faulty reinnervation, large-amplitude and long-duration motor unit potentials, positive sharp waves, giant potentials during slight contraction, and neurogenic recruitment patterns [ NCS and EMG may be consistent with sensory neuropathy [ • Muscle weakness and reduced-to-absent reflexes that can manifest: • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • Note that in individuals with primarily central nervous system involvement the signs of axonal neuropathy may be mild or masked and thus may only be detected on electrophysiologic evaluation. • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • Secondary skeletal involvement due to progressive muscle weakness that can manifest: • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • Spastic paraparesis first involves the lower limbs, manifesting as gait abnormalities and ataxia progressing to spastic quadriparesis and akinesia. Upper limb involvement is less pronounced at disease onset but may progress (over ten to 20 years) during adolescence or adulthood. • Prenatally/perinatally in fetuses/newborns with severe muscular hypotonia resulting in reduced fetal movements and contractures; • In young children as gross motor developmental delays and positive Gower sign and muscle atrophy in those with significantly decreased strength. • In infants and toddlers as foot deformities, contractures, spine deformities, and/or congenital hip dysplasia/dislocation; • In older individuals due to spastic quadri- or paraparesis. • Nerve conduction studies (NCS) may reveal low/decreased motor amplitude [ • Electromyography (EMG) may reveal chronic, axonal neurogenic changes comprising denervation and faulty reinnervation, large-amplitude and long-duration motor unit potentials, positive sharp waves, giant potentials during slight contraction, and neurogenic recruitment patterns [ • NCS and EMG may be consistent with sensory neuropathy [ In addition to axonal neuropathy described above, all individuals with DYNC1H1-NDD have Additionally, some individuals manifest the following: Malformations of cortical development including pachygyria, lissencephaly, polymicrogyria, and other types of cortical dysgyria Dysgenesis or agenesis of the corpus callosum Enlarged ventricles Gray matter heterotopia Pontocerebellar hypoplasia White matter abnormalities (less common) • Malformations of cortical development including pachygyria, lissencephaly, polymicrogyria, and other types of cortical dysgyria • Dysgenesis or agenesis of the corpus callosum • Enlarged ventricles • Gray matter heterotopia • Pontocerebellar hypoplasia • White matter abnormalities (less common) ## Family History Because ## 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. Reference to "pathogenic variants" in this 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, splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, splice site variants and small 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 To date, more than 200 individuals with Based on + = present; ± = variably present; − = absent CNS = central nervous system; Initial findings of lower limb involvement include decreased muscle tone and weakness due to muscle atrophy and reduced muscle mass. In some infants, decreased fetal movements result in secondary contractures evident at birth [ Foot deformities, present in around 50% of individuals, such as pes cavus (in around half of all cases), pes equinus, pes equinovarus, pes adductus, talus verticalis, shortened forefoot, slender/hammer toes, pes calcaneus, hyperextension deformities, and bilateral foot drop [ Other contractures, present in around 10% of individuals, almost exclusively affecting the lower limb, including the hips, iliotibial ligament, knees, and Achilles tendon; can also involve the upper limb (especially the thumbs) [ As neuropathy progresses, the gait may become ataxic and walking aids such as canes or wheelchairs may be required [ Other less common motor involvement includes the following: Difficulty feeding and poor weight gain due to orofacial hypotonia [ Rare instances of weakness in the periscapular or extraocular muscles [ Individuals with Note: Delay of gross motor milestones that manifests in the legs only (e.g., walking) may suggest PNS involvement (i.e., motor axonal neuropathy) in a child with Other reported specific electroclinical syndromes are centrotemporal epilepsy, acquired aphasia syndrome, focal epilepsy of structural origin, and Lennox-Gastaut syndrome [ Electroencephalography (EEG) may show different patterns according to seizure semiology, including the following: Hypsarrhythmia and high-amplitude ictal rhythmic waves in individuals with IESS. With time hypsarrhythmia can evolve into an electrographic pattern characterized by focal or multifocal epileptiform discharges [ Focal or multifocal epileptiform discharges in focal-onset seizures [ Generalized spike-wave complexes, irregular polyspikes, and slow waves, mixed theta and delta frequencies, and periodic spike and slow wave activity in generalized seizures [ Slow background activity in most affected individuals Movement disorders. Parkinsonism, reported in one individual with global developmental delay, extrapyramidal findings (bradykinesia, hypokinesia, cogwheel rigidity, small step walking, difficulty in initiating movements, hypomimic face, and a resting tremor), responded favorably to treatment with levodopa [ Brain MRI abnormalities have been detected on in more than 60% of individuals studied and include the following [ Malformations of cortical development including pachygyria (that may resemble lissencephaly), polymicrogyria, a much broader range of cortical dysgyria (48%), and dysgenesis or agenesis of the corpus callosum (23%) Ventriculomegaly (15%) Cerebellar hypoplasia (14%) Gray matter heterotopia (11%) Brain stem hypoplasia (9%) Other findings seen in one or a few individuals include abnormalities of the white matter [ The following findings have been observed across the entire phenotypic spectrum of Several genotype-phenotype correlations have been observed based on the location of pathogenic variants within the four main functional domains of Penetrance in previously reported families with known recurrences is high for DYNC1H1-related disorders [ It is assumed that penetrance is age-related because of observed disease progression over time [ Phenotypes associated with CNS = central nervous system; PNS = peripheral nervous system Based on Formerly "mental retardation, autosomal dominant 13" (MRD13) The birth prevalence for • Foot deformities, present in around 50% of individuals, such as pes cavus (in around half of all cases), pes equinus, pes equinovarus, pes adductus, talus verticalis, shortened forefoot, slender/hammer toes, pes calcaneus, hyperextension deformities, and bilateral foot drop [ • Other contractures, present in around 10% of individuals, almost exclusively affecting the lower limb, including the hips, iliotibial ligament, knees, and Achilles tendon; can also involve the upper limb (especially the thumbs) [ • Difficulty feeding and poor weight gain due to orofacial hypotonia [ • Rare instances of weakness in the periscapular or extraocular muscles [ • Note: Delay of gross motor milestones that manifests in the legs only (e.g., walking) may suggest PNS involvement (i.e., motor axonal neuropathy) in a child with • Hypsarrhythmia and high-amplitude ictal rhythmic waves in individuals with IESS. With time hypsarrhythmia can evolve into an electrographic pattern characterized by focal or multifocal epileptiform discharges [ • Focal or multifocal epileptiform discharges in focal-onset seizures [ • Generalized spike-wave complexes, irregular polyspikes, and slow waves, mixed theta and delta frequencies, and periodic spike and slow wave activity in generalized seizures [ • Slow background activity in most affected individuals • Malformations of cortical development including pachygyria (that may resemble lissencephaly), polymicrogyria, a much broader range of cortical dysgyria (48%), and dysgenesis or agenesis of the corpus callosum (23%) • Ventriculomegaly (15%) • Cerebellar hypoplasia (14%) • Gray matter heterotopia (11%) • Brain stem hypoplasia (9%) ## Clinical Description To date, more than 200 individuals with Based on + = present; ± = variably present; − = absent CNS = central nervous system; Initial findings of lower limb involvement include decreased muscle tone and weakness due to muscle atrophy and reduced muscle mass. In some infants, decreased fetal movements result in secondary contractures evident at birth [ Foot deformities, present in around 50% of individuals, such as pes cavus (in around half of all cases), pes equinus, pes equinovarus, pes adductus, talus verticalis, shortened forefoot, slender/hammer toes, pes calcaneus, hyperextension deformities, and bilateral foot drop [ Other contractures, present in around 10% of individuals, almost exclusively affecting the lower limb, including the hips, iliotibial ligament, knees, and Achilles tendon; can also involve the upper limb (especially the thumbs) [ As neuropathy progresses, the gait may become ataxic and walking aids such as canes or wheelchairs may be required [ Other less common motor involvement includes the following: Difficulty feeding and poor weight gain due to orofacial hypotonia [ Rare instances of weakness in the periscapular or extraocular muscles [ Individuals with Note: Delay of gross motor milestones that manifests in the legs only (e.g., walking) may suggest PNS involvement (i.e., motor axonal neuropathy) in a child with Other reported specific electroclinical syndromes are centrotemporal epilepsy, acquired aphasia syndrome, focal epilepsy of structural origin, and Lennox-Gastaut syndrome [ Electroencephalography (EEG) may show different patterns according to seizure semiology, including the following: Hypsarrhythmia and high-amplitude ictal rhythmic waves in individuals with IESS. With time hypsarrhythmia can evolve into an electrographic pattern characterized by focal or multifocal epileptiform discharges [ Focal or multifocal epileptiform discharges in focal-onset seizures [ Generalized spike-wave complexes, irregular polyspikes, and slow waves, mixed theta and delta frequencies, and periodic spike and slow wave activity in generalized seizures [ Slow background activity in most affected individuals Movement disorders. Parkinsonism, reported in one individual with global developmental delay, extrapyramidal findings (bradykinesia, hypokinesia, cogwheel rigidity, small step walking, difficulty in initiating movements, hypomimic face, and a resting tremor), responded favorably to treatment with levodopa [ Brain MRI abnormalities have been detected on in more than 60% of individuals studied and include the following [ Malformations of cortical development including pachygyria (that may resemble lissencephaly), polymicrogyria, a much broader range of cortical dysgyria (48%), and dysgenesis or agenesis of the corpus callosum (23%) Ventriculomegaly (15%) Cerebellar hypoplasia (14%) Gray matter heterotopia (11%) Brain stem hypoplasia (9%) Other findings seen in one or a few individuals include abnormalities of the white matter [ The following findings have been observed across the entire phenotypic spectrum of • Foot deformities, present in around 50% of individuals, such as pes cavus (in around half of all cases), pes equinus, pes equinovarus, pes adductus, talus verticalis, shortened forefoot, slender/hammer toes, pes calcaneus, hyperextension deformities, and bilateral foot drop [ • Other contractures, present in around 10% of individuals, almost exclusively affecting the lower limb, including the hips, iliotibial ligament, knees, and Achilles tendon; can also involve the upper limb (especially the thumbs) [ • Difficulty feeding and poor weight gain due to orofacial hypotonia [ • Rare instances of weakness in the periscapular or extraocular muscles [ • Note: Delay of gross motor milestones that manifests in the legs only (e.g., walking) may suggest PNS involvement (i.e., motor axonal neuropathy) in a child with • Hypsarrhythmia and high-amplitude ictal rhythmic waves in individuals with IESS. With time hypsarrhythmia can evolve into an electrographic pattern characterized by focal or multifocal epileptiform discharges [ • Focal or multifocal epileptiform discharges in focal-onset seizures [ • Generalized spike-wave complexes, irregular polyspikes, and slow waves, mixed theta and delta frequencies, and periodic spike and slow wave activity in generalized seizures [ • Slow background activity in most affected individuals • Malformations of cortical development including pachygyria (that may resemble lissencephaly), polymicrogyria, a much broader range of cortical dysgyria (48%), and dysgenesis or agenesis of the corpus callosum (23%) • Ventriculomegaly (15%) • Cerebellar hypoplasia (14%) • Gray matter heterotopia (11%) • Brain stem hypoplasia (9%) Initial findings of lower limb involvement include decreased muscle tone and weakness due to muscle atrophy and reduced muscle mass. In some infants, decreased fetal movements result in secondary contractures evident at birth [ Foot deformities, present in around 50% of individuals, such as pes cavus (in around half of all cases), pes equinus, pes equinovarus, pes adductus, talus verticalis, shortened forefoot, slender/hammer toes, pes calcaneus, hyperextension deformities, and bilateral foot drop [ Other contractures, present in around 10% of individuals, almost exclusively affecting the lower limb, including the hips, iliotibial ligament, knees, and Achilles tendon; can also involve the upper limb (especially the thumbs) [ As neuropathy progresses, the gait may become ataxic and walking aids such as canes or wheelchairs may be required [ Other less common motor involvement includes the following: Difficulty feeding and poor weight gain due to orofacial hypotonia [ Rare instances of weakness in the periscapular or extraocular muscles [ • Foot deformities, present in around 50% of individuals, such as pes cavus (in around half of all cases), pes equinus, pes equinovarus, pes adductus, talus verticalis, shortened forefoot, slender/hammer toes, pes calcaneus, hyperextension deformities, and bilateral foot drop [ • Other contractures, present in around 10% of individuals, almost exclusively affecting the lower limb, including the hips, iliotibial ligament, knees, and Achilles tendon; can also involve the upper limb (especially the thumbs) [ • Difficulty feeding and poor weight gain due to orofacial hypotonia [ • Rare instances of weakness in the periscapular or extraocular muscles [ Individuals with Note: Delay of gross motor milestones that manifests in the legs only (e.g., walking) may suggest PNS involvement (i.e., motor axonal neuropathy) in a child with Other reported specific electroclinical syndromes are centrotemporal epilepsy, acquired aphasia syndrome, focal epilepsy of structural origin, and Lennox-Gastaut syndrome [ Electroencephalography (EEG) may show different patterns according to seizure semiology, including the following: Hypsarrhythmia and high-amplitude ictal rhythmic waves in individuals with IESS. With time hypsarrhythmia can evolve into an electrographic pattern characterized by focal or multifocal epileptiform discharges [ Focal or multifocal epileptiform discharges in focal-onset seizures [ Generalized spike-wave complexes, irregular polyspikes, and slow waves, mixed theta and delta frequencies, and periodic spike and slow wave activity in generalized seizures [ Slow background activity in most affected individuals Movement disorders. Parkinsonism, reported in one individual with global developmental delay, extrapyramidal findings (bradykinesia, hypokinesia, cogwheel rigidity, small step walking, difficulty in initiating movements, hypomimic face, and a resting tremor), responded favorably to treatment with levodopa [ Brain MRI abnormalities have been detected on in more than 60% of individuals studied and include the following [ Malformations of cortical development including pachygyria (that may resemble lissencephaly), polymicrogyria, a much broader range of cortical dysgyria (48%), and dysgenesis or agenesis of the corpus callosum (23%) Ventriculomegaly (15%) Cerebellar hypoplasia (14%) Gray matter heterotopia (11%) Brain stem hypoplasia (9%) Other findings seen in one or a few individuals include abnormalities of the white matter [ • Note: Delay of gross motor milestones that manifests in the legs only (e.g., walking) may suggest PNS involvement (i.e., motor axonal neuropathy) in a child with • Hypsarrhythmia and high-amplitude ictal rhythmic waves in individuals with IESS. With time hypsarrhythmia can evolve into an electrographic pattern characterized by focal or multifocal epileptiform discharges [ • Focal or multifocal epileptiform discharges in focal-onset seizures [ • Generalized spike-wave complexes, irregular polyspikes, and slow waves, mixed theta and delta frequencies, and periodic spike and slow wave activity in generalized seizures [ • Slow background activity in most affected individuals • Malformations of cortical development including pachygyria (that may resemble lissencephaly), polymicrogyria, a much broader range of cortical dysgyria (48%), and dysgenesis or agenesis of the corpus callosum (23%) • Ventriculomegaly (15%) • Cerebellar hypoplasia (14%) • Gray matter heterotopia (11%) • Brain stem hypoplasia (9%) ## Other Findings The following findings have been observed across the entire phenotypic spectrum of ## Genotype-Phenotype Correlations Several genotype-phenotype correlations have been observed based on the location of pathogenic variants within the four main functional domains of ## Penetrance Penetrance in previously reported families with known recurrences is high for DYNC1H1-related disorders [ It is assumed that penetrance is age-related because of observed disease progression over time [ ## Nomenclature Phenotypes associated with CNS = central nervous system; PNS = peripheral nervous system Based on Formerly "mental retardation, autosomal dominant 13" (MRD13) ## Prevalence The birth prevalence for ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because OMIM Phenotypic Series: Specific disorders with a high degree of clinical overlap include those listed in AD = autosomal dominant; AR = autosomal recessive; AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; • • OMIM Phenotypic Series: • • • • • • • • • • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Hyporeflexia, muscle tone, strength, & atrophy Gower sign NCS/EMG to document presence of motor axonal neuropathy Muscle MRI for identifying atrophy, fatty replacement, &/or compensatory hypertrophy Gross motor & fine motor skills Foot deformities, limb contractures, spine deformities, & hip dysplasia Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Baseline brain MRI for structural CNS abnormalities Head circumference for head growth abnormalities EEG (Consider initiation of appropriate ASM if seizures are a concern.) Movement disorders or abnormal movements Gross & fine motor skills, language & cognitive development Behavioral disorders To incl motor, adaptive, cognitive, & speech-language eval Evaluation for early intervention / special education To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia, high risk of aspiration, &/or poor weight gain. Assess gastrointestinal motility. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASM = anti-seizure medication; ASD = autism spectrum disorder; CNS = central nervous system; EMG = electromyography; MOI = mode of inheritance; NCS = nerve conduction studies; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for PT & OT Referral for early intervention & developmental support Neuropathic pain therapy as indicated Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures as needed Consider need for positioning & mobility devices (e.g., walking aids, orthopedic shoes, ankle-foot orthoses, forearm crutches or cane for gait stability, &/or wheelchairs / mobility scooters. Stretching & muscle strengthening exercises as needed Consider orthopedic surgery as needed (e.g., to correct severe pes cavus deformity, kyphoscoliosis). Treatment of neuropathic or musculoskeletal pain as needed Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Infantile spasms are particularly refractory to ASM. Vigabatrin has been reported as effective in individuals w/IESS. Education of parents/caregivers Antispasticity medications (i.e., oral baclofen or botulinum toxin injections), levodopa in case of parkinsonism, surgical tendon release Mobility, ADL, & need for adaptive devices Nutritional supplementation as directed by dietitian &/or nutritionist 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. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ASM = anti-seizure medication; CNS = central nervous system; IESS = infantile epileptic spasms syndrome; 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 and movement disorders including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures. 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 Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. 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 See Search • Hyporeflexia, muscle tone, strength, & atrophy • Gower sign • NCS/EMG to document presence of motor axonal neuropathy • Muscle MRI for identifying atrophy, fatty replacement, &/or compensatory hypertrophy • Gross motor & fine motor skills • Foot deformities, limb contractures, spine deformities, & hip dysplasia • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Baseline brain MRI for structural CNS abnormalities • Head circumference for head growth abnormalities • EEG (Consider initiation of appropriate ASM if seizures are a concern.) • Movement disorders or abnormal movements • Gross & fine motor skills, language & cognitive development • Behavioral disorders • To incl motor, adaptive, cognitive, & speech-language eval • Evaluation for early intervention / special education • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia, high risk of aspiration, &/or poor weight gain. • Assess gastrointestinal motility. • Community or • Social work involvement for parental support • Home nursing referral • PT & OT • Referral for early intervention & developmental support • Neuropathic pain therapy as indicated • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures as needed • Consider need for positioning & mobility devices (e.g., walking aids, orthopedic shoes, ankle-foot orthoses, forearm crutches or cane for gait stability, &/or wheelchairs / mobility scooters. • Stretching & muscle strengthening exercises as needed • Consider orthopedic surgery as needed (e.g., to correct severe pes cavus deformity, kyphoscoliosis). • Treatment of neuropathic or musculoskeletal pain as needed • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Infantile spasms are particularly refractory to ASM. Vigabatrin has been reported as effective in individuals w/IESS. • Education of parents/caregivers • Antispasticity medications (i.e., oral baclofen or botulinum toxin injections), levodopa in case of parkinsonism, surgical tendon release • Mobility, ADL, & need for adaptive devices • Nutritional supplementation as directed by dietitian &/or nutritionist • 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. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 and movement disorders including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as 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 a Hyporeflexia, muscle tone, strength, & atrophy Gower sign NCS/EMG to document presence of motor axonal neuropathy Muscle MRI for identifying atrophy, fatty replacement, &/or compensatory hypertrophy Gross motor & fine motor skills Foot deformities, limb contractures, spine deformities, & hip dysplasia Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Baseline brain MRI for structural CNS abnormalities Head circumference for head growth abnormalities EEG (Consider initiation of appropriate ASM if seizures are a concern.) Movement disorders or abnormal movements Gross & fine motor skills, language & cognitive development Behavioral disorders To incl motor, adaptive, cognitive, & speech-language eval Evaluation for early intervention / special education To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia, high risk of aspiration, &/or poor weight gain. Assess gastrointestinal motility. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASM = anti-seizure medication; ASD = autism spectrum disorder; CNS = central nervous system; EMG = electromyography; MOI = mode of inheritance; NCS = nerve conduction studies; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Hyporeflexia, muscle tone, strength, & atrophy • Gower sign • NCS/EMG to document presence of motor axonal neuropathy • Muscle MRI for identifying atrophy, fatty replacement, &/or compensatory hypertrophy • Gross motor & fine motor skills • Foot deformities, limb contractures, spine deformities, & hip dysplasia • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Baseline brain MRI for structural CNS abnormalities • Head circumference for head growth abnormalities • EEG (Consider initiation of appropriate ASM if seizures are a concern.) • Movement disorders or abnormal movements • Gross & fine motor skills, language & cognitive development • Behavioral disorders • To incl motor, adaptive, cognitive, & speech-language eval • Evaluation for early intervention / special education • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia, high risk of aspiration, &/or poor weight gain. • Assess gastrointestinal motility. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for PT & OT Referral for early intervention & developmental support Neuropathic pain therapy as indicated Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures as needed Consider need for positioning & mobility devices (e.g., walking aids, orthopedic shoes, ankle-foot orthoses, forearm crutches or cane for gait stability, &/or wheelchairs / mobility scooters. Stretching & muscle strengthening exercises as needed Consider orthopedic surgery as needed (e.g., to correct severe pes cavus deformity, kyphoscoliosis). Treatment of neuropathic or musculoskeletal pain as needed Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Infantile spasms are particularly refractory to ASM. Vigabatrin has been reported as effective in individuals w/IESS. Education of parents/caregivers Antispasticity medications (i.e., oral baclofen or botulinum toxin injections), levodopa in case of parkinsonism, surgical tendon release Mobility, ADL, & need for adaptive devices Nutritional supplementation as directed by dietitian &/or nutritionist 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. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ASM = anti-seizure medication; CNS = central nervous system; IESS = infantile epileptic spasms syndrome; 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 and movement disorders including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures. 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 • Referral for early intervention & developmental support • Neuropathic pain therapy as indicated • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures as needed • Consider need for positioning & mobility devices (e.g., walking aids, orthopedic shoes, ankle-foot orthoses, forearm crutches or cane for gait stability, &/or wheelchairs / mobility scooters. • Stretching & muscle strengthening exercises as needed • Consider orthopedic surgery as needed (e.g., to correct severe pes cavus deformity, kyphoscoliosis). • Treatment of neuropathic or musculoskeletal pain as needed • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Infantile spasms are particularly refractory to ASM. Vigabatrin has been reported as effective in individuals w/IESS. • Education of parents/caregivers • Antispasticity medications (i.e., oral baclofen or botulinum toxin injections), levodopa in case of parkinsonism, surgical tendon release • Mobility, ADL, & need for adaptive devices • Nutritional supplementation as directed by dietitian &/or nutritionist • 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. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 and movement disorders including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures. ## 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 and movement disorders including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures. 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). • For muscle tone abnormalities and movement disorders including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, anti-parkinsonian medications, or orthopedic procedures. ## 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. Assess for new manifestations such as seizures, changes in tone, & movement disorders. 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 • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as 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 Most individuals with Almost all individuals diagnosed to date with Most individuals diagnosed with a Very few individuals diagnosed with a Several large families with Transmission of a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to 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 [ * A parent with somatic and germline 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%. If the If the parents have not been tested for the Each child of an individual with Individuals with severe The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most individuals with • Almost all individuals diagnosed to date with • Most individuals diagnosed with a • Very few individuals diagnosed with a • Several large families with • Transmission of a • Several large families with • Transmission of a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to 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 [ • * 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 • Several large families with • Transmission of 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 • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • If the parents have not been tested for the • Each child of an individual with • Individuals with severe • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 Most individuals with Almost all individuals diagnosed to date with • Most individuals with • Almost all individuals diagnosed to date with ## Risk to Family Members Most individuals diagnosed with a Very few individuals diagnosed with a Several large families with Transmission of a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to 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 [ * A parent with somatic and germline 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%. If the If the parents have not been tested for the Each child of an individual with Individuals with severe • Most individuals diagnosed with a • Very few individuals diagnosed with a • Several large families with • Transmission of a • Several large families with • Transmission of a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and to 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 [ • * 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 • Several large families with • Transmission of 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 • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the • If the parents have not been tested for the • Each child of an individual with • Individuals with severe ## 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 centers 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 • ## Molecular Genetics DYNC1H1-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DYNC1H1-Related Disorders ( The cytoplasmic dynein 1 heavy chain 1 complex comprises a core of dimerized heavy chains [ ## Molecular Pathogenesis The cytoplasmic dynein 1 heavy chain 1 complex comprises a core of dimerized heavy chains [ ## Chapter Notes Birk Möller and Hormos Dafsari are actively involved in clinical research regarding individuals with Hormos Dafsari and Heinz Jungbluth are also interested in hearing from clinicians treating families affected by innate errors of autophagy and intracellular trafficking 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 Hormos Dafsari to inquire about review of DYNC1H1 variants of uncertain significance. HSD was supported by the German Society for Muscle Diseases (DGM, Da3/1), Cologne Clinician Scientist Program / Medical Faculty / University of Cologne and German Research Foundation (CCSP, DFG project no. 413543196). HJ was supported by Action Medical Research, United Kingdom, the GOSH Charity / Sparks, and a European Commission H2020-MSCA-ITN-2017 grant. 21 March 2024 (bp) Review posted live 21 February 2023 (hsd) Original submission • 21 March 2024 (bp) Review posted live • 21 February 2023 (hsd) Original submission ## Author Notes Birk Möller and Hormos Dafsari are actively involved in clinical research regarding individuals with Hormos Dafsari and Heinz Jungbluth are also interested in hearing from clinicians treating families affected by innate errors of autophagy and intracellular trafficking 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 Hormos Dafsari to inquire about review of DYNC1H1 variants of uncertain significance. ## Acknowledgments HSD was supported by the German Society for Muscle Diseases (DGM, Da3/1), Cologne Clinician Scientist Program / Medical Faculty / University of Cologne and German Research Foundation (CCSP, DFG project no. 413543196). HJ was supported by Action Medical Research, United Kingdom, the GOSH Charity / Sparks, and a European Commission H2020-MSCA-ITN-2017 grant. ## Revision History 21 March 2024 (bp) Review posted live 21 February 2023 (hsd) Original submission • 21 March 2024 (bp) Review posted live • 21 February 2023 (hsd) Original submission ## References ## Literature Cited Venn diagram provides an overview of key phenotypes and clinical entities in At bottom is an overview of the domains of cytoplasmic dynein 1 heavy chain 1, the protein encoded by Beginning tail (BT): amino acids 1-299 and 1141-1373 Dimerization: amino acids 300-1140 Linker: amino acids 1374-1867 Motor: amino acids 1868-4221 End tail: amino acids 4222-4646 Reproduced from
[]
21/3/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dyrk1a-id
dyrk1a-id
[ "Dual specificity tyrosine-phosphorylation-regulated kinase 1A", "DYRK1A", "DYRK1A Syndrome" ]
Bregje WM van Bon, Bradley P Coe, Bert BA de Vries, Evan E Eichler
Summary The diagnosis of
## Diagnosis Intrauterine growth retardation Microcephaly Typical facial gestalt: During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ Neonatal feeding difficulties that may persist Epilepsy (febrile seizures, atonic seizures, absence seizures, and generalized myoclonic seizures) Hypertonia Abnormal gait Behavioral problems such as autism spectrum disorder, anxiety, and/or sleep disturbances Foot anomalies: mild cutaneous syndactyly of toes 2-4; hallux valgus; and short fifth toe Vision abnormalities (strabismus, myopia, hypermetropia, retinal anomalies, optic atrophy, coloboma) Urogenital anomalies (undescended testes, hypoplastic scrotum, micropenis, inguinal hernia, renal abnormalities) The diagnosis of 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 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. 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 • Intrauterine growth retardation • Microcephaly • Typical facial gestalt: • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ • Neonatal feeding difficulties that may persist • Epilepsy (febrile seizures, atonic seizures, absence seizures, and generalized myoclonic seizures) • Hypertonia • Abnormal gait • Behavioral problems such as autism spectrum disorder, anxiety, and/or sleep disturbances • Foot anomalies: mild cutaneous syndactyly of toes 2-4; hallux valgus; and short fifth toe • Vision abnormalities (strabismus, myopia, hypermetropia, retinal anomalies, optic atrophy, coloboma) • Urogenital anomalies (undescended testes, hypoplastic scrotum, micropenis, inguinal hernia, renal abnormalities) • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Intrauterine growth retardation Microcephaly Typical facial gestalt: During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ Neonatal feeding difficulties that may persist Epilepsy (febrile seizures, atonic seizures, absence seizures, and generalized myoclonic seizures) Hypertonia Abnormal gait Behavioral problems such as autism spectrum disorder, anxiety, and/or sleep disturbances Foot anomalies: mild cutaneous syndactyly of toes 2-4; hallux valgus; and short fifth toe Vision abnormalities (strabismus, myopia, hypermetropia, retinal anomalies, optic atrophy, coloboma) Urogenital anomalies (undescended testes, hypoplastic scrotum, micropenis, inguinal hernia, renal abnormalities) • Intrauterine growth retardation • Microcephaly • Typical facial gestalt: • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ • Neonatal feeding difficulties that may persist • Epilepsy (febrile seizures, atonic seizures, absence seizures, and generalized myoclonic seizures) • Hypertonia • Abnormal gait • Behavioral problems such as autism spectrum disorder, anxiety, and/or sleep disturbances • Foot anomalies: mild cutaneous syndactyly of toes 2-4; hallux valgus; and short fifth toe • Vision abnormalities (strabismus, myopia, hypermetropia, retinal anomalies, optic atrophy, coloboma) • Urogenital anomalies (undescended testes, hypoplastic scrotum, micropenis, inguinal hernia, renal abnormalities) • During infancy and childhood facial features include prominent ears, deep-set eyes, mild upslanted palpebral fissures, a short nose with a broad nasal tip, and retrognathia with a broad chin. • In adulthood, the nasal bridge may become high and the alae nasi underdeveloped, giving the nose a more prominent appearance [ ## Establishing the Diagnosis The diagnosis of 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 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. 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 • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, 68 individuals have been reported with a pathogenic variant in Select Features of ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability Some studies have had limited phenotypic descriptions; thus, information is not available on all features. When the number of individuals evaluated with a particular feature is <50, a fraction (rather than a %) is used, with the denominator indicating the total number evaluated for the feature. Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years. The majority are described as having a broad-based/ataxic gait [ All individuals show delayed development of speech. Some individuals learn to speak; others show a lack of speech or the use of one- to two-word utterances only. In general, expressive language is more severely affected than receptive language. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. No genotype-phenotype correlations have been identified. Penetrance is likely to be 100% in individuals with a Studies have demonstrated that • Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years. • The majority are described as having a broad-based/ataxic gait [ ## Clinical Description To date, 68 individuals have been reported with a pathogenic variant in Select Features of ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability Some studies have had limited phenotypic descriptions; thus, information is not available on all features. When the number of individuals evaluated with a particular feature is <50, a fraction (rather than a %) is used, with the denominator indicating the total number evaluated for the feature. Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years. The majority are described as having a broad-based/ataxic gait [ All individuals show delayed development of speech. Some individuals learn to speak; others show a lack of speech or the use of one- to two-word utterances only. In general, expressive language is more severely affected than receptive language. The majority of affected individuals function in the moderate-to-severe range of intellectual disability; however, individuals with mild intellectual disability have also been reported. • Although some individuals achieve independent walking at the upper age limit of normal, the majority achieve walking after age two to three years. • The majority are described as having a broad-based/ataxic gait [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance Penetrance is likely to be 100% in individuals with a ## Prevalence Studies have demonstrated that ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Individuals with chromosome 21q22.13 deletions that include ## Differential Diagnosis Intellectual disability and microcephaly, the most frequent findings in the In Diagnoses that may be considered in individuals with multiple findings suggestive of Disorders with Multiple Findings Suggestive of AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; ID = intellectual disability; MOI = mode of inheritance The risk to sibs of a proband depends on the genetic mechanism leading to the loss of Microcephaly in Pitt-Hopkins syndrome is caused by haploinsufficiency of Mowat-Wilson syndrome is associated with: a heterozygous pathogenic variant involving • In ## Management No clinical practice guidelines for To establish the extent of the disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Ambulation Hypertonia & spine curvature Mobility, ADL, & need for adaptive devices To incl eval of aspiration risk & nutritional status & gastroesophageal reflux Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Eval for constipation &/or overflow diarrhea Consider brain MRI. Consider EEG if seizures are a concern. Community or Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Standard treatment is recommended for orthopedic, dental, cardiac, urogenital, ophthalmologic, constipation, and other medical issues. Treatment of Manifestations in Individuals with A mobility device (e.g., wheeled walker) may be useful for children w/serious gait disturbances. Consider disability parking placard for parents. 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 Special Olympics. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic 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. Regular lifelong follow up as determined by specialists for issues present affecting heart, eyes, and teeth is recommended. Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Ambulation • Hypertonia & spine curvature • Mobility, ADL, & need for adaptive devices • To incl eval of aspiration risk & nutritional status & gastroesophageal reflux • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • Eval for constipation &/or overflow diarrhea • Consider brain MRI. • Consider EEG if seizures are a concern. • Community or • Social work involvement for parental support. • A mobility device (e.g., wheeled walker) may be useful for children w/serious gait disturbances. • Consider disability parking placard for parents. • 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 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 & safety of oral intake ## Evaluations Following Initial Diagnosis To establish the extent of the disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Ambulation Hypertonia & spine curvature Mobility, ADL, & need for adaptive devices To incl eval of aspiration risk & nutritional status & gastroesophageal reflux Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. Eval for constipation &/or overflow diarrhea Consider brain MRI. Consider EEG if seizures are a concern. Community or Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Ambulation • Hypertonia & spine curvature • Mobility, ADL, & need for adaptive devices • To incl eval of aspiration risk & nutritional status & gastroesophageal reflux • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • Eval for constipation &/or overflow diarrhea • Consider brain MRI. • Consider EEG if seizures are a concern. • Community or • Social work involvement for parental support. ## Treatment of Manifestations Standard treatment is recommended for orthopedic, dental, cardiac, urogenital, ophthalmologic, constipation, and other medical issues. Treatment of Manifestations in Individuals with A mobility device (e.g., wheeled walker) may be useful for children w/serious gait disturbances. Consider disability parking placard for parents. 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 Special Olympics. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic 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. • A mobility device (e.g., wheeled walker) may be useful for children w/serious gait disturbances. • Consider disability parking placard for parents. • 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 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 ## 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 Regular lifelong follow up as determined by specialists for issues present affecting heart, eyes, and teeth is recommended. Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, 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, all individuals with If the If a parent of the proband is known to have the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low, as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, 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. • To date, all individuals with • If the • If a parent of the proband is known to have the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, 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, all individuals with If the If a parent of the proband is known to have the • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • To date, all individuals with • If the • If a parent of the proband is known to have the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low, as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Speaking out for People with Intellectual and Developmental Disabilities • • • • • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics DYRK1A Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DYRK1A Syndrome ( Several missense pathogenic variants have also been identified; most are located in the kinase domain, clustering in the proximity of the ATP binding pocket and the catalytic center. These pathogenic variants affect the catalytic domain, leading to abolishment of kinase activity [ ## Molecular Pathogenesis Several missense pathogenic variants have also been identified; most are located in the kinase domain, clustering in the proximity of the ATP binding pocket and the catalytic center. These pathogenic variants affect the catalytic domain, leading to abolishment of kinase activity [ ## Chapter Notes The authors would like to thank all individuals with 18 March 2021 (ha) Comprehensive update posted live 17 December 2015 (me) Review posted live 31 March 2015 (bvb) Original submission • 18 March 2021 (ha) Comprehensive update posted live • 17 December 2015 (me) Review posted live • 31 March 2015 (bvb) Original submission ## Acknowledgments The authors would like to thank all individuals with ## Revision History 18 March 2021 (ha) Comprehensive update posted live 17 December 2015 (me) Review posted live 31 March 2015 (bvb) Original submission • 18 March 2021 (ha) Comprehensive update posted live • 17 December 2015 (me) Review posted live • 31 March 2015 (bvb) Original submission ## References ## Literature Cited
[ "ATM Blackburn, N Bekheirnia, VC Uma, ME Corkins, Y Xu, JA Rosenfeld, MN Bainbridge, Y Yang, P Liu, S Madan-Khetarpal, MR Delgado, L Hudgins, I Krantz, D Rodriguez-Buritica, PG Wheeler, L Al-Gazali, A Mohamed Saeed Mohamed Al Shamsi, N Gomez-Ospina, HT Chao, GM Mirzaa, AE Scheuerle, MK Kukolich, F Scaglia, C Eng, HR Willsey, MC Braun, DJ Lamb, RK Miller, MR Bekheirnia. DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract.. Genet Med. 2019;21:2755-64", "LM Bronicki, C Redin, S Drunat, A Piton, M Lyons, S Passemard, C Baumann, L Faivre, J Thevenon, JB Rivière, B Isidor, G Gan, C Francannet, M Willems, M Gunel, JR Jones, JG Gleeson, JL Mandel, RE Stevenson, MJ Friez, AS Aylsworth. Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A.. Eur J Hum Genet. 2015;23:1482-7", "JB Courcet, L Faivre, P Malzac, A Masurel-Paulet, E Lopez, P Callier, L Lambert, M Lemesle, J Thevenon, N Gigot, L Duplomb, C Ragon, N Marle, AL Mosca-Boidron, F Huet, C Philippe, A Moncla, C Thauvin-Robinet. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.. J Med Genet. 2012;49:731-6", "Large-scale discovery of novel genetic causes of developmental disorders.. Nature. 2015;519:223-8", "RK Earl, TN Turner, HC Mefford, CM Hudac, J Gerdts, EE Eichler, RA Bernier. Clinical phenotype of ASD-associated DYRK1A haploinsufficiency.. Mol Autism. 2017;8:54", "JM Evers, RA Laskowski, M Bertolli, J Clayton-Smith, C Deshpande, J Eason, F Elmslie, F Flinter, C Gardiner, JA Hurst, H Kingston, U Kini, AK Lampe, D Lim, A Male, S Naik, MJ Parker, S Price, L Robert, A Sarkar, V Straub, G Woods, JM Thornton, CF Wright. Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders.. Hum Mol Genet. 2017;26:519-26", "D Jayaraman, BI Bae, CA Walsh. The genetics of primary microcephaly.. Annu Rev Genomics Hum Genet. 2018;19:177-200", "J Ji, H Lee, B Argiropoulos, N Dorrani, J Mann, JA Martinez-Agosto, N Gomez-Ospina, N Gallant, JA Bernstein, L Hudgins, L Slattery, B Isidor, C Le Caignec, A David, E Obersztyn, B Wiśniowiecka-Kowalnik, M Fox, JL Deignan, E Vilain, E Hendricks, M Horton Harr, SE Noon, JR Jackson, A Wilkens, G Mirzaa, N Salamon, J Abramson, EH Zackai, I Krantz, AM Innes, SF Nelson, WW Grody, F Quintero-Rivera. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies.. Eur J Hum Genet. 2015;23:1473-81", "KS Lee, M Choi, DW Kwon, D Kim, JM Choi, AK Kim, Y Ham, SB Han, S Cho, CK Cheon. A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay.. Sci Rep. 2020;10:9849", "SM Luco, D Pohl, E Sell, JD Wagner, DA Dyment, H Daoud. Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.. BMC Med Genet. 2016;17:15", "RS Møller, S Kübart, M Hoeltzenbein, B Heye, I Vogel, CP Hansen, C Menzel, R Ullmann, N Tommerup, HH Ropers, Z Tümer, VM Kalscheuer. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly.. Am J Hum Genet. 2008;82:1165-70", "CR Murray, SN Abel, MB McClure, J Foster, MI Walke, P Jayakar, G Bademci, M Tekin. Novel causative variants in DYRK1A, KARS, and KAT6A associated with intellectual disability and additional phenotypic features.. J Pediatr Genet. 2017;6:77-83", "R Oegema, A de Klein, AJ Verkerk, R Schot, B Dumee, H Douben, B Eussen, L Dubbel, PJ Poddighe, I van der Laar, WB Dobyns, PJ van der Spek, MH Lequin, IF de Coo, MC de Wit, MW Wessels, GM Mancini. Distinctive phenotypic abnormalities associated with submicroscopic 21q22 deletion including DYRK1A.. Mol Syndromol. 2010;1:113-20", "BJ O'Roak, L Vives, W Fu, JD Egertson, IB Stanaway, IG Phelps, G Carvill, A Kumar, C Lee, K Ankenman, J Munson, JB Hiatt, EH Turner, R Levy, DR O'Day, N Krumm, BP Coe, BK Martin, E Borenstein, DA Nickerson, HC Mefford, D Doherty, JM Akey, R Bernier, EE Eichler, J Shendure. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.. Science. 2012;338:1619-22", "F Qiao, B Shao, C Wang, Y Wang, R Zhou, G Liu, L Meng, P Hu, Z. Xu. Qiao F. A de novo mutation in DYRK1A causes syndromic intellectual disability: a Chinese case report.. Front Genet. 2019;10:1194", "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", "C Redin, B Gérard, J Lauer, Y Herenger, J Muller, A Quartier, A Masurel-Paulet, M Willems, G Lesca, S El-Chehadeh, S Le Gras, S Vicaire, M Philipps, M Dumas, V Geoffroy, C Feger, N Haumesser, Y Alembik, M Barth, D Bonneau, E Colin, H Dollfus, B Doray, MA Delrue, V Drouin-Garraud, E Flori, M Fradin, C Francannet, A Goldenberg, S Lumbroso, M Mathieu-Dramard, D Martin-Coignard, D Lacombe, G Morin, A Polge, S Sukno, C Thauvin-Robinet, J Thevenon, M Doco-Fenzy, D Genevieve, P Sarda, P Edery, B Isidor, B Jost, L Olivier-Faivre, JL Mandel, A Piton. Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.. J Med Genet. 2014;51:724-36", "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 Ruaud, C Mignot, A Guët, C Ohl, C Nava, D Héron, B Keren, C Depienne, V Benoit, I Maystadt, D Lederer, D Amsallem, J. Piard. DYRK1A mutations in two unrelated patients.. Eur J Med Genet. 2015;58:168-74", "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", "A Valetto, A Orsini, V Bertini, B Toschi, A Bonuccelli, F Simi, I Sammartino, G Taddeucci, P Simi, G Saggese. Molecular cytogenetic characterization of an interstitial deletion of chromosome 21 (21q22.13q22.3) in a patient with dysmorphic features, intellectual disability and severe generalized epilepsy.. Eur J Med Genet. 2012;55:362-6", "BW van Bon, BP Coe, R Bernier, C Green, J Gerdts, K Witherspoon, T Kleefstra, MH Willemsen, R Kumar, P Bosco, M Fichera, D Li, D Amaral, F Cristofoli, H Peeters, E Haan, C Romano, HC Mefford, I Scheffer, J Gecz, BB de Vries, EE Eichler. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.. Mol Psychiatry. 2016;21:126-32", "BW van Bon, A Hoischen, J Hehir-Kwa, AP de Brouwer, C Ruivenkamp, AC Gijsbers, CL Marcelis, N de Leeuw, JA Veltman, HG Brunner, BB de Vries. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly.. Clin Genet. 2011;79:296-9", "EW Widowati, S Bamberg-Lemper, W Becker. Mutational analysis of two residues in the DYRK homology box of the protein kinase DYRK1A.. BMC Res Notes. 2018;11:297" ]
17/12/2015
18/3/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dystonia-ov
dystonia-ov
[ "85/88 kDa calcium-independent phospholipase A2", "Arylsulfatase A", "Atrophin-1", "Battenin", "Beta-galactosidase", "Biotinidase", "Bis(monoacylglycero)phosphate synthase CLN5", "BTB/POZ domain-containing protein KCTD7", "Calcium/manganese antiporter SLC30A10", "Cathepsin D", "Cathepsin F", "Ceroid-lipofuscinosis neuronal protein 6", "Ceruloplasmin", "Cobalamin trafficking protein CblD", "Copper-transporting ATPase 2", "Corrinoid adenosyltransferase MMAB", "Cystathionine beta-synthase", "D-2-hydroxyglutarate dehydrogenase, mitochondrial", "DDB1- and CUL4-associated factor 17", "Deoxynucleoside triphosphate triphosphohydrolase SAMHD1", "DNA polymerase subunit gamma-1", "DnaJ homolog subfamily C member 5", "Double-stranded RNA-specific adenosine deaminase", "E3 ubiquitin-protein ligase parkin", "Endoplasmic reticulum membrane adapter protein XK", "Epsilon-sarcoglycan", "Fatty acid 2-hydroxylase", "Ferritin light chain", "Galactocerebrosidase", "Galactose-1-phosphate uridylyltransferase", "Ganglioside GM2 activator", "Glutaryl-CoA dehydrogenase, mitochondrial", "Glycine amidinotransferase, mitochondrial", "GTP cyclohydrolase 1", "Guanidinoacetate N-methyltransferase", "Guanine nucleotide-binding protein G(olf) subunit alpha", "Huntingtin", "Hypoxanthine-guanine phosphoribosyltransferase", "Intermembrane lipid transfer protein VPS13A", "Junctophilin-3", "Major facilitator superfamily domain-containing protein 8", "Methyl-CpG-binding protein 2", "Methylmalonic aciduria type A protein, mitochondrial", "Methylmalonyl-CoA epimerase, mitochondrial", "Methylmalonyl-CoA mutase, mitochondrial", "Mitochondrial import inner membrane translocase subunit Tim8 A", "Myelin proteolipid protein", "NPC intracellular cholesterol transporter 1", "NPC intracellular cholesterol transporter 2", "Palmitoyl-protein thioesterase 1", "Pantothenate kinase 2, mitochondrial", "Phenylalanine-4-hydroxylase", "Platelet-derived growth factor receptor beta", "Platelet-derived growth factor subunit B", "Polyamine-transporting ATPase 13A2", "Probable thioesterase PNKD", "Progranulin", "Proline-rich transmembrane protein 2", "Protein C19orf12", "Protein CLN8", "Ribonuclease H2 subunit A", "Ribonuclease H2 subunit B", "Ribonuclease H2 subunit C", "Sepiapterin reductase", "Sodium- and chloride-dependent creatine transporter 1", "Sodium/potassium-transporting ATPase subunit alpha-3", "Sodium-dependent neutral amino acid transporter B(0)AT1", "Sodium-dependent phosphate transporter 2", "Solute carrier family 2, facilitated glucose transporter member 1", "THAP domain-containing protein 1", "Thiamine transporter 2", "Three prime repair exonuclease 1", "Tissue alpha-L-fucosidase", "Torsin-1A", "Transcription initiation factor TFIID subunit 1", "Tripeptidyl-peptidase 1", "Tyrosine 3-monooxygenase", "WD repeat domain phosphoinositide-interacting protein 4", "ADAR", "ARSA", "ATN1", "ATP13A2", "ATP1A3", "ATP7B", "BTD", "C19orf12", "CBS", "CLN3", "CLN5", "CLN6", "CLN8", "CP", "CTSD", "CTSF", "D2HGDH", "DCAF17", "DNAJC5", "FA2H", "FTL", "FUCA1", "GALC", "GALT", "GAMT", "GATM", "GCDH", "GCH1", "GLB1", "GM2A", "GNAL", "GRN", "HPRT1", "HTT", "JPH3", "KCTD7", "MCEE", "MECP2", "MFSD8", "MMAA", "MMAB", "MMADHC", "MMUT", "NPC1", "NPC2", "PAH", "PANK2", "PDGFB", "PDGFRB", "PLA2G6", "PLP1", "PNKD", "POLG", "PPT1", "PRKN", "PRRT2", "RNASEH2A", "RNASEH2B", "RNASEH2C", "SAMHD1", "SGCE", "SLC19A3", "SLC20A2", "SLC2A1", "SLC30A10", "SLC6A19", "SLC6A8", "SPR", "TAF1", "TH", "THAP1", "TIMM8A", "TOR1A", "TPP1", "TREX1", "VPS13A", "WDR45", "XK", "Hereditary Dystonia", "Overview" ]
Hereditary Dystonia Overview
Christine Klein, Katja Lohmann, Connie Marras, Alexander Münchau
Summary The purpose of this overview is to: Describe the Review the Provide an Review the Provide information regarding
## Clinical Characteristics of Dystonia Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements and/or postures. Dystonic movements are typically patterned and twisting, and may be associated with tremor. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Most forms of dystonia tend to worsen initially. Forms of dystonia without neurodegeneration usually reach a plateau with stable findings, whereas those associated with neuronal loss progressively worsen over time. Dystonia can be classified clinically according to age of onset, body distribution (see Infancy (neonatal – 2 years) Childhood (3-12 years) Adolescence (13-20 years) Early adulthood (21-40 years) Late adulthood (>40 years) Classification of Dystonias by Affected Body Part Eyelids (blepharospasm) Mouth (oromandibular dystonia, musician's cramp) Larynx (dystonic adductor dysphonia, "whispering dysphonia") Neck (cervical dystonia, previously known as spasmodic torticollis) Hand & arm (writer's cramp) Axial (neck & trunk) Brachial (1 arm & trunk; both arms ± neck ± trunk) Crural (1 leg & trunk; both legs ± trunk) Some localized dystonias may spread and eventually generalize. Persistent. Dystonia persists to about the same extent throughout the day. Action-specific (e.g., musician's dystonia, writer's cramp) Diurnal fluctuations (e.g., dopa-responsive dystonia) Paroxysmal. Dystonia/dyskinesia appear suddenly and are self-limited, usually induced by a specific trigger. Isolated dystonia. Dystonia is the only motor feature with the exception of possible tremor (see Combined dystonia. Dystonia is combined with another movement disorder (e.g., myoclonus, parkinsonism) (see Complex dystonia. Dystonia co-occurs with other neurologic or systemic manifestations; dystonia is not necessarily the most prominent disease manifestation and may even be an inconsistent feature (see When dystonic movements are the presenting or predominant sign, the class of dystonia (i.e., isolated, combined, or complex) may be difficult to identify. Whereas gradual-onset focal or segmental dystonia can be classified as isolated in the vast majority of adult-onset dystonia, this is true for fewer than half of those with childhood-onset dystonia [ • Infancy (neonatal – 2 years) • Childhood (3-12 years) • Adolescence (13-20 years) • Early adulthood (21-40 years) • Late adulthood (>40 years) • Eyelids (blepharospasm) • Mouth (oromandibular dystonia, musician's cramp) • Larynx (dystonic adductor dysphonia, "whispering dysphonia") • Neck (cervical dystonia, previously known as spasmodic torticollis) • Hand & arm (writer's cramp) • Axial (neck & trunk) • Brachial (1 arm & trunk; both arms ± neck ± trunk) • Crural (1 leg & trunk; both legs ± trunk) • Persistent. Dystonia persists to about the same extent throughout the day. • Action-specific (e.g., musician's dystonia, writer's cramp) • Diurnal fluctuations (e.g., dopa-responsive dystonia) • Paroxysmal. Dystonia/dyskinesia appear suddenly and are self-limited, usually induced by a specific trigger. • Isolated dystonia. Dystonia is the only motor feature with the exception of possible tremor (see • Combined dystonia. Dystonia is combined with another movement disorder (e.g., myoclonus, parkinsonism) (see • Complex dystonia. Dystonia co-occurs with other neurologic or systemic manifestations; dystonia is not necessarily the most prominent disease manifestation and may even be an inconsistent feature (see ## Causes of Hereditary Dystonia Initially these monogenic disorders were designated DYT followed by a number that represented the chronologic order in which the description of the phenotype and/or genetic discovery first appeared in the literature; see Because of the inconsistencies in the DYT nomenclature, a naming system that combines the "DYT" designation and the name of associated gene was proposed by Nomenclature System for Inherited (Monogenic) Forms of Isolated Dystonia and Combined Dystonia/Dyskinesia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Pathogenicity of Previously known as As Although complex dystonias share dystonia as a manifestation, atypical features and additional neurologic signs are often observed. These may include: Sustained dystonia at rest (whereas isolated or combined dystonia is usually action- or posture-dependent) Prominent tongue and perioral involvement leading to a Pyramidal or cerebellar signs Ataxia Oculomotor abnormalities Cognitive disturbances Hearing loss Intellectual disability / developmental delay Seizures Although the list of complex dystonias is long and unwieldy, certain rules and patterns help to make an accurate diagnosis and tailor management. Grouping the complex dystonias into those that are hereditary neurodegenerative or metabolic disorders (see Complex Dystonias: Inherited Neurodegenerative/Metabolic Disorders AD = autosomal dominant; AR = autosomal recessive; DWI = diffusion-weighted imaging; MOI = mode of inheritance; mt = mitochondrial; SCA = spinocerebellar ataxia; XL = X-linked Genes associated with mitochondrial DNA-associated Leigh syndrome and NARP: Rett syndrome. Asymmetric crural or generalized dystonia is common in Rett syndrome [ Glutaric aciduria type 1 (OMIM Of note, both autosomal dominant spinocerebellar ataxias (SCAs) and autosomal recessive ataxias can be associated with dystonia (see Dystonia is also part of the clinical presentation in some autosomal recessive ataxias including • Sustained dystonia at rest (whereas isolated or combined dystonia is usually action- or posture-dependent) • Prominent tongue and perioral involvement leading to a • Pyramidal or cerebellar signs • Ataxia • Oculomotor abnormalities • Cognitive disturbances • Hearing loss • Intellectual disability / developmental delay • Seizures • Rett syndrome. Asymmetric crural or generalized dystonia is common in Rett syndrome [ • Glutaric aciduria type 1 (OMIM ## Isolated Dystonias As ## Combined Dystonias ## Dystonia Plus Parkinsonism ## Dystonia with Myoclonus ## Paroxysmal Dystonia with Other Dyskinesia ## Complex Dystonias Although complex dystonias share dystonia as a manifestation, atypical features and additional neurologic signs are often observed. These may include: Sustained dystonia at rest (whereas isolated or combined dystonia is usually action- or posture-dependent) Prominent tongue and perioral involvement leading to a Pyramidal or cerebellar signs Ataxia Oculomotor abnormalities Cognitive disturbances Hearing loss Intellectual disability / developmental delay Seizures Although the list of complex dystonias is long and unwieldy, certain rules and patterns help to make an accurate diagnosis and tailor management. Grouping the complex dystonias into those that are hereditary neurodegenerative or metabolic disorders (see Complex Dystonias: Inherited Neurodegenerative/Metabolic Disorders AD = autosomal dominant; AR = autosomal recessive; DWI = diffusion-weighted imaging; MOI = mode of inheritance; mt = mitochondrial; SCA = spinocerebellar ataxia; XL = X-linked Genes associated with mitochondrial DNA-associated Leigh syndrome and NARP: Rett syndrome. Asymmetric crural or generalized dystonia is common in Rett syndrome [ Glutaric aciduria type 1 (OMIM Of note, both autosomal dominant spinocerebellar ataxias (SCAs) and autosomal recessive ataxias can be associated with dystonia (see Dystonia is also part of the clinical presentation in some autosomal recessive ataxias including • Sustained dystonia at rest (whereas isolated or combined dystonia is usually action- or posture-dependent) • Prominent tongue and perioral involvement leading to a • Pyramidal or cerebellar signs • Ataxia • Oculomotor abnormalities • Cognitive disturbances • Hearing loss • Intellectual disability / developmental delay • Seizures • Rett syndrome. Asymmetric crural or generalized dystonia is common in Rett syndrome [ • Glutaric aciduria type 1 (OMIM ## Other Genetic Causes of Complex Dystonia Of note, both autosomal dominant spinocerebellar ataxias (SCAs) and autosomal recessive ataxias can be associated with dystonia (see Dystonia is also part of the clinical presentation in some autosomal recessive ataxias including ## Non-Genetic Causes of Dystonia Non-Genetic Causes of Dystonia The most common and clinically relevant cause of dystonia due to (gross or subtle) brain lesions is cerebral palsy (CP). Dystonia (along with chorea) is the presenting and prevailing finding in persons with dyskinetic CP, but can also be observed in other forms of CP (e.g., spastic hemiparesis, spastic paraparesis, or spastic tetraparesis) [ The manifestations of tardive dystonia are often indistinguishable from those of primary focal dystonia; however, retrocollis and axial involvement are characteristic. Like DYT1 dystonia, the site of onset tends to ascend from the lower limbs cranially as the mean age of onset increases [ Positive signs of psychogenic dystonia include: sudden onset and remissions (e.g., following a psychological or physical trauma); a history of somatization; co-contraction of agonists and antagonists without abnormal postures; distractibility; suggestibility; fluctuating severity within short periods; discrepancies between objective signs and disability; and psychopathologic abnormalities. None of these signs, however, is diagnostic. In individuals with a confirmed diagnosis of psychogenic dystonia, psychotherapy should be undertaken promptly since early initiation of treatment is associated with a better prognosis. Criteria mentioned above and knowledge about the natural history of psychogenic dystonia are predominantly based on studies in adults; however, reports in children with psychogenic movement disorders including dystonia suggest that similar "rules" also apply to children [ • The manifestations of tardive dystonia are often indistinguishable from those of primary focal dystonia; however, retrocollis and axial involvement are characteristic. Like DYT1 dystonia, the site of onset tends to ascend from the lower limbs cranially as the mean age of onset increases [ ## Evaluation Strategy Once the diagnosis of dystonia has been established in an individual, the following approach can be used to determine the specific cause of dystonia to aid in discussions of prognosis and genetic counseling. Establishing the specific cause of dystonia for a given individual usually involves a medical history, physical examination, neurologic examination, and neuroimaging, as well as detailed family history and use of Delineation of the dystonia phenotype and the clinical course, the first step when evaluating persons with dystonia, can be diagnostic. For example, Sudden onset of dystonia over a range of ages is compatible with Many dystonias can be triggered or exacerbated by nonspecific factors, such as stress, fatigue, action, or certain postures. A "therapeutic" response to alcohol is characteristic of Non-DNA-based clinical tests for the following are available (also see Dopa-responsive dystonia ( Diagnostic workup in persons with dystonia and cerebellar signs – even when cerebellar signs are subtle – should include testing for Molecular genetic testing approaches can include a For an introduction to multigene panels click In individuals of Ashkenaki Jewish ancestry, targeted testing for the specific In individuals without clinical findings or ethnic background to suggest a specific gene, single-gene testing is rarely useful and typically NOT recommended given the genetic heterogeneity of dystonia; a multigene panel or comprehensive genomic testing are generally used in lieu of single-gene testing. • Sudden onset of dystonia over a range of ages is compatible with • Many dystonias can be triggered or exacerbated by nonspecific factors, such as stress, fatigue, action, or certain postures. • A "therapeutic" response to alcohol is characteristic of • Dopa-responsive dystonia ( • Diagnostic workup in persons with dystonia and cerebellar signs – even when cerebellar signs are subtle – should include testing for • In individuals of Ashkenaki Jewish ancestry, targeted testing for the specific • In individuals without clinical findings or ethnic background to suggest a specific gene, single-gene testing is rarely useful and typically NOT recommended given the genetic heterogeneity of dystonia; a multigene panel or comprehensive genomic testing are generally used in lieu of single-gene testing. ## Non-DNA Testing Non-DNA-based clinical tests for the following are available (also see Dopa-responsive dystonia ( Diagnostic workup in persons with dystonia and cerebellar signs – even when cerebellar signs are subtle – should include testing for • Dopa-responsive dystonia ( • Diagnostic workup in persons with dystonia and cerebellar signs – even when cerebellar signs are subtle – should include testing for ## Molecular Genetic Testing Molecular genetic testing approaches can include a For an introduction to multigene panels click In individuals of Ashkenaki Jewish ancestry, targeted testing for the specific In individuals without clinical findings or ethnic background to suggest a specific gene, single-gene testing is rarely useful and typically NOT recommended given the genetic heterogeneity of dystonia; a multigene panel or comprehensive genomic testing are generally used in lieu of single-gene testing. • In individuals of Ashkenaki Jewish ancestry, targeted testing for the specific • In individuals without clinical findings or ethnic background to suggest a specific gene, single-gene testing is rarely useful and typically NOT recommended given the genetic heterogeneity of dystonia; a multigene panel or comprehensive genomic testing are generally used in lieu of single-gene testing. ## Option 1 For an introduction to multigene panels click ## Option 2 ## Option 3 In individuals of Ashkenaki Jewish ancestry, targeted testing for the specific In individuals without clinical findings or ethnic background to suggest a specific gene, single-gene testing is rarely useful and typically NOT recommended given the genetic heterogeneity of dystonia; a multigene panel or comprehensive genomic testing are generally used in lieu of single-gene testing. • In individuals of Ashkenaki Jewish ancestry, targeted testing for the specific • In individuals without clinical findings or ethnic background to suggest a specific gene, single-gene testing is rarely useful and typically NOT recommended given the genetic heterogeneity of dystonia; a multigene panel or comprehensive genomic testing are generally used in lieu of single-gene testing. ## Genetic Counseling Importantly, most dominant forms of dystonia are characterized by reduced penetrance, which can be lower than 50%. For two hereditary dystonias, mechanisms affecting penetrance have been identified: DYT- Penetrance of the GAG deletion in Individuals with an autosomal dominant dystonia inherit the pathogenic variant from one parent or have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent The family history may appear to be negative because of failure to recognize the disorder in 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 appropriate molecular genetic testing and/or clinical evaluation have been performed. Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom free. The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the pathogenic variant. Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one dystonia-related pathogenic variant). Heterozygotes are asymptomatic. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes are asymptomatic. Mitochondrial DNA (mtDNA) deletions generally occur When single mtDNA deletions are transmitted, inheritance is from the mother. The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs are at risk of inheriting it. When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [ Offspring of males with a mtDNA pathogenic variant will not inherit the variant. All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. A female with a heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same nuclear family [ The father of an affected male will not have the disorder nor will he be hemizygous for the dystonia-related pathogenic variant; therefore, he does not require further evaluation/testing. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the dystonia-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a If the mother of the proband has the dystonia-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the dystonia-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. • DYT- • Penetrance of the GAG deletion in • Individuals with an autosomal dominant dystonia inherit the pathogenic variant from one parent or have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • The family history may appear to be negative because of failure to recognize the disorder in 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 appropriate molecular genetic testing and/or clinical evaluation have been performed. • Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom free. • The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. • Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. • Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the pathogenic variant. • Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one dystonia-related pathogenic variant). • Heterozygotes are asymptomatic. • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes are asymptomatic. • • Mitochondrial DNA (mtDNA) deletions generally occur • When single mtDNA deletions are transmitted, inheritance is from the mother. • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. • Mitochondrial DNA (mtDNA) deletions generally occur • When single mtDNA deletions are transmitted, inheritance is from the mother. • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. • • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. • Mitochondrial DNA (mtDNA) deletions generally occur • When single mtDNA deletions are transmitted, inheritance is from the mother. • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. • The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs are at risk of inheriting it. • When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [ • Offspring of males with a mtDNA pathogenic variant will not inherit the variant. • All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. • A female with a heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same nuclear family [ • The father of an affected male will not have the disorder nor will he be hemizygous for the dystonia-related pathogenic variant; therefore, he does not require further evaluation/testing. • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the dystonia-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a • If the mother of the proband has the dystonia-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the dystonia-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. ## Mode of Inheritance Importantly, most dominant forms of dystonia are characterized by reduced penetrance, which can be lower than 50%. For two hereditary dystonias, mechanisms affecting penetrance have been identified: DYT- Penetrance of the GAG deletion in • DYT- • Penetrance of the GAG deletion in ## Autosomal Dominant Inheritance – Risk to Family Members Individuals with an autosomal dominant dystonia inherit the pathogenic variant from one parent or have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent The family history may appear to be negative because of failure to recognize the disorder in 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 appropriate molecular genetic testing and/or clinical evaluation have been performed. Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom free. The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the pathogenic variant. Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. • Individuals with an autosomal dominant dystonia inherit the pathogenic variant from one parent or have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • The family history may appear to be negative because of failure to recognize the disorder in 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 appropriate molecular genetic testing and/or clinical evaluation have been performed. • Note: Due to reduced penetrance, there may be asymptomatic family members or several generations of individuals with the pathogenic variant who remain symptom free. • The risk to sibs depends on the genetic status of the proband's parents: if one of the proband's parents has a pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. • Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. • Each child of an individual with autosomal dominant dystonia has a 50% chance of inheriting the pathogenic variant. • Because many of the inherited dystonias demonstrate reduced penetrance, not all individuals who inherit the pathogenic variant will develop dystonia. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., carriers of one dystonia-related pathogenic variant). Heterozygotes are asymptomatic. At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes are asymptomatic. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one dystonia-related pathogenic variant). • Heterozygotes are asymptomatic. • At conception, each sib of a proband has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes are asymptomatic. ## Mitochondrial Inheritance – Risk to Family Members Mitochondrial DNA (mtDNA) deletions generally occur When single mtDNA deletions are transmitted, inheritance is from the mother. The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. The father of a proband is not at risk of having the mtDNA pathogenic variant. The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs are at risk of inheriting it. When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [ Offspring of males with a mtDNA pathogenic variant will not inherit the variant. All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. A female with a heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same nuclear family [ • • Mitochondrial DNA (mtDNA) deletions generally occur • When single mtDNA deletions are transmitted, inheritance is from the mother. • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. • Mitochondrial DNA (mtDNA) deletions generally occur • When single mtDNA deletions are transmitted, inheritance is from the mother. • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. • • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. • Mitochondrial DNA (mtDNA) deletions generally occur • When single mtDNA deletions are transmitted, inheritance is from the mother. • The predisposition to form multiple mtDNA deletions can be inherited as an autosomal dominant or an autosomal recessive trait. • Mitochondrial DNA single-nucleotide variants and duplications may be transmitted through the maternal line. • The father of a proband is not at risk of having the mtDNA pathogenic variant. • The mother of a proband (usually) has the mtDNA pathogenic variant and may or may not have symptoms. • The risk to the sibs depends on the genetic status of the mother: if the mother has the mtDNA pathogenic variant, all sibs are at risk of inheriting it. • When a proband has a single mtDNA deletion, the current best estimate of the recurrence risk to sibs is 1/24 [ • Offspring of males with a mtDNA pathogenic variant will not inherit the variant. • All offspring of females with a mtDNA pathogenic variant are at risk of inheriting the pathogenic variant. • A female with a heteroplasmic mtDNA single-nucleotide variant may transmit a variable amount of mutated mtDNA to her offspring, resulting in considerable clinical variability among sibs within the same nuclear family [ ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the dystonia-related pathogenic variant; therefore, he does not require further evaluation/testing. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the dystonia-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a If the mother of the proband has the dystonia-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the dystonia-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. • The father of an affected male will not have the disorder nor will he be hemizygous for the dystonia-related pathogenic variant; therefore, he does not require further evaluation/testing. • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the dystonia-related pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a • If the mother of the proband has the dystonia-related pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the variant will be affected; females who inherit the variant will be heterozygotes (carriers) and will not typically be affected. • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the dystonia-related pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism. ## Related Genetic Counseling Issues ## Prenatal Testing and Preimplantation Genetic Testing ## Resources Connecting People for Dystonia Belgium United Kingdom Germany Dystonia Medical Research Foundation • • • • Connecting People for Dystonia • Belgium • • • • • United Kingdom • • • • • Germany • • • Dystonia Medical Research Foundation • ## Chapter Notes Christine Klein, MD (2014-present)Katja Lohmann, PhD (2017-present)Connie Marras, MD, PhD (2014-present)Alexander Münchau, MD (2014-present)Andrea H Nemeth, MRCP, DPhil; Churchill Hospital and Institute of Molecular Medicine (2003-2014) 22 June 2017 (sw) Comprehensive update posted live 1 May 2014 (me) Comprehensive update posted live 23 January 2006 (me) Comprehensive update posted live 28 October 2003 (me) Review posted live 8 April 2003 (an) Original submission • 22 June 2017 (sw) Comprehensive update posted live • 1 May 2014 (me) Comprehensive update posted live • 23 January 2006 (me) Comprehensive update posted live • 28 October 2003 (me) Review posted live • 8 April 2003 (an) Original submission ## Author History Christine Klein, MD (2014-present)Katja Lohmann, PhD (2017-present)Connie Marras, MD, PhD (2014-present)Alexander Münchau, MD (2014-present)Andrea H Nemeth, MRCP, DPhil; Churchill Hospital and Institute of Molecular Medicine (2003-2014) ## Revision History 22 June 2017 (sw) Comprehensive update posted live 1 May 2014 (me) Comprehensive update posted live 23 January 2006 (me) Comprehensive update posted live 28 October 2003 (me) Review posted live 8 April 2003 (an) Original submission • 22 June 2017 (sw) Comprehensive update posted live • 1 May 2014 (me) Comprehensive update posted live • 23 January 2006 (me) Comprehensive update posted live • 28 October 2003 (me) Review posted live • 8 April 2003 (an) Original submission ## References ## Literature Cited
[]
28/10/2003
22/6/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
dystonia
dystonia
[ "Early-Onset Torsion Dystonia", "Oppenheim's Dystonia", "Early-Onset Torsion Dystonia", "Oppenheim's Dystonia", "Torsin-1A", "TOR1A", "DYT1 Early-Onset Isolated Dystonia" ]
DYT1 Early-Onset Isolated Dystonia
Laurie Ozelius, Naomi Lubarr
Summary DYT1 early-onset isolated dystonia typically presents in childhood or adolescence and only on occasion in adulthood. Dystonic muscle contractions causing posturing or irregular tremor of a leg or arm are the most common presenting findings. Dystonia is usually first apparent with specific actions such as writing or walking. Over time, the contractions frequently (but not invariably) become evident with less specific actions and spread to other body regions. No other neurologic abnormalities are present. Disease severity varies considerably even within the same family. Isolated writer's cramp may be the only sign. The diagnosis of DYT1 dystonia is established in a proband by identification of a heterozygous DYT1 dystonia is inherited in an autosomal dominant manner with reduced penetrance. Offspring of an affected individual or of an asymptomatic individual known to have a
## Diagnosis DYT1 early-onset isolated dystonia Isolated dystonia (defined as involuntary contraction of muscles that causes repetitive, patterned, and often twisting movements or postures) with: No other abnormalities on neurologic examination (except tremor); Normal routine neuroimaging; No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). Onset of dystonia before age 26 years (Note: Older age of onset may be seen among relatives of affected individuals; family members with later onset tend to have arm dystonia in the form of writer's cramp [ Family history of early-onset dystonia (Note: Lack of a family history of early-onset dystonia does not preclude the diagnosis.) Factors that are more specific to DYT1 early-onset isolated dystonia, including: Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); Onset in a limb before age 26 years; Two or more affected limbs. The diagnosis of DYT1 early-onset isolated dystonia Molecular testing approaches can include In the absence of the Sequence analysis may be followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, since DYT1 early-onset isolated dystonia occurs through a dominant-negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. For an introduction to multigene panels click Molecular Genetic Testing Used in DYT1 Early-Onset Isolated Dystonia 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 individuals with DYT1, regardless of ethnic background, have the three base-pair deletion Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. • Isolated dystonia (defined as involuntary contraction of muscles that causes repetitive, patterned, and often twisting movements or postures) with: • No other abnormalities on neurologic examination (except tremor); • Normal routine neuroimaging; • No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). • No other abnormalities on neurologic examination (except tremor); • Normal routine neuroimaging; • No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). • Onset of dystonia before age 26 years (Note: Older age of onset may be seen among relatives of affected individuals; family members with later onset tend to have arm dystonia in the form of writer's cramp [ • Family history of early-onset dystonia (Note: Lack of a family history of early-onset dystonia does not preclude the diagnosis.) • Factors that are more specific to DYT1 early-onset isolated dystonia, including: • Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); • Onset in a limb before age 26 years; • Two or more affected limbs. • Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); • Onset in a limb before age 26 years; • Two or more affected limbs. • No other abnormalities on neurologic examination (except tremor); • Normal routine neuroimaging; • No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). • Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); • Onset in a limb before age 26 years; • Two or more affected limbs. • In the absence of the • Sequence analysis may be followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, since DYT1 early-onset isolated dystonia occurs through a dominant-negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. • For an introduction to multigene panels click ## Suggestive Findings DYT1 early-onset isolated dystonia Isolated dystonia (defined as involuntary contraction of muscles that causes repetitive, patterned, and often twisting movements or postures) with: No other abnormalities on neurologic examination (except tremor); Normal routine neuroimaging; No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). Onset of dystonia before age 26 years (Note: Older age of onset may be seen among relatives of affected individuals; family members with later onset tend to have arm dystonia in the form of writer's cramp [ Family history of early-onset dystonia (Note: Lack of a family history of early-onset dystonia does not preclude the diagnosis.) Factors that are more specific to DYT1 early-onset isolated dystonia, including: Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); Onset in a limb before age 26 years; Two or more affected limbs. • Isolated dystonia (defined as involuntary contraction of muscles that causes repetitive, patterned, and often twisting movements or postures) with: • No other abnormalities on neurologic examination (except tremor); • Normal routine neuroimaging; • No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). • No other abnormalities on neurologic examination (except tremor); • Normal routine neuroimaging; • No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). • Onset of dystonia before age 26 years (Note: Older age of onset may be seen among relatives of affected individuals; family members with later onset tend to have arm dystonia in the form of writer's cramp [ • Family history of early-onset dystonia (Note: Lack of a family history of early-onset dystonia does not preclude the diagnosis.) • Factors that are more specific to DYT1 early-onset isolated dystonia, including: • Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); • Onset in a limb before age 26 years; • Two or more affected limbs. • Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); • Onset in a limb before age 26 years; • Two or more affected limbs. • No other abnormalities on neurologic examination (except tremor); • Normal routine neuroimaging; • No history of known cause of acquired dystonia (e.g., exposure to neuroleptic medications; cerebral trauma, infarct, infection). • Ashkenazi Jewish ancestry (although DYT1 dystonia can occur in individuals of any ethnicity); • Onset in a limb before age 26 years; • Two or more affected limbs. ## Establishing the Diagnosis The diagnosis of DYT1 early-onset isolated dystonia Molecular testing approaches can include In the absence of the Sequence analysis may be followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, since DYT1 early-onset isolated dystonia occurs through a dominant-negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. For an introduction to multigene panels click Molecular Genetic Testing Used in DYT1 Early-Onset Isolated Dystonia 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 individuals with DYT1, regardless of ethnic background, have the three base-pair deletion Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • In the absence of the • Sequence analysis may be followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, since DYT1 early-onset isolated dystonia occurs through a dominant-negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant. • For an introduction to multigene panels click ## Clinical Characteristics Dystonia is the involuntary sustained or intermittent contraction of muscles that causes movements often resulting in twisting and posturing of the involved body region. An updated definition and classification for dystonia can be found in DYT1 dystonia is a form of early-onset isolated dystonia; it is considered an isolated dystonia because it is not associated with other neurologic or systemic abnormalities. Once they appear, dystonic movements usually persist through life. Pain is not a prominent finding except in cervical dystonia, which is uncommon in DYT1 dystonia. Approximately 20% of DYT1 dystonia is restricted to a single body region, usually as writer's cramp. Unusual phenotypic expression of DYT1 dystonia includes isolated blepharospasm [ Brain CT and routine MRI are normal. For additional information about PET scan studies and diffusion tensor imaging (DTI) studies in DYT1 dystonia, click No genotype-phenotype correlations exist. The penetrance of the The clinical variability of DYT1 dystonia is great; an affected individual may be more or less severely affected than the parent from whom the disease-causing allele was inherited. Clinical heterogeneity within a single family is exemplified by the report of a family with one individual with writer's cramp and another with severe dystonic storm [ A naming system that combines the "DYT" designation (to indicate the main clinical feature) and the name of the (confirmed) gene or chromosome locus has been proposed [ Terms used for DYT1 isolated dystonia in the past include the following: Dystonia muscularum deformans Primary torsion dystonia (PTD) DYT1 dystonia is a common form of early-onset isolated dystonia [ DYT1 dystonia is estimated to account for approximately 16% to 53% of early-onset dystonia in non-Jews and approximately 80% to 90% in Ashkenazi Jews [reviewed in The prevalence of early-onset dystonia in Ashkenazi Jews is estimated at 1:3000-1:9000; because of the reduced penetrance (i.e., 30%), the carrier frequency for the The increased prevalence in Ashkenazim is the result of a founder variant that appeared approximately 350 years ago [ • Brain CT and routine MRI are normal. • For additional information about PET scan studies and diffusion tensor imaging (DTI) studies in DYT1 dystonia, click • Dystonia muscularum deformans • Primary torsion dystonia (PTD) ## Clinical Description Dystonia is the involuntary sustained or intermittent contraction of muscles that causes movements often resulting in twisting and posturing of the involved body region. An updated definition and classification for dystonia can be found in DYT1 dystonia is a form of early-onset isolated dystonia; it is considered an isolated dystonia because it is not associated with other neurologic or systemic abnormalities. Once they appear, dystonic movements usually persist through life. Pain is not a prominent finding except in cervical dystonia, which is uncommon in DYT1 dystonia. Approximately 20% of DYT1 dystonia is restricted to a single body region, usually as writer's cramp. Unusual phenotypic expression of DYT1 dystonia includes isolated blepharospasm [ Brain CT and routine MRI are normal. For additional information about PET scan studies and diffusion tensor imaging (DTI) studies in DYT1 dystonia, click • Brain CT and routine MRI are normal. • For additional information about PET scan studies and diffusion tensor imaging (DTI) studies in DYT1 dystonia, click ## Genotype-Phenotype Correlations No genotype-phenotype correlations exist. ## Penetrance The penetrance of the The clinical variability of DYT1 dystonia is great; an affected individual may be more or less severely affected than the parent from whom the disease-causing allele was inherited. Clinical heterogeneity within a single family is exemplified by the report of a family with one individual with writer's cramp and another with severe dystonic storm [ ## Nomenclature A naming system that combines the "DYT" designation (to indicate the main clinical feature) and the name of the (confirmed) gene or chromosome locus has been proposed [ Terms used for DYT1 isolated dystonia in the past include the following: Dystonia muscularum deformans Primary torsion dystonia (PTD) • Dystonia muscularum deformans • Primary torsion dystonia (PTD) ## Prevalence DYT1 dystonia is a common form of early-onset isolated dystonia [ DYT1 dystonia is estimated to account for approximately 16% to 53% of early-onset dystonia in non-Jews and approximately 80% to 90% in Ashkenazi Jews [reviewed in The prevalence of early-onset dystonia in Ashkenazi Jews is estimated at 1:3000-1:9000; because of the reduced penetrance (i.e., 30%), the carrier frequency for the The increased prevalence in Ashkenazim is the result of a founder variant that appeared approximately 350 years ago [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis In studies of individuals with different forms of dystonia (see Dopa-responsive dystonia ( Other, as-yet unidentified genetic forms of autosomal dominant early-onset dystonia also exist [ Early-onset isolated dystonia can also be inherited in an autosomal recessive manner. Biallelic pathogenic variants in Onset in adulthood (especially age >40 years) Spasmodic torticollis (cervical dystonia) Spasmodic dysphonia (laryngeal dystonia resulting in either broken and strangled or breathy speech) Blepharospasm (involuntary eye closure), which may also include contractions of other facial muscles Oromandibular dystonia (the jaw is held open or shut) Dramatic improvement with levodopa therapy suggests the diagnosis of Abnormal brain CT examination or MRI examination Additional abnormalities on neurologic examination. Findings other than dystonia are indicative of a combined rather than isolated dystonia. Combined dystonia can be due to a genetic or acquired etiology (see A history that suggests an acquired cause of dystonia, such as exposure to neuroleptics or other dopamine-blocking drugs (tardive dystonia), perinatal ischemia/injury, stroke, cerebral trauma, or encephalitis Presence of inconsistent weakness, non-physiologic sensory findings, or incongruous movements that suggest a psychogenic basis. • Onset in adulthood (especially age >40 years) • Spasmodic torticollis (cervical dystonia) • Spasmodic dysphonia (laryngeal dystonia resulting in either broken and strangled or breathy speech) • Blepharospasm (involuntary eye closure), which may also include contractions of other facial muscles • Oromandibular dystonia (the jaw is held open or shut) • Spasmodic torticollis (cervical dystonia) • Spasmodic dysphonia (laryngeal dystonia resulting in either broken and strangled or breathy speech) • Blepharospasm (involuntary eye closure), which may also include contractions of other facial muscles • Oromandibular dystonia (the jaw is held open or shut) • Dramatic improvement with levodopa therapy suggests the diagnosis of • Abnormal brain CT examination or MRI examination • Additional abnormalities on neurologic examination. Findings other than dystonia are indicative of a combined rather than isolated dystonia. Combined dystonia can be due to a genetic or acquired etiology (see • A history that suggests an acquired cause of dystonia, such as exposure to neuroleptics or other dopamine-blocking drugs (tardive dystonia), perinatal ischemia/injury, stroke, cerebral trauma, or encephalitis • Presence of inconsistent weakness, non-physiologic sensory findings, or incongruous movements that suggest a psychogenic basis. • Spasmodic torticollis (cervical dystonia) • Spasmodic dysphonia (laryngeal dystonia resulting in either broken and strangled or breathy speech) • Blepharospasm (involuntary eye closure), which may also include contractions of other facial muscles • Oromandibular dystonia (the jaw is held open or shut) ## Management To establish the extent of disease and needs in an individual diagnosed with DYT1 early-onset isolated dystonia, the following evaluations are recommended: Thorough history, including family history General physical examination Neurologic examination. The standard scale used to measure the clinical extent of dystonia is the Burke-Fahn-Marsden rating scale. If evidence of psychiatric problems (especially depression) exist, consideration of psychiatric assessment Consultation with a clinical geneticist and/or genetic counselor Consideration of occupational and/or physical therapy evaluation Treatment is aimed at relieving symptoms [ Anticholinergics (e.g., trihexyphenidyl) Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. Baclofen (Lioresal Benzodiazepines Other medications including levodopa, antiepileptics, and dopamine-depleting agents; these have been used to treat dystonia with variable effects. Surgery to enable GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. Some, though not all, studies have found that the presence of a Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ Clinical effect has been found to be well sustained at follow up of up to 13 years [ Note: Intrathecal baclofen therapy has been used for treatment of generalized dystonia of various etiologies in the past [ Physical therapy and an appropriate exercise program may be of benefit. Aggressive medical and surgical intervention including regular follow up for adjustment of medicines and timely referral for GPi DBS surgery when indicated is appropriate in order to prevent long-term orthopedic complications such as joint contractures or spine deformities. However, little systematic data support or negate the use of this approach. Follow up several times a year with a neurologist specializing in movement disorders is recommended (especially if there is progression) to prevent secondary complications, although little information regarding the benefit of this approach is available. Individuals treated with GPi DBS surgery require regular follow up, more frequent in the first year after surgery, for programming of the stimulation parameters and monitoring of battery life. The extremities affected by dystonia should not be placed in a brace or cast, unless medically necessary, as this can worsen the dystonia. See Data on the use of the oral medications typically used for treatment of dystonia during pregnancy are limited. Isolated case reports of treatment with trihexyphenidyl or carbidopa/levodopa for various conditions (including certain forms of dystonia) during pregnancy have not found adverse effects on either the affected mother or the fetus [ No adverse fetal or maternal outcomes were reported in two series of women, including four women with DYT1 dystonia, who were treated with DBS implantation prior to pregnancy. [ RNA interference (RNAi) has been used in cell culture systems overexpressing the mutated torsin protein to block aggregate formation and restore normal distribution of wild type torsin-1A (torsinA) [ Search • Thorough history, including family history • General physical examination • Neurologic examination. The standard scale used to measure the clinical extent of dystonia is the Burke-Fahn-Marsden rating scale. • If evidence of psychiatric problems (especially depression) exist, consideration of psychiatric assessment • Consultation with a clinical geneticist and/or genetic counselor • Consideration of occupational and/or physical therapy evaluation • Anticholinergics (e.g., trihexyphenidyl) • Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. • Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. • Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. • Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. • Baclofen (Lioresal • Benzodiazepines • Other medications including levodopa, antiepileptics, and dopamine-depleting agents; these have been used to treat dystonia with variable effects. • Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. • Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. • Surgery to enable • GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. • Some, though not all, studies have found that the presence of a • Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ • Clinical effect has been found to be well sustained at follow up of up to 13 years [ • Note: Intrathecal baclofen therapy has been used for treatment of generalized dystonia of various etiologies in the past [ • GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. • Some, though not all, studies have found that the presence of a • Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ • Clinical effect has been found to be well sustained at follow up of up to 13 years [ • Physical therapy and an appropriate exercise program may be of benefit. • GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. • Some, though not all, studies have found that the presence of a • Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ • Clinical effect has been found to be well sustained at follow up of up to 13 years [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DYT1 early-onset isolated dystonia, the following evaluations are recommended: Thorough history, including family history General physical examination Neurologic examination. The standard scale used to measure the clinical extent of dystonia is the Burke-Fahn-Marsden rating scale. If evidence of psychiatric problems (especially depression) exist, consideration of psychiatric assessment Consultation with a clinical geneticist and/or genetic counselor Consideration of occupational and/or physical therapy evaluation • Thorough history, including family history • General physical examination • Neurologic examination. The standard scale used to measure the clinical extent of dystonia is the Burke-Fahn-Marsden rating scale. • If evidence of psychiatric problems (especially depression) exist, consideration of psychiatric assessment • Consultation with a clinical geneticist and/or genetic counselor • Consideration of occupational and/or physical therapy evaluation ## Treatment of Manifestations Treatment is aimed at relieving symptoms [ Anticholinergics (e.g., trihexyphenidyl) Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. Baclofen (Lioresal Benzodiazepines Other medications including levodopa, antiepileptics, and dopamine-depleting agents; these have been used to treat dystonia with variable effects. Surgery to enable GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. Some, though not all, studies have found that the presence of a Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ Clinical effect has been found to be well sustained at follow up of up to 13 years [ Note: Intrathecal baclofen therapy has been used for treatment of generalized dystonia of various etiologies in the past [ Physical therapy and an appropriate exercise program may be of benefit. • Anticholinergics (e.g., trihexyphenidyl) • Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. • Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. • Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. • Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. • Baclofen (Lioresal • Benzodiazepines • Other medications including levodopa, antiepileptics, and dopamine-depleting agents; these have been used to treat dystonia with variable effects. • Trihexyphenidyl can be titrated to high doses (in the range of 100 mg/day) in children, who tend to tolerate high doses better than adults. • Anticholinergic side effects, particularly cognitive effects, must be monitored closely. Pyridostigmine can be used to counter anticholinergic side effects, but does not improve cognitive side effects. • Surgery to enable • GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. • Some, though not all, studies have found that the presence of a • Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ • Clinical effect has been found to be well sustained at follow up of up to 13 years [ • Note: Intrathecal baclofen therapy has been used for treatment of generalized dystonia of various etiologies in the past [ • GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. • Some, though not all, studies have found that the presence of a • Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ • Clinical effect has been found to be well sustained at follow up of up to 13 years [ • Physical therapy and an appropriate exercise program may be of benefit. • GPi DBS has become a well-established and important treatment option for individuals with medically refractory DYT1 early-onset dystonia. Overall, individuals with DYT1 early-onset dystonia tend to have good outcomes after GPi DBS, with some showing dramatic improvement. • Some, though not all, studies have found that the presence of a • Shorter disease duration has been correlated with improved outcomes, highlighting the importance of early referral for DBS in children with severe, medically refractory DYT1 dystonia. [ • Clinical effect has been found to be well sustained at follow up of up to 13 years [ ## Prevention of Secondary Complications Aggressive medical and surgical intervention including regular follow up for adjustment of medicines and timely referral for GPi DBS surgery when indicated is appropriate in order to prevent long-term orthopedic complications such as joint contractures or spine deformities. However, little systematic data support or negate the use of this approach. ## Surveillance Follow up several times a year with a neurologist specializing in movement disorders is recommended (especially if there is progression) to prevent secondary complications, although little information regarding the benefit of this approach is available. Individuals treated with GPi DBS surgery require regular follow up, more frequent in the first year after surgery, for programming of the stimulation parameters and monitoring of battery life. ## Agents/Circumstances to Avoid The extremities affected by dystonia should not be placed in a brace or cast, unless medically necessary, as this can worsen the dystonia. ## Evaluation of Relatives at Risk See ## Pregnancy Management Data on the use of the oral medications typically used for treatment of dystonia during pregnancy are limited. Isolated case reports of treatment with trihexyphenidyl or carbidopa/levodopa for various conditions (including certain forms of dystonia) during pregnancy have not found adverse effects on either the affected mother or the fetus [ No adverse fetal or maternal outcomes were reported in two series of women, including four women with DYT1 dystonia, who were treated with DBS implantation prior to pregnancy. [ ## Therapies Under Investigation RNA interference (RNAi) has been used in cell culture systems overexpressing the mutated torsin protein to block aggregate formation and restore normal distribution of wild type torsin-1A (torsinA) [ Search ## Genetic Counseling DYT1 early-onset isolated dystonia (DYT1 dystonia) is inherited in an autosomal dominant manner with reduced penetrance and broad clinical variability. Most individuals diagnosed with DYT1 dystonia inherited a In rare cases, a proband with DYT1 dystonia may have the disorder as the result of a It is appropriate to offer molecular genetic testing to both parents of an affected individual to determine if either has the Although most individuals diagnosed with DYT1 dystonia have a parent who has the The risk to the sibs of an affected person depends on the genetic status of the proband's parents. If a parent has the c.907_909delGAG deletion in If the c.907_909delGAG deletion in Each child of an individual with DYT1 dystonia has a 50% chance of inheriting the c.907_909delGAG deletion in Intrafamilial clinical variability is great, and an affected child may be more severely or less severely affected than the parent who transmitted the deletion. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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. Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of DYT1 dystonia regardless of age. See also the National Society of Genetic Counselors Once the • Most individuals diagnosed with DYT1 dystonia inherited a • In rare cases, a proband with DYT1 dystonia may have the disorder as the result of a • It is appropriate to offer molecular genetic testing to both parents of an affected individual to determine if either has the • Although most individuals diagnosed with DYT1 dystonia have a parent who has the • The risk to the sibs of an affected person depends on the genetic status of the proband's parents. • If a parent has the c.907_909delGAG deletion in • If the c.907_909delGAG deletion in • Each child of an individual with DYT1 dystonia has a 50% chance of inheriting the c.907_909delGAG deletion in • Intrafamilial clinical variability is great, and an affected child may be more severely or less severely affected than the parent who transmitted the deletion. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 DYT1 early-onset isolated dystonia (DYT1 dystonia) is inherited in an autosomal dominant manner with reduced penetrance and broad clinical variability. ## Risk to Family Members Most individuals diagnosed with DYT1 dystonia inherited a In rare cases, a proband with DYT1 dystonia may have the disorder as the result of a It is appropriate to offer molecular genetic testing to both parents of an affected individual to determine if either has the Although most individuals diagnosed with DYT1 dystonia have a parent who has the The risk to the sibs of an affected person depends on the genetic status of the proband's parents. If a parent has the c.907_909delGAG deletion in If the c.907_909delGAG deletion in Each child of an individual with DYT1 dystonia has a 50% chance of inheriting the c.907_909delGAG deletion in Intrafamilial clinical variability is great, and an affected child may be more severely or less severely affected than the parent who transmitted the deletion. • Most individuals diagnosed with DYT1 dystonia inherited a • In rare cases, a proband with DYT1 dystonia may have the disorder as the result of a • It is appropriate to offer molecular genetic testing to both parents of an affected individual to determine if either has the • Although most individuals diagnosed with DYT1 dystonia have a parent who has the • The risk to the sibs of an affected person depends on the genetic status of the proband's parents. • If a parent has the c.907_909delGAG deletion in • If the c.907_909delGAG deletion in • Each child of an individual with DYT1 dystonia has a 50% chance of inheriting the c.907_909delGAG deletion in • Intrafamilial clinical variability is great, and an affected child may be more severely or less severely affected than the parent who transmitted the deletion. ## 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. Testing is appropriate to consider in symptomatic individuals in a family with an established diagnosis of DYT1 dystonia regardless of age. See also 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 ## Resources United Kingdom Dystonia Medical Research Foundation • • • • United Kingdom • • • • • • • Dystonia Medical Research Foundation • ## Molecular Genetics DYT1 Early-Onset Isolated Dystonia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for DYT1 Early-Onset Isolated Dystonia ( Three additional in-frame deletions have been reported: An 18-bp deletion ( A 4-bp deletion ( A 6-bp deletion ( In addition, five other novel changes, each identified in a single affected individual and most reported in the ExAC database (see A c.863G>A (p.Arg288Gln) variant in an individual with facial palsy and severe fixed dystonia starting in infancy [ A c.613T>A (p.Phe205Ile) variant in a male with orobulbar dystonia beginning in his forties [ A c.361G>A (p.Glu121Lys) variant in an individual with segmental dystonia including cervical dystonia and spasmodic dysphonia [ A c.581A>T (p.Asp194Val) variant in an individual age 23 years with cervical dystonia, tremor in both hands and slight spasmodic dysphonia. In addition, this individual has a A c.385G>A (p.Val129Ile) variant in a Serbian woman age 38 years with adult onset cervical dystonia [ Interestingly, individuals with a disease-modifying Variants listed in the table have been provided by the authors. In Torsin-1A shuttles between the endoplasmic reticulum (ER) and the nuclear envelope (NE) [ Knock-in, knockout, and knockdown mouse models, a drosophila knockout model, as well as cellular studies support a loss-of-function mechanism in DYT1 dystonia resulting from a dominant-negative effect [ • An 18-bp deletion ( • A 4-bp deletion ( • A 6-bp deletion ( • A c.863G>A (p.Arg288Gln) variant in an individual with facial palsy and severe fixed dystonia starting in infancy [ • A c.613T>A (p.Phe205Ile) variant in a male with orobulbar dystonia beginning in his forties [ • A c.361G>A (p.Glu121Lys) variant in an individual with segmental dystonia including cervical dystonia and spasmodic dysphonia [ • A c.581A>T (p.Asp194Val) variant in an individual age 23 years with cervical dystonia, tremor in both hands and slight spasmodic dysphonia. In addition, this individual has a • A c.385G>A (p.Val129Ile) variant in a Serbian woman age 38 years with adult onset cervical dystonia [ ## 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 ## Chapter Notes Susan B Bressman, MD; Albert Einstein College of Medicine (1999-2014)Deborah de Leon, MS; Beth Israel Medical Center (1999-2005)Naomi Lubarr, MD (2014-present)Laurie Ozelius, PhD (2014-present)Deborah Raymond, MS; Beth Israel Medical Center (2005-2014) 17 November 2016 (sw) Comprehensive update posted live 2 January 2014 (me) Comprehensive update posted live 23 November 2010 (cd) Revision: corrected mutation nomenclature: c.904_906delGAG → c.907_909delGAG 1 July 2008 (me) Comprehensive update posted live 31 August 2006 (cd) Revision: 5 April 2005 (me) Comprehensive update posted live 21 January 2003 (me) Comprehensive update posted live 14 April 1999 (pb) Review posted live 2 December 1998 (ddl) Original submission • 17 November 2016 (sw) Comprehensive update posted live • 2 January 2014 (me) Comprehensive update posted live • 23 November 2010 (cd) Revision: corrected mutation nomenclature: c.904_906delGAG → c.907_909delGAG • 1 July 2008 (me) Comprehensive update posted live • 31 August 2006 (cd) Revision: • 5 April 2005 (me) Comprehensive update posted live • 21 January 2003 (me) Comprehensive update posted live • 14 April 1999 (pb) Review posted live • 2 December 1998 (ddl) Original submission ## Author History Susan B Bressman, MD; Albert Einstein College of Medicine (1999-2014)Deborah de Leon, MS; Beth Israel Medical Center (1999-2005)Naomi Lubarr, MD (2014-present)Laurie Ozelius, PhD (2014-present)Deborah Raymond, MS; Beth Israel Medical Center (2005-2014) ## Revision History 17 November 2016 (sw) Comprehensive update posted live 2 January 2014 (me) Comprehensive update posted live 23 November 2010 (cd) Revision: corrected mutation nomenclature: c.904_906delGAG → c.907_909delGAG 1 July 2008 (me) Comprehensive update posted live 31 August 2006 (cd) Revision: 5 April 2005 (me) Comprehensive update posted live 21 January 2003 (me) Comprehensive update posted live 14 April 1999 (pb) Review posted live 2 December 1998 (ddl) Original submission • 17 November 2016 (sw) Comprehensive update posted live • 2 January 2014 (me) Comprehensive update posted live • 23 November 2010 (cd) Revision: corrected mutation nomenclature: c.904_906delGAG → c.907_909delGAG • 1 July 2008 (me) Comprehensive update posted live • 31 August 2006 (cd) Revision: • 5 April 2005 (me) Comprehensive update posted live • 21 January 2003 (me) Comprehensive update posted live • 14 April 1999 (pb) Review posted live • 2 December 1998 (ddl) Original submission
[]
14/4/1999
17/11/2016
23/11/2010
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ea1
ea1
[ "EA1", "EA1", "Potassium voltage-gated channel subfamily A member 1", "KCNA1", "Episodic Ataxia Type 1" ]
Episodic Ataxia Type 1
Sonia M Hasan, Maria Cristina D'Adamo
Summary Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other possible associations include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence. Diagnosis is based on clinical findings, an electrophysiologic test of axonal superexcitability and threshold electrotonus, and/or the identification of a heterozygous pathogenic variant in EA1 is inherited in an autosomal dominant manner. Most individuals diagnosed with EA1 have an affected parent; however,
## Diagnosis No consensus diagnostic criteria for episodic ataxia type 1 (EA1) have been published. Episodic ataxia type 1 (EA1) Episodic attacks of: Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs Dysarthria Incoordination of hands Weakness Tremors Muscle twitching/stiffening Dizziness Stiffening of the body Blurred vision, diplopia Nausea, headache, and vomiting Neuromyotonia (muscle cramps and stiffness) Myokymia (muscle twitching with a rippling appearance) occurring in the limbs or especially in the muscles of the face or hands Childhood or early-adolescent disease onset (average age of onset: ~8 years) Normal brain MRI Routine laboratory blood tests including serum concentration of creatine kinase and electrolytes EMG that displays a pattern of either rhythmically or arrhythmically occurring singlets, duplets, or multiplets Note: In some individuals myokymic activity on the EMG becomes apparent after the application of regional ischemia. To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac Note: (1) Lack of a family history of EA1 does not preclude the diagnosis. (2) Muscle biopsy is usually not helpful in establishing the diagnosis, although bilateral calf hypertrophy, enlargement of type 1 and type 2 gastrocnemius muscle fibers, abnormal mitochondria, and variable glycogen depletion have been observed [ The diagnosis of EA1 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. Because the phenotype of EA1 is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of EA1 molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of EA1 is not considered because an individual has atypical or complex phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Episodic Ataxia Type 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All affected individuals described thus far are heterozygous for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications of • Episodic attacks of: • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs • Dysarthria • Incoordination of hands • Weakness • Tremors • Muscle twitching/stiffening • Dizziness • Stiffening of the body • Blurred vision, diplopia • Nausea, headache, and vomiting • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs • Dysarthria • Incoordination of hands • Weakness • Tremors • Muscle twitching/stiffening • Dizziness • Stiffening of the body • Blurred vision, diplopia • Nausea, headache, and vomiting • Neuromyotonia (muscle cramps and stiffness) • Myokymia (muscle twitching with a rippling appearance) occurring in the limbs or especially in the muscles of the face or hands • Childhood or early-adolescent disease onset (average age of onset: ~8 years) • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs • Dysarthria • Incoordination of hands • Weakness • Tremors • Muscle twitching/stiffening • Dizziness • Stiffening of the body • Blurred vision, diplopia • Nausea, headache, and vomiting • Normal brain MRI • Routine laboratory blood tests including serum concentration of creatine kinase and electrolytes • EMG that displays a pattern of either rhythmically or arrhythmically occurring singlets, duplets, or multiplets • Note: In some individuals myokymic activity on the EMG becomes apparent after the application of regional ischemia. • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac • For an introduction to multigene panels click ## Suggestive Findings Episodic ataxia type 1 (EA1) Episodic attacks of: Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs Dysarthria Incoordination of hands Weakness Tremors Muscle twitching/stiffening Dizziness Stiffening of the body Blurred vision, diplopia Nausea, headache, and vomiting Neuromyotonia (muscle cramps and stiffness) Myokymia (muscle twitching with a rippling appearance) occurring in the limbs or especially in the muscles of the face or hands Childhood or early-adolescent disease onset (average age of onset: ~8 years) Normal brain MRI Routine laboratory blood tests including serum concentration of creatine kinase and electrolytes EMG that displays a pattern of either rhythmically or arrhythmically occurring singlets, duplets, or multiplets Note: In some individuals myokymic activity on the EMG becomes apparent after the application of regional ischemia. To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac Note: (1) Lack of a family history of EA1 does not preclude the diagnosis. (2) Muscle biopsy is usually not helpful in establishing the diagnosis, although bilateral calf hypertrophy, enlargement of type 1 and type 2 gastrocnemius muscle fibers, abnormal mitochondria, and variable glycogen depletion have been observed [ • Episodic attacks of: • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs • Dysarthria • Incoordination of hands • Weakness • Tremors • Muscle twitching/stiffening • Dizziness • Stiffening of the body • Blurred vision, diplopia • Nausea, headache, and vomiting • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs • Dysarthria • Incoordination of hands • Weakness • Tremors • Muscle twitching/stiffening • Dizziness • Stiffening of the body • Blurred vision, diplopia • Nausea, headache, and vomiting • Neuromyotonia (muscle cramps and stiffness) • Myokymia (muscle twitching with a rippling appearance) occurring in the limbs or especially in the muscles of the face or hands • Childhood or early-adolescent disease onset (average age of onset: ~8 years) • Generalized ataxia, loss of balance, and jerking movements of the head, arms, and legs • Dysarthria • Incoordination of hands • Weakness • Tremors • Muscle twitching/stiffening • Dizziness • Stiffening of the body • Blurred vision, diplopia • Nausea, headache, and vomiting • Normal brain MRI • Routine laboratory blood tests including serum concentration of creatine kinase and electrolytes • EMG that displays a pattern of either rhythmically or arrhythmically occurring singlets, duplets, or multiplets • Note: In some individuals myokymic activity on the EMG becomes apparent after the application of regional ischemia. • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac • To evaluate for interictal motor activity (neuromyotonia/myokymia): surface or needle EMG recordings are performed before, during, and after the application of regional ischemia (e.g., using an inflated sphygmomanometer cuff applied around the upper or lower arm for up to 15 minutes). • In specialized centers, electrophysiologic assessments of axonal superexcitability and threshold electrotonus performed according to the TRONDHM protocol (using Qtrac ## Establishing the Diagnosis The diagnosis of EA1 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. Because the phenotype of EA1 is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of EA1 molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of EA1 is not considered because an individual has atypical or complex phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Episodic Ataxia Type 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All affected individuals described thus far are heterozygous for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications of • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of EA1 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 EA1 is not considered because an individual has atypical or complex phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Episodic Ataxia Type 1 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All affected individuals described thus far are heterozygous for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No deletions or duplications of ## Clinical Characteristics Episodic ataxia type 1 (EA1), first described by Vertigo Diaphoresis Clumsiness Difficulty in breathing, which can occur during ataxic episodes or as isolated episodes [ The duration of the attacks is brief, lasting seconds to minutes, although prolonged attacks lasting hours have been described [ The first symptoms typically manifest in the first or second decade of life. Choreoathetosis Carpal spasm Clenching of the fists Mild lower limb sensory impairment Isolated neuromyotonia Nystagmus [ Hyperthermia [ Hypothermia, which led to the death of an individual with EA1 as a result of exposure to anesthesia [ Note: Anesthetic agents have an inhibitory effect on kv1.1 channels. Stress or anxiety Intercurrent illness or fever Excitement or emotional upset Fatigue Menstruation or pregnancy Environmental temperature, including hot baths or use of a hairdryer [ Startle response Abrupt movements or sudden postural changes (kinesigenic stimulation), including riding a merry-go-round Vestibular stimulation (turning head from side to side while standing still; sitting still on a rotating chair; instillation of cold water [i.e., ≤30° C] into either external auditory canal) Exercise, such as repeat knee bends Ingestion of the following: Caffeine Alcohol Foods rich in salt Bitter oranges Chocolate Interictal ataxia has not been reported to date in individuals with EA1. Myokymia is typically evident as a fine rippling in the perioral or periorbital muscles and by lateral finger movements when the hands are held in a relaxed, prone position. Exposure of the forearm to warm or cold temperatures may increase or decrease, respectively, the spontaneous activity recorded from a hand muscle. Rarely, episodes of intense myokymic activity during attacks without either ataxia or other neurologic deficits may be observed. Myokymic activity is continuous and present in almost all affected individuals [ Severe receptive and expressive language delay Inability to learn to ride a bicycle The need for life-skill programs or schools for children with mild to moderate learning difficulties [ Moderate muscle hypertrophy with generalized increase in muscle tone and bilateral calf hypertrophy are observed. Increased muscle tone can cause the following: Unusual hypercontracted posture Abdominal wall muscle contraction Elbow, hip, and knee contractures Shortened Achilles tendons that may result in tiptoe walking Scoliosis Kyphoscoliosis High-arched palate Minor craniofacial dysmorphism EEG may be characterized by intermittent and generalized slow activity, frequently intermingled with spikes. Sensory conduction test results were normal. Abnormal neuromuscular transmission was reported from Cerebellar atrophy in one family [ Mild vermian hypoplasia [ Small right subcortical frontal gliosis [ Because of significant inter- and intrafamilial phenotypic variability, reliable genotype-phenotype correlations have been extremely difficult to establish. It is now apparent that phenotypic differences exist not only across families, but also among affected individuals within a family. Indeed, differences in severity and frequency of EA1 attacks have been reported even in monozygotic twins [ Most individuals harboring a EA1 has also been known as: Acetazolamide-responsive periodic ataxia Continuous muscle fiber activity Episodic ataxia with myokymia Familial paroxysmal kinesigenic ataxia and continuous myokymia Isaacs-Mertens syndrome Hereditary paroxysmal ataxia with neuromyotonia EA1 is a rare disease and the prevalence can be estimated only roughly. Several families from Australia, Brazil, Canada, Germany, Italy, Russia, Spain, the Netherlands, United Kingdom, and the United States have been described. Based on limited data, a disease prevalence of 1:500,000 has been proposed. Actual prevalence may well be considerably higher, as the disorder may remain either unrecognized in many families or be incorrectly diagnosed. The populations that are more or less at risk are also unknown. • Vertigo • Diaphoresis • Clumsiness • Difficulty in breathing, which can occur during ataxic episodes or as isolated episodes [ • Choreoathetosis • Carpal spasm • Clenching of the fists • Mild lower limb sensory impairment • Isolated neuromyotonia • Nystagmus [ • Hyperthermia [ • Hypothermia, which led to the death of an individual with EA1 as a result of exposure to anesthesia [ • Note: Anesthetic agents have an inhibitory effect on kv1.1 channels. • Stress or anxiety • Intercurrent illness or fever • Excitement or emotional upset • Fatigue • Menstruation or pregnancy • Environmental temperature, including hot baths or use of a hairdryer [ • Startle response • Abrupt movements or sudden postural changes (kinesigenic stimulation), including riding a merry-go-round • Vestibular stimulation (turning head from side to side while standing still; sitting still on a rotating chair; instillation of cold water [i.e., ≤30° C] into either external auditory canal) • Exercise, such as repeat knee bends • Ingestion of the following: • Caffeine • Alcohol • Foods rich in salt • Bitter oranges • Chocolate • Caffeine • Alcohol • Foods rich in salt • Bitter oranges • Chocolate • Caffeine • Alcohol • Foods rich in salt • Bitter oranges • Chocolate • Myokymia is typically evident as a fine rippling in the perioral or periorbital muscles and by lateral finger movements when the hands are held in a relaxed, prone position. • Exposure of the forearm to warm or cold temperatures may increase or decrease, respectively, the spontaneous activity recorded from a hand muscle. • Rarely, episodes of intense myokymic activity during attacks without either ataxia or other neurologic deficits may be observed. • Myokymic activity is continuous and present in almost all affected individuals [ • Severe receptive and expressive language delay • Inability to learn to ride a bicycle • The need for life-skill programs or schools for children with mild to moderate learning difficulties [ • Moderate muscle hypertrophy with generalized increase in muscle tone and bilateral calf hypertrophy are observed. • Increased muscle tone can cause the following: • Unusual hypercontracted posture • Abdominal wall muscle contraction • Elbow, hip, and knee contractures • Shortened Achilles tendons that may result in tiptoe walking • Unusual hypercontracted posture • Abdominal wall muscle contraction • Elbow, hip, and knee contractures • Shortened Achilles tendons that may result in tiptoe walking • Unusual hypercontracted posture • Abdominal wall muscle contraction • Elbow, hip, and knee contractures • Shortened Achilles tendons that may result in tiptoe walking • Scoliosis • Kyphoscoliosis • High-arched palate • Minor craniofacial dysmorphism • EEG may be characterized by intermittent and generalized slow activity, frequently intermingled with spikes. • Sensory conduction test results were normal. • Abnormal neuromuscular transmission was reported from • Cerebellar atrophy in one family [ • Mild vermian hypoplasia [ • Small right subcortical frontal gliosis [ • Acetazolamide-responsive periodic ataxia • Continuous muscle fiber activity • Episodic ataxia with myokymia • Familial paroxysmal kinesigenic ataxia and continuous myokymia • Isaacs-Mertens syndrome • Hereditary paroxysmal ataxia with neuromyotonia ## Clinical Description Episodic ataxia type 1 (EA1), first described by Vertigo Diaphoresis Clumsiness Difficulty in breathing, which can occur during ataxic episodes or as isolated episodes [ The duration of the attacks is brief, lasting seconds to minutes, although prolonged attacks lasting hours have been described [ The first symptoms typically manifest in the first or second decade of life. Choreoathetosis Carpal spasm Clenching of the fists Mild lower limb sensory impairment Isolated neuromyotonia Nystagmus [ Hyperthermia [ Hypothermia, which led to the death of an individual with EA1 as a result of exposure to anesthesia [ Note: Anesthetic agents have an inhibitory effect on kv1.1 channels. Stress or anxiety Intercurrent illness or fever Excitement or emotional upset Fatigue Menstruation or pregnancy Environmental temperature, including hot baths or use of a hairdryer [ Startle response Abrupt movements or sudden postural changes (kinesigenic stimulation), including riding a merry-go-round Vestibular stimulation (turning head from side to side while standing still; sitting still on a rotating chair; instillation of cold water [i.e., ≤30° C] into either external auditory canal) Exercise, such as repeat knee bends Ingestion of the following: Caffeine Alcohol Foods rich in salt Bitter oranges Chocolate Interictal ataxia has not been reported to date in individuals with EA1. Myokymia is typically evident as a fine rippling in the perioral or periorbital muscles and by lateral finger movements when the hands are held in a relaxed, prone position. Exposure of the forearm to warm or cold temperatures may increase or decrease, respectively, the spontaneous activity recorded from a hand muscle. Rarely, episodes of intense myokymic activity during attacks without either ataxia or other neurologic deficits may be observed. Myokymic activity is continuous and present in almost all affected individuals [ Severe receptive and expressive language delay Inability to learn to ride a bicycle The need for life-skill programs or schools for children with mild to moderate learning difficulties [ Moderate muscle hypertrophy with generalized increase in muscle tone and bilateral calf hypertrophy are observed. Increased muscle tone can cause the following: Unusual hypercontracted posture Abdominal wall muscle contraction Elbow, hip, and knee contractures Shortened Achilles tendons that may result in tiptoe walking Scoliosis Kyphoscoliosis High-arched palate Minor craniofacial dysmorphism EEG may be characterized by intermittent and generalized slow activity, frequently intermingled with spikes. Sensory conduction test results were normal. Abnormal neuromuscular transmission was reported from Cerebellar atrophy in one family [ Mild vermian hypoplasia [ Small right subcortical frontal gliosis [ • Vertigo • Diaphoresis • Clumsiness • Difficulty in breathing, which can occur during ataxic episodes or as isolated episodes [ • Choreoathetosis • Carpal spasm • Clenching of the fists • Mild lower limb sensory impairment • Isolated neuromyotonia • Nystagmus [ • Hyperthermia [ • Hypothermia, which led to the death of an individual with EA1 as a result of exposure to anesthesia [ • Note: Anesthetic agents have an inhibitory effect on kv1.1 channels. • Stress or anxiety • Intercurrent illness or fever • Excitement or emotional upset • Fatigue • Menstruation or pregnancy • Environmental temperature, including hot baths or use of a hairdryer [ • Startle response • Abrupt movements or sudden postural changes (kinesigenic stimulation), including riding a merry-go-round • Vestibular stimulation (turning head from side to side while standing still; sitting still on a rotating chair; instillation of cold water [i.e., ≤30° C] into either external auditory canal) • Exercise, such as repeat knee bends • Ingestion of the following: • Caffeine • Alcohol • Foods rich in salt • Bitter oranges • Chocolate • Caffeine • Alcohol • Foods rich in salt • Bitter oranges • Chocolate • Caffeine • Alcohol • Foods rich in salt • Bitter oranges • Chocolate • Myokymia is typically evident as a fine rippling in the perioral or periorbital muscles and by lateral finger movements when the hands are held in a relaxed, prone position. • Exposure of the forearm to warm or cold temperatures may increase or decrease, respectively, the spontaneous activity recorded from a hand muscle. • Rarely, episodes of intense myokymic activity during attacks without either ataxia or other neurologic deficits may be observed. • Myokymic activity is continuous and present in almost all affected individuals [ • Severe receptive and expressive language delay • Inability to learn to ride a bicycle • The need for life-skill programs or schools for children with mild to moderate learning difficulties [ • Moderate muscle hypertrophy with generalized increase in muscle tone and bilateral calf hypertrophy are observed. • Increased muscle tone can cause the following: • Unusual hypercontracted posture • Abdominal wall muscle contraction • Elbow, hip, and knee contractures • Shortened Achilles tendons that may result in tiptoe walking • Unusual hypercontracted posture • Abdominal wall muscle contraction • Elbow, hip, and knee contractures • Shortened Achilles tendons that may result in tiptoe walking • Unusual hypercontracted posture • Abdominal wall muscle contraction • Elbow, hip, and knee contractures • Shortened Achilles tendons that may result in tiptoe walking • Scoliosis • Kyphoscoliosis • High-arched palate • Minor craniofacial dysmorphism • EEG may be characterized by intermittent and generalized slow activity, frequently intermingled with spikes. • Sensory conduction test results were normal. • Abnormal neuromuscular transmission was reported from • Cerebellar atrophy in one family [ • Mild vermian hypoplasia [ • Small right subcortical frontal gliosis [ ## Genotype-Phenotype Correlations Because of significant inter- and intrafamilial phenotypic variability, reliable genotype-phenotype correlations have been extremely difficult to establish. It is now apparent that phenotypic differences exist not only across families, but also among affected individuals within a family. Indeed, differences in severity and frequency of EA1 attacks have been reported even in monozygotic twins [ ## Penetrance Most individuals harboring a ## Nomenclature EA1 has also been known as: Acetazolamide-responsive periodic ataxia Continuous muscle fiber activity Episodic ataxia with myokymia Familial paroxysmal kinesigenic ataxia and continuous myokymia Isaacs-Mertens syndrome Hereditary paroxysmal ataxia with neuromyotonia • Acetazolamide-responsive periodic ataxia • Continuous muscle fiber activity • Episodic ataxia with myokymia • Familial paroxysmal kinesigenic ataxia and continuous myokymia • Isaacs-Mertens syndrome • Hereditary paroxysmal ataxia with neuromyotonia ## Prevalence EA1 is a rare disease and the prevalence can be estimated only roughly. Several families from Australia, Brazil, Canada, Germany, Italy, Russia, Spain, the Netherlands, United Kingdom, and the United States have been described. Based on limited data, a disease prevalence of 1:500,000 has been proposed. Actual prevalence may well be considerably higher, as the disorder may remain either unrecognized in many families or be incorrectly diagnosed. The populations that are more or less at risk are also unknown. ## Genetically Related (Allelic) Disorders It is unclear whether the following truly represent unique phenotypes associated with a pathogenic variant in Hypomagnesemia with accompanying recurrent muscle cramps, tetanic episodes, tremor, and limb muscle weakness has been described in a large Brazilian family harboring a • Hypomagnesemia with accompanying recurrent muscle cramps, tetanic episodes, tremor, and limb muscle weakness has been described in a large Brazilian family harboring a ## Differential Diagnosis Episodic ataxia can occur sporadically or in a number of hereditary or acquired disorders. Disorders to Consider in the Differential Diagnosis of Episodic Ataxia Type 1 Paroxysmal attacks of ataxia, vertigo, nausea lasting minutes to days; can be assoc w/dysarthria, diplopia, tinnitus, dystonia, hemiplegia, & headache (migraine in ~50%) Atrophy of cerebellar vermis on MRI Stress Exertion Caffeine Alcohol Fever Heat Phenytoin Vestibular ataxia Vertigo Tinnitus Recurrent attacks of vertigo, tinnitus, diplopia, & ataxia Abnormal eye movements (incl abnormal smooth pursuit, nystagmus, & abnormal vestibuloocular reflex) Slowly progressive cerebellar ataxia in some Attacks of ataxia precipitated by fever Subclinical seizures Slurred speech followed by headache Bouts of arm jerking w/concomitant confusion Alternating hemiplegia Stress Fatigue Caffeine Alcohol Exercise Excitement Unsteady gait, generalized weakness, & slurred speech lasting mins to hrs In 2 women: improvement during pregnancy; in others: ↓ frequency & severity of attacks w/age Twitching around eyes, nystagmus, myokymia, mild dysarthria, & persistent intention tremor in some Migraine headache w/o aura reported in 2 individuals Epilepsy not reported Unilateral or bilateral involuntary movements Attacks usually last a few secs to 5 mins but can last several hrs & incl dystonia, choreoathetosis, &/or ballism May be preceded by aura, & do not involve loss of consciousness Severity & combinations of symptoms vary Predominantly seen in males Unilateral or bilateral involuntary movements Attacks lasting mins to hrs: dystonic posturing w/choreic & ballistic movements; may be preceded by aura; occur while awake; are not associated w/seizures Frequency, duration, severity, & combinations of symptoms vary w/in & among families Alcohol Caffeine Excitement Stress Fatigue Chocolate Rare neuromuscular disorder Hyperexcitability of motor nerve → continuously contracting or twitching muscles (myokymia) & muscle hypertrophy Cramping, ↑ sweating, & delayed muscle relaxation Stiffness most prominent in limb & trunk muscles A few persons report sleep disorders, anxiety, & memory loss (Morvan syndrome) AD = autosomal dominant: MOI = mode of inheritance; NA = not applicable See EA2 is allelic to EA3 has been described in a large Canadian kindred of Mennonite heritage [ EA4 (also referred to as periodic vestibulocerebellar ataxia) has been described in families from North Carolina of northern European origin by EA4 does not link to loci identified with EA1, EA2, or spinocerebellar ataxia types 1, 2, 3, 4, and 5 [ EA5 can result from pathogenic variants in EA6 can result from pathogenic variants in EA7 has been described in a four-generation family whose affected individuals showed episodic ataxia [ Genome-wide linkage analysis found linkage to an 18.5-Mb locus on chromosome 1p36.13-p34.3 [ The phenotype of paroxysmal kinesigenic dyskinesia can include benign familial infantile epilepsy (BFIE), infantile convulsions and choreoathetosis (ICCA), hemiplegic migraine, migraine with and without aura, and episodic ataxia. The acquired form of Isaac's syndrome occasionally develops in association with peripheral neuropathies or after radiation treatment. Twenty percent of affected individuals have an associated thymoma. Antibodies that involve K+ channels have been detected in approximately 40% of affected individuals [ • Paroxysmal attacks of ataxia, vertigo, nausea lasting minutes to days; can be assoc w/dysarthria, diplopia, tinnitus, dystonia, hemiplegia, & headache (migraine in ~50%) • Atrophy of cerebellar vermis on MRI • Stress • Exertion • Caffeine • Alcohol • Fever • Heat • Phenytoin • Vestibular ataxia • Vertigo • Tinnitus • Recurrent attacks of vertigo, tinnitus, diplopia, & ataxia • Abnormal eye movements (incl abnormal smooth pursuit, nystagmus, & abnormal vestibuloocular reflex) • Slowly progressive cerebellar ataxia in some • Attacks of ataxia precipitated by fever • Subclinical seizures • Slurred speech followed by headache • Bouts of arm jerking w/concomitant confusion • Alternating hemiplegia • Stress • Fatigue • Caffeine • Alcohol • Exercise • Excitement • Unsteady gait, generalized weakness, & slurred speech lasting mins to hrs • In 2 women: improvement during pregnancy; in others: ↓ frequency & severity of attacks w/age • Twitching around eyes, nystagmus, myokymia, mild dysarthria, & persistent intention tremor in some • Migraine headache w/o aura reported in 2 individuals • Epilepsy not reported • Unilateral or bilateral involuntary movements • Attacks usually last a few secs to 5 mins but can last several hrs & incl dystonia, choreoathetosis, &/or ballism • May be preceded by aura, & do not involve loss of consciousness • Severity & combinations of symptoms vary • Predominantly seen in males • Unilateral or bilateral involuntary movements • Attacks lasting mins to hrs: dystonic posturing w/choreic & ballistic movements; may be preceded by aura; occur while awake; are not associated w/seizures • Frequency, duration, severity, & combinations of symptoms vary w/in & among families • Alcohol • Caffeine • Excitement • Stress • Fatigue • Chocolate • Rare neuromuscular disorder • Hyperexcitability of motor nerve → continuously contracting or twitching muscles (myokymia) & muscle hypertrophy • Cramping, ↑ sweating, & delayed muscle relaxation • Stiffness most prominent in limb & trunk muscles • A few persons report sleep disorders, anxiety, & memory loss (Morvan syndrome) ## Management To establish the extent of disease and therapeutic needs in an individual diagnosed with episodic ataxia type 1, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Episodic Ataxia Type 1 Treatment of Manifestations in Individuals with Episodic Ataxia Type 1 Several drugs variably improve EA1 symptoms, but with the lack of clinical trials comparing the efficacy of these drugs, no single medication has been proven to be very effective. Chronic treatment with acetazolamide may result in side effects including neuropsychiatric manifestations, tiredness, paresthesias, rash, and formation of renal calculi, necessitating discontinuation of therapy [ Phenytoin should be used with caution in young patients, as it may cause permanent cerebellar dysfunction and atrophy [ Phenytoin is most often a second-line drug for typical attacks [ The dose needs to be adjusted according to factors including age, weight, the particular carbamazepine product being used, responsiveness of the individual, and other medications being taken. 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 addition to the pharmacologic treatments mentioned above, behavioral measures such as avoidance of stress, abrupt movements, loud noises, and caffeine may be implemented to reduce disease manifestations in either a symptomatic or an asymptomatic person. Contractures occur in a small proportion of individuals and can be prevented by appropriate physiotherapy. Surveillance should include annual neurologic examination. Known triggers of attacks (see Marked generalized myokymia has been reported during induction of anesthesia [ It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from behavioral measures and avoidance of caffeine intake. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. See No published literature addresses management of the pregnancy of an affected mother or the effect of maternal EA1 on a fetus. However, affected women should be made aware that pregnancy may trigger attacks [ 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 during pregnancy reduces this risk. However, exposure to anti-seizure medication 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 anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See Search Morphologic studies on lateral gastrocnemius (LG) muscles derived from a mouse model of EA1 did not reveal changes in muscle mass, fiber type composition, or vascularization [ Homozygous Val408Ala/Val408Ala pathogenic variants are embryonically lethal in an animal model of EA1 [ • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Evaluations Following Initial Diagnosis To establish the extent of disease and therapeutic needs in an individual diagnosed with episodic ataxia type 1, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Episodic Ataxia Type 1 ## Treatment of Manifestations Treatment of Manifestations in Individuals with Episodic Ataxia Type 1 Several drugs variably improve EA1 symptoms, but with the lack of clinical trials comparing the efficacy of these drugs, no single medication has been proven to be very effective. Chronic treatment with acetazolamide may result in side effects including neuropsychiatric manifestations, tiredness, paresthesias, rash, and formation of renal calculi, necessitating discontinuation of therapy [ Phenytoin should be used with caution in young patients, as it may cause permanent cerebellar dysfunction and atrophy [ Phenytoin is most often a second-line drug for typical attacks [ The dose needs to be adjusted according to factors including age, weight, the particular carbamazepine product being used, responsiveness of the individual, and other medications being taken. 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. ## 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 ## Prevention of Primary Manifestations In addition to the pharmacologic treatments mentioned above, behavioral measures such as avoidance of stress, abrupt movements, loud noises, and caffeine may be implemented to reduce disease manifestations in either a symptomatic or an asymptomatic person. ## Prevention of Secondary Complications Contractures occur in a small proportion of individuals and can be prevented by appropriate physiotherapy. ## Surveillance Surveillance should include annual neurologic examination. ## Agents/Circumstances to Avoid Known triggers of attacks (see Marked generalized myokymia has been reported during induction of anesthesia [ ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from behavioral measures and avoidance of caffeine intake. If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. See ## Pregnancy Management No published literature addresses management of the pregnancy of an affected mother or the effect of maternal EA1 on a fetus. However, affected women should be made aware that pregnancy may trigger attacks [ 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 during pregnancy reduces this risk. However, exposure to anti-seizure medication 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 anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [ See ## Therapies Under Investigation Search ## Other Morphologic studies on lateral gastrocnemius (LG) muscles derived from a mouse model of EA1 did not reveal changes in muscle mass, fiber type composition, or vascularization [ Homozygous Val408Ala/Val408Ala pathogenic variants are embryonically lethal in an animal model of EA1 [ ## Genetic Counseling Episodic ataxia type 1 (EA1) is inherited in an autosomal dominant manner. Most individuals diagnosed with EA1 have an affected parent. A proband with EA1 may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent If the The family history of some individuals diagnosed with EA1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic evaluation and molecular genetic testing have been performed on the parents of the proband. Note: 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. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. If the If the parents have not been tested for the See Management, 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 of being affected. Once the • Most individuals diagnosed with EA1 have an affected parent. • A proband with EA1 may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • If the • The family history of some individuals diagnosed with EA1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic evaluation and molecular genetic testing have been performed on the parents of the proband. • Note: 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. • The risk to the sibs of the proband depends on the genetic status of the proband's parents. • If a parent of the proband is affected, the risk to the sibs is 50%. • If the • 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 of being affected. ## Mode of Inheritance Episodic ataxia type 1 (EA1) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with EA1 have an affected parent. A proband with EA1 may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent If the The family history of some individuals diagnosed with EA1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic evaluation and molecular genetic testing have been performed on the parents of the proband. Note: 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. The risk to the sibs of the proband depends on the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. If the If the parents have not been tested for the • Most individuals diagnosed with EA1 have an affected parent. • A proband with EA1 may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • If the • The family history of some individuals diagnosed with EA1 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic evaluation and molecular genetic testing have been performed on the parents of the proband. • Note: 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. • The risk to the sibs of the proband depends on the genetic status of the proband's parents. • If a parent of the proband is affected, the risk to the sibs is 50%. • 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 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 of being affected. • 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 of being affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources United Kingdom United Kingdom Sanford Research • • United Kingdom • • • United Kingdom • • • • • Sanford Research • ## Molecular Genetics Episodic Ataxia Type 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Episodic Ataxia Type 1 ( Functional studies have shown that pathogenic missense variants in Homomeric Kv1.1 channels are tetrameric structures composed of four identical α-subunit monomers. Each monomer is encoded by Kv1.1 channels possess a slow process of inactivation, which has been named C-type or P-type depending on the structural determinants of this process that have been located within the C-terminus and pore region. Kv channels may also exhibit fast Interestingly, four different variants of the highly conserved threonine 226 residue, located within the second transmembrane segment, have been identified [ Variants listed in the table have been provided by the authors. Reference sequences include the correction of a sequence error published by Regarding channel gating, Individuals with EA1 are heterozygous for a A mouse model of EA1 has been generated by introducing a pathogenic variant analogous to the human p.Val408Ala EA1 pathogenic variant into the murine ortholog, The causes that trigger the paroxysms of ataxia remain elusive, although a phenomenon akin to spreading acidification of the cerebellar cortex has been suggested [ ## Molecular Pathogenesis Functional studies have shown that pathogenic missense variants in Homomeric Kv1.1 channels are tetrameric structures composed of four identical α-subunit monomers. Each monomer is encoded by Kv1.1 channels possess a slow process of inactivation, which has been named C-type or P-type depending on the structural determinants of this process that have been located within the C-terminus and pore region. Kv channels may also exhibit fast Interestingly, four different variants of the highly conserved threonine 226 residue, located within the second transmembrane segment, have been identified [ Variants listed in the table have been provided by the authors. Reference sequences include the correction of a sequence error published by Regarding channel gating, Individuals with EA1 are heterozygous for a A mouse model of EA1 has been generated by introducing a pathogenic variant analogous to the human p.Val408Ala EA1 pathogenic variant into the murine ortholog, The causes that trigger the paroxysms of ataxia remain elusive, although a phenomenon akin to spreading acidification of the cerebellar cortex has been suggested [ ## References ## Literature Cited ## Chapter Notes The financial support of Telethon (GGP11188), Ministero della Salute (GR-2009-1580433), and Fondazione Cassa di Risparmio di Perugia to MP is gratefully acknowledged. MGH is supported by an MRC Centre Grant (G0601943). Maria Cristina D'Adamo, PhD (2010-present)Giuseppe Di Giovanni, PhD; Istituto Euro-Mediterraneo di Scienza e Tecnologia (2012-2015)Michael G Hanna, BSc (Hons), MD, FRCP; UCL Institute of Neurology (2010-2015)Sonia M Hasan, PhD (2018-present)Mauro Pessia, PhD; Istituto Euro-Mediterraneo di Scienza e Tecnologia (2010-2015) 1 November 2018 (aa) Revision: findings reported by 31 May 2018 (ma) Comprehensive update posted live 25 June 2015 (me) Comprehensive update posted live 16 August 2012 (me) Comprehensive update posted live 9 February 2010 (me) Review posted live 21 April 2009 (mp) Initial submission • 1 November 2018 (aa) Revision: findings reported by • 31 May 2018 (ma) Comprehensive update posted live • 25 June 2015 (me) Comprehensive update posted live • 16 August 2012 (me) Comprehensive update posted live • 9 February 2010 (me) Review posted live • 21 April 2009 (mp) Initial submission ## Acknowledgments The financial support of Telethon (GGP11188), Ministero della Salute (GR-2009-1580433), and Fondazione Cassa di Risparmio di Perugia to MP is gratefully acknowledged. MGH is supported by an MRC Centre Grant (G0601943). ## Author History Maria Cristina D'Adamo, PhD (2010-present)Giuseppe Di Giovanni, PhD; Istituto Euro-Mediterraneo di Scienza e Tecnologia (2012-2015)Michael G Hanna, BSc (Hons), MD, FRCP; UCL Institute of Neurology (2010-2015)Sonia M Hasan, PhD (2018-present)Mauro Pessia, PhD; Istituto Euro-Mediterraneo di Scienza e Tecnologia (2010-2015) ## Revision History 1 November 2018 (aa) Revision: findings reported by 31 May 2018 (ma) Comprehensive update posted live 25 June 2015 (me) Comprehensive update posted live 16 August 2012 (me) Comprehensive update posted live 9 February 2010 (me) Review posted live 21 April 2009 (mp) Initial submission • 1 November 2018 (aa) Revision: findings reported by • 31 May 2018 (ma) Comprehensive update posted live • 25 June 2015 (me) Comprehensive update posted live • 16 August 2012 (me) Comprehensive update posted live • 9 February 2010 (me) Review posted live • 21 April 2009 (mp) Initial submission Schematic drawing of the conventional membrane topology of a human Kv1.1 subunit. Four such subunits comprise a functional homotetrameric channel. Different subunits belonging to the Kv1 subfamily may form heterotetrameric channels. The positions of pathogenic variants identified to date in individuals with EA1 are indicated. Modified from Proposed effects of EA1-causing pathogenic variants on basket cell and Purkinje cell inhibitory outputs The diagram shows a basket cell that has synapses on the initial segment and soma of a number of Purkinje cells from the cerebellar cortex of an unaffected individual ( Reused by permission of FASEB Journal
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A missense mutation in the Kv1.1 voltage-gated potassium channel-encoding gene KCNA1 is linked to human autosomal dominant hypomagnesemia.. J Clin Invest 2009;119:936-42", "TD Graves, YH Cha, AF Hahn, R Barohn, MK Salajegheh, RC Griggs, BN Bundy, JC Jen, RW Baloh, MG Hanna. CINCH Investigators. Episodic ataxia type 1: clinical characterization, quality of life and genotype-phenotype correlation.. Brain. 2014;137:1009-18", "TD Graves, S Rajakulendran, SM Zuberi, HR Morris, S Schorge, MG Hanna, DM Kullmann. Nongenetic factors influence severity of episodic ataxia type 1 in monozygotic twins.. Neurology. 2010;75:367-72", "IK Hart, P Maddison, J Newsom-Davis, A Vincent, KR Mills. Phenotypic variants of autoimmune peripheral nerve hyperexcitability.. Brain 2002;125:1887-95", "S Hasan, C Bove, G Silvestri, E Mantuano, A Modoni, L Veneziano, L Macchioni, T Hunter, G Hunter, M Pessia, MC D'Adamo. A channelopathy mutation in the voltage-sensor discloses contributions of a conserved phenylalanine to gating properties of Kv1.1 channels and ataxia.. Sci Rep 2017;7:4583", "PS Herson, M Virk, NR Rustay, CT Bond, JC Crabbe, JP Adelman, J Maylie. A mouse model of episodic ataxia type-1.. Nat Neurosci 2003;6:378-83", "P Imbrici, C Altamura, F Gualandi, GF Mangiatordi, M Neri, G De Maria, A Ferlini, A Padovani, MC D'Adamo, O Nicolotti, M Pessia, D Conte, M Filosto, JF Desaphy. A novel KCNA1 mutation in a patient with paroxysmal ataxia, myokymia, painful contractures and metabolic dysfunctions.. Mol Cell Neurosci 2017;83:6-12", "P Imbrici, A Cusimano, MC D'Adamo, A De Curtis, M Pessia. Functional characterization of an episodic ataxia type-1 mutation occurring in the S1 segment of hKv1.1 channels.. Pflugers Arch 2003;446:373-9", "P Imbrici, MC D'Adamo, A Cusimano, M Pessia. Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvbeta1.1.. Am J Physiol Cell Physiol 2007;292:C778-87", "P Imbrici, MC D'Adamo, A Grottesi, A Biscarini, M Pessia. Episodic ataxia type 1 mutations affect fast inactivation of K. Am J Physiol Cell Physiol. 2011;300:C1314-22", "P Imbrici, MC D'Adamo, DM Kullmann, M Pessia. Episodic ataxia type 1 mutations in the KCNA1 gene impair the fast inactivation properties of the human K+ channels Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2.. Eur J Neurosci 2006;24:3073-83", "P Imbrici, A Grottesi, MC D'Adamo, R Mannucci, S Tucker, M Pessia. Contributions of the central hydrophobic residue in the PXP motif of voltage-dependent K+ channels to S6 flexibility and gating properties.. Channels (Austin) 2009;3:39-45", "P Imbrici, F Gualandi, MC D'Adamo, M Taddei Masieri, P Cudia, D De Grandis, R Mannucci, I Nicoletti, SJ Tucker, A Ferlini, M Pessia. 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9/2/2010
31/5/2018
1/11/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ea2
ea2
[ "EA2", "Voltage-dependent P/Q-type calcium channel subunit alpha-1A", "CACNA1A", "Episodic Ataxia Type 2" ]
Episodic Ataxia Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
Sian Spacey
Summary Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting minutes to days in duration. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache. About 50% of individuals with EA2 have migraine headaches. Onset is typically in childhood or early adolescence (age range 2-32 years). Frequency of attacks can range from once or twice a year to three or four times a week. Attacks can be triggered by stress, exertion, caffeine, alcohol, fever, heat, and phenytoin; they can be stopped or decreased in frequency and severity by administration of acetazolamide or 4-aminopyridine. Between attacks, individuals may initially be asymptomatic but commonly develop interictal findings that can include nystagmus, pursuit and saccade alterations, and ataxia. The diagnosis of EA2 is established by identification of a heterozygous pathogenic variant in EA2 is inherited in an autosomal dominant manner. Most individuals with a diagnosis of EA2 have an affected parent. The proportion of cases caused by
## Diagnosis There are no formal clinical diagnostic criteria for the diagnosis of episodic ataxia type 2. Episodic ataxia type 2 (EA2) Episodic attacks: Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat Alleviated or prevented by acetazolamide therapy Presence of interictal ataxia and nystagmus Absence of myokymia (fine twitching or rippling of muscles) on physical examination Brain MRI may demonstrate atrophy of the cerebellar vermis [ Nuclear magnetic spectroscopy may demonstrate abnormal cerebellar intracellular pH levels (in those not treated with acetazolamide) [ Myokymia is absent on EMG. Single fiber EMG may demonstrate jitter and blocking. The diagnosis of EA2 Molecular testing approaches can include Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and over time. (2) Guidelines for the molecular diagnosis of genetic conditions that cause ataxia have been published [ For an introduction to multigene panels click Molecular Genetic Testing Used in Episodic Ataxia Type 2 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In families linked to chromosome 19 Sequence analysis has identified a number of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Partial • Episodic attacks: • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat • Alleviated or prevented by acetazolamide therapy • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat • Alleviated or prevented by acetazolamide therapy • Presence of interictal ataxia and nystagmus • Absence of myokymia (fine twitching or rippling of muscles) on physical examination • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat • Alleviated or prevented by acetazolamide therapy • Brain MRI may demonstrate atrophy of the cerebellar vermis [ • Nuclear magnetic spectroscopy may demonstrate abnormal cerebellar intracellular pH levels (in those not treated with acetazolamide) [ • Myokymia is absent on EMG. • Single fiber EMG may demonstrate jitter and blocking. • Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and over time. (2) Guidelines for the molecular diagnosis of genetic conditions that cause ataxia have been published [ • For an introduction to multigene panels click ## Suggestive Findings Episodic ataxia type 2 (EA2) Episodic attacks: Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat Alleviated or prevented by acetazolamide therapy Presence of interictal ataxia and nystagmus Absence of myokymia (fine twitching or rippling of muscles) on physical examination Brain MRI may demonstrate atrophy of the cerebellar vermis [ Nuclear magnetic spectroscopy may demonstrate abnormal cerebellar intracellular pH levels (in those not treated with acetazolamide) [ Myokymia is absent on EMG. Single fiber EMG may demonstrate jitter and blocking. • Episodic attacks: • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat • Alleviated or prevented by acetazolamide therapy • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat • Alleviated or prevented by acetazolamide therapy • Presence of interictal ataxia and nystagmus • Absence of myokymia (fine twitching or rippling of muscles) on physical examination • Including vertigo, gait and limb ataxia, and nystagmus lasting from five minutes to days, possibly associated with nausea and vomiting • Provoked by exercise, emotional stress, alcohol, caffeine, fever, and heat • Alleviated or prevented by acetazolamide therapy • Brain MRI may demonstrate atrophy of the cerebellar vermis [ • Nuclear magnetic spectroscopy may demonstrate abnormal cerebellar intracellular pH levels (in those not treated with acetazolamide) [ • Myokymia is absent on EMG. • Single fiber EMG may demonstrate jitter and blocking. ## Establishing the Diagnosis The diagnosis of EA2 Molecular testing approaches can include Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and over time. (2) Guidelines for the molecular diagnosis of genetic conditions that cause ataxia have been published [ For an introduction to multigene panels click Molecular Genetic Testing Used in Episodic Ataxia Type 2 See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In families linked to chromosome 19 Sequence analysis has identified a number of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Partial • Note: (1) The genes included and sensitivity of multigene panels vary by laboratory and over time. (2) Guidelines for the molecular diagnosis of genetic conditions that cause ataxia have been published [ • For an introduction to multigene panels click ## Clinical Characteristics Episodic ataxia type 2 (EA2) demonstrates variable expressivity both among and within families [ EA2 is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting hours to days. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache [ Frequency of attacks can range from one to two times per year to three to four times per week [ While individuals with EA2 may initially be asymptomatic between attacks, most eventually develop interictal permanent cerebellar symptoms; 90% have nystagmus and about 80% have ataxia. Other interictal findings include pursuit and saccade alterations and dystonia [ Specific Allelic modifying factors such as number of CAG repeats in exon 47 of CACNA1A do not appear to influence the severity of attacks or the persistence of neurologic symptoms between attacks [ Three pathogenic variants – Penetrance is estimated at 80%-90% [ EA2 has also been known as periodic vestibulocerebellar ataxia and acetazolamide-responsive episodic ataxia. EA2 is rare. The Consortium for Clinical Investigation of Neurological Channelopathies (CLINCH) has estimated the prevalence at lower than 1:100,000 population based on the cases seen by experts in regional centers. ## Clinical Description Episodic ataxia type 2 (EA2) demonstrates variable expressivity both among and within families [ EA2 is characterized by paroxysmal attacks of ataxia, vertigo, and nausea typically lasting hours to days. Attacks can be associated with dysarthria, diplopia, tinnitus, dystonia, hemiplegia, and headache [ Frequency of attacks can range from one to two times per year to three to four times per week [ While individuals with EA2 may initially be asymptomatic between attacks, most eventually develop interictal permanent cerebellar symptoms; 90% have nystagmus and about 80% have ataxia. Other interictal findings include pursuit and saccade alterations and dystonia [ ## Genotype-Phenotype Correlations Specific Allelic modifying factors such as number of CAG repeats in exon 47 of CACNA1A do not appear to influence the severity of attacks or the persistence of neurologic symptoms between attacks [ Three pathogenic variants – ## Penetrance Penetrance is estimated at 80%-90% [ ## Nomenclature EA2 has also been known as periodic vestibulocerebellar ataxia and acetazolamide-responsive episodic ataxia. ## Prevalence EA2 is rare. The Consortium for Clinical Investigation of Neurological Channelopathies (CLINCH) has estimated the prevalence at lower than 1:100,000 population based on the cases seen by experts in regional centers. ## Genetically Related (Allelic) Disorders Pathogenic variants in FHM is characterized by an aura of hemiplegia that is always associated with at least one other aura symptom such as hemianopsia, hemisensory deficit, or aphasia. The aura is followed by a moderate to severe headache. Two clinical forms exist: pure FHM (80% of families), in which interictal examination is normal in all family members, and FHM with permanent cerebellar symptoms (20% of families), in which some family members show interictal nystagmus and/or ataxia [ Their well-described phenotypes notwithstanding, clinical overlap exists among EA2, FHM, and SCA6, even within the same family. In a family with EA2, affected members had hemiplegia, and one affected member had migraine during episodes of ataxia [ In a study of 11 individuals with EA2 and documented heterozygous pathogenic variants in Members of a Portuguese family with a pathogenic missense variant (A>G substitution) in Individuals with SCA6 can present with episodic ataxia, mostly during the first years of the disorder. In one study, up to 33% of individuals with 21 or more CAG repeats in • FHM is characterized by an aura of hemiplegia that is always associated with at least one other aura symptom such as hemianopsia, hemisensory deficit, or aphasia. The aura is followed by a moderate to severe headache. Two clinical forms exist: pure FHM (80% of families), in which interictal examination is normal in all family members, and FHM with permanent cerebellar symptoms (20% of families), in which some family members show interictal nystagmus and/or ataxia [ • In a family with EA2, affected members had hemiplegia, and one affected member had migraine during episodes of ataxia [ • In a study of 11 individuals with EA2 and documented heterozygous pathogenic variants in • Members of a Portuguese family with a pathogenic missense variant (A>G substitution) in ## Differential Diagnosis Episodic ataxia can occur sporadically or in a number of hereditary disorders. Sporadic causes of episodic ataxia include multiple sclerosis, Arnold Chiari malformation, vertebral basilar insufficiency, basilar migraine, and labyrinthine abnormalities. The most common of these is Pyruvate dehydrogenase deficiency (OMIM The identification of a significantly elevated blood ammonia concentration requires immediate treatment by hemodialysis and by IV sodium phenylacetate/sodium benzoate; long-term treatment of urea cycle disorders generally includes a high-calorie, low-protein diet supplemented with essential amino acids. The severe forms of the hyperammonemias present in the first few days of life with lethargy and possible focal and generalized seizures, ultimately leading to coma. The less severe forms develop in early childhood and are characterized by intermittent ataxia, dysarthria, vomiting, headache, ptosis, involuntary movements, seizures, and confusion. These episodes are precipitated by high protein loads and intercurrent illness. Children with argininosuccinase deficiency often have distinctive facial features and brittle hair. See • The most common of these is • Pyruvate dehydrogenase deficiency (OMIM • The identification of a significantly elevated blood ammonia concentration requires immediate treatment by hemodialysis and by IV sodium phenylacetate/sodium benzoate; long-term treatment of urea cycle disorders generally includes a high-calorie, low-protein diet supplemented with essential amino acids. • The severe forms of the hyperammonemias present in the first few days of life with lethargy and possible focal and generalized seizures, ultimately leading to coma. The less severe forms develop in early childhood and are characterized by intermittent ataxia, dysarthria, vomiting, headache, ptosis, involuntary movements, seizures, and confusion. These episodes are precipitated by high protein loads and intercurrent illness. Children with argininosuccinase deficiency often have distinctive facial features and brittle hair. ## Sporadic Disorders Sporadic causes of episodic ataxia include multiple sclerosis, Arnold Chiari malformation, vertebral basilar insufficiency, basilar migraine, and labyrinthine abnormalities. ## Hereditary Disorders The most common of these is Pyruvate dehydrogenase deficiency (OMIM The identification of a significantly elevated blood ammonia concentration requires immediate treatment by hemodialysis and by IV sodium phenylacetate/sodium benzoate; long-term treatment of urea cycle disorders generally includes a high-calorie, low-protein diet supplemented with essential amino acids. The severe forms of the hyperammonemias present in the first few days of life with lethargy and possible focal and generalized seizures, ultimately leading to coma. The less severe forms develop in early childhood and are characterized by intermittent ataxia, dysarthria, vomiting, headache, ptosis, involuntary movements, seizures, and confusion. These episodes are precipitated by high protein loads and intercurrent illness. Children with argininosuccinase deficiency often have distinctive facial features and brittle hair. See • The most common of these is • Pyruvate dehydrogenase deficiency (OMIM • The identification of a significantly elevated blood ammonia concentration requires immediate treatment by hemodialysis and by IV sodium phenylacetate/sodium benzoate; long-term treatment of urea cycle disorders generally includes a high-calorie, low-protein diet supplemented with essential amino acids. • The severe forms of the hyperammonemias present in the first few days of life with lethargy and possible focal and generalized seizures, ultimately leading to coma. The less severe forms develop in early childhood and are characterized by intermittent ataxia, dysarthria, vomiting, headache, ptosis, involuntary movements, seizures, and confusion. These episodes are precipitated by high protein loads and intercurrent illness. Children with argininosuccinase deficiency often have distinctive facial features and brittle hair. ## Management To establish the extent of disease and needs in an individual diagnosed with episodic ataxia type 2 (EA2), the following evaluations are recommended: Neurologic examination for signs of interictal ataxia and nystagmus Neuroimaging of the head (if not performed already), preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy Consultation with a clinical geneticist and/or genetic counselor Generally acetazolomide is used as the firstline therapy, although there are no specific recommendations regarding which medication should be trialed first [ Treatment with acetazolamide does not appear to prevent the progression of interictal symptoms [ To date no data regarding whether 4-aminopyridine can prevent the progression of interictal symptoms are available. Surveillance should include annual neurologic examination. Phenytoin has been reported to exacerbate symptoms. See There is limited published literature addressing the management of the pregnancy of an affected woman or the effect of maternal EA2 on a fetus. However, because physical exertion can trigger attacks, it would be prudent for a pregnant woman to be followed closely by her obstetrician and at term to undergo a trial of labor with the intent to proceed to delivery by C-section should the labor trigger an EA2 attack [ Search • Neurologic examination for signs of interictal ataxia and nystagmus • Neuroimaging of the head (if not performed already), preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy • 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 episodic ataxia type 2 (EA2), the following evaluations are recommended: Neurologic examination for signs of interictal ataxia and nystagmus Neuroimaging of the head (if not performed already), preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy Consultation with a clinical geneticist and/or genetic counselor • Neurologic examination for signs of interictal ataxia and nystagmus • Neuroimaging of the head (if not performed already), preferably MRI, to evaluate for structural lesions and to look for evidence of atrophy • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Generally acetazolomide is used as the firstline therapy, although there are no specific recommendations regarding which medication should be trialed first [ ## Prevention of Primary Manifestations Treatment with acetazolamide does not appear to prevent the progression of interictal symptoms [ To date no data regarding whether 4-aminopyridine can prevent the progression of interictal symptoms are available. ## Surveillance Surveillance should include annual neurologic examination. ## Agents/Circumstances to Avoid Phenytoin has been reported to exacerbate symptoms. ## Evaluation of Relatives at Risk See ## Pregnancy Management There is limited published literature addressing the management of the pregnancy of an affected woman or the effect of maternal EA2 on a fetus. However, because physical exertion can trigger attacks, it would be prudent for a pregnant woman to be followed closely by her obstetrician and at term to undergo a trial of labor with the intent to proceed to delivery by C-section should the labor trigger an EA2 attack [ ## Therapies Under Investigation Search ## Genetic Counseling Episodic ataxia type 2 (EA2) is inherited in an autosomal dominant manner. Most individuals diagnosed with EA2 have an affected parent. A proband with EA2 may have the disorder as the result of a If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a Recommendations for the evaluation of parents of a proband with an apparent The family history of some individuals diagnosed with EA2 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If a parent of a proband is affected, the risk to the sibs is 50%. Since EA2 demonstrates incomplete penetrance, a clinically unaffected parent may have a heterozygous If the The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. • Most individuals diagnosed with EA2 have an affected parent. • A proband with EA2 may have the disorder as the result of a • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a • Recommendations for the evaluation of parents of a proband with an apparent • The family history of some individuals diagnosed with EA2 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If a parent of a proband is affected, the risk to the sibs is 50%. • Since EA2 demonstrates incomplete penetrance, a clinically unaffected parent may have a heterozygous • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Episodic ataxia type 2 (EA2) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with EA2 have an affected parent. A proband with EA2 may have the disorder as the result of a If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a Recommendations for the evaluation of parents of a proband with an apparent The family history of some individuals diagnosed with EA2 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If a parent of a proband is affected, the risk to the sibs is 50%. Since EA2 demonstrates incomplete penetrance, a clinically unaffected parent may have a heterozygous If the • Most individuals diagnosed with EA2 have an affected parent. • A proband with EA2 may have the disorder as the result of a • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are a • Recommendations for the evaluation of parents of a proband with an apparent • The family history of some individuals diagnosed with EA2 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If a parent of a proband is affected, the risk to the sibs is 50%. • Since EA2 demonstrates incomplete penetrance, a clinically unaffected parent may have a heterozygous • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Diagnosis Once the 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. ## Resources Ataxia UK Lincoln House, Kennington Park, 1-3 Brixton Road London SW9 6DE United Kingdom 2600 Fernbrook Lane Suite 119 Minneapolis MN 55447 Sanford Research 2301 East 60th Street North Sioux Falls SD 57104 • • Ataxia UK • Lincoln House, Kennington Park, 1-3 Brixton Road • London SW9 6DE • United Kingdom • • • 2600 Fernbrook Lane • Suite 119 • Minneapolis MN 55447 • • • • • • Sanford Research • 2301 East 60th Street North • Sioux Falls SD 57104 • ## Molecular Genetics Episodic Ataxia Type 2: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Episodic Ataxia Type 2 ( The majority of the pathogenic variants in Large-scale exon deletions or duplications involving one or more exons in Note on variant classification: Variants listed in the table have been provided by the author. Note on nomenclature: Associated with fluctuating weakness manifesting as a myasthenic syndrome in individuals with EA2 [ • The majority of the pathogenic variants in • Large-scale exon deletions or duplications involving one or more exons in ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Chapter Notes 22 October 2020 (ma) Chapter retired: extremely rare 15 October 2015 (me) Comprehensive update posted live 8 December 2011 (me) Comprehensive update posted live 30 June 2009 (cd) Revision: 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for CACNA1A 17 December 2007 (cd) Revision: prenatal testing available for CACNA1A-related EA2 12 April 2007 (me) Comprehensive update posted to live Web site 21 January 2005 (me) Comprehensive update posted to live Web site 29 December 2003 (me) Revision: change in test availability 24 February 2003 (me) Review posted to live Web site 20 August 2002 (ss) Original submission • 22 October 2020 (ma) Chapter retired: extremely rare • 15 October 2015 (me) Comprehensive update posted live • 8 December 2011 (me) Comprehensive update posted live • 30 June 2009 (cd) Revision: • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for CACNA1A • 17 December 2007 (cd) Revision: prenatal testing available for CACNA1A-related EA2 • 12 April 2007 (me) Comprehensive update posted to live Web site • 21 January 2005 (me) Comprehensive update posted to live Web site • 29 December 2003 (me) Revision: change in test availability • 24 February 2003 (me) Review posted to live Web site • 20 August 2002 (ss) Original submission ## Revision History 22 October 2020 (ma) Chapter retired: extremely rare 15 October 2015 (me) Comprehensive update posted live 8 December 2011 (me) Comprehensive update posted live 30 June 2009 (cd) Revision: 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for CACNA1A 17 December 2007 (cd) Revision: prenatal testing available for CACNA1A-related EA2 12 April 2007 (me) Comprehensive update posted to live Web site 21 January 2005 (me) Comprehensive update posted to live Web site 29 December 2003 (me) Revision: change in test availability 24 February 2003 (me) Review posted to live Web site 20 August 2002 (ss) Original submission • 22 October 2020 (ma) Chapter retired: extremely rare • 15 October 2015 (me) Comprehensive update posted live • 8 December 2011 (me) Comprehensive update posted live • 30 June 2009 (cd) Revision: • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for CACNA1A • 17 December 2007 (cd) Revision: prenatal testing available for CACNA1A-related EA2 • 12 April 2007 (me) Comprehensive update posted to live Web site • 21 January 2005 (me) Comprehensive update posted to live Web site • 29 December 2003 (me) Revision: change in test availability • 24 February 2003 (me) Review posted to live Web site • 20 August 2002 (ss) Original submission
[]
24/2/2003
15/10/2015
30/6/2009
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eb-pa
eb-pa
[ "EB-PA", "EB-PA", "Integrin alpha-6", "Integrin beta-4", "Plectin", "ITGA6", "ITGB4", "PLEC", "Epidermolysis Bullosa with Pyloric Atresia" ]
Epidermolysis Bullosa with Pyloric Atresia
Anne W Lucky, Emily Gorell
Summary Epidermolysis bullosa with pyloric atresia (EB-PA) is characterized by fragility of the skin and mucous membranes, manifested by blistering with little or no trauma; congenital pyloric atresia; renal and/or ureteral anomalies; and protein-losing enteropathy. The course of EB-PA is usually severe and most often lethal in the neonatal period. Those who survive may have severe blistering with formation of granulation tissue on the skin around the mouth, nose, diaper area, fingers, and toes, and internally around the trachea. However, some affected individuals have little or no blistering later in life. Additional features shared by EB-PA and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita) affecting the extremities and/or head, milia, nail dystrophy, scarring alopecia, hypotrichosis, and corneal abnormalities. The diagnosis of EB-PA is established in a proband with characteristic clinical findings by identification of biallelic pathogenic variants in EB-PA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an EB-PA-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 EB-PA-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing for EB-PA are possible.
## Diagnosis Epidermolysis bullosa with pyloric atresia (EB-PA) Fragility of the skin with: Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. Significant oral and mucous membrane involvement Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head Congenital pyloric atresia with vomiting and abdominal distention resulting from complete obstruction of the gastric outlet. Radiographs reveal that the stomach is distended and filled with air (see Renal and/or ureteral anomalies, including dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, vesicoureteral reflux, interstitial nephritis, and/or absent bladder Protein-losing enteropathy 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 EB-PA Identification of biallelic pathogenic (or likely pathogenic) variants in a gene associated with EB-PA using molecular genetic testing (See Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (See Note: (1) Molecular genetic testing is the preferred diagnostic method; skin biopsy for diagnostic purposes should only be considered if molecular results are inconclusive. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [ Molecular testing approaches can include a combination of a 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 Epidermolysis Bullosa with Pyloric Atresia EB-PA = epidermolysis bullosa with pyloric atresia; NA = not applicable 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. To date, large exon or multiexon In one report, 50% of persons of Hispanic heritage with EB-PA in the United States had the At least five large single-exon or multiexon Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of EB-PA, although molecular genetic testing is preferred. If skin biopsy is pursued, a punch biopsy that includes the full basement membrane zone should be performed. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). Older blisters undergo change that may obscure the diagnostic morphology. TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of hemidesmosomes. TEM also shows the condition of anchoring filaments, anchoring fibrils, and keratin intermediate filaments. TEM also allows examination of microvesicles that show the tissue cleavage plane. Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples cannot be used for electron microscopy. Findings on TEM in EB-PA include the following: Cleavage may be within the lamina lucida, just above the hemidesmosomes in the lowest layer of the basal keratinocytes, or both [ Hemidesmosomes may be reduced in number, hypoplastic, or dysmorphic [ Specimens should be sent in a sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. Some laboratories prefer flash-frozen tissue. In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific mutated gene products can be assessed. Direct immunofluorescence for immunoglobulins is not appropriate or useful in individuals with EB-PA. Findings on immunofluorescent antibody/antigen mapping in EB-PA include the following: Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either Abnormal or absent staining with antibodies to plectin in EB-PA as a result of pathogenic variants in Normal staining for other antigens (e.g., collagen VII, laminin 332, keratins 5 and 14) confirms the diagnosis of EB-PA. Note: (1) Especially in milder forms of EB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected, and no cleavage plane is observed. (2) Absence of one hemidesmosomal component (e.g., ITGA6 or ITGB4) may reduce the staining of other hemidesmosomal components as well (e.g., PLEC, COL17). In these cases, electron microscopic examination of a skin biopsy must be performed. • Fragility of the skin with: • Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head • Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head • Congenital pyloric atresia with vomiting and abdominal distention resulting from complete obstruction of the gastric outlet. Radiographs reveal that the stomach is distended and filled with air (see • Renal and/or ureteral anomalies, including dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, vesicoureteral reflux, interstitial nephritis, and/or absent bladder • Protein-losing enteropathy • Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head • Identification of biallelic pathogenic (or likely pathogenic) variants in a gene associated with EB-PA using molecular genetic testing (See • Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (See • TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of hemidesmosomes. TEM also shows the condition of anchoring filaments, anchoring fibrils, and keratin intermediate filaments. TEM also allows examination of microvesicles that show the tissue cleavage plane. • Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Cleavage may be within the lamina lucida, just above the hemidesmosomes in the lowest layer of the basal keratinocytes, or both [ • Hemidesmosomes may be reduced in number, hypoplastic, or dysmorphic [ • Specimens should be sent in a sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific mutated gene products can be assessed. • Direct immunofluorescence for immunoglobulins is not appropriate or useful in individuals with EB-PA. • Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either • Abnormal or absent staining with antibodies to plectin in EB-PA as a result of pathogenic variants in ## Suggestive Findings Epidermolysis bullosa with pyloric atresia (EB-PA) Fragility of the skin with: Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. Significant oral and mucous membrane involvement Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head Congenital pyloric atresia with vomiting and abdominal distention resulting from complete obstruction of the gastric outlet. Radiographs reveal that the stomach is distended and filled with air (see Renal and/or ureteral anomalies, including dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, vesicoureteral reflux, interstitial nephritis, and/or absent bladder Protein-losing enteropathy 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. • Fragility of the skin with: • Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head • Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head • Congenital pyloric atresia with vomiting and abdominal distention resulting from complete obstruction of the gastric outlet. Radiographs reveal that the stomach is distended and filled with air (see • Renal and/or ureteral anomalies, including dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, vesicoureteral reflux, interstitial nephritis, and/or absent bladder • Protein-losing enteropathy • Blistering with little or no trauma. Blistering may be mild or severe. Blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Large areas of absent skin (aplasia cutis congenita), often with a thin membranous covering, affecting the extremities or head ## Establishing the Diagnosis The diagnosis of EB-PA Identification of biallelic pathogenic (or likely pathogenic) variants in a gene associated with EB-PA using molecular genetic testing (See Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (See Note: (1) Molecular genetic testing is the preferred diagnostic method; skin biopsy for diagnostic purposes should only be considered if molecular results are inconclusive. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic, and both can be used for clinical decision making [ Molecular testing approaches can include a combination of a 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 Epidermolysis Bullosa with Pyloric Atresia EB-PA = epidermolysis bullosa with pyloric atresia; NA = not applicable 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. To date, large exon or multiexon In one report, 50% of persons of Hispanic heritage with EB-PA in the United States had the At least five large single-exon or multiexon Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of EB-PA, although molecular genetic testing is preferred. If skin biopsy is pursued, a punch biopsy that includes the full basement membrane zone should be performed. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). Older blisters undergo change that may obscure the diagnostic morphology. TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of hemidesmosomes. TEM also shows the condition of anchoring filaments, anchoring fibrils, and keratin intermediate filaments. TEM also allows examination of microvesicles that show the tissue cleavage plane. Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples cannot be used for electron microscopy. Findings on TEM in EB-PA include the following: Cleavage may be within the lamina lucida, just above the hemidesmosomes in the lowest layer of the basal keratinocytes, or both [ Hemidesmosomes may be reduced in number, hypoplastic, or dysmorphic [ Specimens should be sent in a sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. Some laboratories prefer flash-frozen tissue. In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific mutated gene products can be assessed. Direct immunofluorescence for immunoglobulins is not appropriate or useful in individuals with EB-PA. Findings on immunofluorescent antibody/antigen mapping in EB-PA include the following: Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either Abnormal or absent staining with antibodies to plectin in EB-PA as a result of pathogenic variants in Normal staining for other antigens (e.g., collagen VII, laminin 332, keratins 5 and 14) confirms the diagnosis of EB-PA. Note: (1) Especially in milder forms of EB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected, and no cleavage plane is observed. (2) Absence of one hemidesmosomal component (e.g., ITGA6 or ITGB4) may reduce the staining of other hemidesmosomal components as well (e.g., PLEC, COL17). In these cases, electron microscopic examination of a skin biopsy must be performed. • Identification of biallelic pathogenic (or likely pathogenic) variants in a gene associated with EB-PA using molecular genetic testing (See • Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (See • TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of hemidesmosomes. TEM also shows the condition of anchoring filaments, anchoring fibrils, and keratin intermediate filaments. TEM also allows examination of microvesicles that show the tissue cleavage plane. • Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Cleavage may be within the lamina lucida, just above the hemidesmosomes in the lowest layer of the basal keratinocytes, or both [ • Hemidesmosomes may be reduced in number, hypoplastic, or dysmorphic [ • Specimens should be sent in a sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific mutated gene products can be assessed. • Direct immunofluorescence for immunoglobulins is not appropriate or useful in individuals with EB-PA. • Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either • Abnormal or absent staining with antibodies to plectin in EB-PA as a result of pathogenic variants in ## Molecular Genetic Testing Molecular testing approaches can include a combination of a 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 Epidermolysis Bullosa with Pyloric Atresia EB-PA = epidermolysis bullosa with pyloric atresia; NA = not applicable 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. To date, large exon or multiexon In one report, 50% of persons of Hispanic heritage with EB-PA in the United States had the At least five large single-exon or multiexon ## Skin Biopsy Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of EB-PA, although molecular genetic testing is preferred. If skin biopsy is pursued, a punch biopsy that includes the full basement membrane zone should be performed. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). Older blisters undergo change that may obscure the diagnostic morphology. TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of hemidesmosomes. TEM also shows the condition of anchoring filaments, anchoring fibrils, and keratin intermediate filaments. TEM also allows examination of microvesicles that show the tissue cleavage plane. Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples cannot be used for electron microscopy. Findings on TEM in EB-PA include the following: Cleavage may be within the lamina lucida, just above the hemidesmosomes in the lowest layer of the basal keratinocytes, or both [ Hemidesmosomes may be reduced in number, hypoplastic, or dysmorphic [ Specimens should be sent in a sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. Some laboratories prefer flash-frozen tissue. In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific mutated gene products can be assessed. Direct immunofluorescence for immunoglobulins is not appropriate or useful in individuals with EB-PA. Findings on immunofluorescent antibody/antigen mapping in EB-PA include the following: Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either Abnormal or absent staining with antibodies to plectin in EB-PA as a result of pathogenic variants in Normal staining for other antigens (e.g., collagen VII, laminin 332, keratins 5 and 14) confirms the diagnosis of EB-PA. Note: (1) Especially in milder forms of EB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected, and no cleavage plane is observed. (2) Absence of one hemidesmosomal component (e.g., ITGA6 or ITGB4) may reduce the staining of other hemidesmosomal components as well (e.g., PLEC, COL17). In these cases, electron microscopic examination of a skin biopsy must be performed. • TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of hemidesmosomes. TEM also shows the condition of anchoring filaments, anchoring fibrils, and keratin intermediate filaments. TEM also allows examination of microvesicles that show the tissue cleavage plane. • Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Cleavage may be within the lamina lucida, just above the hemidesmosomes in the lowest layer of the basal keratinocytes, or both [ • Hemidesmosomes may be reduced in number, hypoplastic, or dysmorphic [ • Specimens should be sent in a sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has the antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific mutated gene products can be assessed. • Direct immunofluorescence for immunoglobulins is not appropriate or useful in individuals with EB-PA. • Abnormal or absent staining with antibodies to α6β4 integrin in EB-PA and other rare forms of junctional epidermolysis bullosa (JEB) as a result of pathogenic variants in either • Abnormal or absent staining with antibodies to plectin in EB-PA as a result of pathogenic variants in ## Clinical Characteristics The course of epidermolysis bullosa with pyloric atresia (EB-PA) is usually severe and often lethal in the neonatal period. Most affected children die as neonates due to mucosal erosions and blistering, pyloric stenosis or atresia, respiratory failure, or overwhelming infection. In children who survive the newborn period, nutritional deficiencies can include the following: Low calcium and/or vitamin D resulting in osteopenia and osteoporosis Zinc deficiency, which can impair wound healing [ Chronic iron deficiency anemia Although EB-PA is rare, and its prevalence has not been determined. However, it can be conservatively estimated at fewer than one in 5,000 (~10 times rarer than severe junctional EB [previously called Herlitz junctional EB], the carrier frequency of which is ~1:700). • • Low calcium and/or vitamin D resulting in osteopenia and osteoporosis • Zinc deficiency, which can impair wound healing [ • Chronic iron deficiency anemia ## Clinical Description The course of epidermolysis bullosa with pyloric atresia (EB-PA) is usually severe and often lethal in the neonatal period. Most affected children die as neonates due to mucosal erosions and blistering, pyloric stenosis or atresia, respiratory failure, or overwhelming infection. In children who survive the newborn period, nutritional deficiencies can include the following: Low calcium and/or vitamin D resulting in osteopenia and osteoporosis Zinc deficiency, which can impair wound healing [ Chronic iron deficiency anemia • • Low calcium and/or vitamin D resulting in osteopenia and osteoporosis • Zinc deficiency, which can impair wound healing [ • Chronic iron deficiency anemia ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations ## Nomenclature Although ## Prevalence EB-PA is rare, and its prevalence has not been determined. However, it can be conservatively estimated at fewer than one in 5,000 (~10 times rarer than severe junctional EB [previously called Herlitz junctional EB], the carrier frequency of which is ~1:700). ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Disorders EB-PA = epidermolysis bullosa with pyloric atresia; EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa; LGMD = limb-girdle muscular dystrophy ## Differential Diagnosis In contrast to pyloric stenosis, which presents insidiously with vomiting, pyloric atresia is present at birth and causes complete obstruction of the gastric outlet. The diagnosis of epidermolysis bullosa with pyloric atresia (EB-PA) should be considered in every neonate with pyloric atresia regardless of the degree of skin blistering. The 2020 classification system [ All forms of EB are characterized by increased skin (and often mucosa) fragility and blistering with little or no trauma. Subtypes are predominantly determined by clinical features (see Clinical Features Observed in the Four Major Types of Epidermolysis Bullosa DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa Postinflammatory changes, such as those seen in severe EBS, are often mistaken for scarring or mottled pigmentation. Results from extensive scarring of the hands and feet in older children and adults Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates – may not be established or significant enough to allow identification of EB type. Thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. Genes Associated with the Four Major Epidermolysis Bullosa Types Adapted from AD = autosomal dominant; AR = autosomal recessive; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa; MOI = mode of inheritance ## Pyloric Atresia In contrast to pyloric stenosis, which presents insidiously with vomiting, pyloric atresia is present at birth and causes complete obstruction of the gastric outlet. The diagnosis of epidermolysis bullosa with pyloric atresia (EB-PA) should be considered in every neonate with pyloric atresia regardless of the degree of skin blistering. ## Epidermolysis Bullosa The 2020 classification system [ All forms of EB are characterized by increased skin (and often mucosa) fragility and blistering with little or no trauma. Subtypes are predominantly determined by clinical features (see Clinical Features Observed in the Four Major Types of Epidermolysis Bullosa DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa Postinflammatory changes, such as those seen in severe EBS, are often mistaken for scarring or mottled pigmentation. Results from extensive scarring of the hands and feet in older children and adults Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates – may not be established or significant enough to allow identification of EB type. Thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. Genes Associated with the Four Major Epidermolysis Bullosa Types Adapted from AD = autosomal dominant; AR = autosomal recessive; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa; MOI = mode of inheritance ## Management No clinical practice guidelines for epidermolysis bullosa with pyloric atresia (EB-PA) have been published. To establish the extent of disease and needs in an individual diagnosed with EB-PA, the evaluations in Recommended Evaluations Following Initial Diagnosis in Individuals with Epidermolysis Bullosa with Pyloric Atresia Assess renal function w/serum BUN & creatinine Urinalysis Renal ultrasound Community or Social work involvement for parental support; Home nursing referral; Palliative team referral. BUN = blood urea nitrogen; EB-PA = epidermolysis bullosa with pyloric atresia; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for EB-PA, and most infants die in the first years of life from complications secondary to mucosal erosions and blistering; esophageal erosions, stenosis, and/or atresia; pyloric stenosis or atresia; or overwhelming infection. Supportive care to improve quality of life, maximize function, and reduce complications is recommended [ There has been one report of Integra Treatment of Manifestations in Individuals with Epidermolysis Bullosa with Pyloric Atresia Consult w/dietitian or nutritionist if there is significant mucosal blistering in mouth preventing adequate oral intake. Consider placement of gastrostomy. Evaluate & treat protein-losing enteropathy. Additional nutritional support incl gastrostomy tube feeding when necessary Maintenance of tracheostomy & gastrostomy can be difficult due to fragile skin. Teaching caretakers proper handling of infants & children to protect skin from shearing forces; Wrapping & padding extremities; Use of soft & properly fitted clothing & footwear. A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers include: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix A tertiary layer that usually has some elastic properties & ensures integrity of dressing (e.g., Coban Treatment of wound infection using antibiotics & antiseptics Appropriate footwear & physical therapy are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. Surgical intervention to correct pyloric atresia Gastrostomy if indicated Evaluate & treat protein-losing enteropathy. Referral to urologist if there are symptoms of difficulty or discomfort w/voiding Referral to nephrologist if renal function studies &/or urinalysis are abnormal Fluid replacement as needed Calcium & vitamin D supplementation to prevent osteopenia Zinc supplementation for wound healing Supplementation of carnitine, selenium, vitamin A as indicated based on laboratory studies Oral or intravenous iron infusions & red blood cell transfusions as needed for chronic anemia Psychosocial support, incl social services & psychological counseling Palliative care consultation To monitor existing manifestations in survivors, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Recommended Surveillance for Individuals with Epidermolysis Bullosa with Pyloric Atresia Assessment of oral mucosa, feeding, & esophageal involvement Assessment for hoarse cry (tracheal involvement) Assess renal function w/serum BUN & creatinine Urinalysis CBC Iron studies Serum zinc Serum vitamin D Selenium, carnitine, vitamin A BUN = blood urea nitrogen; DXA = dual-energy x-ray absorptiometry Most persons with EB-PA cannot use ordinary medical tape or Band-Aids Poor-fitting or coarse-textured clothing and footwear should be avoided as they can cause trauma. In general, activities that traumatize the skin should be avoided. Affected individuals who are determined to participate in such activities should be encouraged to find creative ways to protect their skin. See Cesarean section is recommended by some obstetricians to reduce trauma to the skin of an affected fetus during delivery. Several therapies are being investigated in treatment of junctional epidermolysis bullosa (JEB) (see Junctional Epidermolysis Bullosa, The antibiotic gentamicin can induce read-through of premature termination codons. Topical and intravenous gentamicin is being investigated as a treatment for JEB [ Topical Oleogel-S10, made from birch bark extract, is approved for treatment of dystrophic epidermolysis bullosa (DEB) and JEB in individuals age six months or older in the European Union under the brand name Filsuvez Search • Assess renal function w/serum BUN & creatinine • Urinalysis • Renal ultrasound • Community or • Social work involvement for parental support; • Home nursing referral; • Palliative team referral. • Consult w/dietitian or nutritionist if there is significant mucosal blistering in mouth preventing adequate oral intake. • Consider placement of gastrostomy. • Evaluate & treat protein-losing enteropathy. • Additional nutritional support incl gastrostomy tube feeding when necessary • Maintenance of tracheostomy & gastrostomy can be difficult due to fragile skin. • Teaching caretakers proper handling of infants & children to protect skin from shearing forces; • Wrapping & padding extremities; • Use of soft & properly fitted clothing & footwear. • A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers include: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa • A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix • A tertiary layer that usually has some elastic properties & ensures integrity of dressing (e.g., Coban • Treatment of wound infection using antibiotics & antiseptics • Appropriate footwear & physical therapy are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. • Surgical intervention to correct pyloric atresia • Gastrostomy if indicated • Evaluate & treat protein-losing enteropathy. • Referral to urologist if there are symptoms of difficulty or discomfort w/voiding • Referral to nephrologist if renal function studies &/or urinalysis are abnormal • Fluid replacement as needed • Calcium & vitamin D supplementation to prevent osteopenia • Zinc supplementation for wound healing • Supplementation of carnitine, selenium, vitamin A as indicated based on laboratory studies • Oral or intravenous iron infusions & red blood cell transfusions as needed for chronic anemia • Psychosocial support, incl social services & psychological counseling • Palliative care consultation • Assessment of oral mucosa, feeding, & esophageal involvement • Assessment for hoarse cry (tracheal involvement) • Assess renal function w/serum BUN & creatinine • Urinalysis • CBC • Iron studies • Serum zinc • Serum vitamin D • Selenium, carnitine, vitamin A ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with EB-PA, the evaluations in Recommended Evaluations Following Initial Diagnosis in Individuals with Epidermolysis Bullosa with Pyloric Atresia Assess renal function w/serum BUN & creatinine Urinalysis Renal ultrasound Community or Social work involvement for parental support; Home nursing referral; Palliative team referral. BUN = blood urea nitrogen; EB-PA = epidermolysis bullosa with pyloric atresia; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assess renal function w/serum BUN & creatinine • Urinalysis • Renal ultrasound • Community or • Social work involvement for parental support; • Home nursing referral; • Palliative team referral. ## Treatment of Manifestations There is no cure for EB-PA, and most infants die in the first years of life from complications secondary to mucosal erosions and blistering; esophageal erosions, stenosis, and/or atresia; pyloric stenosis or atresia; or overwhelming infection. Supportive care to improve quality of life, maximize function, and reduce complications is recommended [ There has been one report of Integra Treatment of Manifestations in Individuals with Epidermolysis Bullosa with Pyloric Atresia Consult w/dietitian or nutritionist if there is significant mucosal blistering in mouth preventing adequate oral intake. Consider placement of gastrostomy. Evaluate & treat protein-losing enteropathy. Additional nutritional support incl gastrostomy tube feeding when necessary Maintenance of tracheostomy & gastrostomy can be difficult due to fragile skin. Teaching caretakers proper handling of infants & children to protect skin from shearing forces; Wrapping & padding extremities; Use of soft & properly fitted clothing & footwear. A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers include: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix A tertiary layer that usually has some elastic properties & ensures integrity of dressing (e.g., Coban Treatment of wound infection using antibiotics & antiseptics Appropriate footwear & physical therapy are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. Surgical intervention to correct pyloric atresia Gastrostomy if indicated Evaluate & treat protein-losing enteropathy. Referral to urologist if there are symptoms of difficulty or discomfort w/voiding Referral to nephrologist if renal function studies &/or urinalysis are abnormal Fluid replacement as needed Calcium & vitamin D supplementation to prevent osteopenia Zinc supplementation for wound healing Supplementation of carnitine, selenium, vitamin A as indicated based on laboratory studies Oral or intravenous iron infusions & red blood cell transfusions as needed for chronic anemia Psychosocial support, incl social services & psychological counseling Palliative care consultation • Consult w/dietitian or nutritionist if there is significant mucosal blistering in mouth preventing adequate oral intake. • Consider placement of gastrostomy. • Evaluate & treat protein-losing enteropathy. • Additional nutritional support incl gastrostomy tube feeding when necessary • Maintenance of tracheostomy & gastrostomy can be difficult due to fragile skin. • Teaching caretakers proper handling of infants & children to protect skin from shearing forces; • Wrapping & padding extremities; • Use of soft & properly fitted clothing & footwear. • A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers include: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa • A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix • A tertiary layer that usually has some elastic properties & ensures integrity of dressing (e.g., Coban • Treatment of wound infection using antibiotics & antiseptics • Appropriate footwear & physical therapy are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. • Surgical intervention to correct pyloric atresia • Gastrostomy if indicated • Evaluate & treat protein-losing enteropathy. • Referral to urologist if there are symptoms of difficulty or discomfort w/voiding • Referral to nephrologist if renal function studies &/or urinalysis are abnormal • Fluid replacement as needed • Calcium & vitamin D supplementation to prevent osteopenia • Zinc supplementation for wound healing • Supplementation of carnitine, selenium, vitamin A as indicated based on laboratory studies • Oral or intravenous iron infusions & red blood cell transfusions as needed for chronic anemia • Psychosocial support, incl social services & psychological counseling • Palliative care consultation ## Surveillance To monitor existing manifestations in survivors, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Recommended Surveillance for Individuals with Epidermolysis Bullosa with Pyloric Atresia Assessment of oral mucosa, feeding, & esophageal involvement Assessment for hoarse cry (tracheal involvement) Assess renal function w/serum BUN & creatinine Urinalysis CBC Iron studies Serum zinc Serum vitamin D Selenium, carnitine, vitamin A BUN = blood urea nitrogen; DXA = dual-energy x-ray absorptiometry • Assessment of oral mucosa, feeding, & esophageal involvement • Assessment for hoarse cry (tracheal involvement) • Assess renal function w/serum BUN & creatinine • Urinalysis • CBC • Iron studies • Serum zinc • Serum vitamin D • Selenium, carnitine, vitamin A ## Agents/Circumstances to Avoid Most persons with EB-PA cannot use ordinary medical tape or Band-Aids Poor-fitting or coarse-textured clothing and footwear should be avoided as they can cause trauma. In general, activities that traumatize the skin should be avoided. Affected individuals who are determined to participate in such activities should be encouraged to find creative ways to protect their skin. ## Evaluation of Relatives at Risk See ## Pregnancy Management Cesarean section is recommended by some obstetricians to reduce trauma to the skin of an affected fetus during delivery. ## Therapies Under Investigation Several therapies are being investigated in treatment of junctional epidermolysis bullosa (JEB) (see Junctional Epidermolysis Bullosa, The antibiotic gentamicin can induce read-through of premature termination codons. Topical and intravenous gentamicin is being investigated as a treatment for JEB [ Topical Oleogel-S10, made from birch bark extract, is approved for treatment of dystrophic epidermolysis bullosa (DEB) and JEB in individuals age six months or older in the European Union under the brand name Filsuvez Search ## Genetic Counseling Epidermolysis bullosa with pyloric atresia (EB-PA) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygotes (i.e., carriers) for an EB-PA-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 (carriers) for an EB-PA-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 (though rare) 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. Germline mosaicism and uniparental isodisomy have been reported in EB-PA and Heterozygotes (carriers) are asymptomatic. To date, there is no evidence to indicate that a heterozygous pathogenic variant in If both parents are known to be heterozygous for an EB-PA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. To date, there is no evidence to indicate that a heterozygous pathogenic variant in Carrier testing for at-risk relatives requires prior identification of the EB-PA-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 prior to 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 being carriers. Carrier testing for the reproductive partners of known carriers should be considered. Carrier testing for the reproductive partners individuals affected with EB-PA should also be considered, particularly if both partners are of the same ethnic background. 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 heterozygotes (i.e., carriers) for an EB-PA-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 (carriers) for an EB-PA-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 (though rare) 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. • Germline mosaicism and uniparental isodisomy have been reported in EB-PA and • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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. To date, there is no evidence to indicate that a heterozygous pathogenic variant in • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 EB-PA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic. To date, there is no evidence to indicate that a heterozygous pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is prior to 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 being carriers. • Carrier testing for the reproductive partners of known carriers should be considered. Carrier testing for the reproductive partners individuals affected with EB-PA should also be considered, particularly if both partners are of the same ethnic background. The ## Mode of Inheritance Epidermolysis bullosa with pyloric atresia (EB-PA) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygotes (i.e., carriers) for an EB-PA-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 (carriers) for an EB-PA-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 (though rare) 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. Germline mosaicism and uniparental isodisomy have been reported in EB-PA and Heterozygotes (carriers) are asymptomatic. To date, there is no evidence to indicate that a heterozygous pathogenic variant in If both parents are known to be heterozygous for an EB-PA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic. To date, there is no evidence to indicate that a heterozygous pathogenic variant in • The parents of an affected child are presumed to be heterozygotes (i.e., carriers) for an EB-PA-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 (carriers) for an EB-PA-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 (though rare) 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. • Germline mosaicism and uniparental isodisomy have been reported in EB-PA and • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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. To date, there is no evidence to indicate that a heterozygous pathogenic variant in • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 EB-PA-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic. To date, there is no evidence to indicate that a heterozygous pathogenic variant in ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the EB-PA-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 prior to 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 being carriers. Carrier testing for the reproductive partners of known carriers should be considered. Carrier testing for the reproductive partners individuals affected with EB-PA should also be considered, particularly if both partners are of the same ethnic background. The • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is prior to 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 being carriers. • Carrier testing for the reproductive partners of known carriers should be considered. Carrier testing for the reproductive partners individuals affected with EB-PA should also be considered, particularly if both partners are of the same ethnic background. The ## 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 Chile United Kingdom • • Chile • • • • • • • United Kingdom • • • • • • • ## Molecular Genetics Epidermolysis Bullosa with Pyloric Atresia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Epidermolysis Bullosa with Pyloric Atresia ( Integrins associate in pairs containing one alpha (α) and one beta (β) chain. The α6β4 integrin comprises one α6 (encoded by Epidermolysis Bullosa with Pyloric Atresia: Gene-Specific Laboratory Considerations Genes from Epidermolysis Bullosa with Pyloric Atresia: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Integrins associate in pairs containing one alpha (α) and one beta (β) chain. The α6β4 integrin comprises one α6 (encoded by Epidermolysis Bullosa with Pyloric Atresia: Gene-Specific Laboratory Considerations Genes from Epidermolysis Bullosa with Pyloric Atresia: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Variant designation that does not conform to current naming conventions ## Chapter Notes Cincinnati Children's We acknowledge support from the Cooperative Society of the Cincinnati Children's Hospital and the Epidermolysis Bullosa Research Partnership (EBRP), Emily Gorell, DO, MS (2023-present)Anne W Lucky, MD (2008-present)Ellen G Pfendner, PhD; GeneDx, Inc (2008-2023) 26 January 2023 (sw) Comprehensive update posted live 7 September 2017 (ma) Comprehensive update posted live 14 February 2013 (me) Comprehensive update posted live 28 April 2009 (cd) Revision: 22 February 2008 (me) Review posted live 10 May 2007 (egp) Original submission • 26 January 2023 (sw) Comprehensive update posted live • 7 September 2017 (ma) Comprehensive update posted live • 14 February 2013 (me) Comprehensive update posted live • 28 April 2009 (cd) Revision: • 22 February 2008 (me) Review posted live • 10 May 2007 (egp) Original submission ## Author Notes Cincinnati Children's ## Acknowledgments We acknowledge support from the Cooperative Society of the Cincinnati Children's Hospital and the Epidermolysis Bullosa Research Partnership (EBRP), ## Author History Emily Gorell, DO, MS (2023-present)Anne W Lucky, MD (2008-present)Ellen G Pfendner, PhD; GeneDx, Inc (2008-2023) ## Revision History 26 January 2023 (sw) Comprehensive update posted live 7 September 2017 (ma) Comprehensive update posted live 14 February 2013 (me) Comprehensive update posted live 28 April 2009 (cd) Revision: 22 February 2008 (me) Review posted live 10 May 2007 (egp) Original submission • 26 January 2023 (sw) Comprehensive update posted live • 7 September 2017 (ma) Comprehensive update posted live • 14 February 2013 (me) Comprehensive update posted live • 28 April 2009 (cd) Revision: • 22 February 2008 (me) Review posted live • 10 May 2007 (egp) Original submission ## References ## Literature Cited Single gastric bubble (white arrow) in a newborn with epidermolysis bullosa with pyloric atresia Child with epidermolysis bullosa with pyloric atresia and extensive aplasia cutis congenita of the extremities (A) and scalp (B). Reproduced with permission from
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J Pediatr. 2012;160:657-61.e1", "MF Jonkman, HH Pas, M Nijenhuis, G Kloosterhuis, G Steege. Deletion of a cytoplasmic domain of integrin beta4 causes epidermolysis bullosa simplex.. J Invest Dermatol. 2002;119:1275-81", "N Kambham, N Tanji, RL Seigle, GS Markowitz, L Pulkkinen, J Uitto, VD D'Agati. Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa.. Am J Kidney Dis. 2000;36:190-6", "H Kaneyasu, K Takahashi, N Ohta, S Okada, S Kimura, S Yasuno, S Murata, S Katsura, N Yamada, K Shiraishi, J Tsuda, S Miyai, H Kurahashi, S Hasegawa, Y Shimomura. Novel compound heterozygous mutations in the PLEC gene in a neonate with epidermolysis bullosa simplex with pyloric atresia.. J Dermatol. 2022", "A Kwong, J Cogan, Y Hou, R Antaya, M Hao, G Kim, V Lincoln, Q Chen, DT Woodley, M Chen. Gentamicin induces laminin 332 and improves wound healing in junctional epidermolysis bullosa patients with nonsense mutations.. Mol Ther. 2020;28:1327-38", "AW Lucky, E Pfendner, E Pillay, J Paskel, M Weiner, F Palisson. Psychosocial aspects of epidermolysis bullosa: proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005.. Int J Dermatol. 2007;46:809-14", "AW Lucky, J Whalen, S Rowe, KS Marathe, E Gorell. Diagnosis and care of the newborn with epidermolysis bullosa.. Neoreviews. 2021;22:e438-e451", "A Martinez-Moreno, J Ocampo-Candiani, E Alba-Rojas. Epidermolysis bullosa with congenital absence of skin: review of the literature.. Pediatr Dermatol. 2020;37:821-6", "L Martínez-Santamaría, R Maseda, MDC de Arriba, JA Membrilla, AI Sigüenza, J Mascías, M García, L Quintana, I Esteban-Rodríguez, CP Hernández-Fernández, N Illera, B Duarte, S Guerrero-Aspizúa, DT Woodley, M Del Río, R de Lucas, F Larcher, MJ Escámez. Evaluation of systemic gentamicin as translational readthrough therapy for a patient with epidermolysis bullosa simplex with muscular dystrophy owing to PLEC1 pathogenic nonsense variants.. JAMA Dermatol. 2022;158:439-43", "T Masunaga, H Niizeki, F Yasuda, K Yoshida, M Amagai, A Ishiko. Splicing abnormality of integrin β4 gene (ITGB4) due to nucleotide substitutions far from splice site underlies pyloric atresia-junctional epidermolysis bullosa syndrome.. J Dermatol Sci. 2015;78:61-6", "T Masunaga, J Ogawa, M Akiyama, T Nishikawa, H Shimizu, A Ishiko. Compound heterozygosity for novel splice site mutations of ITGA6 in lethal junctional epidermolysis bullosa with pyloric atresia.. J Dermatol. 2017;44:160-6", "G Mattioli, A Diociaiuti, S Rossi, G Zambruno, M Carlucci, E Pisaneschi, M. El Hachem. ITGB4-mutated junctional epidermolysis bullosa without pyloric atresia presenting with severe urinary involvement and late-onset minimal skin fragility: diagnostic and therapeutic challenges.. Acta Derm Venereol. 2022;102", "P Maurice, D Eyrolle-Guignot, F Dhombres, C Garel, M Gonzales, F Muller, JM Jouannic. The key role of ultrasound examination in the prenatal diagnosis of epidermolysis bullosa with pyloric atresia.. Prenat Diagn. 2013;33:908-9", "JE Mellerio, M Weiner, JE Denyer, EI Pillay, AW Lucky, A Bruckner, F Palisson. Medical management of epidermolysis bullosa: proceedings of the IInd International Symposium on Epidermolysis Bullosa, Santiago, Chile, 2005.. Int J Dermatol. 2007;46:795-800", "Á Mencía, M García, E García, S Llames, A Charlesworth, R de Lucas, A Vicente, MJ Trujillo-Tiebas, P Coto, M Costa, Á Vera, A López-Pestaña, R Murillas, G Meneguzzi, JL Jorcano, CJ Conti, MJ Escámez Toledano, M del Río Nechaevsky. Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia.. Exp Dermatol. 2016;25:269-74", "AC Merrow, JS Frischer, AW Lucky. 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Int J Dermatol. 2007;46:781-94", "P Pongmee, S Wittayakornrerk, R Lekwuttikarn, S Pakdeeto, P Watcharakuldilok, C Prempunpong, T Tim-Aroon, C Puttanapitak, P Wattanasoontornsakul, T Junhasavasdikul, P Wongkittichote, S Noojarern, D Wattanasirichaigoon. Epidermolysis bullosa with congenital absence of skin: congenital corneal cloudiness and esophagogastric obstruction including extended genotypic spectrum of PLEC, LAMC2, ITGB4 and COL7A1.. Front Genet. 2022;13", "L Pulkkinen, K Kurtz, Y Xu, L Bruckner-Tuderman, J Uitto. Genomic organization of the integrin beta 4 gene (ITGB4): a homozygous splice-site mutation in a patient with junctional epidermolysis bullosa associated with pyloric atresia.. Lab Invest. 1997;76:823-33", "S Puvabanditsin, E Garrow, R Samransamraujkit, LA Lopez, WC Lambert. Epidermolysis bullosa associated with congenital localized absence of skin, fetal abdominal mass, and pyloric atresia.. Pediatr Dermatol. 1997;14:359-62", "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", "C Salvestrini, JA McGrath, L Ozoemena, K Husain, E Buhamrah, N Sabery, A Leichtner, PA Rufo, A Perez-Atayde, CH Orteu, F Torrente, RB Heuschkel, MA Thomson, SH Murch. Desquamative enteropathy and pyloric atresia without skin disease caused by a novel intracellular beta4 integrin mutation.. J Pediatr Gastroenterol Nutr. 2008;47:585-91", "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", "T Soyer, B Karaosmanoglu, EZ Taskiran, PÖŞ Kiper, İ Karnak, K Boduroğlu, GE Utine. Biallelic ITGB4 variants in familial pyloric atresia without epidermolysis bullosa: Report of two families with five siblings.. Am J Med Genet A. 2021;185:3427-32", "MF Theodoro, J Hays, M DiBartolomeo, B Carter. Ethics roundtable: how much is too much?. Am J Hosp Palliat Care. 2023;40:106-10", "J Trah, C Has, I Hausser, H Kutzner, K Reinshagen, I. Königs. Integra®-dermal regeneration template and split-thickness skin grafting: a therapy approach to correct aplasia cutis congenita and epidermolysis bullosa in Carmi syndrome.. Dermatol Ther (Heidelb) 2018;8:313-21", "H Vahidnezhad, L Youssefian, N Harvey, AR Tavasoli, AH Saeidian, S Sotoudeh, A Varghaei, H Mahmoudi, P Mansouri, N Mozafari, O Zargari, S Zeinali, J Uitto. Mutation update: the spectra of PLEC sequence variants and related plectinopathies.. Hum Mutat. 2022;43:1706-31", "M Valari, M Theodoraki, I Loukas, S Gkantseva-Patsoura, G Karavana, V Falaina, L Lykopoulou, R Pons, I Athanasiou, K Wertheim-Tysarowska, C Kanaka-Gantenbein, D. Kiritsi. Novel PLEC variant causes mild skin fragility, pyloric atresia, muscular dystrophy and urological manifestations.. Acta Derm Venereol. 2019;99:1309-10", "R Varki, S Sadowski, E Pfendner, J. Uitto. Epidermolysis bullosa. I. Molecular genetics of the junctional and hemidesmosomal variants.. J Med Genet. 2006;43:641-52", "KP Verma, SJ Robertson, IM Winship. Phenotypic discordance between siblings with junctional epidermolysis bullosa-pyloric atresia.. Clin Exp Dermatol. 2020;45:793-5", "GD Walker, M Woody, E Orrin, JE Mellerio, ML Levy. Epidermolysis bullosa with pyloric atresia and significant urologic involvement.. Pediatr Dermatol. 2017;34:e61-e64", "R Wallerstein, ML Klein, N Genieser, L Pulkkinen, J Uitto. 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22/2/2008
26/1/2023
28/4/2009
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ebd
ebd
[ "DEB", "Epidermolysis Bullosa Dystrophica", "Epidermolysis Bullosa Dystrophica", "DEB", "Dominant DEB (DDEB)", "Compound Heterozygous DEB", "Recessive DEB (RDEB)", "Collagen alpha-1(VII) chain", "COL7A1", "Dystrophic Epidermolysis Bullosa" ]
Dystrophic Epidermolysis Bullosa
Anne W Lucky, Elena Pope, Sarah Crawford
Summary Dystrophic epidermolysis bullosa (DEB) is characterized by skin fragility manifested by blistering and erosions with minimal trauma. Many individuals also have dystrophic or absent nails. DEB is divided into two major types depending on inheritance pattern: recessive dystrophic epidermolysis bullosa (RDEB) and dominant dystrophic epidermolysis bullosa (DDEB). Clinical findings in severe RDEB include skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring. Blistering and erosions affecting the whole body may be present in the neonatal period. Oral involvement may lead to mouth blistering, fusion of the tongue to the floor of the mouth, and progressive diminution of the size of the oral cavity and mouth opening. Esophageal erosions can lead to webs and strictures that can cause severe dysphagia. Malnutrition with vitamin and mineral deficiency may lead to growth deficiency in young children. Corneal erosions can lead to scarring and loss of vision. Blistering of the hands and feet followed by scarring results in contractures and pseudosyndactyly. The lifetime risk of aggressive squamous cell carcinoma (SCC) is greater than 90%. In contrast, the blistering in intermediate RDEB may be localized to hands, feet, knees, and elbows with or without involvement of flexural areas and the trunk, and without severe scarring. In DDEB, blistering is often mild and limited to hands, feet, knees, and elbows, but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common and may be the only manifestation of DDEB. The diagnosis of DEB is established in a proband with characteristic clinical findings and biallelic DEB is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) manner. Some Once the
Recessive DEB (RDEB) Severe Intermediate Inversa Localized Pruriginosa Self-improving Dominant DEB (DDEB) Intermediate Localized Pruriginosa Self-improving Compound heterozygous DEB DEB, severe Based on For synonyms and outdated names see Individuals with one • Recessive DEB (RDEB) • Severe • Intermediate • Inversa • Localized • Pruriginosa • Self-improving • Severe • Intermediate • Inversa • Localized • Pruriginosa • Self-improving • Dominant DEB (DDEB) • Intermediate • Localized • Pruriginosa • Self-improving • Intermediate • Localized • Pruriginosa • Self-improving • Compound heterozygous DEB • DEB, severe • DEB, severe • Severe • Intermediate • Inversa • Localized • Pruriginosa • Self-improving • Intermediate • Localized • Pruriginosa • Self-improving • DEB, severe ## Diagnosis Dystrophic epidermolysis bullosa (DEB) Fragility of the skin, manifested by blistering with minimal trauma that heals with milia and scarring Absent lingual papillae Blistering and erosions that may: Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); Be present in the neonatal period; Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); Lead to pseudosyndactyly of the hands and feet (severe forms); Lead to oral and/or esophageal scarring and strictures; Lead to corneal erosions, scarring, and loss of vision; Predispose to squamous cell carcinoma. Dystrophic or absent nails, especially toenails The diagnosis of DEB Identification of biallelic pathogenic (or likely pathogenic) variants (recessive DEB; RDEB) in Identification of a heterozygous pathogenic (or likely pathogenic) variant (dominant DEB; DDEB) in Characteristic findings on skin biopsy examined via transmission electron microscopy (absent or abnormal anchoring fibrils) and/or immunofluorescent antibody/antigen mapping of the collagen alpha-1(VII) chain (COL7A1) protein consistent with DEB (See Note: (1) Molecular genetic testing is the preferred diagnostic method [ Molecular testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by epidermolysis bullosa, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dystrophic Epidermolysis Bullosa See See Some pathogenic variants 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 Pathogenic variant detection rate by sequence analysis in individuals with biopsy-diagnosed DEB is 95% [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis is <1% for dominant DEB and <2% for recessive DEB [ Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of DEB, although molecular genetic testing is preferred. If skin biopsy for immunofluorescent mapping is pursued, a punch or shave biopsy that includes the full basement membrane zone should be performed. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). Older blisters undergo change that may obscure the diagnostic morphology. TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of anchoring fibrils. TEM shows the condition of anchoring fibrils, as well as anchoring filaments and keratin intermediate filaments important in other types of epidermolysis bullosa. TEM allows examination of microvesicles that show the tissue cleavage plane that is below the basement membrane in DEB. Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples CANNOT be used for TEM. Findings on TEM in DEB include the following: Anchoring fibrils may appear reduced in number and/or show altered morphology. Intracellular retention of collagen VII can be observed in some individuals. Staining of collagen VII using antibodies is diminished or absent. In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa. Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB. Caution: Specimens must be sent to a laboratory that has the appropriate antibodies to detect COL7A1. Routine immunofluorescence only screens for autoantibodies. Especially in milder forms of DEB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal COL7A1 levels are detected, and no cleavage plane is observed. • Fragility of the skin, manifested by blistering with minimal trauma that heals with milia and scarring • Absent lingual papillae • Blistering and erosions that may: • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); • Be present in the neonatal period; • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); • Lead to pseudosyndactyly of the hands and feet (severe forms); • Lead to oral and/or esophageal scarring and strictures; • Lead to corneal erosions, scarring, and loss of vision; • Predispose to squamous cell carcinoma. • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); • Be present in the neonatal period; • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); • Lead to pseudosyndactyly of the hands and feet (severe forms); • Lead to oral and/or esophageal scarring and strictures; • Lead to corneal erosions, scarring, and loss of vision; • Predispose to squamous cell carcinoma. • Dystrophic or absent nails, especially toenails • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); • Be present in the neonatal period; • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); • Lead to pseudosyndactyly of the hands and feet (severe forms); • Lead to oral and/or esophageal scarring and strictures; • Lead to corneal erosions, scarring, and loss of vision; • Predispose to squamous cell carcinoma. • Identification of biallelic pathogenic (or likely pathogenic) variants (recessive DEB; RDEB) in • Identification of a heterozygous pathogenic (or likely pathogenic) variant (dominant DEB; DDEB) in • Characteristic findings on skin biopsy examined via transmission electron microscopy (absent or abnormal anchoring fibrils) and/or immunofluorescent antibody/antigen mapping of the collagen alpha-1(VII) chain (COL7A1) protein consistent with DEB (See • TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of anchoring fibrils. TEM shows the condition of anchoring fibrils, as well as anchoring filaments and keratin intermediate filaments important in other types of epidermolysis bullosa. TEM allows examination of microvesicles that show the tissue cleavage plane that is below the basement membrane in DEB. • Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples CANNOT be used for TEM. • • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Staining of collagen VII using antibodies is diminished or absent. • In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa. • Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB. • Caution: Specimens must be sent to a laboratory that has the appropriate antibodies to detect COL7A1. Routine immunofluorescence only screens for autoantibodies. • Especially in milder forms of DEB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal COL7A1 levels are detected, and no cleavage plane is observed. ## Suggestive Findings Dystrophic epidermolysis bullosa (DEB) Fragility of the skin, manifested by blistering with minimal trauma that heals with milia and scarring Absent lingual papillae Blistering and erosions that may: Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); Be present in the neonatal period; Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); Lead to pseudosyndactyly of the hands and feet (severe forms); Lead to oral and/or esophageal scarring and strictures; Lead to corneal erosions, scarring, and loss of vision; Predispose to squamous cell carcinoma. Dystrophic or absent nails, especially toenails • Fragility of the skin, manifested by blistering with minimal trauma that heals with milia and scarring • Absent lingual papillae • Blistering and erosions that may: • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); • Be present in the neonatal period; • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); • Lead to pseudosyndactyly of the hands and feet (severe forms); • Lead to oral and/or esophageal scarring and strictures; • Lead to corneal erosions, scarring, and loss of vision; • Predispose to squamous cell carcinoma. • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); • Be present in the neonatal period; • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); • Lead to pseudosyndactyly of the hands and feet (severe forms); • Lead to oral and/or esophageal scarring and strictures; • Lead to corneal erosions, scarring, and loss of vision; • Predispose to squamous cell carcinoma. • Dystrophic or absent nails, especially toenails • Lead to aplasia cutis congenita at birth (absence of skin, especially on extremities; noted in all types of epidermolysis bullosa); • Be present in the neonatal period; • Affect the whole body, including mucous membranes (most severe forms), or primarily the hands, feet, knees, and elbows (milder forms); • Lead to pseudosyndactyly of the hands and feet (severe forms); • Lead to oral and/or esophageal scarring and strictures; • Lead to corneal erosions, scarring, and loss of vision; • Predispose to squamous cell carcinoma. ## Establishing the Diagnosis The diagnosis of DEB Identification of biallelic pathogenic (or likely pathogenic) variants (recessive DEB; RDEB) in Identification of a heterozygous pathogenic (or likely pathogenic) variant (dominant DEB; DDEB) in Characteristic findings on skin biopsy examined via transmission electron microscopy (absent or abnormal anchoring fibrils) and/or immunofluorescent antibody/antigen mapping of the collagen alpha-1(VII) chain (COL7A1) protein consistent with DEB (See Note: (1) Molecular genetic testing is the preferred diagnostic method [ Molecular testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by epidermolysis bullosa, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dystrophic Epidermolysis Bullosa See See Some pathogenic variants 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 Pathogenic variant detection rate by sequence analysis in individuals with biopsy-diagnosed DEB is 95% [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis is <1% for dominant DEB and <2% for recessive DEB [ Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of DEB, although molecular genetic testing is preferred. If skin biopsy for immunofluorescent mapping is pursued, a punch or shave biopsy that includes the full basement membrane zone should be performed. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). Older blisters undergo change that may obscure the diagnostic morphology. TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of anchoring fibrils. TEM shows the condition of anchoring fibrils, as well as anchoring filaments and keratin intermediate filaments important in other types of epidermolysis bullosa. TEM allows examination of microvesicles that show the tissue cleavage plane that is below the basement membrane in DEB. Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples CANNOT be used for TEM. Findings on TEM in DEB include the following: Anchoring fibrils may appear reduced in number and/or show altered morphology. Intracellular retention of collagen VII can be observed in some individuals. Staining of collagen VII using antibodies is diminished or absent. In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa. Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB. Caution: Specimens must be sent to a laboratory that has the appropriate antibodies to detect COL7A1. Routine immunofluorescence only screens for autoantibodies. Especially in milder forms of DEB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal COL7A1 levels are detected, and no cleavage plane is observed. • Identification of biallelic pathogenic (or likely pathogenic) variants (recessive DEB; RDEB) in • Identification of a heterozygous pathogenic (or likely pathogenic) variant (dominant DEB; DDEB) in • Characteristic findings on skin biopsy examined via transmission electron microscopy (absent or abnormal anchoring fibrils) and/or immunofluorescent antibody/antigen mapping of the collagen alpha-1(VII) chain (COL7A1) protein consistent with DEB (See • TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of anchoring fibrils. TEM shows the condition of anchoring fibrils, as well as anchoring filaments and keratin intermediate filaments important in other types of epidermolysis bullosa. TEM allows examination of microvesicles that show the tissue cleavage plane that is below the basement membrane in DEB. • Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples CANNOT be used for TEM. • • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Staining of collagen VII using antibodies is diminished or absent. • In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa. • Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB. • Caution: Specimens must be sent to a laboratory that has the appropriate antibodies to detect COL7A1. Routine immunofluorescence only screens for autoantibodies. • Especially in milder forms of DEB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal COL7A1 levels are detected, and no cleavage plane is observed. ## Molecular Genetic Testing Molecular testing approaches can include a combination of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by epidermolysis bullosa, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dystrophic Epidermolysis Bullosa See See Some pathogenic variants 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 Pathogenic variant detection rate by sequence analysis in individuals with biopsy-diagnosed DEB is 95% [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis is <1% for dominant DEB and <2% for recessive DEB [ ## For an introduction to multigene panels click ## When the phenotype is indistinguishable from many other inherited disorders characterized by epidermolysis bullosa, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Dystrophic Epidermolysis Bullosa See See Some pathogenic variants 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 Pathogenic variant detection rate by sequence analysis in individuals with biopsy-diagnosed DEB is 95% [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Proportion of pathogenic variants identified by gene-targeted deletion/duplication analysis is <1% for dominant DEB and <2% for recessive DEB [ ## Skin Biopsy Examination of a skin biopsy by transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of DEB, although molecular genetic testing is preferred. If skin biopsy for immunofluorescent mapping is pursued, a punch or shave biopsy that includes the full basement membrane zone should be performed. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister (with a pencil eraser rubbed on the skin). Older blisters undergo change that may obscure the diagnostic morphology. TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of anchoring fibrils. TEM shows the condition of anchoring fibrils, as well as anchoring filaments and keratin intermediate filaments important in other types of epidermolysis bullosa. TEM allows examination of microvesicles that show the tissue cleavage plane that is below the basement membrane in DEB. Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples CANNOT be used for TEM. Findings on TEM in DEB include the following: Anchoring fibrils may appear reduced in number and/or show altered morphology. Intracellular retention of collagen VII can be observed in some individuals. Staining of collagen VII using antibodies is diminished or absent. In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa. Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB. Caution: Specimens must be sent to a laboratory that has the appropriate antibodies to detect COL7A1. Routine immunofluorescence only screens for autoantibodies. Especially in milder forms of DEB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal COL7A1 levels are detected, and no cleavage plane is observed. • TEM is used to examine the number and morphology of the basement membrane zone structures – in particular, the presence and morphology of anchoring fibrils. TEM shows the condition of anchoring fibrils, as well as anchoring filaments and keratin intermediate filaments important in other types of epidermolysis bullosa. TEM allows examination of microvesicles that show the tissue cleavage plane that is below the basement membrane in DEB. • Specimens must be placed in a special fixation medium (e.g., glutaraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples CANNOT be used for TEM. • • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Anchoring fibrils may appear reduced in number and/or show altered morphology. • Intracellular retention of collagen VII can be observed in some individuals. • Staining of collagen VII using antibodies is diminished or absent. • In milder forms of RDEB and in DDEB, staining for collagen VII may appear normal, but cleavage planes are below the lamina densa. • Normal staining for other antigens (e.g., laminin 332, collagen XVII, plectin, α6β4 integrin, and keratins 5 and 14) helps to confirm the diagnosis of DEB. • Caution: Specimens must be sent to a laboratory that has the appropriate antibodies to detect COL7A1. Routine immunofluorescence only screens for autoantibodies. • Especially in milder forms of DEB, immunofluorescent studies are often not sufficient to make the diagnosis because near-normal COL7A1 levels are detected, and no cleavage plane is observed. ## Clinical Characteristics Dystrophic epidermolysis bullosa (DEB) is characterized by increased skin fragility and dystrophic or absent nails; features are usually present at birth (see Dystrophic Epidermolysis Bullosa: Frequent Features of the Most Common Subtypes DEB = dystrophic epidermolysis bullosa In severe RDEB, blisters are present at birth or become apparent in the neonatal period. Aplasia cutis congenita, especially of the extremities, may be found in the newborn period. Blisters can affect the whole body, including the skin, oral mucosa, esophageal mucosa, and corneas, as early as the newborn period. Chronic non-healing wounds and secondary infection are common, often with Intermediate RDEB may be mild, with blistering localized to hands, feet, knees, and elbows as well as dystrophic nails, or relatively more widespread including flexural areas and trunk. Scarring, milia, and nevi are present but without the severe, mutilating scarring seen in severe RDEB. Onset of blistering ranges from birth to childhood depending on type. Pseudosyndactyly, damaged or absent nails, and oral lesions may occur. Growth deficiency is possible but not as severe as with severe RDEB. SCC also develops in some affected individuals. Inversa RDEB is a rare phenotype. Blistering and skin atrophy occurs on the flexural areas of the breasts, neck, thighs, and legs while few changes are observed on the hands, feet, elbows, or knees. Otherwise, the phenotype resembles DEB types with blistering and resulting scarring. Blisters of the hands and feet may be present in infancy. Localized RDEB is a rare phenotype that exhibits blistering with scarring that may be severe but is localized to the hands and feet. Other sites are not affected. The nails are often absent. Growth restriction and systemic illness are also absent. SCC has not been reported in individuals who have this subtype. Pruriginosa RDEB often affects the shins. Pretibial blisters develop into prurigo-like hyperkeratotic lesions. The lesions occur predominantly on the pretibial areas, sparing the knees and other parts of the skin. Other findings include nail dystrophy, small, white scars (albopapuloid skin lesions), and hypertrophic scars without pretibial predominance. Bullous dermolysis of the newborn often has only transient blistering limited to the newborn period [ In this milder form of DEB, blistering is often limited to the hands, feet, knees, and elbows. Blistering may be relatively benign but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common, and loss of nails may occur. In the mildest forms, dystrophic nails may be the only finding. Blistering in DDEB often improves somewhat with age, possibly as a result of reduced physical activity. The subtypes of DDEB resemble those of RDEB but may present with milder manifestations. There may be significant clinical variability among affected family members. Intermediate DDEB is a milder form of DEB than RDEB. Generalized blistering affects most sites of friction in infancy but often evolves to less severe disease in adulthood. Blisters form with scarring, and the nails are often absent. Other systems are generally unaffected, and growth deficiency and SCC are rarely reported. Localized DDEB includes pruriginosa DDEB as well as acral and nails-only types. Nails-only localized DDEB affects the nails, which are dystrophic and fragile. Other family members, however, may have more severe manifestations. This rare subtype affects the anterior lower legs primarily and is characterized by intense pruritus. In some instances, there is prurigo nodularis. This is the more common dominant form of bullous dermolysis of the newborn. Individuals often have only transient blistering limited to the newborn period [ Individuals with one See also Penetrance for DDEB is reduced; unaffected individuals have been identified [ The nomenclature for DEB has changed five times in the last 20 years. A classification system was developed in 2014, referred to as the "onion skin" terminology, which considers the level of blistering, phenotypic characteristics including distribution and severity of cutaneous blisters and wounding, and associated gene [ The most recent reclassification system for DEB and other skin fragility disorders was published following the 2019 international consensus meeting [ Comparison of Dystrophic Epidermolysis Bullosa Classifications for Major Subtypes DDEB = dominant dystrophic epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa Individuals with one According to the National EB Registry, the overall prevalence of EB is 11.07 in one million live births [ The carrier frequency of RDEB in the US population has been estimated at one in 370 [ ## Clinical Description Dystrophic epidermolysis bullosa (DEB) is characterized by increased skin fragility and dystrophic or absent nails; features are usually present at birth (see Dystrophic Epidermolysis Bullosa: Frequent Features of the Most Common Subtypes DEB = dystrophic epidermolysis bullosa In severe RDEB, blisters are present at birth or become apparent in the neonatal period. Aplasia cutis congenita, especially of the extremities, may be found in the newborn period. Blisters can affect the whole body, including the skin, oral mucosa, esophageal mucosa, and corneas, as early as the newborn period. Chronic non-healing wounds and secondary infection are common, often with Intermediate RDEB may be mild, with blistering localized to hands, feet, knees, and elbows as well as dystrophic nails, or relatively more widespread including flexural areas and trunk. Scarring, milia, and nevi are present but without the severe, mutilating scarring seen in severe RDEB. Onset of blistering ranges from birth to childhood depending on type. Pseudosyndactyly, damaged or absent nails, and oral lesions may occur. Growth deficiency is possible but not as severe as with severe RDEB. SCC also develops in some affected individuals. Inversa RDEB is a rare phenotype. Blistering and skin atrophy occurs on the flexural areas of the breasts, neck, thighs, and legs while few changes are observed on the hands, feet, elbows, or knees. Otherwise, the phenotype resembles DEB types with blistering and resulting scarring. Blisters of the hands and feet may be present in infancy. Localized RDEB is a rare phenotype that exhibits blistering with scarring that may be severe but is localized to the hands and feet. Other sites are not affected. The nails are often absent. Growth restriction and systemic illness are also absent. SCC has not been reported in individuals who have this subtype. Pruriginosa RDEB often affects the shins. Pretibial blisters develop into prurigo-like hyperkeratotic lesions. The lesions occur predominantly on the pretibial areas, sparing the knees and other parts of the skin. Other findings include nail dystrophy, small, white scars (albopapuloid skin lesions), and hypertrophic scars without pretibial predominance. Bullous dermolysis of the newborn often has only transient blistering limited to the newborn period [ In this milder form of DEB, blistering is often limited to the hands, feet, knees, and elbows. Blistering may be relatively benign but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common, and loss of nails may occur. In the mildest forms, dystrophic nails may be the only finding. Blistering in DDEB often improves somewhat with age, possibly as a result of reduced physical activity. The subtypes of DDEB resemble those of RDEB but may present with milder manifestations. There may be significant clinical variability among affected family members. Intermediate DDEB is a milder form of DEB than RDEB. Generalized blistering affects most sites of friction in infancy but often evolves to less severe disease in adulthood. Blisters form with scarring, and the nails are often absent. Other systems are generally unaffected, and growth deficiency and SCC are rarely reported. Localized DDEB includes pruriginosa DDEB as well as acral and nails-only types. Nails-only localized DDEB affects the nails, which are dystrophic and fragile. Other family members, however, may have more severe manifestations. This rare subtype affects the anterior lower legs primarily and is characterized by intense pruritus. In some instances, there is prurigo nodularis. This is the more common dominant form of bullous dermolysis of the newborn. Individuals often have only transient blistering limited to the newborn period [ Individuals with one ## Recessive DEB (RDEB) Phenotypes In severe RDEB, blisters are present at birth or become apparent in the neonatal period. Aplasia cutis congenita, especially of the extremities, may be found in the newborn period. Blisters can affect the whole body, including the skin, oral mucosa, esophageal mucosa, and corneas, as early as the newborn period. Chronic non-healing wounds and secondary infection are common, often with Intermediate RDEB may be mild, with blistering localized to hands, feet, knees, and elbows as well as dystrophic nails, or relatively more widespread including flexural areas and trunk. Scarring, milia, and nevi are present but without the severe, mutilating scarring seen in severe RDEB. Onset of blistering ranges from birth to childhood depending on type. Pseudosyndactyly, damaged or absent nails, and oral lesions may occur. Growth deficiency is possible but not as severe as with severe RDEB. SCC also develops in some affected individuals. Inversa RDEB is a rare phenotype. Blistering and skin atrophy occurs on the flexural areas of the breasts, neck, thighs, and legs while few changes are observed on the hands, feet, elbows, or knees. Otherwise, the phenotype resembles DEB types with blistering and resulting scarring. Blisters of the hands and feet may be present in infancy. Localized RDEB is a rare phenotype that exhibits blistering with scarring that may be severe but is localized to the hands and feet. Other sites are not affected. The nails are often absent. Growth restriction and systemic illness are also absent. SCC has not been reported in individuals who have this subtype. Pruriginosa RDEB often affects the shins. Pretibial blisters develop into prurigo-like hyperkeratotic lesions. The lesions occur predominantly on the pretibial areas, sparing the knees and other parts of the skin. Other findings include nail dystrophy, small, white scars (albopapuloid skin lesions), and hypertrophic scars without pretibial predominance. Bullous dermolysis of the newborn often has only transient blistering limited to the newborn period [ ## In severe RDEB, blisters are present at birth or become apparent in the neonatal period. Aplasia cutis congenita, especially of the extremities, may be found in the newborn period. Blisters can affect the whole body, including the skin, oral mucosa, esophageal mucosa, and corneas, as early as the newborn period. Chronic non-healing wounds and secondary infection are common, often with ## Intermediate RDEB may be mild, with blistering localized to hands, feet, knees, and elbows as well as dystrophic nails, or relatively more widespread including flexural areas and trunk. Scarring, milia, and nevi are present but without the severe, mutilating scarring seen in severe RDEB. Onset of blistering ranges from birth to childhood depending on type. Pseudosyndactyly, damaged or absent nails, and oral lesions may occur. Growth deficiency is possible but not as severe as with severe RDEB. SCC also develops in some affected individuals. ## Inversa RDEB is a rare phenotype. Blistering and skin atrophy occurs on the flexural areas of the breasts, neck, thighs, and legs while few changes are observed on the hands, feet, elbows, or knees. Otherwise, the phenotype resembles DEB types with blistering and resulting scarring. Blisters of the hands and feet may be present in infancy. ## Localized RDEB is a rare phenotype that exhibits blistering with scarring that may be severe but is localized to the hands and feet. Other sites are not affected. The nails are often absent. Growth restriction and systemic illness are also absent. SCC has not been reported in individuals who have this subtype. ## Pruriginosa RDEB often affects the shins. Pretibial blisters develop into prurigo-like hyperkeratotic lesions. The lesions occur predominantly on the pretibial areas, sparing the knees and other parts of the skin. Other findings include nail dystrophy, small, white scars (albopapuloid skin lesions), and hypertrophic scars without pretibial predominance. ## Bullous dermolysis of the newborn often has only transient blistering limited to the newborn period [ ## Dominant DEB (DDEB) Phenotypes In this milder form of DEB, blistering is often limited to the hands, feet, knees, and elbows. Blistering may be relatively benign but nonetheless heals with scarring. Dystrophic nails, especially toenails, are common, and loss of nails may occur. In the mildest forms, dystrophic nails may be the only finding. Blistering in DDEB often improves somewhat with age, possibly as a result of reduced physical activity. The subtypes of DDEB resemble those of RDEB but may present with milder manifestations. There may be significant clinical variability among affected family members. Intermediate DDEB is a milder form of DEB than RDEB. Generalized blistering affects most sites of friction in infancy but often evolves to less severe disease in adulthood. Blisters form with scarring, and the nails are often absent. Other systems are generally unaffected, and growth deficiency and SCC are rarely reported. Localized DDEB includes pruriginosa DDEB as well as acral and nails-only types. Nails-only localized DDEB affects the nails, which are dystrophic and fragile. Other family members, however, may have more severe manifestations. This rare subtype affects the anterior lower legs primarily and is characterized by intense pruritus. In some instances, there is prurigo nodularis. This is the more common dominant form of bullous dermolysis of the newborn. Individuals often have only transient blistering limited to the newborn period [ ## Intermediate DDEB is a milder form of DEB than RDEB. Generalized blistering affects most sites of friction in infancy but often evolves to less severe disease in adulthood. Blisters form with scarring, and the nails are often absent. Other systems are generally unaffected, and growth deficiency and SCC are rarely reported. ## Localized DDEB includes pruriginosa DDEB as well as acral and nails-only types. Nails-only localized DDEB affects the nails, which are dystrophic and fragile. Other family members, however, may have more severe manifestations. ## This rare subtype affects the anterior lower legs primarily and is characterized by intense pruritus. In some instances, there is prurigo nodularis. ## This is the more common dominant form of bullous dermolysis of the newborn. Individuals often have only transient blistering limited to the newborn period [ ## Compound Heterozygous DEB Individuals with one ## Genotype-Phenotype Correlations See also ## Penetrance Penetrance for DDEB is reduced; unaffected individuals have been identified [ ## Nomenclature The nomenclature for DEB has changed five times in the last 20 years. A classification system was developed in 2014, referred to as the "onion skin" terminology, which considers the level of blistering, phenotypic characteristics including distribution and severity of cutaneous blisters and wounding, and associated gene [ The most recent reclassification system for DEB and other skin fragility disorders was published following the 2019 international consensus meeting [ Comparison of Dystrophic Epidermolysis Bullosa Classifications for Major Subtypes DDEB = dominant dystrophic epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa Individuals with one ## Prevalence According to the National EB Registry, the overall prevalence of EB is 11.07 in one million live births [ The carrier frequency of RDEB in the US population has been estimated at one in 370 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Blistering, especially in the neonatal period, should prompt consideration of acquired conditions and congenital genetic disorders. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates – may not be established or significant enough to allow identification of EB type or subtype. Thus, molecular genetic testing (or less commonly skin biopsy) is required to establish the most precise diagnosis. Genes Associated with the Four Major Epidermolysis Bullosa Types Adapted from AD = autosomal dominant; AR = autosomal recessive; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EBS = epidermolysis bullosasimplex; JEB = junctional epidermolysis bullosa; MOI = mode of inheritance ## Management International clinical practice guidelines for dystrophic epidermolysis bullosa (DEB) have been published by DEBRA International. These include guidelines for treatment of anemia, foot care, occupational therapy, palliative and end-of-life care, psychosocial care, neonatal care, cancer management, hand surgery and hand therapy, oral health care, physical therapy, skin and wound care, constipation management, pain care, pregnancy, childbirth, and aftercare, and supporting sexuality. To establish the extent of disease and needs in an individual diagnosed with DEB, the evaluations summarized in Dystrophic Epidermolysis Bullosa: Recommended Evaluations Following Initial Diagnosis Thorough eval of skin surface for blisters, erosions, & infections Eval of crusted, non-healing, or painful lesions in older persons for SCC Dental consult Exam of mouth incl mucosal blistering & erosions Assessment for dental caries & crowding Gastroenterology consult Barium swallow for esophageal strictures if there are symptoms of dysphagia Assessment for GERD & constipation Measurement of height, weight, & BMI Eval of nutritional status & need for gastrostomy feeding Assessment for vitamin & mineral deficiency incl anemia (serum selenium, carnitine, zinc, 25- hydroxyvitamin D Urinalysis to assess for hematuria & proteinuria Assessment for urinary symptoms or abnormal renal tests (BUN, creatinine, cystatin C) Eval of hand function & mobility/dexterity status by PT or OT Assessment of footwear & mobility issues Spine radiographs & DXA scan for osteoporosis beginning at age 8 yrs Eval by professional to assess for anxiety, depression, & substance dependency/abuse (preferably by psychologist on EB team) Assistance w/school-related issues Assistance w/access to needed services, insurance, & disability accommodations BUN = blood urea nitrogen; CBC = complete blood count; DEB = dystrophic epidermolysis bullosa; DXA = dual-energy x-ray absorptiometry; EB = epidermolysis bullosa; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SCC = squamous cell carcinoma; sTfR = soluble transferrin receptor Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Dystrophic Epidermolysis Bullosa: Targeted Therapies FDA approved for wound treatment in those age ≥6 mos w/molecularly confirmed RDEB or DDEB There is a weekly maximum dose by age. FDA approved for wound treatment in pediatric & adult persons w/RDEB Genetically corrected autologous epidermal graft; EMA & FDA approved for wound treatment in those age ≥6 mos w/EB [ Also ↓ inflammation & ↑ blood flow DDEB = dominant dystrophic epidermolysis bullosa; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EMA = European Medicines Agency; FDA = US Food and Drug Administration; RDEB = recessive dystrophic epidermolysis bullosa A health care provider must apply the topical treatment. The maximum weekly dose is 0.8 mL for affected individuals who are age six months to three years. The maximum weekly dose is 1.6 mL for affected individuals age three years and older. The one-time surgical application of Zevanskyn™ must be done through a Zevanskyn™ Qualified Treatment Center. 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 Dystrophic Epidermolysis Bullosa: Treatment of Manifestations Teaching caretakers proper handling of infants & children to protect skin from shearing forces; Wrapping & padding extremities; Use of soft & properly fitted clothing & footwear. Vaginal delivery is preferred, but in certain circumstances, cesarean delivery may be recommended to ↓ skin trauma in affected fetus. Encourage age-appropriate play involving activities that cause minimal trauma to skin. Use dressings & padding to protect bony prominences from blister-inducing impact. A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers incl: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix An elastic mesh-like tertiary layer that ensures integrity of dressing (e.g., burn net, Coban Treatment of wound infection using antibiotics & antiseptics Appropriate footwear & PT are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. Good dental care & frequent exams to ensure adequate caloric intake Extractions for dental caries & crowding as needed Esophageal strictures & webs can be dilated repeatedly to improve swallowing. Mgmt of constipation Fluid electrolyte mgmt in neonatal period & in infants w/widespread disease Nutrition support as needed incl feeding gastrostomy tube to assure adequate caloric intake Vitamin A & zinc replacement when levels are low to improve corneal stability & enhance wound healing Selenium & carnitine replacement when levels are low to possibly prevent dilated cardiomyopathy Refer to urologist for urethral erosions, strictures, or bladder dysfunction. Refer to nephrologist for hematuria or proteinuria to assess for glomerulonephritis & kidney failure. Calcium & vitamin D supplementation as needed Intravenous bisphosphonates for osteopenia/osteoporosis Estrogen replacement as needed for those w/delayed puberty Menstrual periods can be suppressed to prevent exacerbation of anemia. ACE = angiotensin-converting enzyme; DEB = dystrophic epidermolysis bullosa; OT = occupational therapy; PT = physical therapy; SCC = squamous cell carcinoma To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Dystrophic Epidermolysis Bullosa: Recommended Surveillance Eval of crusted, non-healing, painful, abnormal-looking lesions or those w/exuberant scar tissue for risk of SCC Frequent biopsies of suspicious lesions may be necessary followed by local excision. At least annually beginning at age ≥10 yrs Note: Affected persons are often unwilling to undress completely in clinic setting & home photographs during dressing changes may have to suffice. Measurement of height, weight, & BMI Eval of nutritional status Serum vitamin A, selenium, carnitine, & zinc levels Serum 25-hydroxyvitamin D CBC Iron studies Eval of hand function & mobility/dexterity status by PT or OT Assessment of footwear & mobility issues DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy; SCC = squamous cell carcinoma Rarely, individuals with recessive DEB (RDEB) can develop fulminant and even fatal hepatic failure. Some of the medications used in severe RDEB for pain, itch, and/or infection may have adverse effects on liver function. Nasogastric tubes are discouraged because of oral and esophageal fragility [ Poorly fitting or coarse-textured clothing and footwear should be avoided, as they can cause trauma. In general, activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) should be avoided; affected individuals who are committed to participation in such activities should be encouraged to devise ways of protecting the skin. Most persons with DEB cannot tolerate the use of ordinary medical tape or Band-Aids Evaluation of an at-risk newborn for evidence of blistering is appropriate so that trauma to the skin can be avoided as much as possible. Given the significant clinical variability that may be seen among family members with DEB, 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 of the See Data on pregnancy and DEB are limited, but a recent survey did not detect increased risk for pregnancy-related complications in women with various forms of epidermolysis bullosa [ There are several promising therapies currently being studied, including various stem cell therapies including bone marrow transplant, mesenchymal stem cells, stromal cells, induced pluripotent stem (IPS) cells [ There are many new approaches to therapy currently in trial. Clinical trials evaluating antifibrotic, anti-inflammatory, and antipruritic medications are in progress [ Search • Thorough eval of skin surface for blisters, erosions, & infections • Eval of crusted, non-healing, or painful lesions in older persons for SCC • Dental consult • Exam of mouth incl mucosal blistering & erosions • Assessment for dental caries & crowding • Gastroenterology consult • Barium swallow for esophageal strictures if there are symptoms of dysphagia • Assessment for GERD & constipation • Measurement of height, weight, & BMI • Eval of nutritional status & need for gastrostomy feeding • Assessment for vitamin & mineral deficiency incl anemia (serum selenium, carnitine, zinc, 25- hydroxyvitamin D • Urinalysis to assess for hematuria & proteinuria • Assessment for urinary symptoms or abnormal renal tests (BUN, creatinine, cystatin C) • Eval of hand function & mobility/dexterity status by PT or OT • Assessment of footwear & mobility issues • Spine radiographs & DXA scan for osteoporosis beginning at age 8 yrs • Eval by professional to assess for anxiety, depression, & substance dependency/abuse (preferably by psychologist on EB team) • Assistance w/school-related issues • Assistance w/access to needed services, insurance, & disability accommodations • FDA approved for wound treatment in those age ≥6 mos w/molecularly confirmed RDEB or DDEB • There is a weekly maximum dose by age. • FDA approved for wound treatment in pediatric & adult persons w/RDEB • Genetically corrected autologous epidermal graft; • EMA & FDA approved for wound treatment in those age ≥6 mos w/EB [ • Also ↓ inflammation & ↑ blood flow • Teaching caretakers proper handling of infants & children to protect skin from shearing forces; • Wrapping & padding extremities; • Use of soft & properly fitted clothing & footwear. • Vaginal delivery is preferred, but in certain circumstances, cesarean delivery may be recommended to ↓ skin trauma in affected fetus. • Encourage age-appropriate play involving activities that cause minimal trauma to skin. • Use dressings & padding to protect bony prominences from blister-inducing impact. • A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers incl: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa • A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix • An elastic mesh-like tertiary layer that ensures integrity of dressing (e.g., burn net, Coban • Treatment of wound infection using antibiotics & antiseptics • Appropriate footwear & PT are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. • Good dental care & frequent exams to ensure adequate caloric intake • Extractions for dental caries & crowding as needed • Esophageal strictures & webs can be dilated repeatedly to improve swallowing. • Mgmt of constipation • Fluid electrolyte mgmt in neonatal period & in infants w/widespread disease • Nutrition support as needed incl feeding gastrostomy tube to assure adequate caloric intake • Vitamin A & zinc replacement when levels are low to improve corneal stability & enhance wound healing • Selenium & carnitine replacement when levels are low to possibly prevent dilated cardiomyopathy • Refer to urologist for urethral erosions, strictures, or bladder dysfunction. • Refer to nephrologist for hematuria or proteinuria to assess for glomerulonephritis & kidney failure. • Calcium & vitamin D supplementation as needed • Intravenous bisphosphonates for osteopenia/osteoporosis • Estrogen replacement as needed for those w/delayed puberty • Menstrual periods can be suppressed to prevent exacerbation of anemia. • Eval of crusted, non-healing, painful, abnormal-looking lesions or those w/exuberant scar tissue for risk of SCC • Frequent biopsies of suspicious lesions may be necessary followed by local excision. • At least annually beginning at age ≥10 yrs • Note: Affected persons are often unwilling to undress completely in clinic setting & home photographs during dressing changes may have to suffice. • Measurement of height, weight, & BMI • Eval of nutritional status • Serum vitamin A, selenium, carnitine, & zinc levels • Serum 25-hydroxyvitamin D • CBC • Iron studies • Eval of hand function & mobility/dexterity status by PT or OT • Assessment of footwear & mobility issues ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with DEB, the evaluations summarized in Dystrophic Epidermolysis Bullosa: Recommended Evaluations Following Initial Diagnosis Thorough eval of skin surface for blisters, erosions, & infections Eval of crusted, non-healing, or painful lesions in older persons for SCC Dental consult Exam of mouth incl mucosal blistering & erosions Assessment for dental caries & crowding Gastroenterology consult Barium swallow for esophageal strictures if there are symptoms of dysphagia Assessment for GERD & constipation Measurement of height, weight, & BMI Eval of nutritional status & need for gastrostomy feeding Assessment for vitamin & mineral deficiency incl anemia (serum selenium, carnitine, zinc, 25- hydroxyvitamin D Urinalysis to assess for hematuria & proteinuria Assessment for urinary symptoms or abnormal renal tests (BUN, creatinine, cystatin C) Eval of hand function & mobility/dexterity status by PT or OT Assessment of footwear & mobility issues Spine radiographs & DXA scan for osteoporosis beginning at age 8 yrs Eval by professional to assess for anxiety, depression, & substance dependency/abuse (preferably by psychologist on EB team) Assistance w/school-related issues Assistance w/access to needed services, insurance, & disability accommodations BUN = blood urea nitrogen; CBC = complete blood count; DEB = dystrophic epidermolysis bullosa; DXA = dual-energy x-ray absorptiometry; EB = epidermolysis bullosa; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SCC = squamous cell carcinoma; sTfR = soluble transferrin receptor Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Thorough eval of skin surface for blisters, erosions, & infections • Eval of crusted, non-healing, or painful lesions in older persons for SCC • Dental consult • Exam of mouth incl mucosal blistering & erosions • Assessment for dental caries & crowding • Gastroenterology consult • Barium swallow for esophageal strictures if there are symptoms of dysphagia • Assessment for GERD & constipation • Measurement of height, weight, & BMI • Eval of nutritional status & need for gastrostomy feeding • Assessment for vitamin & mineral deficiency incl anemia (serum selenium, carnitine, zinc, 25- hydroxyvitamin D • Urinalysis to assess for hematuria & proteinuria • Assessment for urinary symptoms or abnormal renal tests (BUN, creatinine, cystatin C) • Eval of hand function & mobility/dexterity status by PT or OT • Assessment of footwear & mobility issues • Spine radiographs & DXA scan for osteoporosis beginning at age 8 yrs • Eval by professional to assess for anxiety, depression, & substance dependency/abuse (preferably by psychologist on EB team) • Assistance w/school-related issues • Assistance w/access to needed services, insurance, & disability accommodations ## Treatment of Manifestations Dystrophic Epidermolysis Bullosa: Targeted Therapies FDA approved for wound treatment in those age ≥6 mos w/molecularly confirmed RDEB or DDEB There is a weekly maximum dose by age. FDA approved for wound treatment in pediatric & adult persons w/RDEB Genetically corrected autologous epidermal graft; EMA & FDA approved for wound treatment in those age ≥6 mos w/EB [ Also ↓ inflammation & ↑ blood flow DDEB = dominant dystrophic epidermolysis bullosa; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EMA = European Medicines Agency; FDA = US Food and Drug Administration; RDEB = recessive dystrophic epidermolysis bullosa A health care provider must apply the topical treatment. The maximum weekly dose is 0.8 mL for affected individuals who are age six months to three years. The maximum weekly dose is 1.6 mL for affected individuals age three years and older. The one-time surgical application of Zevanskyn™ must be done through a Zevanskyn™ Qualified Treatment Center. 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 Dystrophic Epidermolysis Bullosa: Treatment of Manifestations Teaching caretakers proper handling of infants & children to protect skin from shearing forces; Wrapping & padding extremities; Use of soft & properly fitted clothing & footwear. Vaginal delivery is preferred, but in certain circumstances, cesarean delivery may be recommended to ↓ skin trauma in affected fetus. Encourage age-appropriate play involving activities that cause minimal trauma to skin. Use dressings & padding to protect bony prominences from blister-inducing impact. A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers incl: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix An elastic mesh-like tertiary layer that ensures integrity of dressing (e.g., burn net, Coban Treatment of wound infection using antibiotics & antiseptics Appropriate footwear & PT are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. Good dental care & frequent exams to ensure adequate caloric intake Extractions for dental caries & crowding as needed Esophageal strictures & webs can be dilated repeatedly to improve swallowing. Mgmt of constipation Fluid electrolyte mgmt in neonatal period & in infants w/widespread disease Nutrition support as needed incl feeding gastrostomy tube to assure adequate caloric intake Vitamin A & zinc replacement when levels are low to improve corneal stability & enhance wound healing Selenium & carnitine replacement when levels are low to possibly prevent dilated cardiomyopathy Refer to urologist for urethral erosions, strictures, or bladder dysfunction. Refer to nephrologist for hematuria or proteinuria to assess for glomerulonephritis & kidney failure. Calcium & vitamin D supplementation as needed Intravenous bisphosphonates for osteopenia/osteoporosis Estrogen replacement as needed for those w/delayed puberty Menstrual periods can be suppressed to prevent exacerbation of anemia. ACE = angiotensin-converting enzyme; DEB = dystrophic epidermolysis bullosa; OT = occupational therapy; PT = physical therapy; SCC = squamous cell carcinoma • FDA approved for wound treatment in those age ≥6 mos w/molecularly confirmed RDEB or DDEB • There is a weekly maximum dose by age. • FDA approved for wound treatment in pediatric & adult persons w/RDEB • Genetically corrected autologous epidermal graft; • EMA & FDA approved for wound treatment in those age ≥6 mos w/EB [ • Also ↓ inflammation & ↑ blood flow • Teaching caretakers proper handling of infants & children to protect skin from shearing forces; • Wrapping & padding extremities; • Use of soft & properly fitted clothing & footwear. • Vaginal delivery is preferred, but in certain circumstances, cesarean delivery may be recommended to ↓ skin trauma in affected fetus. • Encourage age-appropriate play involving activities that cause minimal trauma to skin. • Use dressings & padding to protect bony prominences from blister-inducing impact. • A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers incl: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa • A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix • An elastic mesh-like tertiary layer that ensures integrity of dressing (e.g., burn net, Coban • Treatment of wound infection using antibiotics & antiseptics • Appropriate footwear & PT are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. • Good dental care & frequent exams to ensure adequate caloric intake • Extractions for dental caries & crowding as needed • Esophageal strictures & webs can be dilated repeatedly to improve swallowing. • Mgmt of constipation • Fluid electrolyte mgmt in neonatal period & in infants w/widespread disease • Nutrition support as needed incl feeding gastrostomy tube to assure adequate caloric intake • Vitamin A & zinc replacement when levels are low to improve corneal stability & enhance wound healing • Selenium & carnitine replacement when levels are low to possibly prevent dilated cardiomyopathy • Refer to urologist for urethral erosions, strictures, or bladder dysfunction. • Refer to nephrologist for hematuria or proteinuria to assess for glomerulonephritis & kidney failure. • Calcium & vitamin D supplementation as needed • Intravenous bisphosphonates for osteopenia/osteoporosis • Estrogen replacement as needed for those w/delayed puberty • Menstrual periods can be suppressed to prevent exacerbation of anemia. ## Targeted Therapies Dystrophic Epidermolysis Bullosa: Targeted Therapies FDA approved for wound treatment in those age ≥6 mos w/molecularly confirmed RDEB or DDEB There is a weekly maximum dose by age. FDA approved for wound treatment in pediatric & adult persons w/RDEB Genetically corrected autologous epidermal graft; EMA & FDA approved for wound treatment in those age ≥6 mos w/EB [ Also ↓ inflammation & ↑ blood flow DDEB = dominant dystrophic epidermolysis bullosa; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EMA = European Medicines Agency; FDA = US Food and Drug Administration; RDEB = recessive dystrophic epidermolysis bullosa A health care provider must apply the topical treatment. The maximum weekly dose is 0.8 mL for affected individuals who are age six months to three years. The maximum weekly dose is 1.6 mL for affected individuals age three years and older. The one-time surgical application of Zevanskyn™ must be done through a Zevanskyn™ Qualified Treatment Center. • FDA approved for wound treatment in those age ≥6 mos w/molecularly confirmed RDEB or DDEB • There is a weekly maximum dose by age. • FDA approved for wound treatment in pediatric & adult persons w/RDEB • Genetically corrected autologous epidermal graft; • EMA & FDA approved for wound treatment in those age ≥6 mos w/EB [ • Also ↓ inflammation & ↑ blood flow ## 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 Dystrophic Epidermolysis Bullosa: Treatment of Manifestations Teaching caretakers proper handling of infants & children to protect skin from shearing forces; Wrapping & padding extremities; Use of soft & properly fitted clothing & footwear. Vaginal delivery is preferred, but in certain circumstances, cesarean delivery may be recommended to ↓ skin trauma in affected fetus. Encourage age-appropriate play involving activities that cause minimal trauma to skin. Use dressings & padding to protect bony prominences from blister-inducing impact. A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers incl: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix An elastic mesh-like tertiary layer that ensures integrity of dressing (e.g., burn net, Coban Treatment of wound infection using antibiotics & antiseptics Appropriate footwear & PT are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. Good dental care & frequent exams to ensure adequate caloric intake Extractions for dental caries & crowding as needed Esophageal strictures & webs can be dilated repeatedly to improve swallowing. Mgmt of constipation Fluid electrolyte mgmt in neonatal period & in infants w/widespread disease Nutrition support as needed incl feeding gastrostomy tube to assure adequate caloric intake Vitamin A & zinc replacement when levels are low to improve corneal stability & enhance wound healing Selenium & carnitine replacement when levels are low to possibly prevent dilated cardiomyopathy Refer to urologist for urethral erosions, strictures, or bladder dysfunction. Refer to nephrologist for hematuria or proteinuria to assess for glomerulonephritis & kidney failure. Calcium & vitamin D supplementation as needed Intravenous bisphosphonates for osteopenia/osteoporosis Estrogen replacement as needed for those w/delayed puberty Menstrual periods can be suppressed to prevent exacerbation of anemia. ACE = angiotensin-converting enzyme; DEB = dystrophic epidermolysis bullosa; OT = occupational therapy; PT = physical therapy; SCC = squamous cell carcinoma • Teaching caretakers proper handling of infants & children to protect skin from shearing forces; • Wrapping & padding extremities; • Use of soft & properly fitted clothing & footwear. • Vaginal delivery is preferred, but in certain circumstances, cesarean delivery may be recommended to ↓ skin trauma in affected fetus. • Encourage age-appropriate play involving activities that cause minimal trauma to skin. • Use dressings & padding to protect bony prominences from blister-inducing impact. • A primary nonadherent contact layer that does not strip top layers of epidermis. Tolerance to different primary layers varies. Primary layers incl: dressings impregnated w/emollient (e.g., petrolatum, topical antiseptic); nonstick products (e.g., Telfa • A secondary layer that provides stability for primary layer & adds padding to allow more activity, such as rolls of gauze (e.g., Kerlix • An elastic mesh-like tertiary layer that ensures integrity of dressing (e.g., burn net, Coban • Treatment of wound infection using antibiotics & antiseptics • Appropriate footwear & PT are essential to preserve ambulation in children w/delays or difficulty walking due to blistering &/or hyperkeratosis. • Good dental care & frequent exams to ensure adequate caloric intake • Extractions for dental caries & crowding as needed • Esophageal strictures & webs can be dilated repeatedly to improve swallowing. • Mgmt of constipation • Fluid electrolyte mgmt in neonatal period & in infants w/widespread disease • Nutrition support as needed incl feeding gastrostomy tube to assure adequate caloric intake • Vitamin A & zinc replacement when levels are low to improve corneal stability & enhance wound healing • Selenium & carnitine replacement when levels are low to possibly prevent dilated cardiomyopathy • Refer to urologist for urethral erosions, strictures, or bladder dysfunction. • Refer to nephrologist for hematuria or proteinuria to assess for glomerulonephritis & kidney failure. • Calcium & vitamin D supplementation as needed • Intravenous bisphosphonates for osteopenia/osteoporosis • Estrogen replacement as needed for those w/delayed puberty • Menstrual periods can be suppressed to prevent exacerbation of anemia. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Dystrophic Epidermolysis Bullosa: Recommended Surveillance Eval of crusted, non-healing, painful, abnormal-looking lesions or those w/exuberant scar tissue for risk of SCC Frequent biopsies of suspicious lesions may be necessary followed by local excision. At least annually beginning at age ≥10 yrs Note: Affected persons are often unwilling to undress completely in clinic setting & home photographs during dressing changes may have to suffice. Measurement of height, weight, & BMI Eval of nutritional status Serum vitamin A, selenium, carnitine, & zinc levels Serum 25-hydroxyvitamin D CBC Iron studies Eval of hand function & mobility/dexterity status by PT or OT Assessment of footwear & mobility issues DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy; SCC = squamous cell carcinoma Rarely, individuals with recessive DEB (RDEB) can develop fulminant and even fatal hepatic failure. Some of the medications used in severe RDEB for pain, itch, and/or infection may have adverse effects on liver function. • Eval of crusted, non-healing, painful, abnormal-looking lesions or those w/exuberant scar tissue for risk of SCC • Frequent biopsies of suspicious lesions may be necessary followed by local excision. • At least annually beginning at age ≥10 yrs • Note: Affected persons are often unwilling to undress completely in clinic setting & home photographs during dressing changes may have to suffice. • Measurement of height, weight, & BMI • Eval of nutritional status • Serum vitamin A, selenium, carnitine, & zinc levels • Serum 25-hydroxyvitamin D • CBC • Iron studies • Eval of hand function & mobility/dexterity status by PT or OT • Assessment of footwear & mobility issues ## Agents/Circumstances to Avoid Nasogastric tubes are discouraged because of oral and esophageal fragility [ Poorly fitting or coarse-textured clothing and footwear should be avoided, as they can cause trauma. In general, activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) should be avoided; affected individuals who are committed to participation in such activities should be encouraged to devise ways of protecting the skin. Most persons with DEB cannot tolerate the use of ordinary medical tape or Band-Aids ## Evaluation of Relatives at Risk Evaluation of an at-risk newborn for evidence of blistering is appropriate so that trauma to the skin can be avoided as much as possible. Given the significant clinical variability that may be seen among family members with DEB, 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 of the See ## Pregnancy Management Data on pregnancy and DEB are limited, but a recent survey did not detect increased risk for pregnancy-related complications in women with various forms of epidermolysis bullosa [ ## Therapies Under Investigation There are several promising therapies currently being studied, including various stem cell therapies including bone marrow transplant, mesenchymal stem cells, stromal cells, induced pluripotent stem (IPS) cells [ There are many new approaches to therapy currently in trial. Clinical trials evaluating antifibrotic, anti-inflammatory, and antipruritic medications are in progress [ Search ## Genetic Counseling Dystrophic epidermolysis bullosa (DEB) is inherited in an autosomal recessive (RDEB) or autosomal dominant (DDEB) manner. Some Phenotypic severity and transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping findings alone are not sufficient to determine mode of inheritance and recurrence risk, as phenotypic variability is extreme in RDEB. An individual with a mild phenotype and no family history may have either autosomal dominant or autosomal recessive DEB; numerous descriptions of the spectrum of phenotypes in RDEB document that some are very mild and mimic DDEB. Approximately 70% of individuals diagnosed with DDEB are reported to have an affected parent. About 30% of individuals diagnosed with DDEB may have the disorder as the result of a If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent 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.* Maternal gonadal mosaicism has been reported [ * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to be heterozygous for the If the If the parents appear to be clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for DDEB because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. The parents of a child with RDEB 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 is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygous parents of a proband with RDEB are typically asymptomatic. Heterozygosity for a Heterozygosity for a If both parents are known to be heterozygous for a Heterozygous sibs of a proband with RDEB are typically asymptomatic. Heterozygosity for a Heterozygosity for 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. 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. • Approximately 70% of individuals diagnosed with DDEB are reported to have an affected parent. • About 30% of individuals diagnosed with DDEB may have the disorder as the result of a • If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent 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.* Maternal gonadal mosaicism has been reported [ • * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Maternal gonadal mosaicism has been reported [ • * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Maternal gonadal mosaicism has been reported [ • * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to be heterozygous for the • If the • If the parents appear to be clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for DDEB because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • The parents of a child with RDEB 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 is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygous parents of a proband with RDEB are typically asymptomatic. • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity 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. • Heterozygosity for a • Heterozygosity for a • If both parents are known to be heterozygous for a • Heterozygous sibs of a proband with RDEB are typically asymptomatic. • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Dystrophic epidermolysis bullosa (DEB) is inherited in an autosomal recessive (RDEB) or autosomal dominant (DDEB) manner. Some Phenotypic severity and transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping findings alone are not sufficient to determine mode of inheritance and recurrence risk, as phenotypic variability is extreme in RDEB. An individual with a mild phenotype and no family history may have either autosomal dominant or autosomal recessive DEB; numerous descriptions of the spectrum of phenotypes in RDEB document that some are very mild and mimic DDEB. ## Autosomal Dominant Inheritance – Risk to Family Members Approximately 70% of individuals diagnosed with DDEB are reported to have an affected parent. About 30% of individuals diagnosed with DDEB may have the disorder as the result of a If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent 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.* Maternal gonadal mosaicism has been reported [ * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to be heterozygous for the If the If the parents appear to be clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for DDEB because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • Approximately 70% of individuals diagnosed with DDEB are reported to have an affected parent. • About 30% of individuals diagnosed with DDEB may have the disorder as the result of a • If the proband appears to be the only affected family member, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent 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.* Maternal gonadal mosaicism has been reported [ • * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Maternal gonadal mosaicism has been reported [ • * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Maternal gonadal mosaicism has been reported [ • * Note: If the parent is the individual in whom a pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to be heterozygous for the • If the • If the parents appear to be clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for DDEB because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with RDEB 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 is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygous parents of a proband with RDEB are typically asymptomatic. Heterozygosity for a Heterozygosity for a If both parents are known to be heterozygous for a Heterozygous sibs of a proband with RDEB are typically asymptomatic. Heterozygosity for a Heterozygosity for a • The parents of a child with RDEB 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 is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygous parents of a proband with RDEB are typically asymptomatic. • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity 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. • Heterozygosity for a • Heterozygosity for a • If both parents are known to be heterozygous for a • Heterozygous sibs of a proband with RDEB are typically asymptomatic. • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity for a • Heterozygosity for 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 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 Chile United Kingdom International registry of dystrophic epidermolysis bullosa (DEB) patients and associated COL7A1 mutations. • • Chile • • • • • • • United Kingdom • • • • • • • International registry of dystrophic epidermolysis bullosa (DEB) patients and associated COL7A1 mutations. • • • ## Molecular Genetics Dystrophic Epidermolysis Bullosa: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Dystrophic Epidermolysis Bullosa ( Pathogenic variants in Recessive DEB (RDEB) usually results from the absence of collagen VII as a result of Dominant DEB (DDEB). Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) predominate (>75%) in DDEB and may result in abnormal triple helical coiling and a partially nonfunctional protein product. RDEB variant prevalent in those of Argentinian ancestry Phenotype includes mild blistering & severe mucosal involvement DDEB = dominant dystrophic epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa Variants listed in the table have been provided by the authors. • Recessive DEB (RDEB) usually results from the absence of collagen VII as a result of • Dominant DEB (DDEB). Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) predominate (>75%) in DDEB and may result in abnormal triple helical coiling and a partially nonfunctional protein product. • RDEB variant prevalent in those of Argentinian ancestry • Phenotype includes mild blistering & severe mucosal involvement ## Molecular Pathogenesis Pathogenic variants in Recessive DEB (RDEB) usually results from the absence of collagen VII as a result of Dominant DEB (DDEB). Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) predominate (>75%) in DDEB and may result in abnormal triple helical coiling and a partially nonfunctional protein product. RDEB variant prevalent in those of Argentinian ancestry Phenotype includes mild blistering & severe mucosal involvement DDEB = dominant dystrophic epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa Variants listed in the table have been provided by the authors. • Recessive DEB (RDEB) usually results from the absence of collagen VII as a result of • Dominant DEB (DDEB). Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) predominate (>75%) in DDEB and may result in abnormal triple helical coiling and a partially nonfunctional protein product. • RDEB variant prevalent in those of Argentinian ancestry • Phenotype includes mild blistering & severe mucosal involvement ## Chapter Notes GeneDx Cincinnati Children's Epidermolysis Bullosa Center Sarah Crawford, MMSc, CGC (2025-present)Anne W Lucky, MD (2006-present)Ellen G Pfendner, PhD; GeneDx, Inc (2006-2025)Elena Pope, MD, MSc (2025-present) 7 August 2025 (ma) Revision: prademagene zamikeracel added to 27 March 2025 (sw) Comprehensive update posted live 13 September 2018 (ha) Comprehensive update posted live 26 February 2015 (me) Comprehensive update posted live 4 November 2010 (me) Comprehensive update posted live 21 August 2006 (me) Review posted live 27 December 2005 (ep) Original submission • 7 August 2025 (ma) Revision: prademagene zamikeracel added to • 27 March 2025 (sw) Comprehensive update posted live • 13 September 2018 (ha) Comprehensive update posted live • 26 February 2015 (me) Comprehensive update posted live • 4 November 2010 (me) Comprehensive update posted live • 21 August 2006 (me) Review posted live • 27 December 2005 (ep) Original submission ## Author Notes GeneDx Cincinnati Children's Epidermolysis Bullosa Center ## Author History Sarah Crawford, MMSc, CGC (2025-present)Anne W Lucky, MD (2006-present)Ellen G Pfendner, PhD; GeneDx, Inc (2006-2025)Elena Pope, MD, MSc (2025-present) ## Revision History 7 August 2025 (ma) Revision: prademagene zamikeracel added to 27 March 2025 (sw) Comprehensive update posted live 13 September 2018 (ha) Comprehensive update posted live 26 February 2015 (me) Comprehensive update posted live 4 November 2010 (me) Comprehensive update posted live 21 August 2006 (me) Review posted live 27 December 2005 (ep) Original submission • 7 August 2025 (ma) Revision: prademagene zamikeracel added to • 27 March 2025 (sw) Comprehensive update posted live • 13 September 2018 (ha) Comprehensive update posted live • 26 February 2015 (me) Comprehensive update posted live • 4 November 2010 (me) Comprehensive update posted live • 21 August 2006 (me) Review posted live • 27 December 2005 (ep) Original submission ## Key Sections in This ## References ## Literature Cited Common findings of dystrophic epidermolysis bullosa (DEB) a, b. Scarring on knees and hands and dystrophic nails found in dominant DEB in an adult c. Aplasia cutis congenita in a newborn with recessive DEB d. Generalized blistering in a child with recessive DEB e. Scarring of feet with pseudosyndactyly of toes caused by scarring in recessive DEB f. Severe generalized blistering in recessive DEB in an adult g. Severe generalized scarring in a young adult with recessive DEB h. Pseudosyndactyly caused by scarring in recessive DEB in an adult
[]
21/8/2006
27/3/2025
7/8/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ebf3-ndd
ebf3-ndd
[ "Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS)", "Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS)", "Transcription factor COE3", "EBF3", "EBF3 Neurodevelopmental Disorder" ]
Dhanya Lakshmi Narayanan, Kerstin Kutsche, Katta M Girisha
Summary The diagnosis of
## Diagnosis No consensus clinical diagnostic criteria for Microcephaly Generalized hypotonia Feeding difficulties Genitourinary abnormalities such as micropenis, cryptorchidism, vesicoureteral reflux, renal anomalies Strabismus Speech delay, mainly expressive speech delay, dysarthria Ataxia High pain threshold or decreased pain sensitivity Behavioral anomalies including stereotypic movements (e.g., rotating movements, chewing on clothes, head retropulsion), perseverative social behavior, short attention span Facial dysmorphism. See Cerebellar vermis hypoplasia (5 individuals) [ Cerebellar atrophy or hypoplasia (1 individual) [ Small inferior posterior cerebellar lobes and hypoplasia of the posterior vermis with mild prominence of the ventricles and sulci (1) [ Abnormal configuration of cerebellar folia arranged in radial shape (1) [ The diagnosis of Note: Identification of a heterozygous Testing in a child with developmental delay or an older individual with intellectual disability typically begins with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See 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. • Microcephaly • Generalized hypotonia • Feeding difficulties • Genitourinary abnormalities such as micropenis, cryptorchidism, vesicoureteral reflux, renal anomalies • Strabismus • Speech delay, mainly expressive speech delay, dysarthria • Ataxia • High pain threshold or decreased pain sensitivity • Behavioral anomalies including stereotypic movements (e.g., rotating movements, chewing on clothes, head retropulsion), perseverative social behavior, short attention span • Facial dysmorphism. See • Cerebellar vermis hypoplasia (5 individuals) [ • Cerebellar atrophy or hypoplasia (1 individual) [ • Small inferior posterior cerebellar lobes and hypoplasia of the posterior vermis with mild prominence of the ventricles and sulci (1) [ • Abnormal configuration of cerebellar folia arranged in radial shape (1) [ ## Suggestive Findings Microcephaly Generalized hypotonia Feeding difficulties Genitourinary abnormalities such as micropenis, cryptorchidism, vesicoureteral reflux, renal anomalies Strabismus Speech delay, mainly expressive speech delay, dysarthria Ataxia High pain threshold or decreased pain sensitivity Behavioral anomalies including stereotypic movements (e.g., rotating movements, chewing on clothes, head retropulsion), perseverative social behavior, short attention span Facial dysmorphism. See Cerebellar vermis hypoplasia (5 individuals) [ Cerebellar atrophy or hypoplasia (1 individual) [ Small inferior posterior cerebellar lobes and hypoplasia of the posterior vermis with mild prominence of the ventricles and sulci (1) [ Abnormal configuration of cerebellar folia arranged in radial shape (1) [ • Microcephaly • Generalized hypotonia • Feeding difficulties • Genitourinary abnormalities such as micropenis, cryptorchidism, vesicoureteral reflux, renal anomalies • Strabismus • Speech delay, mainly expressive speech delay, dysarthria • Ataxia • High pain threshold or decreased pain sensitivity • Behavioral anomalies including stereotypic movements (e.g., rotating movements, chewing on clothes, head retropulsion), perseverative social behavior, short attention span • Facial dysmorphism. See • Cerebellar vermis hypoplasia (5 individuals) [ • Cerebellar atrophy or hypoplasia (1 individual) [ • Small inferior posterior cerebellar lobes and hypoplasia of the posterior vermis with mild prominence of the ventricles and sulci (1) [ • Abnormal configuration of cerebellar folia arranged in radial shape (1) [ ## Establishing the Diagnosis The diagnosis of Note: Identification of a heterozygous Testing in a child with developmental delay or an older individual with intellectual disability typically begins with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See 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. ## Molecular Genetic Testing Testing in a child with developmental delay or an older individual with intellectual disability typically begins with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See 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, 42 symptomatic individuals from 39 families have been reported [ Vesicoureteric reflux (4 individuals) Undescended testes (3) Bicornuate uterus (1 of 24 females) Neurogenic/atonic bladder (2 individuals) Renal dysplasia (1) Recurrent urinary tract infections Gastroesophageal reflux disease (3 individuals) Dysphagia (3) Constipation (3) Cyclical vomiting with failure to thrive (1) Syndactyly of second and third toe (2) Pectus excavatum (2) Bilateral talipes (2) Severe scoliosis in a mother and son that required corrective surgery (2) Scoliosis and severe hip and knee contractures (1) Short stature (3) Microcephaly (3) No genotype-phenotype correlations have been identified. To date 42 individuals from 39 families with this disorder have been described (additionally, 2 mothers who are mosaic are asymptomatic). As it is a recently identified condition, exact prevalence is not known. • Vesicoureteric reflux (4 individuals) • Undescended testes (3) • Bicornuate uterus (1 of 24 females) • Neurogenic/atonic bladder (2 individuals) • Renal dysplasia (1) • Recurrent urinary tract infections • Gastroesophageal reflux disease (3 individuals) • Dysphagia (3) • Constipation (3) • Cyclical vomiting with failure to thrive (1) • Syndactyly of second and third toe (2) • Pectus excavatum (2) • Bilateral talipes (2) • Severe scoliosis in a mother and son that required corrective surgery (2) • Scoliosis and severe hip and knee contractures (1) • Short stature (3) • Microcephaly (3) ## Clinical Description To date, 42 symptomatic individuals from 39 families have been reported [ Vesicoureteric reflux (4 individuals) Undescended testes (3) Bicornuate uterus (1 of 24 females) Neurogenic/atonic bladder (2 individuals) Renal dysplasia (1) Recurrent urinary tract infections Gastroesophageal reflux disease (3 individuals) Dysphagia (3) Constipation (3) Cyclical vomiting with failure to thrive (1) Syndactyly of second and third toe (2) Pectus excavatum (2) Bilateral talipes (2) Severe scoliosis in a mother and son that required corrective surgery (2) Scoliosis and severe hip and knee contractures (1) Short stature (3) Microcephaly (3) • Vesicoureteric reflux (4 individuals) • Undescended testes (3) • Bicornuate uterus (1 of 24 females) • Neurogenic/atonic bladder (2 individuals) • Renal dysplasia (1) • Recurrent urinary tract infections • Gastroesophageal reflux disease (3 individuals) • Dysphagia (3) • Constipation (3) • Cyclical vomiting with failure to thrive (1) • Syndactyly of second and third toe (2) • Pectus excavatum (2) • Bilateral talipes (2) • Severe scoliosis in a mother and son that required corrective surgery (2) • Scoliosis and severe hip and knee contractures (1) • Short stature (3) • Microcephaly (3) ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence To date 42 individuals from 39 families with this disorder have been described (additionally, 2 mothers who are mosaic are asymptomatic). As it is a recently identified condition, exact prevalence is not known. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Partial deletion of the terminal portion of the q arm of chromosome 10 (chromosome 10q26 deletion syndrome; OMIM ## Differential Diagnosis Because the phenotypic features associated with Note: Hereditary ataxia syndromes can also be considered in children presenting with developmental delay or intellectual disability in combination with ataxia (see ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Ataxia Mobility, activities of daily living, & need for adaptive devices To assess for vesicoureteral reflux, cryptorchidism, neurogenic bladder, renal dysplasia Ultrasound eval of kidney & urinary bladder Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage subspecialty appointments, equipment, medications, & supplies. 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 be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake OT = occupational therapy; PT = physical therapy Ataxia and intellectual disability could result in frequent falls in childhood; supervision of patient activity at home is recommended to limit the risk. See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Ataxia • Mobility, activities of daily living, & need for adaptive devices • To assess for vesicoureteral reflux, cryptorchidism, neurogenic bladder, renal dysplasia • Ultrasound eval of kidney & urinary bladder • 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 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 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 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 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. • 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 To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Ataxia Mobility, activities of daily living, & need for adaptive devices To assess for vesicoureteral reflux, cryptorchidism, neurogenic bladder, renal dysplasia Ultrasound eval of kidney & urinary bladder Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; GERD = gastroesophageal reflux disease; 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 • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Ataxia • Mobility, activities of daily living, & need for adaptive devices • To assess for vesicoureteral reflux, cryptorchidism, neurogenic bladder, renal dysplasia • Ultrasound eval of kidney & urinary bladder • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage subspecialty appointments, equipment, medications, & supplies. 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 be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage 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 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 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 be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children 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 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 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 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. ## 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 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 ## Agents/Circumstances to Avoid Ataxia and intellectual disability could result in frequent falls in childhood; supervision of patient activity at home is recommended to limit the risk. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most probands reported to date with Some individuals with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, 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.) Maternal somatic/germline mosaicism has been reported [ * A parent with somatic and germline mosaicism for an If a parent 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 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 • Some individuals with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, 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.) • Maternal somatic/germline mosaicism has been reported [ • * 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 only in the germ cells.) • Maternal somatic/germline mosaicism has been reported [ • * 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 only in the germ cells.) • Maternal somatic/germline mosaicism has been reported [ • * A parent with somatic and germline mosaicism for an • If a parent 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 parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members Most probands reported to date with Some individuals with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, 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.) Maternal somatic/germline mosaicism has been reported [ * A parent with somatic and germline mosaicism for an If a parent is known to have the If the • Most probands reported to date with • Some individuals with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, 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.) • Maternal somatic/germline mosaicism has been reported [ • * 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 only in the germ cells.) • Maternal somatic/germline mosaicism has been reported [ • * 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 only in the germ cells.) • Maternal somatic/germline mosaicism has been reported [ • * A parent with somatic and germline mosaicism for an • If a parent 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 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 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 Speaking out for People with Intellectual and Developmental Disabilities • • • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics EBF3 Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EBF3 Neurodevelopmental Disorder ( Notable Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. ## Chapter Notes The authors acknowledge the Indian Council of Medical Research for supporting this work (63/01/2019-Genomics/BMS titled IMCR Virtual Centre for Molecular Medicine with focus on Rare Genetic Disorders). 6 May 2021 (bp) Review posted live 1 February 2021 (kmg) Original submission • 6 May 2021 (bp) Review posted live • 1 February 2021 (kmg) Original submission ## Acknowledgments The authors acknowledge the Indian Council of Medical Research for supporting this work (63/01/2019-Genomics/BMS titled IMCR Virtual Centre for Molecular Medicine with focus on Rare Genetic Disorders). ## Revision History 6 May 2021 (bp) Review posted live 1 February 2021 (kmg) Original submission • 6 May 2021 (bp) Review posted live • 1 February 2021 (kmg) Original submission ## References ## Literature Cited
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6/5/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ebj
ebj
[ "Collagen alpha-1(XVII) chain", "Integrin beta-4", "Laminin subunit alpha-3", "Laminin subunit beta-3", "Laminin subunit gamma-2", "COL17A1", "ITGB4", "LAMA3", "LAMB3", "LAMC2", "Junctional Epidermolysis Bullosa" ]
Junctional Epidermolysis Bullosa
Ellen G Pfendner, Anne W Lucky
Summary Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally around the upper airway. Blisters generally heal with no significant scarring. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate. In JEB generalized severe, blisters are present at birth or become apparent in the neonatal period. Congenital malformations of the urinary tract and bladder may also occur. In JEB generalized intermediate, the phenotype may be mild with blistering localized to hands, feet, knees, and elbows with or without renal or ureteral involvement. Some individuals never blister after the newborn period. Additional features shared by JEB and the other major forms of epidermolysis bullosa (EB) include congenital localized absence of skin (aplasia cutis congenita), milia, nail dystrophy, scarring alopecia, hypotrichosis, pseudosyndactyly, and other contractures. The diagnosis of JEB is established in a proband with characteristic clinical findings by molecular genetic testing that identifies biallelic pathogenic variants in one of the genes associated with JEB: JEB is inherited in an autosomal recessive manner. The parents of an affected child are usually obligate heterozygotes (i.e., carriers). Because germline mosaicism and uniparental isodisomy have been reported, carrier status of parents needs to be confirmed with molecular genetic testing. At conception, each sib of an affected individual whose parents are both carriers 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. The offspring of an individual with autosomal recessive JEB are obligate heterozygotes (carriers) for a pathogenic variant. Carrier testing for family members at increased risk and prenatal testing for a pregnancy at increased risk are possible if both pathogenic variants have been identified in the family.
## Diagnosis Junctional epidermolysis bullosa (JEB) Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring. Significant oral and mucous membrane involvement Note: Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally in and around the upper airway and the trachea (see The diagnosis of JEB Identification by molecular genetic testing of biallelic pathogenic variants in one of the genes listed in Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (see Note: Genetic testing is the preferred diagnostic method. Skin biopsy for diagnostic purposes is no longer routinely performed unless molecular genetic testing is not conclusive. 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 junctional epidermolysis bullosa is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of junctional epidermolysis bullosa, molecular genetic testing approaches can include use of a A junctional epidermolysis bullosa For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by skin fragility and blistering, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Junctional Epidermolysis Bullosa 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. Biallelic pathogenic variants in Care must be taken to sequence the genomic region of the longest transcript of Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of JEB. A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.) Note: Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples cannot be used for electron microscopy. Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. Some laboratories prefer flash-frozen tissue. In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. Findings on TEM in JEB include the following [ Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [ Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants in Normal staining for other antigens (e.g., collagen VII, keratins 5 and 14) confirms the diagnosis of JEB. Note: Especially in milder forms of EB, indirect immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In these cases electron microscopic examination of the skin biopsy must be performed. • Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement • Identification by molecular genetic testing of biallelic pathogenic variants in one of the genes listed in • Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (see • • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [ • Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants in ## Suggestive Findings Junctional epidermolysis bullosa (JEB) Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring. Significant oral and mucous membrane involvement Note: Blistering may be severe and granulation tissue can form on the skin around the oral and nasal cavities, fingers and toes, and internally in and around the upper airway and the trachea (see • Blistering with little or no trauma. Blistering may be mild or severe; however, blisters generally heal with no significant scarring. • Significant oral and mucous membrane involvement ## Establishing the Diagnosis The diagnosis of JEB Identification by molecular genetic testing of biallelic pathogenic variants in one of the genes listed in Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (see Note: Genetic testing is the preferred diagnostic method. Skin biopsy for diagnostic purposes is no longer routinely performed unless molecular genetic testing is not conclusive. 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 junctional epidermolysis bullosa is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of junctional epidermolysis bullosa, molecular genetic testing approaches can include use of a A junctional epidermolysis bullosa For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by skin fragility and blistering, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Junctional Epidermolysis Bullosa 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. Biallelic pathogenic variants in Care must be taken to sequence the genomic region of the longest transcript of Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of JEB. A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.) Note: Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples cannot be used for electron microscopy. Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. Some laboratories prefer flash-frozen tissue. In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. Findings on TEM in JEB include the following [ Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [ Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants in Normal staining for other antigens (e.g., collagen VII, keratins 5 and 14) confirms the diagnosis of JEB. Note: Especially in milder forms of EB, indirect immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In these cases electron microscopic examination of the skin biopsy must be performed. • Identification by molecular genetic testing of biallelic pathogenic variants in one of the genes listed in • Skin biopsy using transmission electron microscopy (TEM) and/or immunofluorescent antibody/antigen mapping (see • • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [ • Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants in ## Molecular Genetic Testing Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of junctional epidermolysis bullosa is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of junctional epidermolysis bullosa, molecular genetic testing approaches can include use of a A junctional epidermolysis bullosa For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by skin fragility and blistering, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Junctional Epidermolysis Bullosa 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. Biallelic pathogenic variants in Care must be taken to sequence the genomic region of the longest transcript of ## Skin Biopsy Examination of a skin biopsy by (1) transmission electron microscopy (TEM) and/or (2) immunofluorescent antibody/antigen mapping is sometimes performed to establish the diagnosis of JEB. A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.) Note: Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. Formaldehyde-fixed samples cannot be used for electron microscopy. Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. Some laboratories prefer flash-frozen tissue. In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. Findings on TEM in JEB include the following [ Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [ Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants in Normal staining for other antigens (e.g., collagen VII, keratins 5 and 14) confirms the diagnosis of JEB. Note: Especially in milder forms of EB, indirect immunofluorescent studies are often not sufficient to make the diagnosis because near-normal antigen levels are detected and no cleavage plane is observed. In these cases electron microscopic examination of the skin biopsy must be performed. • • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Specimens must be placed in fixation medium (e.g., gluteraldehyde) as designated by the laboratory performing the test. • Formaldehyde-fixed samples cannot be used for electron microscopy. • Specimens should be sent in sterile carrying medium (e.g., Michel's or Zeus's) as specified by the laboratory performing the test. • Some laboratories prefer flash-frozen tissue. • In some laboratories the mapping only designates the level of the cleavage by using various marker antibodies of different layers of the basement membrane. A laboratory that has antigens for the proteins of interest in EB is preferred because both the level of cleavage and the presence or absence of the specific gene products mutated in EB can be assessed. • Abnormal or absent staining with antibodies to laminin 332 (aka LAM5) [ • Abnormal or absent staining with antibodies to collagen XVII in JEB caused by pathogenic variants in ## Clinical Characteristics Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate and is based on severity and survival past the first years of life [ In addition to cutaneous involvement, mucosal involvement of the mouth, upper respiratory tract, esophagus, bladder, urethra, and corneas can be seen. Amelogenesis imperfecta with pitting of tooth enamel is common. Accumulation of granulation tissue surrounding the airway is usually subglottic and the first manifestation is a weak, hoarse cry. Eventually, compression and obstruction of the airway result in stridor and respiratory distress. Unless tracheostomy is performed, many children succumb from respiratory complications. However, managing a tracheostomy in a child with such fragile skin is difficult [ Bladder and urethral epithelial involvement can cause dysuria, urinary retention, urinary tract infections, and eventual renal compromise. Renal and ureteral anomalies that can be seen include dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder [ Esophageal narrowing has been reported, but is less common than in children with autosomal recessive dystrophic EB. Secondary complications common in JEB generalized severe include malnutrition and growth retardation, anemia, alopecia, cutaneous infection, sepsis, electrolyte imbalance, osteoporosis [ Most children with JEB generalized severe do not survive past the first year of life. Varying degrees of alopecia and onychodystrophy as well as dental enamel pitting remain hallmarks of this type of JEB. Congenital localized absence of skin (aplasia cutis congenita) Exuberant granulation tissue Nail dystrophy Scarring alopecia Squamous cell carcinoma in individuals with JEB generalized intermediate [ Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet (rare). Milia (rare) Scarring (rare) JEB generalized intermediate generally results from amino acid substitutions and splice-junction variants, although it is difficult to generalize because of the wide phenotypic variability and range of allelic variants that have been identified [ Junctional Epidermolysis Bullosa Nomenclature Epidermolysis bullosa letalis Epidermolysis bullosa junctional Herlitz-Pearson Junctional epidermolysis bullosa mitis Epidermolysis bullosa, generalized atrophic benign (GABEB) Epidermolysis bullosa junctionalis, disentis type Epidermolysis bullosa junctionalis, progressive Epidermolysis bullosa junctionalis, severe non-lethal Adapted from JEB = junctional epidermolysis bullosa According to the National EB Registry, prevalence of all types of JEB is 0.44 per million in the US population [ The prevalence of JEB generalized severe is estimated at 0.4 per million but may be underrepresented. JEB generalized severe incidence is also very low (0.41 per million), but is probably underestimated: many individuals with JEB generalized severe go unreported because infants succumb to the disease in the neonatal period (a mortality rate of 73% in infancy has been reported) [ JEB generalized intermediate incidence is 2.0 per million. Carrier risk of all forms of JEB in the US population has been calculated as 1:270 [Author, personal communication]. Carrier risk of JEB generalized severe has been calculated as 1:781 [ • Congenital localized absence of skin (aplasia cutis congenita) • Exuberant granulation tissue • Nail dystrophy • Scarring alopecia • Squamous cell carcinoma in individuals with JEB generalized intermediate [ • Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet (rare). • Milia (rare) • Scarring (rare) • Epidermolysis bullosa letalis • Epidermolysis bullosa junctional Herlitz-Pearson • Junctional epidermolysis bullosa mitis • Epidermolysis bullosa, generalized atrophic benign (GABEB) • Epidermolysis bullosa junctionalis, disentis type • Epidermolysis bullosa junctionalis, progressive • Epidermolysis bullosa junctionalis, severe non-lethal • The prevalence of JEB generalized severe is estimated at 0.4 per million but may be underrepresented. JEB generalized severe incidence is also very low (0.41 per million), but is probably underestimated: many individuals with JEB generalized severe go unreported because infants succumb to the disease in the neonatal period (a mortality rate of 73% in infancy has been reported) [ • JEB generalized intermediate incidence is 2.0 per million. • Carrier risk of all forms of JEB in the US population has been calculated as 1:270 [Author, personal communication]. • Carrier risk of JEB generalized severe has been calculated as 1:781 [ ## Clinical Description Junctional epidermolysis bullosa (JEB) is characterized by fragility of the skin and mucous membranes, manifest by blistering with little or no trauma. Broad classification of JEB includes JEB generalized severe and JEB generalized intermediate and is based on severity and survival past the first years of life [ In addition to cutaneous involvement, mucosal involvement of the mouth, upper respiratory tract, esophagus, bladder, urethra, and corneas can be seen. Amelogenesis imperfecta with pitting of tooth enamel is common. Accumulation of granulation tissue surrounding the airway is usually subglottic and the first manifestation is a weak, hoarse cry. Eventually, compression and obstruction of the airway result in stridor and respiratory distress. Unless tracheostomy is performed, many children succumb from respiratory complications. However, managing a tracheostomy in a child with such fragile skin is difficult [ Bladder and urethral epithelial involvement can cause dysuria, urinary retention, urinary tract infections, and eventual renal compromise. Renal and ureteral anomalies that can be seen include dysplastic/multicystic kidney, hydronephrosis/hydroureter, acute renal tubular necrosis, obstructive uropathy, ureterocele, duplicated renal collecting system, and absent bladder [ Esophageal narrowing has been reported, but is less common than in children with autosomal recessive dystrophic EB. Secondary complications common in JEB generalized severe include malnutrition and growth retardation, anemia, alopecia, cutaneous infection, sepsis, electrolyte imbalance, osteoporosis [ Most children with JEB generalized severe do not survive past the first year of life. Varying degrees of alopecia and onychodystrophy as well as dental enamel pitting remain hallmarks of this type of JEB. Congenital localized absence of skin (aplasia cutis congenita) Exuberant granulation tissue Nail dystrophy Scarring alopecia Squamous cell carcinoma in individuals with JEB generalized intermediate [ Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet (rare). Milia (rare) Scarring (rare) • Congenital localized absence of skin (aplasia cutis congenita) • Exuberant granulation tissue • Nail dystrophy • Scarring alopecia • Squamous cell carcinoma in individuals with JEB generalized intermediate [ • Pseudosyndactyly and other contractures. Pseudosyndactyly is defined as the partial or complete loss of web spaces between any digits of the hands or feet (rare). • Milia (rare) • Scarring (rare) ## Genotype-Phenotype Correlations JEB generalized intermediate generally results from amino acid substitutions and splice-junction variants, although it is difficult to generalize because of the wide phenotypic variability and range of allelic variants that have been identified [ ## Nomenclature Junctional Epidermolysis Bullosa Nomenclature Epidermolysis bullosa letalis Epidermolysis bullosa junctional Herlitz-Pearson Junctional epidermolysis bullosa mitis Epidermolysis bullosa, generalized atrophic benign (GABEB) Epidermolysis bullosa junctionalis, disentis type Epidermolysis bullosa junctionalis, progressive Epidermolysis bullosa junctionalis, severe non-lethal Adapted from JEB = junctional epidermolysis bullosa • Epidermolysis bullosa letalis • Epidermolysis bullosa junctional Herlitz-Pearson • Junctional epidermolysis bullosa mitis • Epidermolysis bullosa, generalized atrophic benign (GABEB) • Epidermolysis bullosa junctionalis, disentis type • Epidermolysis bullosa junctionalis, progressive • Epidermolysis bullosa junctionalis, severe non-lethal ## Prevalence According to the National EB Registry, prevalence of all types of JEB is 0.44 per million in the US population [ The prevalence of JEB generalized severe is estimated at 0.4 per million but may be underrepresented. JEB generalized severe incidence is also very low (0.41 per million), but is probably underestimated: many individuals with JEB generalized severe go unreported because infants succumb to the disease in the neonatal period (a mortality rate of 73% in infancy has been reported) [ JEB generalized intermediate incidence is 2.0 per million. Carrier risk of all forms of JEB in the US population has been calculated as 1:270 [Author, personal communication]. Carrier risk of JEB generalized severe has been calculated as 1:781 [ • The prevalence of JEB generalized severe is estimated at 0.4 per million but may be underrepresented. JEB generalized severe incidence is also very low (0.41 per million), but is probably underestimated: many individuals with JEB generalized severe go unreported because infants succumb to the disease in the neonatal period (a mortality rate of 73% in infancy has been reported) [ • JEB generalized intermediate incidence is 2.0 per million. • Carrier risk of all forms of JEB in the US population has been calculated as 1:270 [Author, personal communication]. • Carrier risk of JEB generalized severe has been calculated as 1:781 [ ## Genetically Related (Allelic) Disorders Allelic disorders with phenotypic characteristics similar to JEB generalized intermediate: Diagnosis of LOCS may be complicated by the lack of a definitive cleavage plane on TEM and reduced but not absent laminin 5 staining by immunofluorescence for the basement membrane proteins. Sequence analysis of all 76 exons of Other allelic disorders (not in the differential diagnosis of JEB): • Diagnosis of LOCS may be complicated by the lack of a definitive cleavage plane on TEM and reduced but not absent laminin 5 staining by immunofluorescence for the basement membrane proteins. Sequence analysis of all 76 exons of ## Differential Diagnosis The four major types of EB share easy fragility of the skin (and mucosa in many cases), manifested by blistering with little or no trauma. Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates ‒ may not be established or significant enough to allow identification of EB type; thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. The ability to induce blisters with friction (although the amount of friction can vary) and to enlarge blisters by applying pressure to the blister edge is common to all; mucosal and nail involvement and the presence or absence of milia may not be helpful discriminators. Post-inflammatory changes, such as those seen in generalized severe EBS (EBS-gen sev), are often mistaken for scarring or mottled pigmentation. Scarring can occur in EBS and JEB as a result of infection of erosions or scratching, which further damage the exposed surface. Congenital absence of the skin can be seen in any of the four major types of EB and is not a discriminating diagnostic feature. Corneal erosions, esophageal strictures, and nail involvement may indicate either DEB or JEB. In milder presentations, scarring (especially of the dorsal hands and feet) suggests DEB. Pseudosyndactyly (mitten deformities) resulting from scarring of the hands and feet in older children and adults usually suggests DEB. In In In In • In • In • In • In ## Management To establish the extent of disease and needs in an individual diagnosed with junctional epidermolysis bullosa (JEB), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Evaluation of the sites of blister formation, including mouth, esophagus, and airway in a child with progressive hoarseness or stridor Direct examination of the airway by an experienced otolaryngologist with appropriately small and lubricated instruments to determine the extent of airway compromise so that decisions regarding tracheostomy can be discussed with the family Evaluation for gastroesophageal reflux disease, which may cause additional trauma to the upper airway [ Evaluation for existing osteopenia through skeletal radiographs or DXA (dual-energy x-ray absorptiometry) scan Evaluation for cardiomyopathy by clinical evaluation and/or echocardiogram [Fine et all 2008] Measurements of hemoglobin and electrolytes to evaluate for anemia and electrolyte imbalance Skin bacterial cultures and blood cultures in clinically ill infants to decide appropriate antibiotic treatment Consultation with a clinical geneticist and/or genetic counselor Note: Clinical decision making in children who manifest sign and symptoms of severe JEB with a very poor prognosis has been debated and remains difficult [ New blisters should be lanced and drained to prevent further spread from fluid pressure. In most cases, dressings for blisters involve three layers: A primary non-adherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers include the following: Ordinary Band-Aids Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline Nonstick products (e.g., Telfa Silicone-based products without adhesive (e.g., Mepitel A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Conform A tertiary layer that usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban Treatment of granulation tissue can be attempted with high-potency topical steroids, silver nitrate, electrocautery, or autologous skin grafts. Esophageal strictures and webs can be dilated repeatedly to improve swallowing [ A hoarse cry in an infant should alert to the possibility of airway obstruction with granulation tissue or other upper airway abnormalities. Decisions about tracheostomy should involve the family and take into consideration the medical condition of the infant. Because of the poor prognosis and severe pain and discomfort experienced by these infants, discussions with the family and a hospital ethics committee often help to determine the type of intervention and comfort care to provide [ Gastroesophageal reflux disease, when present, should be treated as in the general population. Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation. Psychosocial support, including social services and psychological counseling, is essential [ Pain management becomes an important part of daily care [ Dental care is necessary because of inherent enamel abnormalities [ Urologic and renal problems may be serious in this population [ The following are indicated: Management of fluid and electrolyte deficiencies in the neonatal period and in infants with widespread disease Nutritional support including a feeding gastrostomy tube for infants and children with inadequate caloric intake and failure to thrive Calcium and vitamin D replacement for osteopenia and osteoporosis Zinc supplementation for wound healing Treatment of iron-deficiency anemia with oral or intravenous iron infusions and red blood cell transfusions Surveillance includes the following: Annual complete blood counts and measurement of serum iron concentration to screen for iron-deficiency anemia Annual measurement of serum zinc concentration to screen for zinc deficiency Annual measurement of serum vitamin D Screening with bone mineral density scanning may detect early osteopenia and/or osteoporosis. No guidelines have been established regarding the age at which this should be initiated. Screening for dilated cardiomyopathy with periodic echocardiograms [ Skin examination starting in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal to screen for squamous cell carcinoma. Frequent biopsies of suspicious lesions followed by local excision may be necessary. Most persons with JEB cannot use ordinary medical tape or Band-Aids Poorly fitting or coarse-textured clothing and footwear can cause trauma. Activities such as hiking, mountain biking, and contact sports traumatize the skin; affected individuals who are determined to participate in such activities should be encouraged to find creative ways to protect their skin. See Several approaches to gene therapy for JEB, focused on retroviral modification of in vitro epidermal cells, have been proposed [ The use of a variety of viral vectors, including AAV [ Natural gene therapy is being investigated using autologous revertant cells cultured from patches of non-blistering skin [ The knockout mouse model for all JEB-related genes should facilitate the development of these therapeutic approaches [ Induced pleuripotent stem cells (IPS) are being studied in several laboratories around the world to address the treatment of JEB and other types of EB [ Protein replacement therapy with LAMB3 has been studied in vitro [ The use of gentamicin as a chemical agent to induce read-through of pathogenic premature termination codons in keratinocytes containing expression vectors with various nonsense variants has also been explored and has shown promising results in cell cultures, but has not yet been demonstrated in individuals with JEB [ Search • Evaluation of the sites of blister formation, including mouth, esophagus, and airway in a child with progressive hoarseness or stridor • Direct examination of the airway by an experienced otolaryngologist with appropriately small and lubricated instruments to determine the extent of airway compromise so that decisions regarding tracheostomy can be discussed with the family • Evaluation for gastroesophageal reflux disease, which may cause additional trauma to the upper airway [ • Evaluation for existing osteopenia through skeletal radiographs or DXA (dual-energy x-ray absorptiometry) scan • Evaluation for cardiomyopathy by clinical evaluation and/or echocardiogram [Fine et all 2008] • Measurements of hemoglobin and electrolytes to evaluate for anemia and electrolyte imbalance • Skin bacterial cultures and blood cultures in clinically ill infants to decide appropriate antibiotic treatment • Consultation with a clinical geneticist and/or genetic counselor • A primary non-adherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers include the following: • Ordinary Band-Aids • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • Nonstick products (e.g., Telfa • Silicone-based products without adhesive (e.g., Mepitel • Ordinary Band-Aids • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • Nonstick products (e.g., Telfa • Silicone-based products without adhesive (e.g., Mepitel • A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Conform • A tertiary layer that usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban • Ordinary Band-Aids • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • Nonstick products (e.g., Telfa • Silicone-based products without adhesive (e.g., Mepitel • Management of fluid and electrolyte deficiencies in the neonatal period and in infants with widespread disease • Nutritional support including a feeding gastrostomy tube for infants and children with inadequate caloric intake and failure to thrive • Calcium and vitamin D replacement for osteopenia and osteoporosis • Zinc supplementation for wound healing • Treatment of iron-deficiency anemia with oral or intravenous iron infusions and red blood cell transfusions • Annual complete blood counts and measurement of serum iron concentration to screen for iron-deficiency anemia • Annual measurement of serum zinc concentration to screen for zinc deficiency • Annual measurement of serum vitamin D • Screening with bone mineral density scanning may detect early osteopenia and/or osteoporosis. No guidelines have been established regarding the age at which this should be initiated. • Screening for dilated cardiomyopathy with periodic echocardiograms [ • Skin examination starting in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal to screen for squamous cell carcinoma. Frequent biopsies of suspicious lesions followed by local excision may be necessary. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with junctional epidermolysis bullosa (JEB), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Evaluation of the sites of blister formation, including mouth, esophagus, and airway in a child with progressive hoarseness or stridor Direct examination of the airway by an experienced otolaryngologist with appropriately small and lubricated instruments to determine the extent of airway compromise so that decisions regarding tracheostomy can be discussed with the family Evaluation for gastroesophageal reflux disease, which may cause additional trauma to the upper airway [ Evaluation for existing osteopenia through skeletal radiographs or DXA (dual-energy x-ray absorptiometry) scan Evaluation for cardiomyopathy by clinical evaluation and/or echocardiogram [Fine et all 2008] Measurements of hemoglobin and electrolytes to evaluate for anemia and electrolyte imbalance Skin bacterial cultures and blood cultures in clinically ill infants to decide appropriate antibiotic treatment Consultation with a clinical geneticist and/or genetic counselor Note: Clinical decision making in children who manifest sign and symptoms of severe JEB with a very poor prognosis has been debated and remains difficult [ • Evaluation of the sites of blister formation, including mouth, esophagus, and airway in a child with progressive hoarseness or stridor • Direct examination of the airway by an experienced otolaryngologist with appropriately small and lubricated instruments to determine the extent of airway compromise so that decisions regarding tracheostomy can be discussed with the family • Evaluation for gastroesophageal reflux disease, which may cause additional trauma to the upper airway [ • Evaluation for existing osteopenia through skeletal radiographs or DXA (dual-energy x-ray absorptiometry) scan • Evaluation for cardiomyopathy by clinical evaluation and/or echocardiogram [Fine et all 2008] • Measurements of hemoglobin and electrolytes to evaluate for anemia and electrolyte imbalance • Skin bacterial cultures and blood cultures in clinically ill infants to decide appropriate antibiotic treatment • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations New blisters should be lanced and drained to prevent further spread from fluid pressure. In most cases, dressings for blisters involve three layers: A primary non-adherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers include the following: Ordinary Band-Aids Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline Nonstick products (e.g., Telfa Silicone-based products without adhesive (e.g., Mepitel A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Conform A tertiary layer that usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban Treatment of granulation tissue can be attempted with high-potency topical steroids, silver nitrate, electrocautery, or autologous skin grafts. Esophageal strictures and webs can be dilated repeatedly to improve swallowing [ A hoarse cry in an infant should alert to the possibility of airway obstruction with granulation tissue or other upper airway abnormalities. Decisions about tracheostomy should involve the family and take into consideration the medical condition of the infant. Because of the poor prognosis and severe pain and discomfort experienced by these infants, discussions with the family and a hospital ethics committee often help to determine the type of intervention and comfort care to provide [ Gastroesophageal reflux disease, when present, should be treated as in the general population. Some children have delays or difficulty walking because of blistering and hyperkeratosis. Appropriate footwear and physical therapy are essential to preserve ambulation. Psychosocial support, including social services and psychological counseling, is essential [ Pain management becomes an important part of daily care [ Dental care is necessary because of inherent enamel abnormalities [ Urologic and renal problems may be serious in this population [ • A primary non-adherent dressing that does not strip the top layers of the epidermis. Tolerance to different primary layers varies. Primary layers include the following: • Ordinary Band-Aids • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • Nonstick products (e.g., Telfa • Silicone-based products without adhesive (e.g., Mepitel • Ordinary Band-Aids • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • Nonstick products (e.g., Telfa • Silicone-based products without adhesive (e.g., Mepitel • A secondary layer that provides stability for the primary layer and adds padding to allow more activity. Rolls of gauze (e.g., Conform • A tertiary layer that usually has some elastic properties and ensures the integrity of the dressing (e.g., Coban • Ordinary Band-Aids • Dressings impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • Nonstick products (e.g., Telfa • Silicone-based products without adhesive (e.g., Mepitel ## Prevention of Secondary Complications The following are indicated: Management of fluid and electrolyte deficiencies in the neonatal period and in infants with widespread disease Nutritional support including a feeding gastrostomy tube for infants and children with inadequate caloric intake and failure to thrive Calcium and vitamin D replacement for osteopenia and osteoporosis Zinc supplementation for wound healing Treatment of iron-deficiency anemia with oral or intravenous iron infusions and red blood cell transfusions • Management of fluid and electrolyte deficiencies in the neonatal period and in infants with widespread disease • Nutritional support including a feeding gastrostomy tube for infants and children with inadequate caloric intake and failure to thrive • Calcium and vitamin D replacement for osteopenia and osteoporosis • Zinc supplementation for wound healing • Treatment of iron-deficiency anemia with oral or intravenous iron infusions and red blood cell transfusions ## Surveillance Surveillance includes the following: Annual complete blood counts and measurement of serum iron concentration to screen for iron-deficiency anemia Annual measurement of serum zinc concentration to screen for zinc deficiency Annual measurement of serum vitamin D Screening with bone mineral density scanning may detect early osteopenia and/or osteoporosis. No guidelines have been established regarding the age at which this should be initiated. Screening for dilated cardiomyopathy with periodic echocardiograms [ Skin examination starting in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal to screen for squamous cell carcinoma. Frequent biopsies of suspicious lesions followed by local excision may be necessary. • Annual complete blood counts and measurement of serum iron concentration to screen for iron-deficiency anemia • Annual measurement of serum zinc concentration to screen for zinc deficiency • Annual measurement of serum vitamin D • Screening with bone mineral density scanning may detect early osteopenia and/or osteoporosis. No guidelines have been established regarding the age at which this should be initiated. • Screening for dilated cardiomyopathy with periodic echocardiograms [ • Skin examination starting in the second decade of life for wounds that do not heal, have exuberant scar tissue, or otherwise look abnormal to screen for squamous cell carcinoma. Frequent biopsies of suspicious lesions followed by local excision may be necessary. ## Agents/Circumstances to Avoid Most persons with JEB cannot use ordinary medical tape or Band-Aids Poorly fitting or coarse-textured clothing and footwear can cause trauma. Activities such as hiking, mountain biking, and contact sports traumatize the skin; affected individuals who are determined to participate in such activities should be encouraged to find creative ways to protect their skin. ## Evaluation of Relatives at Risk See ## Pregnancy Management ## Therapies Under Investigation Several approaches to gene therapy for JEB, focused on retroviral modification of in vitro epidermal cells, have been proposed [ The use of a variety of viral vectors, including AAV [ Natural gene therapy is being investigated using autologous revertant cells cultured from patches of non-blistering skin [ The knockout mouse model for all JEB-related genes should facilitate the development of these therapeutic approaches [ Induced pleuripotent stem cells (IPS) are being studied in several laboratories around the world to address the treatment of JEB and other types of EB [ Protein replacement therapy with LAMB3 has been studied in vitro [ The use of gentamicin as a chemical agent to induce read-through of pathogenic premature termination codons in keratinocytes containing expression vectors with various nonsense variants has also been explored and has shown promising results in cell cultures, but has not yet been demonstrated in individuals with JEB [ Search ## Genetic Counseling Junctional epidermolysis bullosa (JEB) is inherited in an autosomal recessive manner. While there is no evidence to date that a single (i.e., heterozygous) pathogenic variant in The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one Because germline mosaicism and uniparental isodisomy have been reported [ Heterozygotes (carriers) are asymptomatic except in a few rare instances where carriers of a At conception, each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic except in the case of Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. 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 usually obligate heterozygotes (i.e., carriers of one • Because germline mosaicism and uniparental isodisomy have been reported [ • Heterozygotes (carriers) are asymptomatic except in a few rare instances where carriers of a • At conception, each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic except in the case 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 Junctional epidermolysis bullosa (JEB) is inherited in an autosomal recessive manner. While there is no evidence to date that a single (i.e., heterozygous) pathogenic variant in ## Risk to Family Members The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one Because germline mosaicism and uniparental isodisomy have been reported [ Heterozygotes (carriers) are asymptomatic except in a few rare instances where carriers of a At conception, each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic except in the case of • The parents of an affected child are usually obligate heterozygotes (i.e., carriers of one • Because germline mosaicism and uniparental isodisomy have been reported [ • Heterozygotes (carriers) are asymptomatic except in a few rare instances where carriers of a • At conception, each sib of an affected individual whose parents are both carriers has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic except in the case of ## Carrier (Heterozygote) Detection Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. ## 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 ## Resources United Kingdom • • • • • • United Kingdom • • • • • • • ## Molecular Genetics Junctional Epidermolysis Bullosa: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Junctional Epidermolysis Bullosa ( The proteins encoded by Collagen XVII forms an integral part of the hemidesmosome and has an intracellular as well as extracellular component. There is evidence that it interacts with alpha-6 integrin within the hemidesmosome. The hemidesmosomes – structures made up of several protein components including COLXVII, alpha-6 beta-4 integrin, BPAG1, and plectin – anchor the epidermal cells to the underlying dermis. The type and position of variants in Integrins associate in pairs containing one alpha and one beta chain. α6β4 integrin comprises one α6 and one β4 integrin from the integrin family of proteins and is a component of the hemidesmosomes of the epidermis. Integrins are known to participate in cell adhesion as well as cell-surface-mediated signaling. Insertion/deletion, splice junction, and amino acid substitution variants in both α6 and β4 integrin have been described and would result in EB-PA [ Variants listed in the table have been provided by the authors. Variants listed in the table have been provided by the authors. See Cited by See Exon numbers based on Longest transcript; the genomic sequence of The laminin A3 protein associates with laminin B3 and C2 proteins to form the laminin 332 heterotrimer that comprises the anchoring fibrils in the epidermis. The anchoring fibrils hold the layers of the basal lamina together and form associations with collagen VII on the dermal side and plectin and α6β4 integrin in the hemidesmosomes on the epidermal side. This interaction allows the formation of the protein network of the epidermis, which results in a flexible and resilient barrier to resist trauma. Variants listed in the table have been provided by the authors. Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The proteins encoded by Collagen XVII forms an integral part of the hemidesmosome and has an intracellular as well as extracellular component. There is evidence that it interacts with alpha-6 integrin within the hemidesmosome. The hemidesmosomes – structures made up of several protein components including COLXVII, alpha-6 beta-4 integrin, BPAG1, and plectin – anchor the epidermal cells to the underlying dermis. The type and position of variants in Integrins associate in pairs containing one alpha and one beta chain. α6β4 integrin comprises one α6 and one β4 integrin from the integrin family of proteins and is a component of the hemidesmosomes of the epidermis. Integrins are known to participate in cell adhesion as well as cell-surface-mediated signaling. Insertion/deletion, splice junction, and amino acid substitution variants in both α6 and β4 integrin have been described and would result in EB-PA [ Variants listed in the table have been provided by the authors. Variants listed in the table have been provided by the authors. See Cited by See Exon numbers based on Longest transcript; the genomic sequence of The laminin A3 protein associates with laminin B3 and C2 proteins to form the laminin 332 heterotrimer that comprises the anchoring fibrils in the epidermis. The anchoring fibrils hold the layers of the basal lamina together and form associations with collagen VII on the dermal side and plectin and α6β4 integrin in the hemidesmosomes on the epidermal side. This interaction allows the formation of the protein network of the epidermis, which results in a flexible and resilient barrier to resist trauma. Variants listed in the table have been provided by the authors. Variants listed in the table have been provided by the authors. ## ## Variants listed in the table have been provided by the authors. ## Variants listed in the table have been provided by the authors. See Cited by See Exon numbers based on Longest transcript; the genomic sequence of The laminin A3 protein associates with laminin B3 and C2 proteins to form the laminin 332 heterotrimer that comprises the anchoring fibrils in the epidermis. The anchoring fibrils hold the layers of the basal lamina together and form associations with collagen VII on the dermal side and plectin and α6β4 integrin in the hemidesmosomes on the epidermal side. This interaction allows the formation of the protein network of the epidermis, which results in a flexible and resilient barrier to resist trauma. ## Variants listed in the table have been provided by the authors. ## Variants listed in the table have been provided by the authors. ## References ## Literature Cited ## Chapter Notes GeneDx Cincinnati Children's Epidermolysis Bullosa Center 20 December 2018 (sw) Comprehensive update posted live 2 January 2014 (me) Comprehensive update posted live 22 February 2008 (me) Review posted live 10 May 2007 (egp) Original submission • 20 December 2018 (sw) Comprehensive update posted live • 2 January 2014 (me) Comprehensive update posted live • 22 February 2008 (me) Review posted live • 10 May 2007 (egp) Original submission ## Author Notes GeneDx Cincinnati Children's Epidermolysis Bullosa Center ## Revision History 20 December 2018 (sw) Comprehensive update posted live 2 January 2014 (me) Comprehensive update posted live 22 February 2008 (me) Review posted live 10 May 2007 (egp) Original submission • 20 December 2018 (sw) Comprehensive update posted live • 2 January 2014 (me) Comprehensive update posted live • 22 February 2008 (me) Review posted live • 10 May 2007 (egp) Original submission JEB generalized severe a. Extensive widespread blistering and granulation tissue on ear b. Hand of a child showing aplasia cutis congenita c. Foot of an affected child d. Exuberant perioral granulation tissue and tracheostomy in a child JEB generalized intermediate e. Minor nail dystrophy in an older child f. Multiple blisters on the hands of an active toddler g. Non-scarring superficial axillary erosions
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22/2/2008
20/12/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ebs
ebs
[ "Severe Epidermolysis Bullosa Simplex", "Intermediate Epidermolysis Bullosa Simplex", "Localized Epidermolysis Bullosa Simplex", "Epidermolysis Bullosa Simplex with Mottled Pigmentation", "Epidermolysis Bullosa Simplex, Intermediate with Muscular Dystrophy", "Epidermolysis Bullosa Simplex, Intermediate with PLEC Pathogenic Variants", "Epidermolysis Bullosa Simplex with Migratory Circinate Erythema", "Epidermolysis Bullosa Simplex, Severe with Pyloric Atresia", "Epidermolysis Bullosa Simplex, Intermediate with Cardiomyopathy", "Epidermolysis Bullosa Simplex, Localized or Intermediate with BP230 Deficiency", "Epidermolysis Bullosa Simplex, Localized or Intermediate with Exophilin 5 Deficiency", "Epidermolysis Bullosa Simplex, Localized with Nephropathy with CD151 Deficiency", "CD151 antigen", "Dystonin", "Exophilin-5", "Kelch-like protein 24", "Keratin, type I cytoskeletal 14", "Keratin, type II cytoskeletal 5", "Plectin", "CD151", "DST", "EXPH5", "KLHL24", "KRT14", "KRT5", "PLEC", "Epidermolysis Bullosa Simplex" ]
Epidermolysis Bullosa Simplex
Jodi Y So, Joyce Teng
Summary Epidermolysis bullosa simplex (EBS) is characterized by fragility of the skin (and mucosal epithelia in some instances) that results in non-scarring blisters and erosions caused by minor mechanical trauma. EBS is distinguished from other types of epidermolysis bullosa (EB) or non-EB skin fragility syndromes by the location of the blistering in relation to the dermal-epidermal junction. In EBS, blistering occurs within basal keratinocytes. The severity of blistering ranges from limited to hands and feet to widespread involvement. Additional features can include hyperkeratosis of the palms and soles (keratoderma), nail dystrophy, milia, and hyper- and/or hypopigmentation. Rare EBS subtypes have been associated with additional clinical features including pyloric atresia, muscular dystrophy, cardiomyopathy, and/or nephropathy. The diagnosis of EBS is established in a proband by: the identification of a heterozygous dominant-negative variant or biallelic loss-of-function variants in EBS is typically inherited in an autosomal recessive or an autosomal dominant manner. Autosomal recessive EBS is associated with either biallelic loss-of-function variants in Once the EBS-related pathogenic variant(s) have been identified in an affected family member, molecular genetic testing for at-risk family members and prenatal and preimplantation genetic testing are possible.
Epidermolysis Bullosa Simplex (EBS): Included Phenotypes Localized EBS Intermediate EBS Severe EBS EBS with mottled pigmentation EBS, intermediate with EBS, intermediate with muscular dystrophy EBS, severe with pyloric atresia EBS with migratory circinate erythema EBS, intermediate with cardiomyopathy EBS, localized or intermediate with BP230 deficiency EBS, localized or intermediate with exophilin 5 deficiency EBS, localized with nephropathy with CD151 deficiency For synonyms and outdated names see • Localized EBS • Intermediate EBS • Severe EBS • EBS with mottled pigmentation • EBS, intermediate with • EBS, intermediate with muscular dystrophy • EBS, severe with pyloric atresia • EBS with migratory circinate erythema • EBS, intermediate with cardiomyopathy • EBS, localized or intermediate with BP230 deficiency • EBS, localized or intermediate with exophilin 5 deficiency • EBS, localized with nephropathy with CD151 deficiency ## Diagnosis Epidermolysis bullosa simplex (EBS) Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring Blistering that: May be present in the neonatal period Primarily affects the hands and feet but can affect the whole body Occurs in annular or curvilinear groups or clusters Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life Is associated with palmar and plantar hyperkeratosis that may be severe Nail dystrophy Milia Natal teeth The diagnosis of EBS is Identification of a heterozygous dominant-negative or biallelic loss-of-function pathogenic (or likely pathogenic) variants in Characteristic findings on skin biopsy examined via immunofluorescent mapping (IFM) and/or transmission electron microscopy (TEM) (See Note: (1) Both genetic testing and skin biopsy for IFM are often recommended to improve the sensitivity of the diagnostic tests. TEM may also be performed to assess for ultrastructural abnormalities in individuals with inconclusive genetic testing and IFM. (2) 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. (3) Identification of a variant(s) of uncertain significance does not establish or rule out the diagnosis of EBS. Molecular testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratories conducting the tests and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex NA = not applicable Genes are listed in alphabetic order. See Data derived from the subscription-based professional view of Human Gene Mutation Database [ See In individuals with EBS diagnosed by findings on skin biopsy. 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 a skin biopsy by (1) immunofluorescent mapping (IFM) and/or (2) transmission electron microscopy (TEM) may be performed to establish the diagnosis of EBS. IFM is generally preferred as it can yield results rapidly. Moreover, IFM is less expensive and is therefore more widely performed; it may also be used in prognostication and assessment of disease severity [ A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.) Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB. Normal staining with antibodies to keratin 5, keratin 14, or plectin resulting from heterozygous pathogenic variants in Abnormal or absent staining with antibodies to keratin 5, keratin 14, plectin, BP230 (i.e., BPAG1, BPAG1-e), exophilin 5, and CD151 resulting from biallelic pathogenic variants in Keratin intermediate filaments (i.e., tonofilaments) may be clumped in severe EBS [ The absence of keratin intermediate filaments is a distinguishing feature of In EBS caused by biallelic pathogenic variants in • Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring • Blistering that: • May be present in the neonatal period • Primarily affects the hands and feet but can affect the whole body • Occurs in annular or curvilinear groups or clusters • Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life • Is associated with palmar and plantar hyperkeratosis that may be severe • May be present in the neonatal period • Primarily affects the hands and feet but can affect the whole body • Occurs in annular or curvilinear groups or clusters • Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life • Is associated with palmar and plantar hyperkeratosis that may be severe • Nail dystrophy • Milia • Natal teeth • May be present in the neonatal period • Primarily affects the hands and feet but can affect the whole body • Occurs in annular or curvilinear groups or clusters • Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life • Is associated with palmar and plantar hyperkeratosis that may be severe • Identification of a heterozygous dominant-negative or biallelic loss-of-function pathogenic (or likely pathogenic) variants in • Characteristic findings on skin biopsy examined via immunofluorescent mapping (IFM) and/or transmission electron microscopy (TEM) (See • Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB. • Normal staining with antibodies to keratin 5, keratin 14, or plectin resulting from heterozygous pathogenic variants in • Abnormal or absent staining with antibodies to keratin 5, keratin 14, plectin, BP230 (i.e., BPAG1, BPAG1-e), exophilin 5, and CD151 resulting from biallelic pathogenic variants in • Keratin intermediate filaments (i.e., tonofilaments) may be clumped in severe EBS [ • The absence of keratin intermediate filaments is a distinguishing feature of • In EBS caused by biallelic pathogenic variants in ## Suggestive Findings Epidermolysis bullosa simplex (EBS) Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring Blistering that: May be present in the neonatal period Primarily affects the hands and feet but can affect the whole body Occurs in annular or curvilinear groups or clusters Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life Is associated with palmar and plantar hyperkeratosis that may be severe Nail dystrophy Milia Natal teeth • Fragility of the skin manifested by blistering with little or no trauma, which typically heals without scarring • Blistering that: • May be present in the neonatal period • Primarily affects the hands and feet but can affect the whole body • Occurs in annular or curvilinear groups or clusters • Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life • Is associated with palmar and plantar hyperkeratosis that may be severe • May be present in the neonatal period • Primarily affects the hands and feet but can affect the whole body • Occurs in annular or curvilinear groups or clusters • Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life • Is associated with palmar and plantar hyperkeratosis that may be severe • Nail dystrophy • Milia • Natal teeth • May be present in the neonatal period • Primarily affects the hands and feet but can affect the whole body • Occurs in annular or curvilinear groups or clusters • Can lead to progressive hyperpigmentation interspersed with hypopigmented spots on the trunk and extremities that frequently disappears in adult life • Is associated with palmar and plantar hyperkeratosis that may be severe ## Establishing the Diagnosis The diagnosis of EBS is Identification of a heterozygous dominant-negative or biallelic loss-of-function pathogenic (or likely pathogenic) variants in Characteristic findings on skin biopsy examined via immunofluorescent mapping (IFM) and/or transmission electron microscopy (TEM) (See Note: (1) Both genetic testing and skin biopsy for IFM are often recommended to improve the sensitivity of the diagnostic tests. TEM may also be performed to assess for ultrastructural abnormalities in individuals with inconclusive genetic testing and IFM. (2) 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. (3) Identification of a variant(s) of uncertain significance does not establish or rule out the diagnosis of EBS. Molecular testing approaches can include Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratories conducting the tests and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex NA = not applicable Genes are listed in alphabetic order. See Data derived from the subscription-based professional view of Human Gene Mutation Database [ See In individuals with EBS diagnosed by findings on skin biopsy. 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 a skin biopsy by (1) immunofluorescent mapping (IFM) and/or (2) transmission electron microscopy (TEM) may be performed to establish the diagnosis of EBS. IFM is generally preferred as it can yield results rapidly. Moreover, IFM is less expensive and is therefore more widely performed; it may also be used in prognostication and assessment of disease severity [ A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.) Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB. Normal staining with antibodies to keratin 5, keratin 14, or plectin resulting from heterozygous pathogenic variants in Abnormal or absent staining with antibodies to keratin 5, keratin 14, plectin, BP230 (i.e., BPAG1, BPAG1-e), exophilin 5, and CD151 resulting from biallelic pathogenic variants in Keratin intermediate filaments (i.e., tonofilaments) may be clumped in severe EBS [ The absence of keratin intermediate filaments is a distinguishing feature of In EBS caused by biallelic pathogenic variants in • Identification of a heterozygous dominant-negative or biallelic loss-of-function pathogenic (or likely pathogenic) variants in • Characteristic findings on skin biopsy examined via immunofluorescent mapping (IFM) and/or transmission electron microscopy (TEM) (See • Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB. • Normal staining with antibodies to keratin 5, keratin 14, or plectin resulting from heterozygous pathogenic variants in • Abnormal or absent staining with antibodies to keratin 5, keratin 14, plectin, BP230 (i.e., BPAG1, BPAG1-e), exophilin 5, and CD151 resulting from biallelic pathogenic variants in • Keratin intermediate filaments (i.e., tonofilaments) may be clumped in severe EBS [ • The absence of keratin intermediate filaments is a distinguishing feature of • In EBS caused by biallelic pathogenic variants in ## Option 1 Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratories conducting the tests and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Epidermolysis Bullosa Simplex NA = not applicable Genes are listed in alphabetic order. See Data derived from the subscription-based professional view of Human Gene Mutation Database [ See In individuals with EBS diagnosed by findings on skin biopsy. 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. ## Skin Biopsy Examination of a skin biopsy by (1) immunofluorescent mapping (IFM) and/or (2) transmission electron microscopy (TEM) may be performed to establish the diagnosis of EBS. IFM is generally preferred as it can yield results rapidly. Moreover, IFM is less expensive and is therefore more widely performed; it may also be used in prognostication and assessment of disease severity [ A punch biopsy that includes the full basement membrane zone is preferred. The biopsy should be taken from the leading edge of a fresh (<12 hours old) blister or from a mechanically induced blister and should include some normal adjacent skin. (Older blisters undergo change that may obscure the diagnostic morphology and can be misleading.) Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB. Normal staining with antibodies to keratin 5, keratin 14, or plectin resulting from heterozygous pathogenic variants in Abnormal or absent staining with antibodies to keratin 5, keratin 14, plectin, BP230 (i.e., BPAG1, BPAG1-e), exophilin 5, and CD151 resulting from biallelic pathogenic variants in Keratin intermediate filaments (i.e., tonofilaments) may be clumped in severe EBS [ The absence of keratin intermediate filaments is a distinguishing feature of In EBS caused by biallelic pathogenic variants in • Note: Light microscopy is inadequate and unacceptable for the accurate diagnosis of any subtypes of EB. • Normal staining with antibodies to keratin 5, keratin 14, or plectin resulting from heterozygous pathogenic variants in • Abnormal or absent staining with antibodies to keratin 5, keratin 14, plectin, BP230 (i.e., BPAG1, BPAG1-e), exophilin 5, and CD151 resulting from biallelic pathogenic variants in • Keratin intermediate filaments (i.e., tonofilaments) may be clumped in severe EBS [ • The absence of keratin intermediate filaments is a distinguishing feature of • In EBS caused by biallelic pathogenic variants in ## Clinical Characteristics In contrast to prior classification schemes, the most recent 2020 reclassification system distinguishes between EBS, defined by blistering The most common forms of EBS – localized EBS, intermediate EBS, severe EBS, and EBS with mottled pigmentation – are distinguished primarily on dermatologic, genetic, and histopathologic findings. The clinical features of these disorders are summarized in Select Features of the Four Most Common EBS Subtypes Blisters usually limited to hands, feet; can occur at sites of repeated trauma Rare mucosal blisters Generalized Occasional mucosal blisters Generalized Grouped (herpetiform) blisters Mucosal blisters Generalized ± grouped (herpetiform) blisters ± mucosal blisters Localized EBS, the most common EBS subtype, occurs in approximately 60% of individuals with EBS. Blisters begin in infancy and can present at birth; severity is usually mild. The first episodes may occur on the knees and shins with crawling or on the feet at approximately age 12-18 months, after walking is firmly established. Some affected individuals do not manifest the disease until adolescence or early adult life. Although blisters are usually confined to the hands and feet, they can occur anywhere given adequate trauma; for example, blisters can develop on the buttocks after horseback riding or around the waist after wearing a tight belt. Symptoms can be seasonal, worsening with warm weather and sweating. The palms and soles are usually more involved than the backs of the hands and the tops of the feet, and lesions may be associated with pain and pruritus resulting in reduced mobility during active disease flares. Affected individuals may additionally develop hyperhidrosis of the palms and soles, which in turn can further worsen blistering. Mucosal involvement is rare. Focal hyperkeratosis of the palms and soles at sites of repeated mechanical friction and trauma can develop beginning in late childhood and early adulthood and can cause significant pain and reduced mobility. Occasionally, a large blister in a nail bed may result in shedding of the nail. Intermediate EBS occurs in 15% of individuals with EBS. Blisters can be present at birth or develop within the first few months of life. Blistering and wounding may be severe and life-threatening in neonates and infants, but typically improves as individuals approach late childhood and early adulthood. In general, intermediate EBS is milder than severe EBS, but clinical overlap is high. Similarly, mild intermediate EBS can be indistinguishable from localized EBS. Intermediate EBS is distinguished from localized EBS by its more widespread involvement, and from severe EBS by the absence of clumped keratin intermediate filaments (tonofilaments) in basal keratinocytes on electron microscopy (see Establishing the Diagnosis, Severe EBS occurs in approximately 25% of individuals with EBS. Onset is usually at birth and severity varies greatly both between and within families. Blisters may be large, hemorrhagic, and severe, particularly within the neonatal period. In newborns, there may be significant overlap in clinical presentation with other forms of inherited EB, including dystrophic EB and junctional EB. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical. Hemorrhagic blisters are common. Mucosal involvement such as oral and esophageal blisters and erosions can occur and may interfere with feeding, particularly during infancy and early childhood; this usually improves with age. Laryngeal involvement including laryngeal stenoses or strictures may manifest as hoarseness but is not life threatening. Decreased frequency of blistering occurs during mid- to late childhood and blistering may be a minimal component of the disorder in adult life. Dysphagia and constipation are uncommon but can develop in a subset of individuals; other gastrointestinal involvement more frequently identified in other forms of inherited EB (e.g., esophageal strictures) are not observed in EBS. Progressive hyperkeratosis (focal or diffuse) of the palms and soles begins in childhood and may be the major feature in affected adults. Nail dystrophy (thickened, deformed nails) is common. Both hyper- and hypopigmentation can occur, typically in areas of blistering. Increased cumulative risk of basal cell carcinomas have been identified in individuals with severe EBS; however, increased development of basal cell carcinomas has not been observed in localized EBS or intermediate EBS [ EBS with mottled pigmentation is rare and occurs in fewer than 1% of individuals with EBS. Skin fragility is evident at birth and is clinically indistinguishable from that seen in generalized forms of EBS, including severe EBS. The defining characteristic is the development of small hyperpigmented macules that begin to appear in early childhood, progress over time, and coalesce to a reticulate pattern. Hypopigmented macules may be interspersed. These changes tend to develop on the trunk (particularly in flexural areas; e.g., the neck, groin, and axillae) and then on the extremities (particularly the arms). This pigmentation is not preceded by blistering, which distinguishes it from post-inflammatory hyperpigmentation and hypopigmentation, and often disappears during adulthood. Focal palmar and plantar hyperkeratoses may occur. Infections may be associated with significant morbidity and mortality, particularly among neonates and infants with severe EBS who are at increased risk of death due to sepsis [ Epidermolysis Bullosa Simplex Phenotype Correlations by Gene EBS, intermediate w/ EBS, intermediate w/muscular dystrophy EBS, severe w/pyloric atresia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Pathogenic variants associated with autosomal dominant inheritance act in a dominant-negative manner. The heterozygous pathogenic Limited genotype-phenotype correlations have been reported. Digenic inheritance adds further complexity to genotype-phenotype associations observed in EBS [ Heterozygous pathogenic variants in the nonhelical head and linker segments (L1 and L2), and in the 1A segment of the rod domain are associated with localized EBS. Heterozygous pathogenic variants in the 1A or 2B segments of the rod domain of Heterozygous pathogenic variants in the beginning of the 1A or the end of the 2B segments of the rod domain of Heterozygous In rare consanguineous families, biallelic Penetrance is 100% for biallelic In 1886, Koebner coined the term epidermolysis bullosa hereditaria. In the late nineteenth and early twentieth centuries, Brocq and Hallopeau coined the terms traumatic pemphigus, congenital traumatic blistering, and acantholysis bullosa; these terms are no longer in use [ The nomenclature for EBS has changed five times in the last 20 years. The eponyms EBS-Weber-Cockayne and EBS-Koebner were changed to EBS, localized and EBS, other generalized in the 2008 classification system [ In February 2020, the most recent reclassification system for EB and other skin fragility disorders was published following the 2019 international consensus meeting [ Comparison of 2008 Epidermolysis Bullosa Simplex Nomenclature with 2020 Nomenclature EBS = epidermolysis bullosa simplex; MP = mottled pigmentation Representative examples The prevalence of EBS is uncertain; estimates from different countries range from 6:1,000,000 to 28.6:1,000,000 live births and vary by geographic location [ • Blisters usually limited to hands, feet; can occur at sites of repeated trauma • Rare mucosal blisters • Generalized • Occasional mucosal blisters • Generalized • Grouped (herpetiform) blisters • Mucosal blisters • Generalized • ± grouped (herpetiform) blisters • ± mucosal blisters • EBS, intermediate w/ • EBS, intermediate w/muscular dystrophy • EBS, severe w/pyloric atresia • Heterozygous pathogenic variants in the nonhelical head and linker segments (L1 and L2), and in the 1A segment of the rod domain are associated with localized EBS. • Heterozygous pathogenic variants in the 1A or 2B segments of the rod domain of • Heterozygous pathogenic variants in the beginning of the 1A or the end of the 2B segments of the rod domain of • Heterozygous • In rare consanguineous families, biallelic ## Clinical Description In contrast to prior classification schemes, the most recent 2020 reclassification system distinguishes between EBS, defined by blistering The most common forms of EBS – localized EBS, intermediate EBS, severe EBS, and EBS with mottled pigmentation – are distinguished primarily on dermatologic, genetic, and histopathologic findings. The clinical features of these disorders are summarized in Select Features of the Four Most Common EBS Subtypes Blisters usually limited to hands, feet; can occur at sites of repeated trauma Rare mucosal blisters Generalized Occasional mucosal blisters Generalized Grouped (herpetiform) blisters Mucosal blisters Generalized ± grouped (herpetiform) blisters ± mucosal blisters Localized EBS, the most common EBS subtype, occurs in approximately 60% of individuals with EBS. Blisters begin in infancy and can present at birth; severity is usually mild. The first episodes may occur on the knees and shins with crawling or on the feet at approximately age 12-18 months, after walking is firmly established. Some affected individuals do not manifest the disease until adolescence or early adult life. Although blisters are usually confined to the hands and feet, they can occur anywhere given adequate trauma; for example, blisters can develop on the buttocks after horseback riding or around the waist after wearing a tight belt. Symptoms can be seasonal, worsening with warm weather and sweating. The palms and soles are usually more involved than the backs of the hands and the tops of the feet, and lesions may be associated with pain and pruritus resulting in reduced mobility during active disease flares. Affected individuals may additionally develop hyperhidrosis of the palms and soles, which in turn can further worsen blistering. Mucosal involvement is rare. Focal hyperkeratosis of the palms and soles at sites of repeated mechanical friction and trauma can develop beginning in late childhood and early adulthood and can cause significant pain and reduced mobility. Occasionally, a large blister in a nail bed may result in shedding of the nail. Intermediate EBS occurs in 15% of individuals with EBS. Blisters can be present at birth or develop within the first few months of life. Blistering and wounding may be severe and life-threatening in neonates and infants, but typically improves as individuals approach late childhood and early adulthood. In general, intermediate EBS is milder than severe EBS, but clinical overlap is high. Similarly, mild intermediate EBS can be indistinguishable from localized EBS. Intermediate EBS is distinguished from localized EBS by its more widespread involvement, and from severe EBS by the absence of clumped keratin intermediate filaments (tonofilaments) in basal keratinocytes on electron microscopy (see Establishing the Diagnosis, Severe EBS occurs in approximately 25% of individuals with EBS. Onset is usually at birth and severity varies greatly both between and within families. Blisters may be large, hemorrhagic, and severe, particularly within the neonatal period. In newborns, there may be significant overlap in clinical presentation with other forms of inherited EB, including dystrophic EB and junctional EB. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical. Hemorrhagic blisters are common. Mucosal involvement such as oral and esophageal blisters and erosions can occur and may interfere with feeding, particularly during infancy and early childhood; this usually improves with age. Laryngeal involvement including laryngeal stenoses or strictures may manifest as hoarseness but is not life threatening. Decreased frequency of blistering occurs during mid- to late childhood and blistering may be a minimal component of the disorder in adult life. Dysphagia and constipation are uncommon but can develop in a subset of individuals; other gastrointestinal involvement more frequently identified in other forms of inherited EB (e.g., esophageal strictures) are not observed in EBS. Progressive hyperkeratosis (focal or diffuse) of the palms and soles begins in childhood and may be the major feature in affected adults. Nail dystrophy (thickened, deformed nails) is common. Both hyper- and hypopigmentation can occur, typically in areas of blistering. Increased cumulative risk of basal cell carcinomas have been identified in individuals with severe EBS; however, increased development of basal cell carcinomas has not been observed in localized EBS or intermediate EBS [ EBS with mottled pigmentation is rare and occurs in fewer than 1% of individuals with EBS. Skin fragility is evident at birth and is clinically indistinguishable from that seen in generalized forms of EBS, including severe EBS. The defining characteristic is the development of small hyperpigmented macules that begin to appear in early childhood, progress over time, and coalesce to a reticulate pattern. Hypopigmented macules may be interspersed. These changes tend to develop on the trunk (particularly in flexural areas; e.g., the neck, groin, and axillae) and then on the extremities (particularly the arms). This pigmentation is not preceded by blistering, which distinguishes it from post-inflammatory hyperpigmentation and hypopigmentation, and often disappears during adulthood. Focal palmar and plantar hyperkeratoses may occur. Infections may be associated with significant morbidity and mortality, particularly among neonates and infants with severe EBS who are at increased risk of death due to sepsis [ • Blisters usually limited to hands, feet; can occur at sites of repeated trauma • Rare mucosal blisters • Generalized • Occasional mucosal blisters • Generalized • Grouped (herpetiform) blisters • Mucosal blisters • Generalized • ± grouped (herpetiform) blisters • ± mucosal blisters ## Localized EBS Localized EBS, the most common EBS subtype, occurs in approximately 60% of individuals with EBS. Blisters begin in infancy and can present at birth; severity is usually mild. The first episodes may occur on the knees and shins with crawling or on the feet at approximately age 12-18 months, after walking is firmly established. Some affected individuals do not manifest the disease until adolescence or early adult life. Although blisters are usually confined to the hands and feet, they can occur anywhere given adequate trauma; for example, blisters can develop on the buttocks after horseback riding or around the waist after wearing a tight belt. Symptoms can be seasonal, worsening with warm weather and sweating. The palms and soles are usually more involved than the backs of the hands and the tops of the feet, and lesions may be associated with pain and pruritus resulting in reduced mobility during active disease flares. Affected individuals may additionally develop hyperhidrosis of the palms and soles, which in turn can further worsen blistering. Mucosal involvement is rare. Focal hyperkeratosis of the palms and soles at sites of repeated mechanical friction and trauma can develop beginning in late childhood and early adulthood and can cause significant pain and reduced mobility. Occasionally, a large blister in a nail bed may result in shedding of the nail. ## Intermediate EBS Intermediate EBS occurs in 15% of individuals with EBS. Blisters can be present at birth or develop within the first few months of life. Blistering and wounding may be severe and life-threatening in neonates and infants, but typically improves as individuals approach late childhood and early adulthood. In general, intermediate EBS is milder than severe EBS, but clinical overlap is high. Similarly, mild intermediate EBS can be indistinguishable from localized EBS. Intermediate EBS is distinguished from localized EBS by its more widespread involvement, and from severe EBS by the absence of clumped keratin intermediate filaments (tonofilaments) in basal keratinocytes on electron microscopy (see Establishing the Diagnosis, ## Severe EBS Severe EBS occurs in approximately 25% of individuals with EBS. Onset is usually at birth and severity varies greatly both between and within families. Blisters may be large, hemorrhagic, and severe, particularly within the neonatal period. In newborns, there may be significant overlap in clinical presentation with other forms of inherited EB, including dystrophic EB and junctional EB. Widespread and severe blistering and/or multiple grouped clumps of small blisters are typical. Hemorrhagic blisters are common. Mucosal involvement such as oral and esophageal blisters and erosions can occur and may interfere with feeding, particularly during infancy and early childhood; this usually improves with age. Laryngeal involvement including laryngeal stenoses or strictures may manifest as hoarseness but is not life threatening. Decreased frequency of blistering occurs during mid- to late childhood and blistering may be a minimal component of the disorder in adult life. Dysphagia and constipation are uncommon but can develop in a subset of individuals; other gastrointestinal involvement more frequently identified in other forms of inherited EB (e.g., esophageal strictures) are not observed in EBS. Progressive hyperkeratosis (focal or diffuse) of the palms and soles begins in childhood and may be the major feature in affected adults. Nail dystrophy (thickened, deformed nails) is common. Both hyper- and hypopigmentation can occur, typically in areas of blistering. Increased cumulative risk of basal cell carcinomas have been identified in individuals with severe EBS; however, increased development of basal cell carcinomas has not been observed in localized EBS or intermediate EBS [ ## EBS with Mottled Pigmentation EBS with mottled pigmentation is rare and occurs in fewer than 1% of individuals with EBS. Skin fragility is evident at birth and is clinically indistinguishable from that seen in generalized forms of EBS, including severe EBS. The defining characteristic is the development of small hyperpigmented macules that begin to appear in early childhood, progress over time, and coalesce to a reticulate pattern. Hypopigmented macules may be interspersed. These changes tend to develop on the trunk (particularly in flexural areas; e.g., the neck, groin, and axillae) and then on the extremities (particularly the arms). This pigmentation is not preceded by blistering, which distinguishes it from post-inflammatory hyperpigmentation and hypopigmentation, and often disappears during adulthood. Focal palmar and plantar hyperkeratoses may occur. ## Additional Rare Forms of EBS ## Secondary Complications Infections may be associated with significant morbidity and mortality, particularly among neonates and infants with severe EBS who are at increased risk of death due to sepsis [ ## Phenotype Correlations by Gene Epidermolysis Bullosa Simplex Phenotype Correlations by Gene EBS, intermediate w/ EBS, intermediate w/muscular dystrophy EBS, severe w/pyloric atresia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Pathogenic variants associated with autosomal dominant inheritance act in a dominant-negative manner. The heterozygous pathogenic • EBS, intermediate w/ • EBS, intermediate w/muscular dystrophy • EBS, severe w/pyloric atresia ## Genotype-Phenotype Correlations Limited genotype-phenotype correlations have been reported. Digenic inheritance adds further complexity to genotype-phenotype associations observed in EBS [ Heterozygous pathogenic variants in the nonhelical head and linker segments (L1 and L2), and in the 1A segment of the rod domain are associated with localized EBS. Heterozygous pathogenic variants in the 1A or 2B segments of the rod domain of Heterozygous pathogenic variants in the beginning of the 1A or the end of the 2B segments of the rod domain of Heterozygous In rare consanguineous families, biallelic • Heterozygous pathogenic variants in the nonhelical head and linker segments (L1 and L2), and in the 1A segment of the rod domain are associated with localized EBS. • Heterozygous pathogenic variants in the 1A or 2B segments of the rod domain of • Heterozygous pathogenic variants in the beginning of the 1A or the end of the 2B segments of the rod domain of • Heterozygous • In rare consanguineous families, biallelic ## Penetrance Penetrance is 100% for biallelic ## Nomenclature In 1886, Koebner coined the term epidermolysis bullosa hereditaria. In the late nineteenth and early twentieth centuries, Brocq and Hallopeau coined the terms traumatic pemphigus, congenital traumatic blistering, and acantholysis bullosa; these terms are no longer in use [ The nomenclature for EBS has changed five times in the last 20 years. The eponyms EBS-Weber-Cockayne and EBS-Koebner were changed to EBS, localized and EBS, other generalized in the 2008 classification system [ In February 2020, the most recent reclassification system for EB and other skin fragility disorders was published following the 2019 international consensus meeting [ Comparison of 2008 Epidermolysis Bullosa Simplex Nomenclature with 2020 Nomenclature EBS = epidermolysis bullosa simplex; MP = mottled pigmentation Representative examples ## Prevalence The prevalence of EBS is uncertain; estimates from different countries range from 6:1,000,000 to 28.6:1,000,000 live births and vary by geographic location [ ## Genetically Related (Allelic) Disorders Genetically Related Disorders ## Differential Diagnosis The 2020 classification system [ EB simplex (EBS) Junctional EB (JEB) Dystrophic EB (DEB) Kindler syndrome All forms of EB are characterized by increased skin fragility (and often mucosa) and blistering with little or no trauma. Classification into major type is based on the location of blistering in relation to the dermal-epidermal junction of skin. Subtypes are predominantly determined by clinical features (see Clinical Features Observed in the Four Major Types of Epidermolysis Bullosa DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; EBS = epidermolysis bullosa simplex; JEB = junctional epidermolysis bullosa Post-inflammatory changes, such as those seen in severe EBS, are often mistaken for scarring or mottled pigmentation. Results from extensive scarring of the hands and feet in older children and adults Although clinical examination is useful in determining the extent of blistering and the presence of oral and other mucous membrane lesions, defining characteristics such as the presence and extent of scarring – especially in young children and neonates – may not be established or significant enough to allow identification of EB type; thus, molecular genetic testing (or less commonly skin biopsy) is usually required to establish the most precise diagnosis. Genes of Interest in the Differential Diagnosis of Epidermolysis Bullosa Simplex Adapted from Tables 1 and 2 in AD = autosomal dominant; AR = autosomal recessive; DEB = dystrophic epidermolysis bullosa; EB = epidermolysis bullosa; JEB-PA = junctional epidermolysis bullosa with pyloric atresia; MOI = mode of inheritance • EB simplex (EBS) • Junctional EB (JEB) • Dystrophic EB (DEB) • Kindler syndrome ## Management To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa simplex (EBS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Epidermolysis Bullosa Simplex Consultation w/dermatologist to evaluate sites of blister formation Assess for signs/symptoms of wound infection. Assess for involvement of oral mucosa. Assess feeding & growth in those w/oral disease. Refer to feeding therapist or consider nutritional interventions incl feeding supplementation & gastrostomy tube placement if indicated. Assess need for vitamin & mineral supplementation incl assessment for anemia. Assess weight gain. Assess footwear & for mobility issues. Referral to PT as needed Community or Social work involvement for parental support; Home nursing referral. EBS = epidermolysis bullosa simplex; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing of open wounds, and prevention and treatment of secondary infection are the mainstays of treatment. Lance and drain new blisters (without unroofing the blisters) to prevent further spread from fluid pressure. Dressings usually involve three layers: A primary nonadherent dressing that will adhere to the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers; some individuals with EBS can use ordinary bandages. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline A secondary layer absorbs drainage, provides stability for the primary layer, and adds padding to allow more activity. Foam dressings and/or rolls of gauze (e.g., Kerlix A tertiary layer, usually with some elastic properties, ensures the integrity of the dressing (e.g., Coban™ or elasticized tube gauze of varying diameters such as BandNet Note: Many individuals with EBS, in contrast to those with junctional EB and dystrophic EB, find that excessive bandaging may actually lead to more blistering, presumably as a result of increased heat and sweating. Such individuals may benefit from dusting the affected areas with cornstarch or Zeasorb Newer generations of antimicrobial dressing with impregnated silver, iodine, gentian violet blue, or medical-grade honey may be used to reduce bacterial colonization and promote wound healing. However, these dressings are usually much more costly. In the following studies, small sample sizes limit the statistical validity and generalizability of the results; however, given the lack of effective treatments for EBS, these potentially helpful treatments should be considered: In some individuals with EBS, 20% aluminum chloride applied to palms and soles can reduce blister formation, presumably by decreasing sweating. Case reports and small studies suggest that injection of botulinum toxin into the feet is effective in reducing blistering and associated pain. The mechanism of action is unclear, but likely relates to reduction of sweating and subsequent maceration of the skin [ In one study of a limited number of individuals with severe EBS, cyproheptadine (Periactin In another study, tetracycline reduced blister counts in two thirds of persons with localized EBS [ In a clinical trial, topical diacerein cream reduced blister counts in 60% of individuals with severe EBS [ One pilot study of two individuals suggested that topical application of sirolimus, an mTOR inhibitor, may reduce plantar blistering and keratoderma and improve ambulation [ In a small pilot study of individuals with severe EBS, treatment with apremilast resulted in decreased blistering, potentially through the downregulation of Th17-associated inflammation [ A small case series noted anecdotal reductions in blistering and pain with walking, and increased speed of wound healing following treatment of affected areas with topical cannabidiol oil [ A case report suggested that treatment with intravenous gentamicin may improve translational readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by Management of dehydration and electrolyte disturbances Nutritional support including age-appropriate vitamin and mineral supplementation, and dietary modifications with nutrient-rich feeds. Gastrostomy tubes may be required to ensure adequate intake and to treat or prevent failure to thrive in neonates, infants, and children with intermediate EBS or severe EBS [ Feeding modifications such as Haberman feeders to reduce trauma to the oral mucosa during breastfeeding, soft or pureed foods, and early involvement with a feeding therapist in those with oral aversion as a result of severe oral disease [ Iron supplementation should be considered in those with anemia due to chronic inflammation from ongoing blistering and wounding. Standard treatment is indicated for other manifestations reported, including Recommended Surveillance for Individuals with Epidermolysis Bullosa Simplex Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs/symptoms of wound infection, pain, & itching Assess hydration status. Neurologic assessment for those w/muscular dystrophy Nephrology assessment for those w/nephropathy BNP = B-type natriuretic peptide Excessive heat and sweating may exacerbate blistering, wounding, and infection in EBS. Poorly fitting or coarse-textured clothing and footwear can cause trauma and should be avoided. Avoiding activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) can reduce skin damage; however, affected individuals who are determined to find ways to participate in these endeavors should be encouraged. Many individuals with EBS cannot use medical tape or Band-Aids See If a fetus is known to be affected with any form of EBS, cæsarean delivery may reduce the trauma to the skin during delivery. Vigorous rubbing of the infant after delivery should be avoided to reduce skin trauma. In pregnant mothers with EBS, vaginal delivery is not strictly contraindicated; early discussion of individual preferences and planning with a multidisciplinary care team including obstetricians, anesthesiologists, and neonatologists is recommended to ensure the safety and well-being of both the mother and baby [ Proposed approaches for gene therapy in EBS include the use of CRISPR/Cas9-mediated DNA repair [ Several clinical trials investigating new or repurposed therapeutics to reduce blistering, pain, and itch in EBS are ongoing, and novel computational methods leveraging transcriptome analysis may facilitate further identification of potential drug candidates for repurposing [ Search The use of vitamin E in treating EBS has been reported anecdotally [ • Consultation w/dermatologist to evaluate sites of blister formation • Assess for signs/symptoms of wound infection. • Assess for involvement of oral mucosa. • Assess feeding & growth in those w/oral disease. • Refer to feeding therapist or consider nutritional interventions incl feeding supplementation & gastrostomy tube placement if indicated. • Assess need for vitamin & mineral supplementation incl assessment for anemia. • Assess weight gain. • Assess footwear & for mobility issues. • Referral to PT as needed • Community or • Social work involvement for parental support; • Home nursing referral. • A primary nonadherent dressing that will adhere to the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers; some individuals with EBS can use ordinary bandages. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • A secondary layer absorbs drainage, provides stability for the primary layer, and adds padding to allow more activity. Foam dressings and/or rolls of gauze (e.g., Kerlix • A tertiary layer, usually with some elastic properties, ensures the integrity of the dressing (e.g., Coban™ or elasticized tube gauze of varying diameters such as BandNet • In some individuals with EBS, 20% aluminum chloride applied to palms and soles can reduce blister formation, presumably by decreasing sweating. • Case reports and small studies suggest that injection of botulinum toxin into the feet is effective in reducing blistering and associated pain. The mechanism of action is unclear, but likely relates to reduction of sweating and subsequent maceration of the skin [ • In one study of a limited number of individuals with severe EBS, cyproheptadine (Periactin • In another study, tetracycline reduced blister counts in two thirds of persons with localized EBS [ • In a clinical trial, topical diacerein cream reduced blister counts in 60% of individuals with severe EBS [ • One pilot study of two individuals suggested that topical application of sirolimus, an mTOR inhibitor, may reduce plantar blistering and keratoderma and improve ambulation [ • In a small pilot study of individuals with severe EBS, treatment with apremilast resulted in decreased blistering, potentially through the downregulation of Th17-associated inflammation [ • A small case series noted anecdotal reductions in blistering and pain with walking, and increased speed of wound healing following treatment of affected areas with topical cannabidiol oil [ • A case report suggested that treatment with intravenous gentamicin may improve translational readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by • Management of dehydration and electrolyte disturbances • Nutritional support including age-appropriate vitamin and mineral supplementation, and dietary modifications with nutrient-rich feeds. Gastrostomy tubes may be required to ensure adequate intake and to treat or prevent failure to thrive in neonates, infants, and children with intermediate EBS or severe EBS [ • Feeding modifications such as Haberman feeders to reduce trauma to the oral mucosa during breastfeeding, soft or pureed foods, and early involvement with a feeding therapist in those with oral aversion as a result of severe oral disease [ • Iron supplementation should be considered in those with anemia due to chronic inflammation from ongoing blistering and wounding. • Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs/symptoms of wound infection, pain, & itching • Assess hydration status. • Neurologic assessment for those w/muscular dystrophy • Nephrology assessment for those w/nephropathy ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with epidermolysis bullosa simplex (EBS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Epidermolysis Bullosa Simplex Consultation w/dermatologist to evaluate sites of blister formation Assess for signs/symptoms of wound infection. Assess for involvement of oral mucosa. Assess feeding & growth in those w/oral disease. Refer to feeding therapist or consider nutritional interventions incl feeding supplementation & gastrostomy tube placement if indicated. Assess need for vitamin & mineral supplementation incl assessment for anemia. Assess weight gain. Assess footwear & for mobility issues. Referral to PT as needed Community or Social work involvement for parental support; Home nursing referral. EBS = epidermolysis bullosa simplex; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Consultation w/dermatologist to evaluate sites of blister formation • Assess for signs/symptoms of wound infection. • Assess for involvement of oral mucosa. • Assess feeding & growth in those w/oral disease. • Refer to feeding therapist or consider nutritional interventions incl feeding supplementation & gastrostomy tube placement if indicated. • Assess need for vitamin & mineral supplementation incl assessment for anemia. • Assess weight gain. • Assess footwear & for mobility issues. • Referral to PT as needed • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Supportive care to protect the skin from blistering, appropriate dressings that will not further damage the skin and will promote healing of open wounds, and prevention and treatment of secondary infection are the mainstays of treatment. Lance and drain new blisters (without unroofing the blisters) to prevent further spread from fluid pressure. Dressings usually involve three layers: A primary nonadherent dressing that will adhere to the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers; some individuals with EBS can use ordinary bandages. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline A secondary layer absorbs drainage, provides stability for the primary layer, and adds padding to allow more activity. Foam dressings and/or rolls of gauze (e.g., Kerlix A tertiary layer, usually with some elastic properties, ensures the integrity of the dressing (e.g., Coban™ or elasticized tube gauze of varying diameters such as BandNet Note: Many individuals with EBS, in contrast to those with junctional EB and dystrophic EB, find that excessive bandaging may actually lead to more blistering, presumably as a result of increased heat and sweating. Such individuals may benefit from dusting the affected areas with cornstarch or Zeasorb Newer generations of antimicrobial dressing with impregnated silver, iodine, gentian violet blue, or medical-grade honey may be used to reduce bacterial colonization and promote wound healing. However, these dressings are usually much more costly. In the following studies, small sample sizes limit the statistical validity and generalizability of the results; however, given the lack of effective treatments for EBS, these potentially helpful treatments should be considered: In some individuals with EBS, 20% aluminum chloride applied to palms and soles can reduce blister formation, presumably by decreasing sweating. Case reports and small studies suggest that injection of botulinum toxin into the feet is effective in reducing blistering and associated pain. The mechanism of action is unclear, but likely relates to reduction of sweating and subsequent maceration of the skin [ In one study of a limited number of individuals with severe EBS, cyproheptadine (Periactin In another study, tetracycline reduced blister counts in two thirds of persons with localized EBS [ In a clinical trial, topical diacerein cream reduced blister counts in 60% of individuals with severe EBS [ One pilot study of two individuals suggested that topical application of sirolimus, an mTOR inhibitor, may reduce plantar blistering and keratoderma and improve ambulation [ In a small pilot study of individuals with severe EBS, treatment with apremilast resulted in decreased blistering, potentially through the downregulation of Th17-associated inflammation [ A small case series noted anecdotal reductions in blistering and pain with walking, and increased speed of wound healing following treatment of affected areas with topical cannabidiol oil [ A case report suggested that treatment with intravenous gentamicin may improve translational readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by Management of dehydration and electrolyte disturbances Nutritional support including age-appropriate vitamin and mineral supplementation, and dietary modifications with nutrient-rich feeds. Gastrostomy tubes may be required to ensure adequate intake and to treat or prevent failure to thrive in neonates, infants, and children with intermediate EBS or severe EBS [ Feeding modifications such as Haberman feeders to reduce trauma to the oral mucosa during breastfeeding, soft or pureed foods, and early involvement with a feeding therapist in those with oral aversion as a result of severe oral disease [ Iron supplementation should be considered in those with anemia due to chronic inflammation from ongoing blistering and wounding. Standard treatment is indicated for other manifestations reported, including • A primary nonadherent dressing that will adhere to the top layers of the epidermis must be used. There is wide variability in tolerance to different primary layers; some individuals with EBS can use ordinary bandages. Some dressings are impregnated with an emollient such as petrolatum or topical antiseptic (e.g., Vaseline • A secondary layer absorbs drainage, provides stability for the primary layer, and adds padding to allow more activity. Foam dressings and/or rolls of gauze (e.g., Kerlix • A tertiary layer, usually with some elastic properties, ensures the integrity of the dressing (e.g., Coban™ or elasticized tube gauze of varying diameters such as BandNet • In some individuals with EBS, 20% aluminum chloride applied to palms and soles can reduce blister formation, presumably by decreasing sweating. • Case reports and small studies suggest that injection of botulinum toxin into the feet is effective in reducing blistering and associated pain. The mechanism of action is unclear, but likely relates to reduction of sweating and subsequent maceration of the skin [ • In one study of a limited number of individuals with severe EBS, cyproheptadine (Periactin • In another study, tetracycline reduced blister counts in two thirds of persons with localized EBS [ • In a clinical trial, topical diacerein cream reduced blister counts in 60% of individuals with severe EBS [ • One pilot study of two individuals suggested that topical application of sirolimus, an mTOR inhibitor, may reduce plantar blistering and keratoderma and improve ambulation [ • In a small pilot study of individuals with severe EBS, treatment with apremilast resulted in decreased blistering, potentially through the downregulation of Th17-associated inflammation [ • A small case series noted anecdotal reductions in blistering and pain with walking, and increased speed of wound healing following treatment of affected areas with topical cannabidiol oil [ • A case report suggested that treatment with intravenous gentamicin may improve translational readthrough and increase plectin expression in individuals with EBS, intermediate with muscular dystrophy caused by • Management of dehydration and electrolyte disturbances • Nutritional support including age-appropriate vitamin and mineral supplementation, and dietary modifications with nutrient-rich feeds. Gastrostomy tubes may be required to ensure adequate intake and to treat or prevent failure to thrive in neonates, infants, and children with intermediate EBS or severe EBS [ • Feeding modifications such as Haberman feeders to reduce trauma to the oral mucosa during breastfeeding, soft or pureed foods, and early involvement with a feeding therapist in those with oral aversion as a result of severe oral disease [ • Iron supplementation should be considered in those with anemia due to chronic inflammation from ongoing blistering and wounding. ## Surveillance Recommended Surveillance for Individuals with Epidermolysis Bullosa Simplex Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs/symptoms of wound infection, pain, & itching Assess hydration status. Neurologic assessment for those w/muscular dystrophy Nephrology assessment for those w/nephropathy BNP = B-type natriuretic peptide • Dermatologic assessment for blisters, oral disease, hyperkeratosis, hyperhidrosis, signs/symptoms of wound infection, pain, & itching • Assess hydration status. • Neurologic assessment for those w/muscular dystrophy • Nephrology assessment for those w/nephropathy ## Agents/Circumstances to Avoid Excessive heat and sweating may exacerbate blistering, wounding, and infection in EBS. Poorly fitting or coarse-textured clothing and footwear can cause trauma and should be avoided. Avoiding activities that traumatize the skin (e.g., hiking, mountain biking, contact sports) can reduce skin damage; however, affected individuals who are determined to find ways to participate in these endeavors should be encouraged. Many individuals with EBS cannot use medical tape or Band-Aids ## Evaluation of Relatives at Risk See ## Pregnancy Management If a fetus is known to be affected with any form of EBS, cæsarean delivery may reduce the trauma to the skin during delivery. Vigorous rubbing of the infant after delivery should be avoided to reduce skin trauma. In pregnant mothers with EBS, vaginal delivery is not strictly contraindicated; early discussion of individual preferences and planning with a multidisciplinary care team including obstetricians, anesthesiologists, and neonatologists is recommended to ensure the safety and well-being of both the mother and baby [ ## Therapies Under Investigation Proposed approaches for gene therapy in EBS include the use of CRISPR/Cas9-mediated DNA repair [ Several clinical trials investigating new or repurposed therapeutics to reduce blistering, pain, and itch in EBS are ongoing, and novel computational methods leveraging transcriptome analysis may facilitate further identification of potential drug candidates for repurposing [ Search ## Other The use of vitamin E in treating EBS has been reported anecdotally [ ## Genetic Counseling Epidermolysis bullosa simplex (EBS) is typically inherited in an autosomal recessive or an autosomal dominant manner. Genetic counseling regarding risk to family members depends on accurate molecular diagnosis (i.e., identification of the causative pathogenic variant[s] in an affected family member) and confirmation of the mode of inheritance in each family. Autosomal recessive EBS is associated with: Biallelic loss-of-function variants in Biallelic pathogenic variants in Autosomal dominant EBS is associated with: Heterozygous dominant-negative variants in Heterozygous pathogenic variants in In rare instances, EBS is caused by the presence of heterozygous pathogenic variants in both The parents of an affected child are presumed to be heterozygous for an EBS-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EBS-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. Typically, heterozygous parents of a child with autosomal recessive EBS are unaffected. ( If both parents are known to be heterozygous for an EBS-related pathogenic variant, each sib of an affected individual has at conception 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Typically, heterozygous sibs of a proband with autosomal recessive EBS are unaffected. ( Heterozygote testing for at-risk relatives requires prior identification of the EBS-related pathogenic variants in the family. Individuals diagnosed with EBS caused by a heterozygous dominant-negative Some individuals diagnosed with autosomal dominant EBS 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 [ Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome and/or a milder phenotypic presentation in affected family members. Many families include individuals with a history of "blistering" but are unaware that these individuals have EBS. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance appears to be less than 100% for known heterozygous dominant-negative Heterozygous dominant-negative variants in If the EBS-related pathogenic variant found in the proband 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 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. Each child of an individual with autosomal dominant EBS has a 50% chance of inheriting the EBS-related pathogenic variant. In the rare situation in which both parents have an autosomal dominant pathogenic variant in the same gene (e.g., in consanguineous unions), each child has a 75% chance of having at least one pathogenic variant. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous for an EBS-related pathogenic variant. Once the EBS-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. • Biallelic loss-of-function variants in • Biallelic pathogenic variants in • Heterozygous dominant-negative variants in • Heterozygous pathogenic variants in • The parents of an affected child are presumed to be heterozygous for an EBS-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EBS-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. • Typically, heterozygous parents of a child with autosomal recessive EBS are unaffected. ( • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 EBS-related pathogenic variant, each sib of an affected individual has at conception 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • Typically, heterozygous sibs of a proband with autosomal recessive EBS are unaffected. ( • Individuals diagnosed with EBS caused by a heterozygous dominant-negative • Some individuals diagnosed with autosomal dominant EBS 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 [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome and/or a milder phenotypic presentation in affected family members. Many families include individuals with a history of "blistering" but are unaware that these individuals have EBS. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • The 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 of inheriting the pathogenic variant is 50%. • Penetrance appears to be less than 100% for known heterozygous dominant-negative • Heterozygous dominant-negative variants in • Penetrance appears to be less than 100% for known heterozygous dominant-negative • Heterozygous dominant-negative variants in • If the EBS-related pathogenic variant found in the proband 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 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. • Penetrance appears to be less than 100% for known heterozygous dominant-negative • Heterozygous dominant-negative variants in • Each child of an individual with autosomal dominant EBS has a 50% chance of inheriting the EBS-related pathogenic variant. • In the rare situation in which both parents have an autosomal dominant pathogenic variant in the same gene (e.g., in consanguineous unions), each child has a 75% chance of having at least one pathogenic variant. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous for an EBS-related pathogenic variant. ## Mode of Inheritance Epidermolysis bullosa simplex (EBS) is typically inherited in an autosomal recessive or an autosomal dominant manner. Genetic counseling regarding risk to family members depends on accurate molecular diagnosis (i.e., identification of the causative pathogenic variant[s] in an affected family member) and confirmation of the mode of inheritance in each family. Autosomal recessive EBS is associated with: Biallelic loss-of-function variants in Biallelic pathogenic variants in Autosomal dominant EBS is associated with: Heterozygous dominant-negative variants in Heterozygous pathogenic variants in In rare instances, EBS is caused by the presence of heterozygous pathogenic variants in both • Biallelic loss-of-function variants in • Biallelic pathogenic variants in • Heterozygous dominant-negative variants in • Heterozygous pathogenic variants in ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are presumed to be heterozygous for an EBS-related pathogenic variant. If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EBS-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. Typically, heterozygous parents of a child with autosomal recessive EBS are unaffected. ( If both parents are known to be heterozygous for an EBS-related pathogenic variant, each sib of an affected individual has at conception 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Typically, heterozygous sibs of a proband with autosomal recessive EBS are unaffected. ( Heterozygote testing for at-risk relatives requires prior identification of the EBS-related pathogenic variants in the family. • The parents of an affected child are presumed to be heterozygous for an EBS-related pathogenic variant. • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EBS-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. • Typically, heterozygous parents of a child with autosomal recessive EBS are unaffected. ( • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 EBS-related pathogenic variant, each sib of an affected individual has at conception 25% chance of inheriting biallelic pathogenic variants being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • Typically, heterozygous sibs of a proband with autosomal recessive EBS are unaffected. ( ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the EBS-related pathogenic variants in the family. ## Autosomal Dominant Inheritance – Risk to Family Members Individuals diagnosed with EBS caused by a heterozygous dominant-negative Some individuals diagnosed with autosomal dominant EBS 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 [ Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome and/or a milder phenotypic presentation in affected family members. Many families include individuals with a history of "blistering" but are unaware that these individuals have EBS. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance appears to be less than 100% for known heterozygous dominant-negative Heterozygous dominant-negative variants in If the EBS-related pathogenic variant found in the proband 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 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. Each child of an individual with autosomal dominant EBS has a 50% chance of inheriting the EBS-related pathogenic variant. In the rare situation in which both parents have an autosomal dominant pathogenic variant in the same gene (e.g., in consanguineous unions), each child has a 75% chance of having at least one pathogenic variant. • Individuals diagnosed with EBS caused by a heterozygous dominant-negative • Some individuals diagnosed with autosomal dominant EBS 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 [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure to recognize the syndrome and/or a milder phenotypic presentation in affected family members. Many families include individuals with a history of "blistering" but are unaware that these individuals have EBS. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • The 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 of inheriting the pathogenic variant is 50%. • Penetrance appears to be less than 100% for known heterozygous dominant-negative • Heterozygous dominant-negative variants in • Penetrance appears to be less than 100% for known heterozygous dominant-negative • Heterozygous dominant-negative variants in • If the EBS-related pathogenic variant found in the proband 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 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. • Penetrance appears to be less than 100% for known heterozygous dominant-negative • Heterozygous dominant-negative variants in • Each child of an individual with autosomal dominant EBS has a 50% chance of inheriting the EBS-related pathogenic variant. • In the rare situation in which both parents have an autosomal dominant pathogenic variant in the same gene (e.g., in consanguineous unions), each child has a 75% chance of having at least one pathogenic variant. ## 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 being heterozygous for an EBS-related pathogenic variant. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being heterozygous for an EBS-related pathogenic variant. ## Prenatal Testing and Preimplantation Genetic Testing Once the EBS-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 United Kingdom • • • • • • United Kingdom • • • • • • • • • ## Molecular Genetics Epidermolysis Bullosa Simplex: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Epidermolysis Bullosa Simplex ( Within the epidermis, EBS may also be caused by pathogenic variants in nonstructural proteins. Dominant-negative missense variants in Epidermolysis Bullosa Simplex: Mechanism of Disease Causation Dominant-negative missense variants assoc w/AD inheritance. The mechanism of disease is dependent on the variant, but often results in protein that prevents proper assoc w/the protein partner (e.g., keratin 5, keratin 14) & assembly of those assoc dimers into bundles & fibers. Loss-of-function (typically functionally null alleles) variants assoc w/AR inheritance Dominant-negative missense variants assoc w/AD inheritance Loss-of-function (typically functionally null alleles) variants that have been assoc w/AR inheritance The missense variant Loss-of-function variants assoc w/AR subtypes incl EBS, intermediate w/PLEC pathogenic variants; EBS, intermediate w/muscular dystrophy; & EBS, severe w/ pyloric atresia AD = autosomal dominant; AR = autosomal recessive; EBS = epidermolysis bullosa simplex Genes from Epidermolysis Bullosa Simplex: Gene-Specific Laboratory Considerations Epidermolysis Bullosa Simplex: Notable Pathogenic Variants by Gene AD = autosomal dominant; EBS = epidermolysis bullosa simplex Variants listed in the table have been provided by the authors. Genes from • Dominant-negative missense variants assoc w/AD inheritance. The mechanism of disease is dependent on the variant, but often results in protein that prevents proper assoc w/the protein partner (e.g., keratin 5, keratin 14) & assembly of those assoc dimers into bundles & fibers. • Loss-of-function (typically functionally null alleles) variants assoc w/AR inheritance • Dominant-negative missense variants assoc w/AD inheritance • Loss-of-function (typically functionally null alleles) variants that have been assoc w/AR inheritance • The missense variant • Loss-of-function variants assoc w/AR subtypes incl EBS, intermediate w/PLEC pathogenic variants; EBS, intermediate w/muscular dystrophy; & EBS, severe w/ pyloric atresia ## Molecular Pathogenesis Within the epidermis, EBS may also be caused by pathogenic variants in nonstructural proteins. Dominant-negative missense variants in Epidermolysis Bullosa Simplex: Mechanism of Disease Causation Dominant-negative missense variants assoc w/AD inheritance. The mechanism of disease is dependent on the variant, but often results in protein that prevents proper assoc w/the protein partner (e.g., keratin 5, keratin 14) & assembly of those assoc dimers into bundles & fibers. Loss-of-function (typically functionally null alleles) variants assoc w/AR inheritance Dominant-negative missense variants assoc w/AD inheritance Loss-of-function (typically functionally null alleles) variants that have been assoc w/AR inheritance The missense variant Loss-of-function variants assoc w/AR subtypes incl EBS, intermediate w/PLEC pathogenic variants; EBS, intermediate w/muscular dystrophy; & EBS, severe w/ pyloric atresia AD = autosomal dominant; AR = autosomal recessive; EBS = epidermolysis bullosa simplex Genes from Epidermolysis Bullosa Simplex: Gene-Specific Laboratory Considerations Epidermolysis Bullosa Simplex: Notable Pathogenic Variants by Gene AD = autosomal dominant; EBS = epidermolysis bullosa simplex Variants listed in the table have been provided by the authors. Genes from • Dominant-negative missense variants assoc w/AD inheritance. The mechanism of disease is dependent on the variant, but often results in protein that prevents proper assoc w/the protein partner (e.g., keratin 5, keratin 14) & assembly of those assoc dimers into bundles & fibers. • Loss-of-function (typically functionally null alleles) variants assoc w/AR inheritance • Dominant-negative missense variants assoc w/AD inheritance • Loss-of-function (typically functionally null alleles) variants that have been assoc w/AR inheritance • The missense variant • Loss-of-function variants assoc w/AR subtypes incl EBS, intermediate w/PLEC pathogenic variants; EBS, intermediate w/muscular dystrophy; & EBS, severe w/ pyloric atresia ## Chapter Notes Anna L Bruckner, MD; University of Colorado School of Medicine (2008-2022)Anne W Lucky, MD; Cincinnati Children's Hospital (2005-2008)Ellen G Pfendner, PhD; GeneDx, Inc (2005-2022)Jodi Y So, BA (2022-present)Karen Stephens, PhD; University of Washington, Seattle (1998-2005)Virginia P Sybert, MD; University of Washington, Seattle (1998-2005)Joyce Teng, MD, PhD (2022-present) 4 August 2022 (sw) Comprehensive update posted live 13 October 2016 (ma) Comprehensive update posted live 1 September 2011 (me) Comprehensive update posted live 11 August 2008 (et) Comprehensive update posted live 3 November 2005 (me) Comprehensive update posted live 16 July 2003 (me) Comprehensive update posted live 2 February 2001 (me) Comprehensive update posted live 7 October 1998 (me) Review posted live 13 February 1998 (vs) Original submission • 4 August 2022 (sw) Comprehensive update posted live • 13 October 2016 (ma) Comprehensive update posted live • 1 September 2011 (me) Comprehensive update posted live • 11 August 2008 (et) Comprehensive update posted live • 3 November 2005 (me) Comprehensive update posted live • 16 July 2003 (me) Comprehensive update posted live • 2 February 2001 (me) Comprehensive update posted live • 7 October 1998 (me) Review posted live • 13 February 1998 (vs) Original submission ## Author Notes ## Author History Anna L Bruckner, MD; University of Colorado School of Medicine (2008-2022)Anne W Lucky, MD; Cincinnati Children's Hospital (2005-2008)Ellen G Pfendner, PhD; GeneDx, Inc (2005-2022)Jodi Y So, BA (2022-present)Karen Stephens, PhD; University of Washington, Seattle (1998-2005)Virginia P Sybert, MD; University of Washington, Seattle (1998-2005)Joyce Teng, MD, PhD (2022-present) ## Revision History 4 August 2022 (sw) Comprehensive update posted live 13 October 2016 (ma) Comprehensive update posted live 1 September 2011 (me) Comprehensive update posted live 11 August 2008 (et) Comprehensive update posted live 3 November 2005 (me) Comprehensive update posted live 16 July 2003 (me) Comprehensive update posted live 2 February 2001 (me) Comprehensive update posted live 7 October 1998 (me) Review posted live 13 February 1998 (vs) Original submission • 4 August 2022 (sw) Comprehensive update posted live • 13 October 2016 (ma) Comprehensive update posted live • 1 September 2011 (me) Comprehensive update posted live • 11 August 2008 (et) Comprehensive update posted live • 3 November 2005 (me) Comprehensive update posted live • 16 July 2003 (me) Comprehensive update posted live • 2 February 2001 (me) Comprehensive update posted live • 7 October 1998 (me) Review posted live • 13 February 1998 (vs) Original submission ## References ## Literature Cited
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7/10/1998
4/8/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eccl
eccl
[ "Fishman Syndrome", "Haberland Syndrome", "Fishman Syndrome", "Haberland Syndrome", "Fibroblast growth factor receptor 1", "GTPase KRas", "FGFR1", "KRAS", "Encephalocraniocutaneous Lipomatosis" ]
Encephalocraniocutaneous Lipomatosis
Ute Moog, William B Dobyns
Summary Encephalocraniocutaneous lipomatosis (ECCL) comprises a spectrum of predominantly congenital anomalies. In its typical form, ECCL is characterized by congenital anomalies of the skin (nevus psiloliparus, patchy or streaky non-scarring alopecia, subcutaneous lipomas in the frontotemporal region, focal skin aplasia or hypoplasia on the scalp, and/or small nodular skin tags on the eyelids or between the outer canthus and tragus), eye (choristoma), and brain (in particular intracranial and spinal lipomas). To a much lesser degree, the bones and the heart can be affected. About 40% of affected individuals have bilateral abnormalities of the skin or the eyes. About one third of affected individuals have normal cognitive development, another one third have mild developmental delay (DD) or intellectual disability (ID), and the final one third have severe or unspecified DD/ID. Half of individuals have seizures. Affected individuals are at an increased (i.e., above the general population) risk of developing brain tumors, particularly low-grade gliomas such as pilocytic astrocytomas. There is evidence that oculoectodermal syndrome (OES) may constitute a clinical spectrum with ECCL, with OES on the mild end and ECCL on the more severe end of the spectrum. A clinical diagnosis of ECCL can be made in individuals with: Involvement of at least three systems, with major criteria in at least two of the three systems; Involvement of at least three systems, in which one major criterion is either a biopsy-proven nevus psiloliparus (NP) OR a possible NP with at least one other minor skin criterion; At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP or a possible NP with at least one other minor skin criterion. A molecular diagnosis can be established in a proband with suggestive findings and a mosaic activating pathogenic variant identified in either ECCL is not known to be inherited. No confirmed vertical transmission or sib recurrence has been reported. Given the postzygotic mutational mechanism of ECCL, the risk for an affected sib would be expected to be the same as in the general population.
## Diagnosis Clinical diagnostic criteria for encephalocraniocutaneous lipomatosis (ECCL) have been published [ ECCL Biopsy-proven nevus psiloliparus (NP) ( Possible NP in addition to one or more of the other minor skin criteria listed below Two or more minor skin criteria listed Intracranial lipoma ( Intraspinal lipoma ( Low-grade glioma (if associated with other suggestive findings) Two minor CNS criteria listed below Jaw tumor (osteoma, odontoma, or ossifying fibroma) ( Multiple bone cysts ( Aortic coarctation Possible NP Patchy or streaky non-scarring alopecia (without fatty nevus) ( Subcutaneous lipoma(s) in the frontotemporal region ( Focal skin aplasia/hypoplasia on the scalp Small nodular skin tags on the eyelids or between outer canthus and tragus Corneal and other anterior chamber anomalies Ocular or eyelid coloboma Calcification of the globe Abnormal intracranial vessels (e.g., angioma, excessive vessels) Arachnoid cyst or other abnormality of meninges Complete or partial atrophy of a hemisphere Porencephalic cysts(s) Asymmetrically dilated ventricles or hydrocephalus Calcification not involving the basal ganglia The A clinical diagnosis can be made in an individual with: Involvement of at least three systems, with major criteria in at least two out of the three systems; Involvement of at least three systems, in which one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion; At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion. Molecular genetic testing approaches typically include use of Experience suggests that sequence analysis of DNA derived from affected tissue has the best detection rate with the highest levels detected in fibroblast culture derived from skin overlying nevus psiloliparus, non-ossifying fibromas, and dermoids. Pathogenic variants have been detected in DNA derived from skin biopsy-based fibroblast cultures; however, the impact of cell culture on pathogenic variant levels remains uncertain. DNA directly obtained from these tissues, without culture, should be prioritized for genetic testing. Intermediate levels of somatic pathogenic variants have been detected in lipoma, bone, and non-affected skin, but these should be used primarily when biopsies of higher-yield lesions are not available. The level of mosaicism for an activating variant in skin is variable, whether a lesion (aplasia, alopecia, or hyperpigmentation) is seen or not. Sequence analysis of DNA from blood, buccal swabs, and saliva has been uniformly normal (i.e., it did not identify a mosaic-activating pathogenic variant) ‒ with the exception of one individual in whom ultra-deep sequencing by digital droplet PCR (ddPCR) detected a pathogenic variant allele fraction (level of mosaicism) at or below 1% [ 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest a diagnosis of ECCL, molecular genetic testing approaches can include use of a For an introduction to multigene panels click Notes: (1) The mosaic pathogenic variants observed in both When the diagnosis of ECCL has not been considered because an individual has atypical phenotypic features, Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Encephalocraniocutaneous Lipomatosis 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 The specific pathogenic variants in Due to the somatic mosaic nature of ECCL, the actual detection rate depends on the sample provided, the molecular genetic testing method used, and the targeted variants evaluated. However, targeted variant analysis has the potential to detect the specific pathogenic variants listed in footnote 6 for Sequence analysis should detect all of the pathogenic variants detectable by targeted variant analysis, although sequence analysis may also detect other pathogenic variants that are causative of other phenotypes (see The numbers include four individuals with an ECCL phenotype [ It is controversial whether OES is within the spectrum of ECCL. Some individuals who have a clinical diagnosis of OES do not meet the clinical diagnostic criteria for ECCL and do not have an identifiable pathogenic variant in KRAS, and therefore do not meet either diagnostic criteria for ECCL. However, this could be because molecular genetic testing for ECCL is challenging due to the mosaic nature of the pathogenic variant. Some individuals diagnosed with OES have pathogenic variants in NRAS (see The specific pathogenic variants in • Biopsy-proven nevus psiloliparus (NP) ( • Possible NP in addition to one or more of the other minor skin criteria listed below • Two or more minor skin criteria listed • Intracranial lipoma ( • Intraspinal lipoma ( • Low-grade glioma (if associated with other suggestive findings) • Two minor CNS criteria listed below • Jaw tumor (osteoma, odontoma, or ossifying fibroma) ( • Multiple bone cysts ( • Aortic coarctation • Possible NP • Patchy or streaky non-scarring alopecia (without fatty nevus) ( • Subcutaneous lipoma(s) in the frontotemporal region ( • Focal skin aplasia/hypoplasia on the scalp • Small nodular skin tags on the eyelids or between outer canthus and tragus • Corneal and other anterior chamber anomalies • Ocular or eyelid coloboma • Calcification of the globe • Abnormal intracranial vessels (e.g., angioma, excessive vessels) • Arachnoid cyst or other abnormality of meninges • Complete or partial atrophy of a hemisphere • Porencephalic cysts(s) • Asymmetrically dilated ventricles or hydrocephalus • Calcification not involving the basal ganglia • Involvement of at least three systems, with major criteria in at least two out of the three systems; • Involvement of at least three systems, in which one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion; • At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion. • Experience suggests that sequence analysis of DNA derived from affected tissue has the best detection rate with the highest levels detected in fibroblast culture derived from skin overlying nevus psiloliparus, non-ossifying fibromas, and dermoids. Pathogenic variants have been detected in DNA derived from skin biopsy-based fibroblast cultures; however, the impact of cell culture on pathogenic variant levels remains uncertain. DNA directly obtained from these tissues, without culture, should be prioritized for genetic testing. • Intermediate levels of somatic pathogenic variants have been detected in lipoma, bone, and non-affected skin, but these should be used primarily when biopsies of higher-yield lesions are not available. • The level of mosaicism for an activating variant in skin is variable, whether a lesion (aplasia, alopecia, or hyperpigmentation) is seen or not. • Sequence analysis of DNA from blood, buccal swabs, and saliva has been uniformly normal (i.e., it did not identify a mosaic-activating pathogenic variant) ‒ with the exception of one individual in whom ultra-deep sequencing by digital droplet PCR (ddPCR) detected a pathogenic variant allele fraction (level of mosaicism) at or below 1% [ • For an introduction to multigene panels click ## Suggestive Findings ECCL Biopsy-proven nevus psiloliparus (NP) ( Possible NP in addition to one or more of the other minor skin criteria listed below Two or more minor skin criteria listed Intracranial lipoma ( Intraspinal lipoma ( Low-grade glioma (if associated with other suggestive findings) Two minor CNS criteria listed below Jaw tumor (osteoma, odontoma, or ossifying fibroma) ( Multiple bone cysts ( Aortic coarctation Possible NP Patchy or streaky non-scarring alopecia (without fatty nevus) ( Subcutaneous lipoma(s) in the frontotemporal region ( Focal skin aplasia/hypoplasia on the scalp Small nodular skin tags on the eyelids or between outer canthus and tragus Corneal and other anterior chamber anomalies Ocular or eyelid coloboma Calcification of the globe Abnormal intracranial vessels (e.g., angioma, excessive vessels) Arachnoid cyst or other abnormality of meninges Complete or partial atrophy of a hemisphere Porencephalic cysts(s) Asymmetrically dilated ventricles or hydrocephalus Calcification not involving the basal ganglia • Biopsy-proven nevus psiloliparus (NP) ( • Possible NP in addition to one or more of the other minor skin criteria listed below • Two or more minor skin criteria listed • Intracranial lipoma ( • Intraspinal lipoma ( • Low-grade glioma (if associated with other suggestive findings) • Two minor CNS criteria listed below • Jaw tumor (osteoma, odontoma, or ossifying fibroma) ( • Multiple bone cysts ( • Aortic coarctation • Possible NP • Patchy or streaky non-scarring alopecia (without fatty nevus) ( • Subcutaneous lipoma(s) in the frontotemporal region ( • Focal skin aplasia/hypoplasia on the scalp • Small nodular skin tags on the eyelids or between outer canthus and tragus • Corneal and other anterior chamber anomalies • Ocular or eyelid coloboma • Calcification of the globe • Abnormal intracranial vessels (e.g., angioma, excessive vessels) • Arachnoid cyst or other abnormality of meninges • Complete or partial atrophy of a hemisphere • Porencephalic cysts(s) • Asymmetrically dilated ventricles or hydrocephalus • Calcification not involving the basal ganglia ## Major Criteria Biopsy-proven nevus psiloliparus (NP) ( Possible NP in addition to one or more of the other minor skin criteria listed below Two or more minor skin criteria listed Intracranial lipoma ( Intraspinal lipoma ( Low-grade glioma (if associated with other suggestive findings) Two minor CNS criteria listed below Jaw tumor (osteoma, odontoma, or ossifying fibroma) ( Multiple bone cysts ( Aortic coarctation • Biopsy-proven nevus psiloliparus (NP) ( • Possible NP in addition to one or more of the other minor skin criteria listed below • Two or more minor skin criteria listed • Intracranial lipoma ( • Intraspinal lipoma ( • Low-grade glioma (if associated with other suggestive findings) • Two minor CNS criteria listed below • Jaw tumor (osteoma, odontoma, or ossifying fibroma) ( • Multiple bone cysts ( • Aortic coarctation ## Minor Criteria Possible NP Patchy or streaky non-scarring alopecia (without fatty nevus) ( Subcutaneous lipoma(s) in the frontotemporal region ( Focal skin aplasia/hypoplasia on the scalp Small nodular skin tags on the eyelids or between outer canthus and tragus Corneal and other anterior chamber anomalies Ocular or eyelid coloboma Calcification of the globe Abnormal intracranial vessels (e.g., angioma, excessive vessels) Arachnoid cyst or other abnormality of meninges Complete or partial atrophy of a hemisphere Porencephalic cysts(s) Asymmetrically dilated ventricles or hydrocephalus Calcification not involving the basal ganglia • Possible NP • Patchy or streaky non-scarring alopecia (without fatty nevus) ( • Subcutaneous lipoma(s) in the frontotemporal region ( • Focal skin aplasia/hypoplasia on the scalp • Small nodular skin tags on the eyelids or between outer canthus and tragus • Corneal and other anterior chamber anomalies • Ocular or eyelid coloboma • Calcification of the globe • Abnormal intracranial vessels (e.g., angioma, excessive vessels) • Arachnoid cyst or other abnormality of meninges • Complete or partial atrophy of a hemisphere • Porencephalic cysts(s) • Asymmetrically dilated ventricles or hydrocephalus • Calcification not involving the basal ganglia ## Establishing the Diagnosis The A clinical diagnosis can be made in an individual with: Involvement of at least three systems, with major criteria in at least two out of the three systems; Involvement of at least three systems, in which one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion; At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion. Molecular genetic testing approaches typically include use of Experience suggests that sequence analysis of DNA derived from affected tissue has the best detection rate with the highest levels detected in fibroblast culture derived from skin overlying nevus psiloliparus, non-ossifying fibromas, and dermoids. Pathogenic variants have been detected in DNA derived from skin biopsy-based fibroblast cultures; however, the impact of cell culture on pathogenic variant levels remains uncertain. DNA directly obtained from these tissues, without culture, should be prioritized for genetic testing. Intermediate levels of somatic pathogenic variants have been detected in lipoma, bone, and non-affected skin, but these should be used primarily when biopsies of higher-yield lesions are not available. The level of mosaicism for an activating variant in skin is variable, whether a lesion (aplasia, alopecia, or hyperpigmentation) is seen or not. Sequence analysis of DNA from blood, buccal swabs, and saliva has been uniformly normal (i.e., it did not identify a mosaic-activating pathogenic variant) ‒ with the exception of one individual in whom ultra-deep sequencing by digital droplet PCR (ddPCR) detected a pathogenic variant allele fraction (level of mosaicism) at or below 1% [ 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest a diagnosis of ECCL, molecular genetic testing approaches can include use of a For an introduction to multigene panels click Notes: (1) The mosaic pathogenic variants observed in both When the diagnosis of ECCL has not been considered because an individual has atypical phenotypic features, Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Encephalocraniocutaneous Lipomatosis 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 The specific pathogenic variants in Due to the somatic mosaic nature of ECCL, the actual detection rate depends on the sample provided, the molecular genetic testing method used, and the targeted variants evaluated. However, targeted variant analysis has the potential to detect the specific pathogenic variants listed in footnote 6 for Sequence analysis should detect all of the pathogenic variants detectable by targeted variant analysis, although sequence analysis may also detect other pathogenic variants that are causative of other phenotypes (see The numbers include four individuals with an ECCL phenotype [ It is controversial whether OES is within the spectrum of ECCL. Some individuals who have a clinical diagnosis of OES do not meet the clinical diagnostic criteria for ECCL and do not have an identifiable pathogenic variant in KRAS, and therefore do not meet either diagnostic criteria for ECCL. However, this could be because molecular genetic testing for ECCL is challenging due to the mosaic nature of the pathogenic variant. Some individuals diagnosed with OES have pathogenic variants in NRAS (see The specific pathogenic variants in • Involvement of at least three systems, with major criteria in at least two out of the three systems; • Involvement of at least three systems, in which one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion; • At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion. • Experience suggests that sequence analysis of DNA derived from affected tissue has the best detection rate with the highest levels detected in fibroblast culture derived from skin overlying nevus psiloliparus, non-ossifying fibromas, and dermoids. Pathogenic variants have been detected in DNA derived from skin biopsy-based fibroblast cultures; however, the impact of cell culture on pathogenic variant levels remains uncertain. DNA directly obtained from these tissues, without culture, should be prioritized for genetic testing. • Intermediate levels of somatic pathogenic variants have been detected in lipoma, bone, and non-affected skin, but these should be used primarily when biopsies of higher-yield lesions are not available. • The level of mosaicism for an activating variant in skin is variable, whether a lesion (aplasia, alopecia, or hyperpigmentation) is seen or not. • Sequence analysis of DNA from blood, buccal swabs, and saliva has been uniformly normal (i.e., it did not identify a mosaic-activating pathogenic variant) ‒ with the exception of one individual in whom ultra-deep sequencing by digital droplet PCR (ddPCR) detected a pathogenic variant allele fraction (level of mosaicism) at or below 1% [ • For an introduction to multigene panels click ## Clinical Diagnosis A clinical diagnosis can be made in an individual with: Involvement of at least three systems, with major criteria in at least two out of the three systems; Involvement of at least three systems, in which one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion; At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion. • Involvement of at least three systems, with major criteria in at least two out of the three systems; • Involvement of at least three systems, in which one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion; • At least one major criterion in each of two systems, where one major criterion is either a biopsy-proven NP OR a possible NP with at least one other minor skin criterion. ## Molecular Diagnosis Molecular genetic testing approaches typically include use of Experience suggests that sequence analysis of DNA derived from affected tissue has the best detection rate with the highest levels detected in fibroblast culture derived from skin overlying nevus psiloliparus, non-ossifying fibromas, and dermoids. Pathogenic variants have been detected in DNA derived from skin biopsy-based fibroblast cultures; however, the impact of cell culture on pathogenic variant levels remains uncertain. DNA directly obtained from these tissues, without culture, should be prioritized for genetic testing. Intermediate levels of somatic pathogenic variants have been detected in lipoma, bone, and non-affected skin, but these should be used primarily when biopsies of higher-yield lesions are not available. The level of mosaicism for an activating variant in skin is variable, whether a lesion (aplasia, alopecia, or hyperpigmentation) is seen or not. Sequence analysis of DNA from blood, buccal swabs, and saliva has been uniformly normal (i.e., it did not identify a mosaic-activating pathogenic variant) ‒ with the exception of one individual in whom ultra-deep sequencing by digital droplet PCR (ddPCR) detected a pathogenic variant allele fraction (level of mosaicism) at or below 1% [ 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in When the phenotypic findings suggest a diagnosis of ECCL, molecular genetic testing approaches can include use of a For an introduction to multigene panels click Notes: (1) The mosaic pathogenic variants observed in both When the diagnosis of ECCL has not been considered because an individual has atypical phenotypic features, Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Encephalocraniocutaneous Lipomatosis 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 The specific pathogenic variants in Due to the somatic mosaic nature of ECCL, the actual detection rate depends on the sample provided, the molecular genetic testing method used, and the targeted variants evaluated. However, targeted variant analysis has the potential to detect the specific pathogenic variants listed in footnote 6 for Sequence analysis should detect all of the pathogenic variants detectable by targeted variant analysis, although sequence analysis may also detect other pathogenic variants that are causative of other phenotypes (see The numbers include four individuals with an ECCL phenotype [ It is controversial whether OES is within the spectrum of ECCL. Some individuals who have a clinical diagnosis of OES do not meet the clinical diagnostic criteria for ECCL and do not have an identifiable pathogenic variant in KRAS, and therefore do not meet either diagnostic criteria for ECCL. However, this could be because molecular genetic testing for ECCL is challenging due to the mosaic nature of the pathogenic variant. Some individuals diagnosed with OES have pathogenic variants in NRAS (see The specific pathogenic variants in • Experience suggests that sequence analysis of DNA derived from affected tissue has the best detection rate with the highest levels detected in fibroblast culture derived from skin overlying nevus psiloliparus, non-ossifying fibromas, and dermoids. Pathogenic variants have been detected in DNA derived from skin biopsy-based fibroblast cultures; however, the impact of cell culture on pathogenic variant levels remains uncertain. DNA directly obtained from these tissues, without culture, should be prioritized for genetic testing. • Intermediate levels of somatic pathogenic variants have been detected in lipoma, bone, and non-affected skin, but these should be used primarily when biopsies of higher-yield lesions are not available. • The level of mosaicism for an activating variant in skin is variable, whether a lesion (aplasia, alopecia, or hyperpigmentation) is seen or not. • Sequence analysis of DNA from blood, buccal swabs, and saliva has been uniformly normal (i.e., it did not identify a mosaic-activating pathogenic variant) ‒ with the exception of one individual in whom ultra-deep sequencing by digital droplet PCR (ddPCR) detected a pathogenic variant allele fraction (level of mosaicism) at or below 1% [ • For an introduction to multigene panels click ## When the phenotypic findings suggest a diagnosis of ECCL, molecular genetic testing approaches can include use of a For an introduction to multigene panels click Notes: (1) The mosaic pathogenic variants observed in both • For an introduction to multigene panels click ## When the diagnosis of ECCL has not been considered because an individual has atypical phenotypic features, Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Encephalocraniocutaneous Lipomatosis 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 The specific pathogenic variants in Due to the somatic mosaic nature of ECCL, the actual detection rate depends on the sample provided, the molecular genetic testing method used, and the targeted variants evaluated. However, targeted variant analysis has the potential to detect the specific pathogenic variants listed in footnote 6 for Sequence analysis should detect all of the pathogenic variants detectable by targeted variant analysis, although sequence analysis may also detect other pathogenic variants that are causative of other phenotypes (see The numbers include four individuals with an ECCL phenotype [ It is controversial whether OES is within the spectrum of ECCL. Some individuals who have a clinical diagnosis of OES do not meet the clinical diagnostic criteria for ECCL and do not have an identifiable pathogenic variant in KRAS, and therefore do not meet either diagnostic criteria for ECCL. However, this could be because molecular genetic testing for ECCL is challenging due to the mosaic nature of the pathogenic variant. Some individuals diagnosed with OES have pathogenic variants in NRAS (see The specific pathogenic variants in ## Clinical Characteristics To date, at least 85 individuals with a clinical and/or molecular diagnosis of encephalocraniocutaneous lipomatosis (ECCL) have been reported [ Note: There is evidence that oculoectodermal syndrome (OES) may constitute a clinical spectrum with ECCL, with OES on the mild end and ECCL on the more severe end of the spectrum. Individuals who do not fulfill the clinical diagnostic criteria for ECCL but display some features have sometimes been reported as having OES (see ECCL comprises a spectrum of predominantly congenital anomalies. In its typical form, ECCL is characterized by congenital skin, eye, and brain anomalies, in particular intracranial and spinal lipomas. To a much lesser degree, the bones and the heart can be affected. About 40% of affected individuals have bilateral abnormalities of the skin or the eyes. Although variable in its extent and severity, the pattern of skin and eye findings is often consistent and recognizable. Since 2016, ECCL has also been recognized as a tumor predisposition syndrome [ Encephalocraniocutaneous Lipomatosis: Frequency of Select Features Based on CNS = central nervous system A smooth, hairless fatty tissue nevus of the scalp, the so-called nevus psiloliparus (NP) ( In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( Rarely, subcutaneous lipomas are seen outside the craniofacial region. Alopecia without a fatty nevus can be linear or patchy, and may follow the lines of Blaschko ( Areas of focal skin aplasia are usually not extensive (up to a few cm in size) and there have been no reports of affected individuals requiring surgical treatment, such as skin graft, for focal skin aplasia. Small nodular skin tags (which histologically are fibromas, lipomas, fibrolipomas, or choristomas) are found in about 70%-75% of affected individuals, most often on the eyelids or following a line from the outer canthus to the tragus. Some individuals have several café au lait spots. Linear hyperpigmentation following the lines of Blaschko and (rarely) asymmetric growth may be seen [ Choristomas are benign ocular tumors and include epibulbar or limbal dermoids (dermolipomas) derived from epidermis and dermis, and lipodermoids, which consist mainly of fat and rarely decrease vision [ Dermolipomas can be associated with significant additional eye anomalies listed below. Most affected individuals without choristomas have one or more of the following associated eye anomalies: Corneal and scleral anomalies Other anterior chamber abnormalities Ocular and palpebral colobomas Aniridia Microphthalmia Calcification of the globe Almost 60% of these are located in the cerebello-pontine angle. Spinal lipomas, which can extend over the whole length of the spinal cord ( Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( While this finding could represent ascertainment bias, it is suspected that these vascular abnormalities are common, as many of the other brain abnormalities observed could result from prenatal (or, less likely, postnatal) vascular perfusion defects or hemorrhage, including asymmetric brain atrophy, porencephaly, ventriculomegaly, and calcifications [ Encephalocraniocutaneous Lipomatosis: Frequency of Central Nervous System Anomalies in 52 Affected Individuals Who Underwent Imaging Adapted from Unless otherwise specified, the denominator used for calculating the percentages is 52. The numbers shown include only those individuals for whom information about the respective abnormality was available. Many others had no information available; thus, actual numbers and percentages are very likely higher. Among reported individuals with ECCL, about one third have normal cognitive development, one third have mild developmental delay (DD) or ID, and the final one third have severe or unspecified DD/ID. About half of affected individuals had a history of typically infant- or childhood-onset epileptic seizures of different types that may be refractory or difficult to treat. Jaw tumors identified as osteomas, odontomas, or ossifying fibromas have been described in affected individuals [ In severely affected individuals, possibly progressive, multiple lytic bone lesions affecting the long bones have been described ( Brain tumors, specifically low-grade gliomas (although high-grade gliomas have also been observed) [ Pilocytic astrocytomas have been reported in six of 14 (43%) individuals with Possibly Wilms tumor The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic Macrocephaly (in ~20% of affected individuals); Congenital heart malformations, in particular aortic coarctation. In at least seven individuals with a clinical diagnosis of OES, postzygotic activating variants in Comparing Compared to individuals with Less likely to have central nervous system lipomas Less likely to develop an astrocytoma (none reported to date) More likely to have: Body asymmetry Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) Epidermal nevi Other malformations Although these are preliminary considerations based on a small number of known affected individuals, the difference between To date, all individuals with molecularly confirmed ECCL have had mosaicism for one of a few known gain-of-function pathogenic variants in either ECCL refers to the characteristic phenotypic findings involving the skin, eye, and central nervous system. OES may be at one end of the ECCL spectrum [ The prevalence of ECCL is unknown. At least 85 individuals who meet the clinical diagnostic criteria or who have a molecular diagnosis of ECCL have been reported. • A smooth, hairless fatty tissue nevus of the scalp, the so-called nevus psiloliparus (NP) ( • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( • Rarely, subcutaneous lipomas are seen outside the craniofacial region. • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( • Rarely, subcutaneous lipomas are seen outside the craniofacial region. • Alopecia without a fatty nevus can be linear or patchy, and may follow the lines of Blaschko ( • Areas of focal skin aplasia are usually not extensive (up to a few cm in size) and there have been no reports of affected individuals requiring surgical treatment, such as skin graft, for focal skin aplasia. • Small nodular skin tags (which histologically are fibromas, lipomas, fibrolipomas, or choristomas) are found in about 70%-75% of affected individuals, most often on the eyelids or following a line from the outer canthus to the tragus. • Some individuals have several café au lait spots. Linear hyperpigmentation following the lines of Blaschko and (rarely) asymmetric growth may be seen [ • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( • Rarely, subcutaneous lipomas are seen outside the craniofacial region. • Choristomas are benign ocular tumors and include epibulbar or limbal dermoids (dermolipomas) derived from epidermis and dermis, and lipodermoids, which consist mainly of fat and rarely decrease vision [ • Dermolipomas can be associated with significant additional eye anomalies listed below. • Most affected individuals without choristomas have one or more of the following associated eye anomalies: • Corneal and scleral anomalies • Other anterior chamber abnormalities • Ocular and palpebral colobomas • Aniridia • Microphthalmia • Calcification of the globe • Corneal and scleral anomalies • Other anterior chamber abnormalities • Ocular and palpebral colobomas • Aniridia • Microphthalmia • Calcification of the globe • Corneal and scleral anomalies • Other anterior chamber abnormalities • Ocular and palpebral colobomas • Aniridia • Microphthalmia • Calcification of the globe • Almost 60% of these are located in the cerebello-pontine angle. • Spinal lipomas, which can extend over the whole length of the spinal cord ( • Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( • Almost 60% of these are located in the cerebello-pontine angle. • Spinal lipomas, which can extend over the whole length of the spinal cord ( • Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( • While this finding could represent ascertainment bias, it is suspected that these vascular abnormalities are common, as many of the other brain abnormalities observed could result from prenatal (or, less likely, postnatal) vascular perfusion defects or hemorrhage, including asymmetric brain atrophy, porencephaly, ventriculomegaly, and calcifications [ • Almost 60% of these are located in the cerebello-pontine angle. • Spinal lipomas, which can extend over the whole length of the spinal cord ( • Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( • Among reported individuals with ECCL, about one third have normal cognitive development, one third have mild developmental delay (DD) or ID, and the final one third have severe or unspecified DD/ID. • About half of affected individuals had a history of typically infant- or childhood-onset epileptic seizures of different types that may be refractory or difficult to treat. • Jaw tumors identified as osteomas, odontomas, or ossifying fibromas have been described in affected individuals [ • In severely affected individuals, possibly progressive, multiple lytic bone lesions affecting the long bones have been described ( • Brain tumors, specifically low-grade gliomas (although high-grade gliomas have also been observed) [ • Pilocytic astrocytomas have been reported in six of 14 (43%) individuals with • Possibly Wilms tumor • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic • Macrocephaly (in ~20% of affected individuals); • Congenital heart malformations, in particular aortic coarctation. • Less likely to have central nervous system lipomas • Less likely to develop an astrocytoma (none reported to date) • More likely to have: • Body asymmetry • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) • Epidermal nevi • Other malformations • Body asymmetry • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) • Epidermal nevi • Other malformations • Body asymmetry • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) • Epidermal nevi • Other malformations ## Clinical Description To date, at least 85 individuals with a clinical and/or molecular diagnosis of encephalocraniocutaneous lipomatosis (ECCL) have been reported [ Note: There is evidence that oculoectodermal syndrome (OES) may constitute a clinical spectrum with ECCL, with OES on the mild end and ECCL on the more severe end of the spectrum. Individuals who do not fulfill the clinical diagnostic criteria for ECCL but display some features have sometimes been reported as having OES (see ECCL comprises a spectrum of predominantly congenital anomalies. In its typical form, ECCL is characterized by congenital skin, eye, and brain anomalies, in particular intracranial and spinal lipomas. To a much lesser degree, the bones and the heart can be affected. About 40% of affected individuals have bilateral abnormalities of the skin or the eyes. Although variable in its extent and severity, the pattern of skin and eye findings is often consistent and recognizable. Since 2016, ECCL has also been recognized as a tumor predisposition syndrome [ Encephalocraniocutaneous Lipomatosis: Frequency of Select Features Based on CNS = central nervous system A smooth, hairless fatty tissue nevus of the scalp, the so-called nevus psiloliparus (NP) ( In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( Rarely, subcutaneous lipomas are seen outside the craniofacial region. Alopecia without a fatty nevus can be linear or patchy, and may follow the lines of Blaschko ( Areas of focal skin aplasia are usually not extensive (up to a few cm in size) and there have been no reports of affected individuals requiring surgical treatment, such as skin graft, for focal skin aplasia. Small nodular skin tags (which histologically are fibromas, lipomas, fibrolipomas, or choristomas) are found in about 70%-75% of affected individuals, most often on the eyelids or following a line from the outer canthus to the tragus. Some individuals have several café au lait spots. Linear hyperpigmentation following the lines of Blaschko and (rarely) asymmetric growth may be seen [ Choristomas are benign ocular tumors and include epibulbar or limbal dermoids (dermolipomas) derived from epidermis and dermis, and lipodermoids, which consist mainly of fat and rarely decrease vision [ Dermolipomas can be associated with significant additional eye anomalies listed below. Most affected individuals without choristomas have one or more of the following associated eye anomalies: Corneal and scleral anomalies Other anterior chamber abnormalities Ocular and palpebral colobomas Aniridia Microphthalmia Calcification of the globe Almost 60% of these are located in the cerebello-pontine angle. Spinal lipomas, which can extend over the whole length of the spinal cord ( Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( While this finding could represent ascertainment bias, it is suspected that these vascular abnormalities are common, as many of the other brain abnormalities observed could result from prenatal (or, less likely, postnatal) vascular perfusion defects or hemorrhage, including asymmetric brain atrophy, porencephaly, ventriculomegaly, and calcifications [ Encephalocraniocutaneous Lipomatosis: Frequency of Central Nervous System Anomalies in 52 Affected Individuals Who Underwent Imaging Adapted from Unless otherwise specified, the denominator used for calculating the percentages is 52. The numbers shown include only those individuals for whom information about the respective abnormality was available. Many others had no information available; thus, actual numbers and percentages are very likely higher. Among reported individuals with ECCL, about one third have normal cognitive development, one third have mild developmental delay (DD) or ID, and the final one third have severe or unspecified DD/ID. About half of affected individuals had a history of typically infant- or childhood-onset epileptic seizures of different types that may be refractory or difficult to treat. Jaw tumors identified as osteomas, odontomas, or ossifying fibromas have been described in affected individuals [ In severely affected individuals, possibly progressive, multiple lytic bone lesions affecting the long bones have been described ( Brain tumors, specifically low-grade gliomas (although high-grade gliomas have also been observed) [ Pilocytic astrocytomas have been reported in six of 14 (43%) individuals with Possibly Wilms tumor The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic Macrocephaly (in ~20% of affected individuals); Congenital heart malformations, in particular aortic coarctation. In at least seven individuals with a clinical diagnosis of OES, postzygotic activating variants in • A smooth, hairless fatty tissue nevus of the scalp, the so-called nevus psiloliparus (NP) ( • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( • Rarely, subcutaneous lipomas are seen outside the craniofacial region. • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( • Rarely, subcutaneous lipomas are seen outside the craniofacial region. • Alopecia without a fatty nevus can be linear or patchy, and may follow the lines of Blaschko ( • Areas of focal skin aplasia are usually not extensive (up to a few cm in size) and there have been no reports of affected individuals requiring surgical treatment, such as skin graft, for focal skin aplasia. • Small nodular skin tags (which histologically are fibromas, lipomas, fibrolipomas, or choristomas) are found in about 70%-75% of affected individuals, most often on the eyelids or following a line from the outer canthus to the tragus. • Some individuals have several café au lait spots. Linear hyperpigmentation following the lines of Blaschko and (rarely) asymmetric growth may be seen [ • In about 40%, fatty subcutaneous masses are seen in the frontotemporal or zygomatic region ( • Rarely, subcutaneous lipomas are seen outside the craniofacial region. • Choristomas are benign ocular tumors and include epibulbar or limbal dermoids (dermolipomas) derived from epidermis and dermis, and lipodermoids, which consist mainly of fat and rarely decrease vision [ • Dermolipomas can be associated with significant additional eye anomalies listed below. • Most affected individuals without choristomas have one or more of the following associated eye anomalies: • Corneal and scleral anomalies • Other anterior chamber abnormalities • Ocular and palpebral colobomas • Aniridia • Microphthalmia • Calcification of the globe • Corneal and scleral anomalies • Other anterior chamber abnormalities • Ocular and palpebral colobomas • Aniridia • Microphthalmia • Calcification of the globe • Corneal and scleral anomalies • Other anterior chamber abnormalities • Ocular and palpebral colobomas • Aniridia • Microphthalmia • Calcification of the globe • Almost 60% of these are located in the cerebello-pontine angle. • Spinal lipomas, which can extend over the whole length of the spinal cord ( • Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( • Almost 60% of these are located in the cerebello-pontine angle. • Spinal lipomas, which can extend over the whole length of the spinal cord ( • Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( • While this finding could represent ascertainment bias, it is suspected that these vascular abnormalities are common, as many of the other brain abnormalities observed could result from prenatal (or, less likely, postnatal) vascular perfusion defects or hemorrhage, including asymmetric brain atrophy, porencephaly, ventriculomegaly, and calcifications [ • Almost 60% of these are located in the cerebello-pontine angle. • Spinal lipomas, which can extend over the whole length of the spinal cord ( • Subcutaneous fatty masses may overlie the spinal lipomas or be found adjacent to the spinal cord ( • Among reported individuals with ECCL, about one third have normal cognitive development, one third have mild developmental delay (DD) or ID, and the final one third have severe or unspecified DD/ID. • About half of affected individuals had a history of typically infant- or childhood-onset epileptic seizures of different types that may be refractory or difficult to treat. • Jaw tumors identified as osteomas, odontomas, or ossifying fibromas have been described in affected individuals [ • In severely affected individuals, possibly progressive, multiple lytic bone lesions affecting the long bones have been described ( • Brain tumors, specifically low-grade gliomas (although high-grade gliomas have also been observed) [ • Pilocytic astrocytomas have been reported in six of 14 (43%) individuals with • Possibly Wilms tumor • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic • The first reported child with ECCL and Wilms tumor also had severe growth restriction, which is unusual in individuals with ECCL, such that Wilms tumor in this situation could represent a rare co-occurrence with ECCL [ • Currently, insufficient evidence has accumulated to support a general recommendation for Wilms tumor screening in individuals with ECCL. Such screening may, however, be considered in individuals with • Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic • Macrocephaly (in ~20% of affected individuals); • Congenital heart malformations, in particular aortic coarctation. ## Phenotype Correlations by Gene Comparing Compared to individuals with Less likely to have central nervous system lipomas Less likely to develop an astrocytoma (none reported to date) More likely to have: Body asymmetry Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) Epidermal nevi Other malformations Although these are preliminary considerations based on a small number of known affected individuals, the difference between • Less likely to have central nervous system lipomas • Less likely to develop an astrocytoma (none reported to date) • More likely to have: • Body asymmetry • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) • Epidermal nevi • Other malformations • Body asymmetry • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) • Epidermal nevi • Other malformations • Body asymmetry • Pigmentary mosaicism (hyperpigmented, hypopigmented, or both) • Epidermal nevi • Other malformations ## Genotype-Phenotype Correlations To date, all individuals with molecularly confirmed ECCL have had mosaicism for one of a few known gain-of-function pathogenic variants in either ## Nomenclature ECCL refers to the characteristic phenotypic findings involving the skin, eye, and central nervous system. OES may be at one end of the ECCL spectrum [ ## Prevalence The prevalence of ECCL is unknown. At least 85 individuals who meet the clinical diagnostic criteria or who have a molecular diagnosis of ECCL have been reported. ## Genetically Related (Allelic) Disorders GnRH = gonadotropin-releasing hormone The c.35G>A (p.Gly12Asp) Note: Wilms tumor and nephroblastomatosis have been reported in two individuals with postzygotic ## Differential Diagnosis The differential diagnosis of encephalocraniocutaneous lipomatosis (ECCL) also includes other mosaic RASopathies (a group of syndromes caused by mosaic mutations of the Ras/MAPK signaling pathway [ ## Management No clinical practice guidelines for encephalocraniocutaneous lipomatosis (ECCL) have been published. To establish the extent of disease and needs in an individual diagnosed with ECCL, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Encephalocraniocutaneous Lipomatosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Assess for odontomas. Further imaging of jaw for jaw tumors may be considered. Community or Social work involvement for parental support; Home nursing referral. CNS =- central nervous system; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Encephalocraniocutaneous Lipomatosis Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers It is currently unclear if persons w/ECCL are at ↑ risk for development of Wilms tumor. See also Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; NP = nevus psiloliparus 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). Recommended Surveillance for Individuals with Encephalocraniocutaneous Lipomatosis Brain tumors have not been reported in individuals with Unless the affected individuals have molecularly confirmed There is insufficient evidence to support a general recommendation for Wilms tumor screening in individuals with ECCL, but such screening may be considered in those with a See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Assess for odontomas. • Further imaging of jaw for jaw tumors may be considered. • 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 • It is currently unclear if persons w/ECCL are at ↑ risk for development of Wilms tumor. • See also • 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 (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 ECCL, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Encephalocraniocutaneous Lipomatosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Assess for odontomas. Further imaging of jaw for jaw tumors may be considered. Community or Social work involvement for parental support; Home nursing referral. CNS =- central nervous system; 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 • Assess for odontomas. • Further imaging of jaw for jaw tumors may be considered. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Encephalocraniocutaneous Lipomatosis Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers It is currently unclear if persons w/ECCL are at ↑ risk for development of Wilms tumor. See also Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; NP = nevus psiloliparus 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 has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • It is currently unclear if persons w/ECCL are at ↑ risk for development of Wilms tumor. • See also • 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 (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 Recommended Surveillance for Individuals with Encephalocraniocutaneous Lipomatosis Brain tumors have not been reported in individuals with Unless the affected individuals have molecularly confirmed There is insufficient evidence to support a general recommendation for Wilms tumor screening in individuals with ECCL, but such screening may be considered in those with a ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Encephalocraniocutaneous lipomatosis (ECCL) is not known to be inherited. No confirmed vertical transmission or sib recurrence has 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. As ECCL is not known to be inherited, prenatal diagnosis is usually not indicated. The authors recognize no potential role for preimplantation genetic testing in ECCL. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 Encephalocraniocutaneous lipomatosis (ECCL) is not known to be inherited. No confirmed vertical transmission or sib recurrence has been reported. ## Risk to Family Members ## 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 As ECCL is not known to be inherited, prenatal diagnosis is usually not indicated. The authors recognize no potential role for preimplantation genetic testing in ECCL. ## Resources • • • • ## Molecular Genetics Encephalocraniocutaneous Lipomatosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Encephalocraniocutaneous Lipomatosis ( Note: It is currently unknown why different gain-of-function pathogenic variants cause different, completely nonoverlapping phenotypes (e.g., Encephalocraniocutaneous Lipomatosis: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Somatic Finally, somatic pathogenic variants in both ## Molecular Pathogenesis Note: It is currently unknown why different gain-of-function pathogenic variants cause different, completely nonoverlapping phenotypes (e.g., Encephalocraniocutaneous Lipomatosis: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from ## Cancer and Benign Tumors Somatic Finally, somatic pathogenic variants in both ## Chapter Notes 27 January 2022 (ma) Review posted live 1 March 2021 (um) Original submission • 27 January 2022 (ma) Review posted live • 1 March 2021 (um) Original submission ## Revision History 27 January 2022 (ma) Review posted live 1 March 2021 (um) Original submission • 27 January 2022 (ma) Review posted live • 1 March 2021 (um) Original submission ## References ## Literature Cited Nevus psiloliparus: a smooth hairless fatty tissue nevus on the scalp Reproduced with permission from Linear alopecia (white arrows in A and B) and choristoma (C) in an affected individual age 2.5 years. Note overgrowth of the left lower face and epibulbar dermoid (white arrow in C), subcutaneous fatty masses (black arrows in B and C) and small nodular skin tags, both extending to the canthus. Adapted with permission from Brain and spinal cord MRI in two individuals with ECCL Images from one affected individual (A–C) demonstrate hydrocephalus (A), moderate cerebellar vermis hypoplasia with large fluid collections or cysts behind and below the vermis (white asterisk in A), and a massive midline lipoma extending from several centimeters above the cerebellum, around the cerebellum and brain stem and down into the spinal cord (black asterisks in A, B, and C). Adjacent structures such as the thalamus and hypothalamus are deviated upwards and outwards by the lipoma. Images from another affected individual (D–F) show a large lipoma of the corpus callosum containing a large dysplastic vessel in the middle (black arrow in E) and deficiency of the anterior falx (D and F). The latter is suggested by close apposition and inappropriate interdigitation of the mesial frontal gyri at lower levels (offset white arrows in D) compared to higher levels (linear white arrows in F). Adapted with permission from Brain and spinal cord MRI in ECCL An image from one affected individual (A) shows several large lipomas ventral to the spinal cord (black asterisks) and a subcutaneous nuchal fatty mass. Images from another affected individual (B) demonstrate lipomatosis along the full length of the spinal cord (asterisk and other areas). Adapted with permission from Panoramic radiographs of an affected individual showing hypoplasia of the left maxillary sinus (single white arrow), a bulky mass of dentine structures consistent with left maxillary odontomas (black arrow), and a solitary odontoma of the left lower jaw incorporating misshaped dental structures (double white arrows). Deciduous teeth in the lower jaw and teeth buds in the right maxilla are normal. Adapted with permission from Multiple lytic bone lesions in the humerus Reproduced with permission from An affected individual age 5 months. Note the bilateral subcutaneous fatty accumulations (white arrows). Adapted with permission from
[]
27/1/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
echs1-def
echs1-def
[ "ECHS1D", "ECHS1 Deficiency", "Mitochondrial Short-Chain Enoyl-CoA Hydratase Deficiency", "SCEH Deficiency", "ECHS1D", "ECHS1 Deficiency", "Mitochondrial Short-Chain Enoyl-CoA Hydratase Deficiency", "SCEH Deficiency", "Enoyl-CoA hydratase, mitochondrial", "ECHS1", "Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency" ]
Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency
Rebecca Ganetzky, Carol Stojinski
Summary Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) represents a clinical spectrum in which several phenotypes have been described: The most common phenotype presents in the neonatal period with severe encephalopathy and lactic acidosis and later manifests Leigh-like signs and symptoms. Those with presentation in the neonatal period typically have severe hypotonia, encephalopathy, or neonatal seizures within the first few days of life. Signs and symptoms typically progress quickly and the affected individual ultimately succumbs to central apnea or arrhythmia. A second group of affected individuals present in infancy with developmental regression resulting in severe developmental delay. A third group of affected individuals have normal development with isolated paroxysmal dystonia that may be exacerbated by illness or exertion. Across all three groups, T The diagnosis of ECHS1D is established in a proband by the identification of biallelic pathogenic variants in ECHS1 deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% change 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 the
## Diagnosis No consensus clinical diagnostic criteria for ECHS1 deficiency (ECHS1D) have been published. Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) Developmental delay, often severe [ Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ Dystonia (exercise induced) and/or choreoathetotic movements [ Hypertrophic or dilated cardiomyopathy [ Pulmonary hypertension [ Optic atrophy [ Nystagmus [ Glaucoma [ Strabismus [ Corneal clouding [ Sensorineural hearing loss [ Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ T Cerebral atrophy [ Agenesis or thinning of the corpus callosum [ High lactate with normal lactate to pyruvate ratio peak on MR-spectroscopy [ Lactic acidosis. Pyruvate may be mildly elevated, elevated proportionally to the lactate, or normal [ Abnormal urine organic acids, including elevations of: 2-methyl-2,3-dihydroxybutyrate [ Branched-chain ketoacids [ 3-hydroxyisovalerate [ 3-methylglutaconic acid, ketones, and lactate [ Elevations of urine acryloyl-cysteamine, acryloyl-l-cysteamine, N-acetyl-acryloyl-cysteine, methacryl-cysteamine, methacryl-cysteamine, or N-acetyl-methacryl-l-cysteamine [ While plasma acylcarnitine profile is often normal, slight elevations of C4 acylcarnitines may be seen [ If performed, muscle or fibroblast electron transport chain function (ETC) is typically normal, although mild decreases in complex I, III, IV, or multiple complexes, with residual activity above 30% of control function, can be seen [ Note: Muscle biopsy is not required to make a diagnosis of ECHS1D. The diagnosis of ECHS1D 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ECHS1D is broad, individuals with the distinctive biochemical findings described in When the phenotypic and laboratory findings suggest the diagnosis of ECHS1D, 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 early epileptic encephalopathy, Leigh Syndrome, or lactic acidosis, If exome sequencing is not diagnostic (particularly if only one pathogenic variant has been identified), an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ECHS1 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. One affected individual had a larger deletion that included • • Developmental delay, often severe [ • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ • Dystonia (exercise induced) and/or choreoathetotic movements [ • Developmental delay, often severe [ • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ • Dystonia (exercise induced) and/or choreoathetotic movements [ • • Hypertrophic or dilated cardiomyopathy [ • Pulmonary hypertension [ • Hypertrophic or dilated cardiomyopathy [ • Pulmonary hypertension [ • • Optic atrophy [ • Nystagmus [ • Glaucoma [ • Strabismus [ • Corneal clouding [ • Optic atrophy [ • Nystagmus [ • Glaucoma [ • Strabismus [ • Corneal clouding [ • • Sensorineural hearing loss [ • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ • Sensorineural hearing loss [ • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ • Developmental delay, often severe [ • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ • Dystonia (exercise induced) and/or choreoathetotic movements [ • Hypertrophic or dilated cardiomyopathy [ • Pulmonary hypertension [ • Optic atrophy [ • Nystagmus [ • Glaucoma [ • Strabismus [ • Corneal clouding [ • Sensorineural hearing loss [ • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ • T • Cerebral atrophy [ • Agenesis or thinning of the corpus callosum [ • High lactate with normal lactate to pyruvate ratio peak on MR-spectroscopy [ • Lactic acidosis. Pyruvate may be mildly elevated, elevated proportionally to the lactate, or normal [ • Abnormal urine organic acids, including elevations of: • 2-methyl-2,3-dihydroxybutyrate [ • Branched-chain ketoacids [ • 3-hydroxyisovalerate [ • 3-methylglutaconic acid, ketones, and lactate [ • 2-methyl-2,3-dihydroxybutyrate [ • Branched-chain ketoacids [ • 3-hydroxyisovalerate [ • 3-methylglutaconic acid, ketones, and lactate [ • Elevations of urine acryloyl-cysteamine, acryloyl-l-cysteamine, N-acetyl-acryloyl-cysteine, methacryl-cysteamine, methacryl-cysteamine, or N-acetyl-methacryl-l-cysteamine [ • While plasma acylcarnitine profile is often normal, slight elevations of C4 acylcarnitines may be seen [ • If performed, muscle or fibroblast electron transport chain function (ETC) is typically normal, although mild decreases in complex I, III, IV, or multiple complexes, with residual activity above 30% of control function, can be seen [ • 2-methyl-2,3-dihydroxybutyrate [ • Branched-chain ketoacids [ • 3-hydroxyisovalerate [ • 3-methylglutaconic acid, ketones, and lactate [ • For an introduction to multigene panels click ## Suggestive Findings Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) Developmental delay, often severe [ Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ Dystonia (exercise induced) and/or choreoathetotic movements [ Hypertrophic or dilated cardiomyopathy [ Pulmonary hypertension [ Optic atrophy [ Nystagmus [ Glaucoma [ Strabismus [ Corneal clouding [ Sensorineural hearing loss [ Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ T Cerebral atrophy [ Agenesis or thinning of the corpus callosum [ High lactate with normal lactate to pyruvate ratio peak on MR-spectroscopy [ Lactic acidosis. Pyruvate may be mildly elevated, elevated proportionally to the lactate, or normal [ Abnormal urine organic acids, including elevations of: 2-methyl-2,3-dihydroxybutyrate [ Branched-chain ketoacids [ 3-hydroxyisovalerate [ 3-methylglutaconic acid, ketones, and lactate [ Elevations of urine acryloyl-cysteamine, acryloyl-l-cysteamine, N-acetyl-acryloyl-cysteine, methacryl-cysteamine, methacryl-cysteamine, or N-acetyl-methacryl-l-cysteamine [ While plasma acylcarnitine profile is often normal, slight elevations of C4 acylcarnitines may be seen [ If performed, muscle or fibroblast electron transport chain function (ETC) is typically normal, although mild decreases in complex I, III, IV, or multiple complexes, with residual activity above 30% of control function, can be seen [ Note: Muscle biopsy is not required to make a diagnosis of ECHS1D. • • Developmental delay, often severe [ • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ • Dystonia (exercise induced) and/or choreoathetotic movements [ • Developmental delay, often severe [ • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ • Dystonia (exercise induced) and/or choreoathetotic movements [ • • Hypertrophic or dilated cardiomyopathy [ • Pulmonary hypertension [ • Hypertrophic or dilated cardiomyopathy [ • Pulmonary hypertension [ • • Optic atrophy [ • Nystagmus [ • Glaucoma [ • Strabismus [ • Corneal clouding [ • Optic atrophy [ • Nystagmus [ • Glaucoma [ • Strabismus [ • Corneal clouding [ • • Sensorineural hearing loss [ • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ • Sensorineural hearing loss [ • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ • Developmental delay, often severe [ • Infantile encephalopathy (may be epileptic), hypotonia, and/or spasticity [ • Dystonia (exercise induced) and/or choreoathetotic movements [ • Hypertrophic or dilated cardiomyopathy [ • Pulmonary hypertension [ • Optic atrophy [ • Nystagmus [ • Glaucoma [ • Strabismus [ • Corneal clouding [ • Sensorineural hearing loss [ • Nonspecific dysmorphic features or structural abnormalities (no consistent pattern has emerged) [ • T • Cerebral atrophy [ • Agenesis or thinning of the corpus callosum [ • High lactate with normal lactate to pyruvate ratio peak on MR-spectroscopy [ • Lactic acidosis. Pyruvate may be mildly elevated, elevated proportionally to the lactate, or normal [ • Abnormal urine organic acids, including elevations of: • 2-methyl-2,3-dihydroxybutyrate [ • Branched-chain ketoacids [ • 3-hydroxyisovalerate [ • 3-methylglutaconic acid, ketones, and lactate [ • 2-methyl-2,3-dihydroxybutyrate [ • Branched-chain ketoacids [ • 3-hydroxyisovalerate [ • 3-methylglutaconic acid, ketones, and lactate [ • Elevations of urine acryloyl-cysteamine, acryloyl-l-cysteamine, N-acetyl-acryloyl-cysteine, methacryl-cysteamine, methacryl-cysteamine, or N-acetyl-methacryl-l-cysteamine [ • While plasma acylcarnitine profile is often normal, slight elevations of C4 acylcarnitines may be seen [ • If performed, muscle or fibroblast electron transport chain function (ETC) is typically normal, although mild decreases in complex I, III, IV, or multiple complexes, with residual activity above 30% of control function, can be seen [ • 2-methyl-2,3-dihydroxybutyrate [ • Branched-chain ketoacids [ • 3-hydroxyisovalerate [ • 3-methylglutaconic acid, ketones, and lactate [ ## Establishing the Diagnosis The diagnosis of ECHS1D 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of ECHS1D is broad, individuals with the distinctive biochemical findings described in When the phenotypic and laboratory findings suggest the diagnosis of ECHS1D, 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 early epileptic encephalopathy, Leigh Syndrome, or lactic acidosis, If exome sequencing is not diagnostic (particularly if only one pathogenic variant has been identified), an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ECHS1 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. One affected individual had a larger deletion that included • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of ECHS1D, 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 early epileptic encephalopathy, Leigh Syndrome, or lactic acidosis, If exome sequencing is not diagnostic (particularly if only one pathogenic variant has been identified), an For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ECHS1 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. One affected individual had a larger deletion that included ## Clinical Characteristics Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) has been reported in 40 individuals representing 31 families [ Common clinical manifestations are summarized in Common Clinical Manifestations of ECHS1 Deficiency Neurologic manifestations were seen in all 40 individuals reported [ A second group of affected individuals present in infancy (after the neonatal period up to age 24 months) with developmental regression [ There have been two reports of individuals with isolated paroxysmal dystonia and otherwise normal development. In one report, two of three affected individuals were sibs, one of whom had learning disabilities [ Dystonia, or less commonly choreoathetosis and/or ataxia, is usually chronically present, but is exacerbated by illness or exertion [ Across all three phenotypes, T Lactate levels may be extremely high, causing metabolic acidosis as the primary clinical finding [ Two affected individuals have had moderate hyperammonemia in the setting of profound neonatal metabolic stress, potentially related to their severe metabolic acidosis and/or low ATP secondary to impaired aerobic oxidation. Levels have been reported ranging from 150 to 800 µmol/L in cases with a concommittent pH < 7.1 [ Elevated creatine kinase (CK) levels (hyperCKemia) to about 3,000 IU/L in a critically ill newborn [ In affected individuals, low pyruvate dehydrogenase complex (PDC) activity in cultured fibroblasts is noted in about 40% of cases [ Facial features are variable, but may include a long philtrum, similar to what is seen in individuals with pyruvate dehydrogenase deficiency [ The only recurrent structural abnormality is thinning or absence of the corpus callosum [ The following have each been described in one affected individual: Hypospadias [ Gastroschisis [ Cutis laxa [ Hypertrichosis [ Abnormal lung septation, multiple splenules, and a preauricular tag [ In contrast, those with the paroxysmal dystonia phenotype have been mildly affected with no reported deaths and relatively normal cognitive development. There is likely a broad spectrum between the infantile phenotype and the paroxysmal dystonia phenotype, as individuals with paroxysmal dystonia have been diagnosed after metabolic decompensation [ All affected individuals with the paroxysmal dystonia phenotype have been compound heterozygous for the pathogenic ECHS1 deficiency is rare; the exact prevalence and incidence are unknown. To date, 40 affected individuals representing 31 families from different ethnic backgrounds / geographic locations – including European, East Asian, French Canadian, and Middle Eastern – have been reported [ Additional data are required to determine if the • Lactate levels may be extremely high, causing metabolic acidosis as the primary clinical finding [ • Two affected individuals have had moderate hyperammonemia in the setting of profound neonatal metabolic stress, potentially related to their severe metabolic acidosis and/or low ATP secondary to impaired aerobic oxidation. Levels have been reported ranging from 150 to 800 µmol/L in cases with a concommittent pH < 7.1 [ • Elevated creatine kinase (CK) levels (hyperCKemia) to about 3,000 IU/L in a critically ill newborn [ • In affected individuals, low pyruvate dehydrogenase complex (PDC) activity in cultured fibroblasts is noted in about 40% of cases [ • Facial features are variable, but may include a long philtrum, similar to what is seen in individuals with pyruvate dehydrogenase deficiency [ • The only recurrent structural abnormality is thinning or absence of the corpus callosum [ • The following have each been described in one affected individual: • Hypospadias [ • Gastroschisis [ • Cutis laxa [ • Hypertrichosis [ • Abnormal lung septation, multiple splenules, and a preauricular tag [ • Hypospadias [ • Gastroschisis [ • Cutis laxa [ • Hypertrichosis [ • Abnormal lung septation, multiple splenules, and a preauricular tag [ • Hypospadias [ • Gastroschisis [ • Cutis laxa [ • Hypertrichosis [ • Abnormal lung septation, multiple splenules, and a preauricular tag [ ## Clinical Description Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) has been reported in 40 individuals representing 31 families [ Common clinical manifestations are summarized in Common Clinical Manifestations of ECHS1 Deficiency Neurologic manifestations were seen in all 40 individuals reported [ A second group of affected individuals present in infancy (after the neonatal period up to age 24 months) with developmental regression [ There have been two reports of individuals with isolated paroxysmal dystonia and otherwise normal development. In one report, two of three affected individuals were sibs, one of whom had learning disabilities [ Dystonia, or less commonly choreoathetosis and/or ataxia, is usually chronically present, but is exacerbated by illness or exertion [ Across all three phenotypes, T Lactate levels may be extremely high, causing metabolic acidosis as the primary clinical finding [ Two affected individuals have had moderate hyperammonemia in the setting of profound neonatal metabolic stress, potentially related to their severe metabolic acidosis and/or low ATP secondary to impaired aerobic oxidation. Levels have been reported ranging from 150 to 800 µmol/L in cases with a concommittent pH < 7.1 [ Elevated creatine kinase (CK) levels (hyperCKemia) to about 3,000 IU/L in a critically ill newborn [ In affected individuals, low pyruvate dehydrogenase complex (PDC) activity in cultured fibroblasts is noted in about 40% of cases [ Facial features are variable, but may include a long philtrum, similar to what is seen in individuals with pyruvate dehydrogenase deficiency [ The only recurrent structural abnormality is thinning or absence of the corpus callosum [ The following have each been described in one affected individual: Hypospadias [ Gastroschisis [ Cutis laxa [ Hypertrichosis [ Abnormal lung septation, multiple splenules, and a preauricular tag [ In contrast, those with the paroxysmal dystonia phenotype have been mildly affected with no reported deaths and relatively normal cognitive development. There is likely a broad spectrum between the infantile phenotype and the paroxysmal dystonia phenotype, as individuals with paroxysmal dystonia have been diagnosed after metabolic decompensation [ • Lactate levels may be extremely high, causing metabolic acidosis as the primary clinical finding [ • Two affected individuals have had moderate hyperammonemia in the setting of profound neonatal metabolic stress, potentially related to their severe metabolic acidosis and/or low ATP secondary to impaired aerobic oxidation. Levels have been reported ranging from 150 to 800 µmol/L in cases with a concommittent pH < 7.1 [ • Elevated creatine kinase (CK) levels (hyperCKemia) to about 3,000 IU/L in a critically ill newborn [ • In affected individuals, low pyruvate dehydrogenase complex (PDC) activity in cultured fibroblasts is noted in about 40% of cases [ • Facial features are variable, but may include a long philtrum, similar to what is seen in individuals with pyruvate dehydrogenase deficiency [ • The only recurrent structural abnormality is thinning or absence of the corpus callosum [ • The following have each been described in one affected individual: • Hypospadias [ • Gastroschisis [ • Cutis laxa [ • Hypertrichosis [ • Abnormal lung septation, multiple splenules, and a preauricular tag [ • Hypospadias [ • Gastroschisis [ • Cutis laxa [ • Hypertrichosis [ • Abnormal lung septation, multiple splenules, and a preauricular tag [ • Hypospadias [ • Gastroschisis [ • Cutis laxa [ • Hypertrichosis [ • Abnormal lung septation, multiple splenules, and a preauricular tag [ ## Genotype-Phenotype Correlations All affected individuals with the paroxysmal dystonia phenotype have been compound heterozygous for the pathogenic ## Prevalence ECHS1 deficiency is rare; the exact prevalence and incidence are unknown. To date, 40 affected individuals representing 31 families from different ethnic backgrounds / geographic locations – including European, East Asian, French Canadian, and Middle Eastern – have been reported [ Additional data are required to determine if the ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of ECHS1 Deficiency (ECHS1D) Pyruvate dehydrogenase complex deficiency Lactic acidosis ↑ pyruvate Nl lactate to pyruvate ratio Long philtrum Corpus callosum hypoplasia May be a complete phenocopy Persons w/ECHS1D may have abnl acylcarnitine profile or urine organic acids not typically seen in primary PDCD. Lactic acidosis Basal gangliar lesions ↑ 2-methyl-2,3-dihydroxybutyrate Neonatal/primary lactic acidosis Variable cardiomyopathy FBXL4 deficiency typically has more striking hyperammonemia. ATP synthase deficiency typically has more prominent 3-methylglutaconic aciduria. ECHS1D may be suspected (rather than FBXL4 or TMEM70 deficiency) if 2-methyl-2,3-dihydroxybutyrate is present or lactate-to-pyruvate ratio is nl. T Dystonia Developmental regression Lactic acidosis More striking hyperammonemia Ketonuria Nl organic acids AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; mt = mitochondrial; nl = normal; XL = X-linked Autosomal recessive inheritance is rare. • Pyruvate dehydrogenase complex deficiency • Lactic acidosis • ↑ pyruvate • Nl lactate to pyruvate ratio • Long philtrum • Corpus callosum hypoplasia • May be a complete phenocopy • Persons w/ECHS1D may have abnl acylcarnitine profile or urine organic acids not typically seen in primary PDCD. • Lactic acidosis • Basal gangliar lesions • ↑ 2-methyl-2,3-dihydroxybutyrate • Neonatal/primary lactic acidosis • Variable cardiomyopathy • FBXL4 deficiency typically has more striking hyperammonemia. • ATP synthase deficiency typically has more prominent 3-methylglutaconic aciduria. • ECHS1D may be suspected (rather than FBXL4 or TMEM70 deficiency) if 2-methyl-2,3-dihydroxybutyrate is present or lactate-to-pyruvate ratio is nl. • T • Dystonia • Developmental regression • Lactic acidosis • More striking hyperammonemia • Ketonuria • Nl organic acids ## Management To establish the extent of disease and needs in an individual diagnosed with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ECHS1 Deficiency Nutritional eval Swallowing assessment Liver ultrasound to evaluate for hepatosplenomegaly Blood glucose level Urine organic acids Blood ammonia level Creatine kinase level Management is best provided by a multidisciplinary team including specialists in clinical genetics / metabolism, neurology, nutrition, and developmental pediatrics. Other specialists, such as a cardiologist and an ophthalmologist, may be involved based on the associated complications. In those presenting in the neonatal period, involvement of a palliative care team is also essential to determine goals of care given the poor prognosis for this group. This should be especially considered for neonates with major structural abnormalities in whom surgical management is being considered. No definite treatment is available to date; treatment is mainly supportive (see Treatment of Manifestations in Individuals with ECHS1 Deficiency The origin of the hyperammonemia is unclear. It may be secondary to metabolic acidosis, as it has only been observed in children with profound metabolic acidosis or as a result of low ATP secondary to impaired aerobic oxidation. Correction of acidosis is a reasonable first strategy. Anecdotal reports of treatment with N-aceylcysteine to detoxify the reactive metabolites of methacrylyl-CoA and acroyacryl-CoA are mixed. Valine restriction would be a rational biochemical approach; it has never been attempted. Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered [ In one affected individual with paroxysmal exercise-induced dystonia, this "cocktail" produced a subjective improvement [ 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 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. Recommended Surveillance for Individuals with ECHS1 Deficiency Mitochondrial toxins, such as valproic acid and prolonged propofol infusions, should be avoided [ The ketogenic diet may be poorly tolerated because of partially impaired fatty acid oxidation [ It is appropriate to clarify the genetic status of apparently asymptomatic younger sibs of an individual affected by the paroxysmal exercise-induced dystonia phenotype by molecular genetic testing of the In an at-risk newborn, it is crucial to ensure metabolic stability by evaluating a lactic acid level and a blood gas. Urine organic acids and acylcarnitine profile may also be used as biochemical screening testing while waiting for molecular genetic testing results; they can have high specificity, but sensitivity may be low. See Search • Nutritional eval • Swallowing assessment • Liver ultrasound to evaluate for hepatosplenomegaly • Blood glucose level • Urine organic acids • Blood ammonia level • Creatine kinase level • Anecdotal reports of treatment with N-aceylcysteine to detoxify the reactive metabolites of methacrylyl-CoA and acroyacryl-CoA are mixed. • Valine restriction would be a rational biochemical approach; it has never been attempted. • Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered [ • In one affected individual with paroxysmal exercise-induced dystonia, this "cocktail" produced a subjective improvement [ • 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 and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ECHS1 Deficiency Nutritional eval Swallowing assessment Liver ultrasound to evaluate for hepatosplenomegaly Blood glucose level Urine organic acids Blood ammonia level Creatine kinase level • Nutritional eval • Swallowing assessment • Liver ultrasound to evaluate for hepatosplenomegaly • Blood glucose level • Urine organic acids • Blood ammonia level • Creatine kinase level ## Treatment of Manifestations Management is best provided by a multidisciplinary team including specialists in clinical genetics / metabolism, neurology, nutrition, and developmental pediatrics. Other specialists, such as a cardiologist and an ophthalmologist, may be involved based on the associated complications. In those presenting in the neonatal period, involvement of a palliative care team is also essential to determine goals of care given the poor prognosis for this group. This should be especially considered for neonates with major structural abnormalities in whom surgical management is being considered. No definite treatment is available to date; treatment is mainly supportive (see Treatment of Manifestations in Individuals with ECHS1 Deficiency The origin of the hyperammonemia is unclear. It may be secondary to metabolic acidosis, as it has only been observed in children with profound metabolic acidosis or as a result of low ATP secondary to impaired aerobic oxidation. Correction of acidosis is a reasonable first strategy. Anecdotal reports of treatment with N-aceylcysteine to detoxify the reactive metabolites of methacrylyl-CoA and acroyacryl-CoA are mixed. Valine restriction would be a rational biochemical approach; it has never been attempted. Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered [ In one affected individual with paroxysmal exercise-induced dystonia, this "cocktail" produced a subjective improvement [ 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 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. • Anecdotal reports of treatment with N-aceylcysteine to detoxify the reactive metabolites of methacrylyl-CoA and acroyacryl-CoA are mixed. • Valine restriction would be a rational biochemical approach; it has never been attempted. • Administration of cofactors and antioxidants, used in mitochondrial disorders with (generally) limited evidence of benefit, may be considered [ • In one affected individual with paroxysmal exercise-induced dystonia, this "cocktail" produced a subjective improvement [ • 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 and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; 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 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 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. ## Surveillance Recommended Surveillance for Individuals with ECHS1 Deficiency ## Agents/Circumstances to Avoid Mitochondrial toxins, such as valproic acid and prolonged propofol infusions, should be avoided [ The ketogenic diet may be poorly tolerated because of partially impaired fatty acid oxidation [ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic younger sibs of an individual affected by the paroxysmal exercise-induced dystonia phenotype by molecular genetic testing of the In an at-risk newborn, it is crucial to ensure metabolic stability by evaluating a lactic acid level and a blood gas. Urine organic acids and acylcarnitine profile may also be used as biochemical screening testing while waiting for molecular genetic testing results; they can have high specificity, but sensitivity may be low. See ## Therapies Under Investigation Search ## Genetic Counseling Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is inherited in an autosomal recessive manner. In most instances, the parents of an affected child are heterozygotes (i.e., carriers of one In rare cases, a proband has one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are carriers, 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. If only one parent is a carrier (i.e., the proband is compound heterozygous for an inherited pathogenic variant and a Sibs who inherit two pathogenic variants will be affected. Sibs who inherit one pathogenic variant (heterozygotes) are expected to be asymptomatic. A sib who is heterozygous for an inherited pathogenic variant could be affected if the sib also has another To date, individuals with the neonatal and infantile forms of ECHS1D are not known to reproduce. Each child of an individual with the paroxysmal dystonia form of ECHS1D has a 50% chance of inheriting the 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 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. • In most instances, the parents of an affected child are heterozygotes (i.e., carriers of one • In rare cases, a proband has one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are carriers, 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. • If only one parent is a carrier (i.e., the proband is compound heterozygous for an inherited pathogenic variant and a • Sibs who inherit two pathogenic variants will be affected. Sibs who inherit one pathogenic variant (heterozygotes) are expected to be asymptomatic. A sib who is heterozygous for an inherited pathogenic variant could be affected if the sib also has another • To date, individuals with the neonatal and infantile forms of ECHS1D are not known to reproduce. • Each child of an individual with the paroxysmal dystonia form of ECHS1D has a 50% chance of inheriting 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. ## Mode of Inheritance Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is inherited in an autosomal recessive manner. In most instances, the parents of an affected child are heterozygotes (i.e., carriers of one In rare cases, a proband has one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are carriers, 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. If only one parent is a carrier (i.e., the proband is compound heterozygous for an inherited pathogenic variant and a Sibs who inherit two pathogenic variants will be affected. Sibs who inherit one pathogenic variant (heterozygotes) are expected to be asymptomatic. A sib who is heterozygous for an inherited pathogenic variant could be affected if the sib also has another To date, individuals with the neonatal and infantile forms of ECHS1D are not known to reproduce. Each child of an individual with the paroxysmal dystonia form of ECHS1D has a 50% chance of inheriting the • In most instances, the parents of an affected child are heterozygotes (i.e., carriers of one • In rare cases, a proband has one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are carriers, 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. • If only one parent is a carrier (i.e., the proband is compound heterozygous for an inherited pathogenic variant and a • Sibs who inherit two pathogenic variants will be affected. Sibs who inherit one pathogenic variant (heterozygotes) are expected to be asymptomatic. A sib who is heterozygous for an inherited pathogenic variant could be affected if the sib also has another • To date, individuals with the neonatal and infantile forms of ECHS1D are not known to reproduce. • Each child of an individual with the paroxysmal dystonia form of ECHS1D has a 50% chance of inheriting the ## 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 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 United Kingdom • • United Kingdom • • • • • ## Molecular Genetics Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Mitochondrial Short-Chain Enoyl-CoA Hydratase 1 Deficiency ( The mitochondrial short-chain enoyl-CoA hydratase (SCEH) has a primary function in the beta-oxidation of short-chain fats. However, the same enzyme also is involved in branched-chain amino acid metabolism, particularly valine metabolism [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The mitochondrial short-chain enoyl-CoA hydratase (SCEH) has a primary function in the beta-oxidation of short-chain fats. However, the same enzyme also is involved in branched-chain amino acid metabolism, particularly valine metabolism [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Rebecca Ganetzky is an attending physician in the 20 June 2019 (ma) Review posted live 9 April 2018 (rg) Original submission • 20 June 2019 (ma) Review posted live • 9 April 2018 (rg) Original submission ## Author Notes Rebecca Ganetzky is an attending physician in the ## Revision History 20 June 2019 (ma) Review posted live 9 April 2018 (rg) Original submission • 20 June 2019 (ma) Review posted live • 9 April 2018 (rg) Original submission ## References ## Literature Cited
[]
20/6/2019
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ed2
ed2
[ "Clouston Syndrome", "Clouston Syndrome", "Gap junction beta-6 protein", "GJB6", "Hidrotic Ectodermal Dysplasia 2" ]
Hidrotic Ectodermal Dysplasia 2
Jemima Mellerio, Danielle Greenblatt
Summary Hidrotic ectodermal dysplasia 2, or Clouston syndrome (referred to as HED2 throughout this Sparse scalp hair and dysplastic nails are seen early in life. In infancy, scalp hair is fine, sparse, and brittle. Progressive hair loss may lead to total alopecia by puberty. The nails may be milky white in early childhood; they gradually become dystrophic, thick, and distally separated from the nail bed. Palmoplantar keratoderma may develop during childhood and increases in severity with age. Associated features may include cutaneous hyperpigmentation (particularly over the joints) and finger clubbing. The clinical manifestations are highly variable even within the same family. The diagnosis of HED2 is established in a proband with suggestive findings and a heterozygous pathogenic variant in HED2 is inherited in an autosomal dominant manner. Most individuals with HED2 have an affected parent;
## Diagnosis Hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) The molecular diagnosis of HED2 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 ectodermal dysplasia, 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 Hidrotic Ectodermal Dysplasia 2 See See Pathogenic variants detected include Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Suggestive Findings Hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) ## Establishing the Diagnosis The molecular diagnosis of HED2 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 ectodermal dysplasia, 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 Hidrotic Ectodermal Dysplasia 2 See See Pathogenic variants detected include Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by ectodermal dysplasia, 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 Hidrotic Ectodermal Dysplasia 2 See See Pathogenic variants detected include Data derived from the subscription-based professional view of Human Gene Mutation Database [ Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) is characterized by dystrophy of the nails, alopecia (partial or total), hyperpigmentation of the skin (especially over the joints), palmoplantar hyperkeratosis, and clubbing of the fingers. Sweat glands, sebaceous glands, and teeth are normal. The clinical manifestations are highly variable even within the same family. To date, more than 150 individuals with HED2 have been identified [ Hidrotic Ectodermal Dysplasia 2: Frequency of Select Features Hair often sparse & fine w/progressive thinning & alopecia in adulthood Involvement of eyebrows, lashes, & axillary & pubic hair Typically present from birth or early childhood; often short, thick & slow growing May be cone shaped or triangular; may be assoc w/finger clubbing Onset usually from early childhood to adolescence; when present, may be focal or diffuse Often has a cobblestoned appearance w/multiple small fissures Hyperkeratosis may also be found on knuckles, knees, & elbows. Teeth and ability to sweat are normal, as are physical growth and psychomotor development. Whereas most In some families, HED2 caused by the Penetrance is high [ When referring to HED2 (Clouston syndrome), the nonspecific term "hidrotic ectodermal dysplasia" should not be used, as other forms of ectodermal dysplasia are associated with normal sweating. HED2 is relatively common in the French-Canadian population of southwest Quebec [ • Hair often sparse & fine w/progressive thinning & alopecia in adulthood • Involvement of eyebrows, lashes, & axillary & pubic hair • Typically present from birth or early childhood; often short, thick & slow growing • May be cone shaped or triangular; may be assoc w/finger clubbing • Onset usually from early childhood to adolescence; when present, may be focal or diffuse • Often has a cobblestoned appearance w/multiple small fissures • Hyperkeratosis may also be found on knuckles, knees, & elbows. ## Clinical Description Hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome) is characterized by dystrophy of the nails, alopecia (partial or total), hyperpigmentation of the skin (especially over the joints), palmoplantar hyperkeratosis, and clubbing of the fingers. Sweat glands, sebaceous glands, and teeth are normal. The clinical manifestations are highly variable even within the same family. To date, more than 150 individuals with HED2 have been identified [ Hidrotic Ectodermal Dysplasia 2: Frequency of Select Features Hair often sparse & fine w/progressive thinning & alopecia in adulthood Involvement of eyebrows, lashes, & axillary & pubic hair Typically present from birth or early childhood; often short, thick & slow growing May be cone shaped or triangular; may be assoc w/finger clubbing Onset usually from early childhood to adolescence; when present, may be focal or diffuse Often has a cobblestoned appearance w/multiple small fissures Hyperkeratosis may also be found on knuckles, knees, & elbows. Teeth and ability to sweat are normal, as are physical growth and psychomotor development. • Hair often sparse & fine w/progressive thinning & alopecia in adulthood • Involvement of eyebrows, lashes, & axillary & pubic hair • Typically present from birth or early childhood; often short, thick & slow growing • May be cone shaped or triangular; may be assoc w/finger clubbing • Onset usually from early childhood to adolescence; when present, may be focal or diffuse • Often has a cobblestoned appearance w/multiple small fissures • Hyperkeratosis may also be found on knuckles, knees, & elbows. ## Genotype-Phenotype Correlations Whereas most In some families, HED2 caused by the ## Penetrance Penetrance is high [ ## Nomenclature When referring to HED2 (Clouston syndrome), the nonspecific term "hidrotic ectodermal dysplasia" should not be used, as other forms of ectodermal dysplasia are associated with normal sweating. ## Prevalence HED2 is relatively common in the French-Canadian population of southwest Quebec [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Various types of hidrotic ectodermal dysplasia exist, and it is likely that new types will be described [ Hidrotic ectodermal dysplasia 2 (HED2) must be differentiated from other ectodermal dysplasias that can affect nails and hair (see Ectodermal Dysplasias in the Differential Diagnosis of Hidrotic Ectodermal Dysplasia 2 Hypotrichosis: thin, lightly pigmented, slow-growing scalp hair Hypohidrosis: deficient sweating w/episodes of hyperthermia Hypodontia: few & abnormally formed teeth erupt, later than average Hypohidrosis & dental abnormalities are the major distinguishing features. Eyelid papules may develop in Sensorineural deafness Photophobia, corneal ulceration & scarring Progressive hyperkeratotic plaques & palmoplantar hyperkeratosis Sparse hair & nail dystrophy: less pronounced than in HED2 Generalized congenital atrichia Nail dystrophy Hypertrophic nail dystrophy w/subungual hyperkeratosis Painful focal palmoplantar keratoderma & blistering Variably present: oral leukokeratosis, pilosebaceous cysts, palmoplantar hyperhidrosis, follicular keratoses on the trunk & extremities, natal teeth Absence of hypotrichosis or atrichia is the main distinguishing feature. Palmoplantar keratoderma is focal in PC (vs diffuse in most cases of HED2). Generalized hypotrichosis or atrichia Nail dystrophy Sparse or absent scalp hair Absent eyebrows, eyelashes, pubic & axillary hair Nail dystrophy AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked • Hypotrichosis: thin, lightly pigmented, slow-growing scalp hair • Hypohidrosis: deficient sweating w/episodes of hyperthermia • Hypodontia: few & abnormally formed teeth erupt, later than average • Hypohidrosis & dental abnormalities are the major distinguishing features. • Eyelid papules may develop in • Sensorineural deafness • Photophobia, corneal ulceration & scarring • Progressive hyperkeratotic plaques & palmoplantar hyperkeratosis • Sparse hair & nail dystrophy: less pronounced than in HED2 • Generalized congenital atrichia • Nail dystrophy • Hypertrophic nail dystrophy w/subungual hyperkeratosis • Painful focal palmoplantar keratoderma & blistering • Variably present: oral leukokeratosis, pilosebaceous cysts, palmoplantar hyperhidrosis, follicular keratoses on the trunk & extremities, natal teeth • Absence of hypotrichosis or atrichia is the main distinguishing feature. • Palmoplantar keratoderma is focal in PC (vs diffuse in most cases of HED2). • Generalized hypotrichosis or atrichia • Nail dystrophy • Sparse or absent scalp hair • Absent eyebrows, eyelashes, pubic & axillary hair • Nail dystrophy ## Management To establish the extent of disease and needs in an individual diagnosed with hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hidrotic Ectodermal Dysplasia 2 HED2 = hidrotic ectodermal dysplasia 2; MOI= mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with Hidrotic Ectodermal Dysplasia 2 Filing or drilling of hyperkeratotic nails Artificial nails May improve appearance of hands/feet & ↓ trauma from footwear. May be especially helpful to girls & women. Conditioning hair care products may help to manage dry & sparse hair. Wigs or hair weaves for alopecia Use of artificial hair fibers to improve appearance of hair Use of eyebrow tattoos Alopecia improved w/combination of topical minoxidil & tretinoin in a person w/clinical features of HED2. Alopecia improved w/topical minoxidil in a child w/hypohidrotic ED. Bland skin emollients may help soften hyperkeratosis. Keratolytic preparations (containing e.g. urea, salicylic acid, lactic acid) may be helpful. Regular filing or paring of hard skin can ↓ pain & improve function. A molecular diagnosis of HED2 was not confirmed. The authors also noted that the efficacy and safety of long-term treatment need to be explored further [ See Tretinoin and minoxidil should be avoided in pregnancy. See Search • Filing or drilling of hyperkeratotic nails • Artificial nails • May improve appearance of hands/feet & ↓ trauma from footwear. • May be especially helpful to girls & women. • Conditioning hair care products may help to manage dry & sparse hair. • Wigs or hair weaves for alopecia • Use of artificial hair fibers to improve appearance of hair • Use of eyebrow tattoos • Alopecia improved w/combination of topical minoxidil & tretinoin in a person w/clinical features of HED2. • Alopecia improved w/topical minoxidil in a child w/hypohidrotic ED. • Bland skin emollients may help soften hyperkeratosis. • Keratolytic preparations (containing e.g. urea, salicylic acid, lactic acid) may be helpful. • Regular filing or paring of hard skin can ↓ pain & improve function. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hidrotic ectodermal dysplasia 2 (HED2, Clouston syndrome), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hidrotic Ectodermal Dysplasia 2 HED2 = hidrotic ectodermal dysplasia 2; MOI= mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations Treatment of Manifestations in Individuals with Hidrotic Ectodermal Dysplasia 2 Filing or drilling of hyperkeratotic nails Artificial nails May improve appearance of hands/feet & ↓ trauma from footwear. May be especially helpful to girls & women. Conditioning hair care products may help to manage dry & sparse hair. Wigs or hair weaves for alopecia Use of artificial hair fibers to improve appearance of hair Use of eyebrow tattoos Alopecia improved w/combination of topical minoxidil & tretinoin in a person w/clinical features of HED2. Alopecia improved w/topical minoxidil in a child w/hypohidrotic ED. Bland skin emollients may help soften hyperkeratosis. Keratolytic preparations (containing e.g. urea, salicylic acid, lactic acid) may be helpful. Regular filing or paring of hard skin can ↓ pain & improve function. A molecular diagnosis of HED2 was not confirmed. The authors also noted that the efficacy and safety of long-term treatment need to be explored further [ • Filing or drilling of hyperkeratotic nails • Artificial nails • May improve appearance of hands/feet & ↓ trauma from footwear. • May be especially helpful to girls & women. • Conditioning hair care products may help to manage dry & sparse hair. • Wigs or hair weaves for alopecia • Use of artificial hair fibers to improve appearance of hair • Use of eyebrow tattoos • Alopecia improved w/combination of topical minoxidil & tretinoin in a person w/clinical features of HED2. • Alopecia improved w/topical minoxidil in a child w/hypohidrotic ED. • Bland skin emollients may help soften hyperkeratosis. • Keratolytic preparations (containing e.g. urea, salicylic acid, lactic acid) may be helpful. • Regular filing or paring of hard skin can ↓ pain & improve function. ## Evaluation of Relatives at Risk See ## Pregnancy Management Tretinoin and minoxidil should be avoided in pregnancy. See ## Therapies Under Investigation Search ## Genetic Counseling Hidrotic ectodermal dysplasia 2 (HED2) is inherited in an autosomal dominant manner. Most individuals diagnosed with HED2 have an affected parent and a family history of other affected individuals in the same or previous generations. A proband with HED2 may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant 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; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. The family history of some individuals diagnosed with HED2 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 evaluations (physical examination and molecular genetic testing for the pathogenic variant identified in the proband) have demonstrated that neither parent has manifestations of the disorder or is heterozygous for the pathogenic variant. 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 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 may be helpful. • Most individuals diagnosed with HED2 have an affected parent and a family history of other affected individuals in the same or previous generations. • A proband with HED2 may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant 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; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The family history of some individuals diagnosed with HED2 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 evaluations (physical examination and molecular genetic testing for the pathogenic variant identified in the proband) have demonstrated that neither parent has manifestations of the disorder or is heterozygous for the pathogenic variant. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • If the • If the parents have not been tested for the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Hidrotic ectodermal dysplasia 2 (HED2) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with HED2 have an affected parent and a family history of other affected individuals in the same or previous generations. A proband with HED2 may have the disorder as the result of a Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant 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; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. The family history of some individuals diagnosed with HED2 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 evaluations (physical examination and molecular genetic testing for the pathogenic variant identified in the proband) have demonstrated that neither parent has manifestations of the disorder or is heterozygous for the pathogenic variant. 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 If the parents have not been tested for the • Most individuals diagnosed with HED2 have an affected parent and a family history of other affected individuals in the same or previous generations. • A proband with HED2 may have the disorder as the result of a • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant 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; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • The family history of some individuals diagnosed with HED2 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 evaluations (physical examination and molecular genetic testing for the pathogenic variant identified in the proband) have demonstrated that neither parent has manifestations of the disorder or is heterozygous for the pathogenic variant. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism; although no instances of germline mosaicism have been reported, it remains a possibility. Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • 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 may be helpful. ## Resources United Kingdom • • United Kingdom • • • • • • • ## Molecular Genetics Hidrotic Ectodermal Dysplasia 2: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hidrotic Ectodermal Dysplasia 2 ( Gap junction beta-6 protein comprises 261 amino acids and four transmembrane domains, two extracellular domains, and three cytoplasmic domains including the amino- and carboxy-terminal regions. Gap junction beta-6 protein, with five other similar subunits, forms a gap junction channel, the connexon, which mediates the direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Notable Variants listed in the table have been provided by the authors. Certain ## Molecular Pathogenesis Gap junction beta-6 protein comprises 261 amino acids and four transmembrane domains, two extracellular domains, and three cytoplasmic domains including the amino- and carboxy-terminal regions. Gap junction beta-6 protein, with five other similar subunits, forms a gap junction channel, the connexon, which mediates the direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Notable Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors Certain ## Chapter Notes Danielle Greenblatt, MB ChB, FRCP (2020-present)Vazken M Der Kaloustian, MD; McGill University (2005-2020)Jemima Mellerio, BSc, MB BS, MD, FRCP (2020-present) 3 April 2025 (ma) Revision: prevalence data updated 15 October 2020 (sw) Comprehensive update posted live 22 January 2015 (me) Comprehensive update posted live 3 February 2011 (me) Comprehensive update posted live 7 August 2007 (me) Comprehensive update posted live 25 April 2005 (me) Review posted live 23 November 2004 (vdk) Original submission • 3 April 2025 (ma) Revision: prevalence data updated • 15 October 2020 (sw) Comprehensive update posted live • 22 January 2015 (me) Comprehensive update posted live • 3 February 2011 (me) Comprehensive update posted live • 7 August 2007 (me) Comprehensive update posted live • 25 April 2005 (me) Review posted live • 23 November 2004 (vdk) Original submission ## Author History Danielle Greenblatt, MB ChB, FRCP (2020-present)Vazken M Der Kaloustian, MD; McGill University (2005-2020)Jemima Mellerio, BSc, MB BS, MD, FRCP (2020-present) ## Revision History 3 April 2025 (ma) Revision: prevalence data updated 15 October 2020 (sw) Comprehensive update posted live 22 January 2015 (me) Comprehensive update posted live 3 February 2011 (me) Comprehensive update posted live 7 August 2007 (me) Comprehensive update posted live 25 April 2005 (me) Review posted live 23 November 2004 (vdk) Original submission • 3 April 2025 (ma) Revision: prevalence data updated • 15 October 2020 (sw) Comprehensive update posted live • 22 January 2015 (me) Comprehensive update posted live • 3 February 2011 (me) Comprehensive update posted live • 7 August 2007 (me) Comprehensive update posted live • 25 April 2005 (me) Review posted live • 23 November 2004 (vdk) Original submission ## References ## Literature Cited
[]
25/4/2005
15/10/2020
3/4/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
edm-ad
edm-ad
[ "Cartilage oligomeric matrix protein", "Collagen alpha-1(IX) chain", "Collagen alpha-2(IX) chain", "Collagen alpha-3(IX) chain", "Matrilin-3", "COL9A1", "COL9A2", "COL9A3", "COMP", "MATN3", "Multiple Epiphyseal Dysplasia, Autosomal Dominant" ]
Multiple Epiphyseal Dysplasia, Autosomal Dominant
Michael D Briggs, Michael J Wright, Geert R Mortier
Summary Autosomal dominant multiple epiphyseal dysplasia (MED) presents in early childhood, usually with pain in the hips and/or knees after exercise. Affected children report fatigue with long-distance walking. Waddling gait may be present. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis, particularly of the large weight-bearing joints. The diagnosis of autosomal dominant MED is established in a proband with typical clinical and radiographic findings and/or a heterozygous pathogenic variant in By definition, autosomal dominant MED is inherited in an autosomal dominant manner. Many individuals with autosomal dominant MED have an affected parent. The proportion of individuals with autosomal dominant MED who have the disorder as the result of a
## Diagnosis Autosomal dominant multiple epiphyseal dysplasia (MED) Pain in the hips and/or knees and fatigue, often after exercise (frequently starting in early childhood) Adult height in the lower range of normal or mildly shortened Restricted range of movement at the major joints (e.g., elbows) Early-onset osteoarthritis, often requiring joint replacement in the second or third decade of life Initially, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is observed. When the epiphyses appear, the ossification centers are small with irregular contours. Epiphyseal abnormalities are usually most pronounced in the knees and/or hips, where they may resemble bilateral Perthes disease (see In childhood, the tubular bones may be mildly shortened. Ivory (very dense) epiphyses may be present in the hands. By definition, the spine is normal; however, Schmorl bodies (i.e., the displacement of intervertebral disk tissue into the vertebral bodies) and irregular vertebral end plates can be observed. In adulthood, signs of osteoarthritis are usually observed. It is often impossible to make a diagnosis of MED on adult radiographs alone. The diagnosis of autosomal dominant MED 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 When the clinical and radiographic findings suggest the diagnosis of autosomal dominant MED, the recommended molecular genetic testing approach is to use a For an introduction to multigene panels click When the diagnosis of autosomal dominant MED has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Multiple Epiphyseal Dysplasia MED = multiple epiphyseal dysplasia; NA = not applicable Genes are listed in alphabetic order. See In individuals with autosomal dominant MED in whom a pathogenic variant in one of the five confirmed genes has been identified. However, the relative proportions are different depending on ethnicity. For example, a study by the European Skeletal Dysplasia Network (ESDN) [ The proportion of 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 whole-gene deletions or duplications involving A tandem duplication involving exons 2-5 was reported in one individual with MED [ Pathogenic variants remain undetected in approximately 20% of individuals with MED. Rarely, individuals with clinical and radiographic features that overlap MED and mild spondyloepiphyseal dysplasia congenita have been found to have heterozygous • Pain in the hips and/or knees and fatigue, often after exercise (frequently starting in early childhood) • Adult height in the lower range of normal or mildly shortened • Restricted range of movement at the major joints (e.g., elbows) • Early-onset osteoarthritis, often requiring joint replacement in the second or third decade of life • Initially, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is observed. When the epiphyses appear, the ossification centers are small with irregular contours. Epiphyseal abnormalities are usually most pronounced in the knees and/or hips, where they may resemble bilateral Perthes disease (see • In childhood, the tubular bones may be mildly shortened. Ivory (very dense) epiphyses may be present in the hands. By definition, the spine is normal; however, Schmorl bodies (i.e., the displacement of intervertebral disk tissue into the vertebral bodies) and irregular vertebral end plates can be observed. • In adulthood, signs of osteoarthritis are usually observed. It is often impossible to make a diagnosis of MED on adult radiographs alone. ## Suggestive Findings Autosomal dominant multiple epiphyseal dysplasia (MED) Pain in the hips and/or knees and fatigue, often after exercise (frequently starting in early childhood) Adult height in the lower range of normal or mildly shortened Restricted range of movement at the major joints (e.g., elbows) Early-onset osteoarthritis, often requiring joint replacement in the second or third decade of life Initially, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is observed. When the epiphyses appear, the ossification centers are small with irregular contours. Epiphyseal abnormalities are usually most pronounced in the knees and/or hips, where they may resemble bilateral Perthes disease (see In childhood, the tubular bones may be mildly shortened. Ivory (very dense) epiphyses may be present in the hands. By definition, the spine is normal; however, Schmorl bodies (i.e., the displacement of intervertebral disk tissue into the vertebral bodies) and irregular vertebral end plates can be observed. In adulthood, signs of osteoarthritis are usually observed. It is often impossible to make a diagnosis of MED on adult radiographs alone. • Pain in the hips and/or knees and fatigue, often after exercise (frequently starting in early childhood) • Adult height in the lower range of normal or mildly shortened • Restricted range of movement at the major joints (e.g., elbows) • Early-onset osteoarthritis, often requiring joint replacement in the second or third decade of life • Initially, often before the onset of clinical symptoms, delayed ossification of the epiphyses of the long tubular bones is observed. When the epiphyses appear, the ossification centers are small with irregular contours. Epiphyseal abnormalities are usually most pronounced in the knees and/or hips, where they may resemble bilateral Perthes disease (see • In childhood, the tubular bones may be mildly shortened. Ivory (very dense) epiphyses may be present in the hands. By definition, the spine is normal; however, Schmorl bodies (i.e., the displacement of intervertebral disk tissue into the vertebral bodies) and irregular vertebral end plates can be observed. • In adulthood, signs of osteoarthritis are usually observed. It is often impossible to make a diagnosis of MED on adult radiographs alone. ## Establishing the Diagnosis The diagnosis of autosomal dominant MED 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 When the clinical and radiographic findings suggest the diagnosis of autosomal dominant MED, the recommended molecular genetic testing approach is to use a For an introduction to multigene panels click When the diagnosis of autosomal dominant MED has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Multiple Epiphyseal Dysplasia MED = multiple epiphyseal dysplasia; NA = not applicable Genes are listed in alphabetic order. See In individuals with autosomal dominant MED in whom a pathogenic variant in one of the five confirmed genes has been identified. However, the relative proportions are different depending on ethnicity. For example, a study by the European Skeletal Dysplasia Network (ESDN) [ The proportion of 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 whole-gene deletions or duplications involving A tandem duplication involving exons 2-5 was reported in one individual with MED [ Pathogenic variants remain undetected in approximately 20% of individuals with MED. Rarely, individuals with clinical and radiographic features that overlap MED and mild spondyloepiphyseal dysplasia congenita have been found to have heterozygous ## Option 1 When the clinical and radiographic findings suggest the diagnosis of autosomal dominant MED, the recommended molecular genetic testing approach is to use a For an introduction to multigene panels click ## Option 2 When the diagnosis of autosomal dominant MED has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Multiple Epiphyseal Dysplasia MED = multiple epiphyseal dysplasia; NA = not applicable Genes are listed in alphabetic order. See In individuals with autosomal dominant MED in whom a pathogenic variant in one of the five confirmed genes has been identified. However, the relative proportions are different depending on ethnicity. For example, a study by the European Skeletal Dysplasia Network (ESDN) [ The proportion of 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 whole-gene deletions or duplications involving A tandem duplication involving exons 2-5 was reported in one individual with MED [ Pathogenic variants remain undetected in approximately 20% of individuals with MED. Rarely, individuals with clinical and radiographic features that overlap MED and mild spondyloepiphyseal dysplasia congenita have been found to have heterozygous ## Clinical Characteristics Autosomal dominant multiple epiphyseal dysplasia (MED) includes a spectrum of severity from early-onset joint pain, joint deformity, and short stature to milder forms of MED that remain undiagnosed or are misdiagnosed as bilateral Perthes disease or even early-onset familial osteoarthritis. Affected children report fatigue with long-distance walking. Waddling gait may be present. Angular deformities, including coxa vara and genu varum or genu valgum, are relatively rare. In contrast to the restricted mobility in the elbows, hypermobility in the knee and finger joints can be observed. Intra- and interfamilial variability in There is some evidence for reduced penetrance in Multiple epiphyseal dysplasia was originally classified into the severe Fairbank type (MED-Fairbank) and milder Ribbing type (MED-Ribbing). MED-Fairbank type is probably the same disease as "enchondral dysostosis" described by MED-Ribbing should not be confused with Ribbing disease (OMIM The prevalence of autosomal dominant MED is estimated to be least one in 10,000 births. However, as MED is usually not diagnosed at birth, the figure is most likely an underestimate. • Affected children report fatigue with long-distance walking. • Waddling gait may be present. • Angular deformities, including coxa vara and genu varum or genu valgum, are relatively rare. • In contrast to the restricted mobility in the elbows, hypermobility in the knee and finger joints can be observed. ## Clinical Description Autosomal dominant multiple epiphyseal dysplasia (MED) includes a spectrum of severity from early-onset joint pain, joint deformity, and short stature to milder forms of MED that remain undiagnosed or are misdiagnosed as bilateral Perthes disease or even early-onset familial osteoarthritis. Affected children report fatigue with long-distance walking. Waddling gait may be present. Angular deformities, including coxa vara and genu varum or genu valgum, are relatively rare. In contrast to the restricted mobility in the elbows, hypermobility in the knee and finger joints can be observed. • Affected children report fatigue with long-distance walking. • Waddling gait may be present. • Angular deformities, including coxa vara and genu varum or genu valgum, are relatively rare. • In contrast to the restricted mobility in the elbows, hypermobility in the knee and finger joints can be observed. ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations Intra- and interfamilial variability in ## Penetrance There is some evidence for reduced penetrance in ## Nomenclature Multiple epiphyseal dysplasia was originally classified into the severe Fairbank type (MED-Fairbank) and milder Ribbing type (MED-Ribbing). MED-Fairbank type is probably the same disease as "enchondral dysostosis" described by MED-Ribbing should not be confused with Ribbing disease (OMIM ## Prevalence The prevalence of autosomal dominant MED is estimated to be least one in 10,000 births. However, as MED is usually not diagnosed at birth, the figure is most likely an underestimate. ## Genetically Related (Allelic) Disorders Pseudoachondroplasia was originally defined as a condition resembling Other phenotypes caused by germline pathogenic variants in Allelic Disorders Described in consanguineous family w/AR form of SEMD. Affected persons presented w/disproportionate short stature, severe bowing of lower limbs, & lumbar lordosis. AR = autosomal recessive Studies have shown that the p.Thr303Met variant allows the secretion of matrilin-3 [ All affected members of this family were homozygous for a p.Cys304Ser pathogenic variant in the first EGF domain of matrilin-3. Previous studies have demonstrated that p.Cys304Ser causes the intracellular retention of misfolded matrilin-3 [ • Described in consanguineous family w/AR form of SEMD. • Affected persons presented w/disproportionate short stature, severe bowing of lower limbs, & lumbar lordosis. ## Pseudoachondroplasia was originally defined as a condition resembling Other phenotypes caused by germline pathogenic variants in Allelic Disorders Described in consanguineous family w/AR form of SEMD. Affected persons presented w/disproportionate short stature, severe bowing of lower limbs, & lumbar lordosis. AR = autosomal recessive Studies have shown that the p.Thr303Met variant allows the secretion of matrilin-3 [ All affected members of this family were homozygous for a p.Cys304Ser pathogenic variant in the first EGF domain of matrilin-3. Previous studies have demonstrated that p.Cys304Ser causes the intracellular retention of misfolded matrilin-3 [ • Described in consanguineous family w/AR form of SEMD. • Affected persons presented w/disproportionate short stature, severe bowing of lower limbs, & lumbar lordosis. ## Differential Diagnosis Other disorders with features that overlap with those of autosomal dominant multiple epiphyseal dysplasia (MED) are summarized in Disorders to Consider in the Differential Diagnosis of Autosomal Dominant Multiple Epiphyseal Dysplasia Radiographic changes in LCPD show more involvement of metaphyses & femoral neck. Usually affects males ages 3-15 yrs Up to 20% have bilateral involvement Clinical & radiographic features may be similar to MED. Double-layered patella on lateral knee radiographs in ~60% of children (evident before skeletal maturity; may not be apparent in adults) Onset of joint pain variable, but usually in late childhood (usually hips &/or knees); malformations of hands, feet, & knees; scoliosis Stature usually normal prior to puberty; in adulthood, stature only slightly diminished (range: 150-180 cm) 50% w/abnormal finding at birth, incl clubfoot, clinodactyly, or (rarely) cystic ear swelling Disproportionate short stature Radiographically characterized by vertebral, epiphyseal, & metaphyseal irregularities AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance • Radiographic changes in LCPD show more involvement of metaphyses & femoral neck. • Usually affects males ages 3-15 yrs • Up to 20% have bilateral involvement • Clinical & radiographic features may be similar to MED. • Double-layered patella on lateral knee radiographs in ~60% of children (evident before skeletal maturity; may not be apparent in adults) • Onset of joint pain variable, but usually in late childhood (usually hips &/or knees); malformations of hands, feet, & knees; scoliosis • Stature usually normal prior to puberty; in adulthood, stature only slightly diminished (range: 150-180 cm) • 50% w/abnormal finding at birth, incl clubfoot, clinodactyly, or (rarely) cystic ear swelling • Disproportionate short stature • Radiographically characterized by vertebral, epiphyseal, & metaphyseal irregularities ## Management No clinical practice guidelines for autosomal dominant multiple epiphyseal dysplasia (MED) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. To establish the extent of disease and needs in an individual diagnosed with autosomal dominant MED, the evaluations summarized in Autosomal Dominant Multiple Epiphyseal Dysplasia: Recommended Evaluations Following Initial Diagnosis Eval w/experts in skeletal dysplasia Elicitation of pain history Assessment of joint mobility Radiographs to determine extent & severity of joint involvement AD = autosomal dominant; MED = multiple epiphyseal dysplasia; 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 Autosomal Dominant Multiple Epiphyseal Dysplasia: Treatment of Manifestations For pain control, combination of analgesics & physiotherapy incl hydrotherapy is helpful for many affected persons. Referral to rheumatologist or pain specialist may be indicated. Consultation w/orthopedic surgeon can determine if realignment osteotomy &/or acetabular osteotomy may be helpful in slowing progression of symptoms. In some persons, total joint arthroplasty may be required if degenerative hip changes are causing too much pain or dysfunction. Evaluation by an orthopedic surgeon is recommended if the affected individual has chronic pain or limb deformities (genu varum, genu valgum). The following should be avoided: Obesity, which increases stress on joints Exercise that causes repetitive strain on affected joints See Search • Eval w/experts in skeletal dysplasia • Elicitation of pain history • Assessment of joint mobility • Radiographs to determine extent & severity of joint involvement • For pain control, combination of analgesics & physiotherapy incl hydrotherapy is helpful for many affected persons. • Referral to rheumatologist or pain specialist may be indicated. • Consultation w/orthopedic surgeon can determine if realignment osteotomy &/or acetabular osteotomy may be helpful in slowing progression of symptoms. • In some persons, total joint arthroplasty may be required if degenerative hip changes are causing too much pain or dysfunction. • Obesity, which increases stress on joints • Exercise that causes repetitive strain on affected joints ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with autosomal dominant MED, the evaluations summarized in Autosomal Dominant Multiple Epiphyseal Dysplasia: Recommended Evaluations Following Initial Diagnosis Eval w/experts in skeletal dysplasia Elicitation of pain history Assessment of joint mobility Radiographs to determine extent & severity of joint involvement AD = autosomal dominant; MED = multiple epiphyseal dysplasia; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Eval w/experts in skeletal dysplasia • Elicitation of pain history • Assessment of joint mobility • Radiographs to determine extent & severity of joint involvement ## 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 Autosomal Dominant Multiple Epiphyseal Dysplasia: Treatment of Manifestations For pain control, combination of analgesics & physiotherapy incl hydrotherapy is helpful for many affected persons. Referral to rheumatologist or pain specialist may be indicated. Consultation w/orthopedic surgeon can determine if realignment osteotomy &/or acetabular osteotomy may be helpful in slowing progression of symptoms. In some persons, total joint arthroplasty may be required if degenerative hip changes are causing too much pain or dysfunction. • For pain control, combination of analgesics & physiotherapy incl hydrotherapy is helpful for many affected persons. • Referral to rheumatologist or pain specialist may be indicated. • Consultation w/orthopedic surgeon can determine if realignment osteotomy &/or acetabular osteotomy may be helpful in slowing progression of symptoms. • In some persons, total joint arthroplasty may be required if degenerative hip changes are causing too much pain or dysfunction. ## Surveillance Evaluation by an orthopedic surgeon is recommended if the affected individual has chronic pain or limb deformities (genu varum, genu valgum). ## Agents/Circumstances to Avoid The following should be avoided: Obesity, which increases stress on joints Exercise that causes repetitive strain on affected joints • Obesity, which increases stress on joints • Exercise that causes repetitive strain on affected joints ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling By definition, autosomal dominant multiple epiphyseal dysplasia (MED) is inherited in an autosomal dominant manner. Many individuals with autosomal dominant MED have an affected parent. An individual with autosomal dominant MED 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 to evaluate their genetic status and inform recurrence risk assessment include: Evaluation for signs of MED or early-onset osteoarthritis; Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). 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.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * If the 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. The family history of some individuals diagnosed with autosomal dominant MED may appear to be negative because of failure to recognize the disorder in affected family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband). If a parent of the proband has autosomal dominant MED and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%. Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in If the proband has a known autosomal dominant MED-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 gonadal 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 (see The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the autosomal dominant MED-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 centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Many individuals with autosomal dominant MED have an affected parent. • An individual with autosomal dominant MED 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 to evaluate their genetic status and inform recurrence risk assessment include: • Evaluation for signs of MED or early-onset osteoarthritis; • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). • Evaluation for signs of MED or early-onset osteoarthritis; • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). • 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.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. • The family history of some individuals diagnosed with autosomal dominant MED may appear to be negative because of failure to recognize the disorder in affected family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband). • Evaluation for signs of MED or early-onset osteoarthritis; • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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 of the proband has autosomal dominant MED and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%. • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in • If the proband has a known autosomal dominant MED-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 gonadal 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 (see • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related 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 or at risk. ## Mode of Inheritance By definition, autosomal dominant multiple epiphyseal dysplasia (MED) is inherited in an autosomal dominant manner. ## Risk to Family Members Many individuals with autosomal dominant MED have an affected parent. An individual with autosomal dominant MED 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 to evaluate their genetic status and inform recurrence risk assessment include: Evaluation for signs of MED or early-onset osteoarthritis; Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). 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.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * If the 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. The family history of some individuals diagnosed with autosomal dominant MED may appear to be negative because of failure to recognize the disorder in affected family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband). If a parent of the proband has autosomal dominant MED and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%. Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in If the proband has a known autosomal dominant MED-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 gonadal 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 (see • Many individuals with autosomal dominant MED have an affected parent. • An individual with autosomal dominant MED 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 to evaluate their genetic status and inform recurrence risk assessment include: • Evaluation for signs of MED or early-onset osteoarthritis; • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). • Evaluation for signs of MED or early-onset osteoarthritis; • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). • 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.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. • The family history of some individuals diagnosed with autosomal dominant MED may appear to be negative because of failure to recognize the disorder in affected family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (if a molecular diagnosis has been established in the proband). • Evaluation for signs of MED or early-onset osteoarthritis; • Molecular genetic testing (if a molecular diagnosis has been established in an affected family member). • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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 of the proband has autosomal dominant MED and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%. • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related pathogenic variants in • If the proband has a known autosomal dominant MED-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 gonadal 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 (see • Striking clinical variability may be observed among heterozygous individuals in families segregating autosomal dominant MED-related 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 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 autosomal dominant MED-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 centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • United Kingdom • • • ## Molecular Genetics Multiple Epiphyseal Dysplasia, Dominant: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Multiple Epiphyseal Dysplasia, Dominant ( The five genes ( All reported A coiled-coil oligomerization domain; Four type II (EGF-like) repeats; Eight type III (CaM-like) repeats; A large COOH-terminal globular domain. The type III repeats bind Ca All MED-related One or two vWFA domains; A varying number of EGF-like repeats; A coiled-coil domain, which facilitates oligomerization. Matrilins have been found in collagen-dependent and collagen-independent filament networks within the tissues in which they are expressed and may perform analogous functions in these different tissues. Matrilin-3 has been shown to interact with COMP and other cartilage collagens through the A domain [ With one exception, all Autosomal Dominant Multiple Epiphyseal Dysplasia: Mechanism of Disease Causation ECM = extracellular matrix; rER = rough endoplasmic reticulum Genes from Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. Genes from • A coiled-coil oligomerization domain; • Four type II (EGF-like) repeats; • Eight type III (CaM-like) repeats; • A large COOH-terminal globular domain. • One or two vWFA domains; • A varying number of EGF-like repeats; • A coiled-coil domain, which facilitates oligomerization. ## Molecular Pathogenesis The five genes ( All reported A coiled-coil oligomerization domain; Four type II (EGF-like) repeats; Eight type III (CaM-like) repeats; A large COOH-terminal globular domain. The type III repeats bind Ca All MED-related One or two vWFA domains; A varying number of EGF-like repeats; A coiled-coil domain, which facilitates oligomerization. Matrilins have been found in collagen-dependent and collagen-independent filament networks within the tissues in which they are expressed and may perform analogous functions in these different tissues. Matrilin-3 has been shown to interact with COMP and other cartilage collagens through the A domain [ With one exception, all Autosomal Dominant Multiple Epiphyseal Dysplasia: Mechanism of Disease Causation ECM = extracellular matrix; rER = rough endoplasmic reticulum Genes from Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. Genes from • A coiled-coil oligomerization domain; • Four type II (EGF-like) repeats; • Eight type III (CaM-like) repeats; • A large COOH-terminal globular domain. • One or two vWFA domains; • A varying number of EGF-like repeats; • A coiled-coil domain, which facilitates oligomerization. ## Chapter Notes 4 July 2024 (sw) Comprehensive update posted live 25 April 2019 (ha) Comprehensive update posted live 19 November 2015 (me) Comprehensive update posted live 25 July 2013 (me) Comprehensive update posted live 1 February 2011 (me) Comprehensive update posted live 18 April 2007 (me) Comprehensive update posted live 24 January 2005 (me) Comprehensive update posted live 8 January 2003 (me) Review posted live 10 October 2002 (gm) Original submission • 4 July 2024 (sw) Comprehensive update posted live • 25 April 2019 (ha) Comprehensive update posted live • 19 November 2015 (me) Comprehensive update posted live • 25 July 2013 (me) Comprehensive update posted live • 1 February 2011 (me) Comprehensive update posted live • 18 April 2007 (me) Comprehensive update posted live • 24 January 2005 (me) Comprehensive update posted live • 8 January 2003 (me) Review posted live • 10 October 2002 (gm) Original submission ## Author Notes ## Revision History 4 July 2024 (sw) Comprehensive update posted live 25 April 2019 (ha) Comprehensive update posted live 19 November 2015 (me) Comprehensive update posted live 25 July 2013 (me) Comprehensive update posted live 1 February 2011 (me) Comprehensive update posted live 18 April 2007 (me) Comprehensive update posted live 24 January 2005 (me) Comprehensive update posted live 8 January 2003 (me) Review posted live 10 October 2002 (gm) Original submission • 4 July 2024 (sw) Comprehensive update posted live • 25 April 2019 (ha) Comprehensive update posted live • 19 November 2015 (me) Comprehensive update posted live • 25 July 2013 (me) Comprehensive update posted live • 1 February 2011 (me) Comprehensive update posted live • 18 April 2007 (me) Comprehensive update posted live • 24 January 2005 (me) Comprehensive update posted live • 8 January 2003 (me) Review posted live • 10 October 2002 (gm) Original submission ## References ## Literature Cited
[]
8/1/2003
4/7/2024
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
edm
edm
[ "SLC26A2-Related Recessive MED (SLC26A2-rMED)", "SLC26A2-Related Recessive MED (SLC26A2-rMED)", "Sulfate transporter", "SLC26A2", "SLC26A2-Related Multiple Epiphyseal Dysplasia" ]
Sheila Unger, Andrea Superti-Furga
Summary Diagnosis of
## Diagnosis Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain. Deformity of hands, feet, and knees Scoliosis Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint) Mild brachydactyly Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) (see 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. Individuals with the distinctive findings described in For an introduction to multigene panels click When the phenotype is indistinguishable from other skeletal dysplasias, 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 The four most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ • Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain. • Deformity of hands, feet, and knees • Scoliosis • Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint) • Mild brachydactyly • Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) (see ## Suggestive Findings Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain. Deformity of hands, feet, and knees Scoliosis Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint) Mild brachydactyly Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) (see • Joint pain (usually in the hips and knees). Onset of pain is variable, but usually occurs in late childhood. Some individuals have no pain. • Deformity of hands, feet, and knees • Scoliosis • Flat epiphyses with early arthritis (degenerative and painful changes in the articular cartilage of the hip joint) • Mild brachydactyly • Double-layered patella (i.e., presence of a separate anterior and posterior ossification layer) (see ## 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. Individuals with the distinctive findings described in For an introduction to multigene panels click When the phenotype is indistinguishable from other skeletal dysplasias, 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 The four most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from other skeletal dysplasias, 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 The four most common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Waddling gait, hand/foot deformities (mild brachydactyly, clinodactyly, clubfoot, broadening of the space between the first and second toes), and mild scoliosis are also reported. Brachydactyly is evident after puberty in most individuals. Habitus is unremarkable in most affected individuals, except for genu valgum in some. Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders, which extends from lethal The pathogenic variant Pathogenic variant Pathogenic variants Pathogenic variant Pathogenic variant The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (AO2 and DTD) if the second allele is a relatively mild variant. Indeed, missense variants located outside of the transmembrane domain of the sulfate transporter are often associated with residual activity that can "rescue" the effect of a null allele [ Multiple epiphyseal dysplasia (MED) is a disorder with clinical and genetic heterogeneity. In the past, the disorder was clinically subdivided into the milder Ribbing type, with flattened epiphysis and normal or near-normal stature; the more severe Fairbank type, with round, small epiphyses and short stature; and the unclassified types [ The genetic dissection of this heterogeneous group of conditions in recent years has provided a molecular-pathogenic classification of the different subtypes according to the gene involved: The other subtypes of MED are classified in the pseudoachondroplasia and the multiple epiphyseal dysplasias group in the 2023 revised nosology [ Some individuals with MED do not have pathogenic variants in a known gene [ Exact data about the prevalence of MED and its subtypes are not available. Based on the number of individuals seen in growth clinics, rheumatology clinics, and genetics clinics, and compared to conditions whose incidences are more precisely known (e.g., • The other subtypes of MED are classified in the pseudoachondroplasia and the multiple epiphyseal dysplasias group in the 2023 revised nosology [ • Some individuals with MED do not have pathogenic variants in a known gene [ ## Clinical Description Waddling gait, hand/foot deformities (mild brachydactyly, clinodactyly, clubfoot, broadening of the space between the first and second toes), and mild scoliosis are also reported. Brachydactyly is evident after puberty in most individuals. Habitus is unremarkable in most affected individuals, except for genu valgum in some. ## Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders, which extends from lethal The pathogenic variant Pathogenic variant Pathogenic variants Pathogenic variant Pathogenic variant The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes (AO2 and DTD) if the second allele is a relatively mild variant. Indeed, missense variants located outside of the transmembrane domain of the sulfate transporter are often associated with residual activity that can "rescue" the effect of a null allele [ ## Nomenclature Multiple epiphyseal dysplasia (MED) is a disorder with clinical and genetic heterogeneity. In the past, the disorder was clinically subdivided into the milder Ribbing type, with flattened epiphysis and normal or near-normal stature; the more severe Fairbank type, with round, small epiphyses and short stature; and the unclassified types [ The genetic dissection of this heterogeneous group of conditions in recent years has provided a molecular-pathogenic classification of the different subtypes according to the gene involved: The other subtypes of MED are classified in the pseudoachondroplasia and the multiple epiphyseal dysplasias group in the 2023 revised nosology [ Some individuals with MED do not have pathogenic variants in a known gene [ • The other subtypes of MED are classified in the pseudoachondroplasia and the multiple epiphyseal dysplasias group in the 2023 revised nosology [ • Some individuals with MED do not have pathogenic variants in a known gene [ ## Prevalence Exact data about the prevalence of MED and its subtypes are not available. Based on the number of individuals seen in growth clinics, rheumatology clinics, and genetics clinics, and compared to conditions whose incidences are more precisely known (e.g., ## Genetically Related (Allelic) Disorders Extremely short limbs w/short fingers & toes; hypoplasia of the thorax; & protuberant abdomen Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton Death occurs prenatally or shortly after birth Commonly lethal in perinatal period Presents around birth or before Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced Short limb type of dwarfism assoc w/clubfeet & other joint restrictions incl "hitchhiker thumbs" Progressive scoliosis in childhood • Extremely short limbs w/short fingers & toes; hypoplasia of the thorax; & protuberant abdomen • Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton • Death occurs prenatally or shortly after birth • Commonly lethal in perinatal period • Presents around birth or before • Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced • Short limb type of dwarfism assoc w/clubfeet & other joint restrictions incl "hitchhiker thumbs" • Progressive scoliosis in childhood ## Differential Diagnosis Note: In contrast to autosomal dominant MED, prepubertal children with Autosomal Dominant Multiple Epiphyseal Dysplasia * * See MED = multiple epiphyseal dysplasia Pathogenic variants in ## Management To establish the extent of disease in an individual diagnosed with Height measurement Elicitation of pain history Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral), to determine the extent and severity of joint involvement 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 Symptomatic individuals should be seen by a physical therapist and an orthopedist to assess the possibility of treatment (physiotherapy for muscular strengthening and maintaining mobility, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs) and the optimal time for surgery (joint replacement), if indicated. Intensive physiotherapy may delay joint contractures and help maintain mobility. Psychosocial support addressing issues of chronic pain and career counseling is warranted. Radiographic surveillance by an orthopedist is appropriate. Sports involving joint overload are to be avoided. Predictive testing of at-risk sibs is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are available. See Women affected by See Search • Height measurement • Elicitation of pain history • Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral), to determine the extent and severity of joint involvement • 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 ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Height measurement Elicitation of pain history Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral), to determine the extent and severity of joint involvement 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 • Height measurement • Elicitation of pain history • Radiographs of the entire spine (AP and lateral), pelvis (AP), and knees (AP and lateral), to determine the extent and severity of joint involvement • 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 ## Treatment of Manifestations Symptomatic individuals should be seen by a physical therapist and an orthopedist to assess the possibility of treatment (physiotherapy for muscular strengthening and maintaining mobility, cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs) and the optimal time for surgery (joint replacement), if indicated. Intensive physiotherapy may delay joint contractures and help maintain mobility. Psychosocial support addressing issues of chronic pain and career counseling is warranted. ## Surveillance Radiographic surveillance by an orthopedist is appropriate. ## Agents/Circumstances to Avoid Sports involving joint overload are to be avoided. ## Evaluation of Relatives at Risk Predictive testing of at-risk sibs is not indicated because no preventive measures or therapeutic interventions to reduce morbidity are available. See ## Pregnancy Management Women affected by See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of the 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 have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers should be considered. A Once the Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of the 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 have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. • The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered. • A ## Mode of Inheritance ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of the 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 have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. • The parents of an affected individual are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of the 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 have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 have normal stature. No evidence that carriers are at increased risk of developing degenerative joint disease has been presented. ## 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 availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers should be considered. A • The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered. • A ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and in families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • • • • • • • ## Molecular Genetics SLC26A2-Related Multiple Epiphyseal Dysplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SLC26A2-Related Multiple Epiphyseal Dysplasia ( In a Notable ACG1B = achondrogenesis type 1B; AO2 = atelosteogenesis type 2; DTD = diastrophic dysplasia; MED = multiple epiphyseal dysplasia Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis In a Notable ACG1B = achondrogenesis type 1B; AO2 = atelosteogenesis type 2; DTD = diastrophic dysplasia; MED = multiple epiphyseal dysplasia Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes Diana Ballhausen, MD; Lausanne University Hospital (2002-2023)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2023)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2023)Andrea Superti-Furga, MD (2002-present)Sheila Unger, MD (2023-present) 19 January 2023 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 18 March 2010 (me) Comprehensive update posted live 27 December 2006 (me) Comprehensive update posted live 20 July 2004 (me) Comprehensive update posted live 29 August 2002 (me) Review posted live 25 February 2002 (db) Original submission • 19 January 2023 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 18 March 2010 (me) Comprehensive update posted live • 27 December 2006 (me) Comprehensive update posted live • 20 July 2004 (me) Comprehensive update posted live • 29 August 2002 (me) Review posted live • 25 February 2002 (db) Original submission ## Author History Diana Ballhausen, MD; Lausanne University Hospital (2002-2023)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2023)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2023)Andrea Superti-Furga, MD (2002-present)Sheila Unger, MD (2023-present) ## Revision History 19 January 2023 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 18 March 2010 (me) Comprehensive update posted live 27 December 2006 (me) Comprehensive update posted live 20 July 2004 (me) Comprehensive update posted live 29 August 2002 (me) Review posted live 25 February 2002 (db) Original submission • 19 January 2023 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 18 March 2010 (me) Comprehensive update posted live • 27 December 2006 (me) Comprehensive update posted live • 20 July 2004 (me) Comprehensive update posted live • 29 August 2002 (me) Review posted live • 25 February 2002 (db) Original submission ## References ## Literature Cited Double-layered patella
[]
29/8/2002
19/1/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
edmd
edmd
[ "Emerin", "Four and a half LIM domains protein 1", "Prelamin-A/C", "EMD", "FHL1", "LMNA", "Emery-Dreifuss Muscular Dystrophy" ]
Emery-Dreifuss Muscular Dystrophy
Gisèle Bonne, France Leturcq, Rabah Ben Yaou
Summary Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals. The diagnosis of EDMD is established in a proband with: A clearly relevant clinical picture including limb muscle wasting and/or weakness and elbow or neck/spine joint contractures (cardiac disease may be missing in the first decades of life); AND A hemizygous pathogenic variant in EDMD is inherited in an X-linked, autosomal dominant, or, rarely, autosomal recessive manner. Once the pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for EDMD are possible.
## Diagnosis Emery-Dreifuss muscular dystrophy (EDMD) Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. Note: Diagnosis guidelines have been published [ The diagnosis of EDMD 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 EDMD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of EDMD, molecular genetic testing approaches can include The likelihood of identifying a causative variant in In cases of X-linked inheritance, In cases of autosomal dominant or recessive inheritance, In the absence of a clear inheritance pattern, In an affected female who represents a simplex case (i.e., a single occurrence in a family) For an introduction to multigene panels click When the diagnosis of EDMD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Emery-Dreifuss Muscular Dystrophy (EDMD) 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. Intragenic • • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. • In cases of X-linked inheritance, • In cases of autosomal dominant or recessive inheritance, • In the absence of a clear inheritance pattern, ## Suggestive Findings Emery-Dreifuss muscular dystrophy (EDMD) Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. Note: Diagnosis guidelines have been published [ • • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. • Atrial fibrillation, flutter and standstill, supraventricular and ventricular arrhythmias, and atrio-ventricular and bundle-branch blocks may be identified on resting electrocardiography (EKG) or by 24-hour ambulatory EKG. • Dilated or hypertrophic cardiomyopathy may be detected by the performance of echocardiographic evaluation. ## Establishing the Diagnosis The diagnosis of EDMD 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 EDMD is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of EDMD, molecular genetic testing approaches can include The likelihood of identifying a causative variant in In cases of X-linked inheritance, In cases of autosomal dominant or recessive inheritance, In the absence of a clear inheritance pattern, In an affected female who represents a simplex case (i.e., a single occurrence in a family) For an introduction to multigene panels click When the diagnosis of EDMD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Emery-Dreifuss Muscular Dystrophy (EDMD) 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. Intragenic • In cases of X-linked inheritance, • In cases of autosomal dominant or recessive inheritance, • In the absence of a clear inheritance pattern, ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of EDMD, molecular genetic testing approaches can include The likelihood of identifying a causative variant in In cases of X-linked inheritance, In cases of autosomal dominant or recessive inheritance, In the absence of a clear inheritance pattern, In an affected female who represents a simplex case (i.e., a single occurrence in a family) For an introduction to multigene panels click • In cases of X-linked inheritance, • In cases of autosomal dominant or recessive inheritance, • In the absence of a clear inheritance pattern, ## Option 2 When the diagnosis of EDMD is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Emery-Dreifuss Muscular Dystrophy (EDMD) 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. Intragenic ## Clinical Characteristics Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) and X-linked EDMD (XL-EDMD) have similar but not identical neuromuscular and cardiac involvement [ EDMD is characterized by the presence of the following clinical triad: Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ A generalized dilated (in Other clinical findings may be nonspecific: Other laboratory findings: In individuals with XL-EDMD, emerin is absent in 95% [ In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. In individuals with AD-EDMD, emerin is normally expressed. In individuals with In female carriers of Nine individuals with genetically confirmed isolated autosomal recessive EDMD (i.e., homozygous or compound heterozygous for a Clinical Characteristics in Ten Reported Individuals with Biallelic Null variants, the majority of Missense variants associated with decreased or normal amounts of emerin and result in a milder phenotype [ Missense variants have been associated with early skeletal muscle involvement and joint contractures (i.e., EDMD type) while frameshift variants have been associated with later-onset muscle symptoms of limb girdle type [ Homozygous and compound heterozygous pathogenic variants appear to lead to a more severe muscular phenotype [ Pathogenic variants destabilizing the 3D structure of the C-terminal domain of lamin A/C lead to EDMD [ Five The prevalence of XL-EDMD has been estimated at 0.13:100,000-0.2:100,000 [ • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with • In female carriers of • In individuals with • In female carriers of • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with • In female carriers of • Null variants, the majority of • Missense variants associated with decreased or normal amounts of emerin and result in a milder phenotype [ • Missense variants have been associated with early skeletal muscle involvement and joint contractures (i.e., EDMD type) while frameshift variants have been associated with later-onset muscle symptoms of limb girdle type [ • Homozygous and compound heterozygous pathogenic variants appear to lead to a more severe muscular phenotype [ • Pathogenic variants destabilizing the 3D structure of the C-terminal domain of lamin A/C lead to EDMD [ ## Clinical Description Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) and X-linked EDMD (XL-EDMD) have similar but not identical neuromuscular and cardiac involvement [ EDMD is characterized by the presence of the following clinical triad: Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ A generalized dilated (in Other clinical findings may be nonspecific: Other laboratory findings: In individuals with XL-EDMD, emerin is absent in 95% [ In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. In individuals with AD-EDMD, emerin is normally expressed. In individuals with In female carriers of Nine individuals with genetically confirmed isolated autosomal recessive EDMD (i.e., homozygous or compound heterozygous for a Clinical Characteristics in Ten Reported Individuals with Biallelic • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with • In female carriers of • In individuals with • In female carriers of • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with • In female carriers of ## AD-EDMD and XL-EDMD Autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) and X-linked EDMD (XL-EDMD) have similar but not identical neuromuscular and cardiac involvement [ EDMD is characterized by the presence of the following clinical triad: Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ A generalized dilated (in Other clinical findings may be nonspecific: Other laboratory findings: In individuals with XL-EDMD, emerin is absent in 95% [ In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. In individuals with AD-EDMD, emerin is normally expressed. In individuals with In female carriers of • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • Cardiac conduction defects can include sinus bradycardia, first-degree atrioventricular block, bundle-branch blocks, Wenckebach phenomenon, and third-degree atrioventricular block requiring pacemaker implantation. • Atrial arrhythmias (extrasystoles, atrial fibrillation, flutter) and ventricular arrhythmias (extrasystoles, ventricular tachycardia) are frequent. • The risk for ventricular tachyarrhythmia and dilated cardiomyopathy manifested by left ventricular dilatation and dysfunction is higher in AD-EDMD than in XL-EDMD. • In both XL- and AD/AR-EDMD, affected individuals are at risk for cerebral emboli and sudden death [ • A generalized dilated (in • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with • In female carriers of • In individuals with • In female carriers of • In individuals with XL-EDMD, emerin is absent in 95% [ • In female carriers of XL-EDMD, emerin is absent in varying proportions in nuclei, as demonstrated by immunofluorescence. However, western blot is not reliable in carrier detection because it may show either a normal or a reduced amount of emerin, depending on the proportion of nuclei expressing emerin. • In individuals with AD-EDMD, emerin is normally expressed. • In individuals with • In female carriers of ## AR-EDMD Nine individuals with genetically confirmed isolated autosomal recessive EDMD (i.e., homozygous or compound heterozygous for a Clinical Characteristics in Ten Reported Individuals with Biallelic ## Genotype-Phenotype Correlations Null variants, the majority of Missense variants associated with decreased or normal amounts of emerin and result in a milder phenotype [ Missense variants have been associated with early skeletal muscle involvement and joint contractures (i.e., EDMD type) while frameshift variants have been associated with later-onset muscle symptoms of limb girdle type [ Homozygous and compound heterozygous pathogenic variants appear to lead to a more severe muscular phenotype [ Pathogenic variants destabilizing the 3D structure of the C-terminal domain of lamin A/C lead to EDMD [ • Null variants, the majority of • Missense variants associated with decreased or normal amounts of emerin and result in a milder phenotype [ • Missense variants have been associated with early skeletal muscle involvement and joint contractures (i.e., EDMD type) while frameshift variants have been associated with later-onset muscle symptoms of limb girdle type [ • Homozygous and compound heterozygous pathogenic variants appear to lead to a more severe muscular phenotype [ • Pathogenic variants destabilizing the 3D structure of the C-terminal domain of lamin A/C lead to EDMD [ ## Penetrance Five ## Prevalence The prevalence of XL-EDMD has been estimated at 0.13:100,000-0.2:100,000 [ ## Genetically Related (Allelic) Disorders The disorders caused by pathogenic variants in X-linked limb-girdle muscular dystrophy (LGMD) phenotype caused by pathogenic variants in X-linked isolated cardiac disease with prominent sinus node disease and atrial fibrillation [ Reducing body myopathy [ X-linked scapuloperoneal myopathy [ Some cases of rigid spine syndrome [ Other allelic X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized muscle hypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is reduced on immunodetection (making this disorder similar to X-linked hypertrophic cardiomyopathy [ The disorders caused by pathogenic variants in LGMD1B, an autosomal dominant form of limb-girdle muscular dystrophy associated with atrioventricular conduction defect [ CMD1A or DCM-CD, an autosomal dominant form of dilated cardiomyopathy with cardiac conduction defects [ Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy and cardiac conduction defects [ Neurogenic variant of EDMD [ Note: (1) These may not truly be allelic disorders because the phenotype overlaps with EDMD. See comments in CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with the pathogenic founder variant p.Arg298Cys [ Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy, and leukonychia [ Autosomal dominant CMT2 associated with myopathy [ Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial lipodystrophy [ Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder pathogenic variants are reported in MAD (p.Arg527His) [ Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [ Atypical Werner syndrome (autosomal dominant) [ Restrictive dermopathy [ Progeria, arthropathy, and calcinosis of tendons [ Heart-hand syndrome, Slovenian type [ • X-linked limb-girdle muscular dystrophy (LGMD) phenotype caused by pathogenic variants in • X-linked isolated cardiac disease with prominent sinus node disease and atrial fibrillation [ • Reducing body myopathy [ • X-linked scapuloperoneal myopathy [ • Some cases of rigid spine syndrome [ • X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized muscle hypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is reduced on immunodetection (making this disorder similar to • X-linked hypertrophic cardiomyopathy [ • LGMD1B, an autosomal dominant form of limb-girdle muscular dystrophy associated with atrioventricular conduction defect [ • CMD1A or DCM-CD, an autosomal dominant form of dilated cardiomyopathy with cardiac conduction defects [ • Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy and cardiac conduction defects [ • Neurogenic variant of EDMD [ • CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with the pathogenic founder variant p.Arg298Cys [ • Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy, and leukonychia [ • Autosomal dominant CMT2 associated with myopathy [ • Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial lipodystrophy [ • Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder pathogenic variants are reported in MAD (p.Arg527His) [ • Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [ • Atypical Werner syndrome (autosomal dominant) [ • Restrictive dermopathy [ • Progeria, arthropathy, and calcinosis of tendons [ • Heart-hand syndrome, Slovenian type [ ## The disorders caused by pathogenic variants in X-linked limb-girdle muscular dystrophy (LGMD) phenotype caused by pathogenic variants in X-linked isolated cardiac disease with prominent sinus node disease and atrial fibrillation [ • X-linked limb-girdle muscular dystrophy (LGMD) phenotype caused by pathogenic variants in • X-linked isolated cardiac disease with prominent sinus node disease and atrial fibrillation [ ## Reducing body myopathy [ X-linked scapuloperoneal myopathy [ Some cases of rigid spine syndrome [ Other allelic X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized muscle hypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is reduced on immunodetection (making this disorder similar to X-linked hypertrophic cardiomyopathy [ • Reducing body myopathy [ • X-linked scapuloperoneal myopathy [ • Some cases of rigid spine syndrome [ • X-linked myopathy with postural muscle atrophy (X-MPMA) and generalized muscle hypertrophy or X-MPMA in which reducing bodies are absent and FHL1 protein is reduced on immunodetection (making this disorder similar to • X-linked hypertrophic cardiomyopathy [ ## The disorders caused by pathogenic variants in LGMD1B, an autosomal dominant form of limb-girdle muscular dystrophy associated with atrioventricular conduction defect [ CMD1A or DCM-CD, an autosomal dominant form of dilated cardiomyopathy with cardiac conduction defects [ Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy and cardiac conduction defects [ Neurogenic variant of EDMD [ Note: (1) These may not truly be allelic disorders because the phenotype overlaps with EDMD. See comments in CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with the pathogenic founder variant p.Arg298Cys [ Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy, and leukonychia [ Autosomal dominant CMT2 associated with myopathy [ Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial lipodystrophy [ Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder pathogenic variants are reported in MAD (p.Arg527His) [ Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [ Atypical Werner syndrome (autosomal dominant) [ Restrictive dermopathy [ Progeria, arthropathy, and calcinosis of tendons [ Heart-hand syndrome, Slovenian type [ • LGMD1B, an autosomal dominant form of limb-girdle muscular dystrophy associated with atrioventricular conduction defect [ • CMD1A or DCM-CD, an autosomal dominant form of dilated cardiomyopathy with cardiac conduction defects [ • Autosomal dominant quadriceps myopathy associated with dilated cardiomyopathy and cardiac conduction defects [ • Neurogenic variant of EDMD [ • CMT2B1, an autosomal recessive form of axonal Charcot-Marie-Tooth disease with the pathogenic founder variant p.Arg298Cys [ • Autosomal dominant CMT2 associated with muscular dystrophy, cardiomyopathy, and leukonychia [ • Autosomal dominant CMT2 associated with myopathy [ • Autosomal dominant muscular dystrophy, dilated cardiomyopathy, and partial lipodystrophy [ • Mandibuloacral dysplasia (MAD) (autosomal recessive). Founder pathogenic variants are reported in MAD (p.Arg527His) [ • Generalized lipoatrophy, insulin-resistant diabetes mellitus, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy (LDHCP) [ • Atypical Werner syndrome (autosomal dominant) [ • Restrictive dermopathy [ • Progeria, arthropathy, and calcinosis of tendons [ • Heart-hand syndrome, Slovenian type [ ## Differential Diagnosis Some neuromuscular disorders result in a similar pattern of muscle involvement, joint contractures, or cardiac disease, but most do not feature the complete triad observed in Emery-Dreifuss muscular dystrophy (EDMD). Disorders to Consider in the Differential Diagnosis of Emery-Dreifuss Muscular Dystrophy No joint contractures ( No cardiac disease ( No cardiac disease Early & severe respiratory failure Variably present cardiac disease Severe respiratory involvement Specific muscle pathology Variably present cardiac disease Possible CNS involvement No cardiac disease Specific muscle imaging pattern No joint contractures Myotonia No joint contractures Peculiar muscle pathology Peculiar muscle pathology Peripheral neuropathy AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; MOI = mode of inheritance; XL = X-linked Typical MOI; exceptions occur See • No joint contractures ( • No cardiac disease ( • No cardiac disease • Early & severe respiratory failure • Variably present cardiac disease • Severe respiratory involvement • Specific muscle pathology • Variably present cardiac disease • Possible CNS involvement • No cardiac disease • Specific muscle imaging pattern • No joint contractures • Myotonia • No joint contractures • Peculiar muscle pathology • Peculiar muscle pathology • Peripheral neuropathy ## Management To establish the extent of disease and needs in an individual diagnosed with Emery-Dreifuss muscular dystrophy (EDMD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Emery-Dreifuss Muscular Dystrophy EKG Holter-EKG monitoring Echocardiography Cardiac MRI Electrophysiologic study PT = physical therapist Treatment of Manifestations in Individuals with Emery-Dreifuss Muscular Dystrophy Orthopedic surgeries to release Achilles tendons & other contractures or scoliosis as needed Mechanical aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation PT & stretching exercises to promote mobility & help prevent contractures PT = physical therapy Recommended Surveillance for Individuals with Emery-Dreifuss Muscular Dystrophy EKG, Holter monitoring, & echocardiography to detect asymptomatic cardiac disease More advanced & invasive cardiac assessment may be required for those w/cardiac disease. Although Body weight should be monitored, as affected individuals may be predisposed to obesity. It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with EDMD because of the high risk for cardiac complications (including sudden death) associated with EDMD. Evaluation may allow early identification of family members who would benefit from initiation of treatment and preventive measures [ Molecular genetic testing if the pathogenic variant(s) in the family are known; Clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known. See In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant. Pregnancy management is challenging, with very limited literature addressing the issue. Caesarean section delivery may be required. Referral of an affected pregnant woman to a specialized obstetric unit in close collaboration with a cardiologist is recommended for optimal pregnancy outcome. Search • EKG • Holter-EKG monitoring • Echocardiography • Cardiac MRI • Electrophysiologic study • Orthopedic surgeries to release Achilles tendons & other contractures or scoliosis as needed • Mechanical aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation • PT & stretching exercises to promote mobility & help prevent contractures • EKG, Holter monitoring, & echocardiography to detect asymptomatic cardiac disease • More advanced & invasive cardiac assessment may be required for those w/cardiac disease. • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Emery-Dreifuss muscular dystrophy (EDMD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Emery-Dreifuss Muscular Dystrophy EKG Holter-EKG monitoring Echocardiography Cardiac MRI Electrophysiologic study PT = physical therapist • EKG • Holter-EKG monitoring • Echocardiography • Cardiac MRI • Electrophysiologic study ## Treatment of Manifestations Treatment of Manifestations in Individuals with Emery-Dreifuss Muscular Dystrophy Orthopedic surgeries to release Achilles tendons & other contractures or scoliosis as needed Mechanical aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation PT & stretching exercises to promote mobility & help prevent contractures PT = physical therapy • Orthopedic surgeries to release Achilles tendons & other contractures or scoliosis as needed • Mechanical aids (canes, walkers, orthoses, wheelchairs) as needed to help ambulation • PT & stretching exercises to promote mobility & help prevent contractures ## Surveillance Recommended Surveillance for Individuals with Emery-Dreifuss Muscular Dystrophy EKG, Holter monitoring, & echocardiography to detect asymptomatic cardiac disease More advanced & invasive cardiac assessment may be required for those w/cardiac disease. • EKG, Holter monitoring, & echocardiography to detect asymptomatic cardiac disease • More advanced & invasive cardiac assessment may be required for those w/cardiac disease. ## Agents/Circumstances to Avoid Although Body weight should be monitored, as affected individuals may be predisposed to obesity. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with EDMD because of the high risk for cardiac complications (including sudden death) associated with EDMD. Evaluation may allow early identification of family members who would benefit from initiation of treatment and preventive measures [ Molecular genetic testing if the pathogenic variant(s) in the family are known; Clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known. See • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Clinical evaluation, including at least muscular and cardiac assessments if the pathogenic variant(s) in the family are not known. ## Pregnancy Management In a woman with EDMD, pregnancy complications may include the development of cardiomyopathy or progression of preexisting cardiomyopathy, preterm delivery, respiratory involvement, cephalopelvic disproportion, and delivery of a low birth-weight infant. Pregnancy management is challenging, with very limited literature addressing the issue. Caesarean section delivery may be required. Referral of an affected pregnant woman to a specialized obstetric unit in close collaboration with a cardiologist is recommended for optimal pregnancy outcome. ## Therapies Under Investigation Search ## Genetic Counseling Emery-Dreifuss muscular dystrophy (EDMD) is inherited in an X-linked (XL-EDMD), an autosomal dominant (AD-EDMD), or, rarely, an autosomal recessive (AR-EDMD) manner. The father of an affected male will not have the disease 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 son and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ 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 All of their daughters, who will be heterozygotes. Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ None of their sons. Note: Females heterozygous for an Some individuals diagnosed with AD-EDMD have an affected parent. A proband with AD-EDMD often has the disorder as the result of a 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 AD-EDMD 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 appropriate evaluations (e.g., molecular genetic testing and cardiac evaluation) have been performed on the parents of the proband. (See If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. If the If the parents have not been tested for the The parents of an affected individual are typically obligate heterozygotes (i.e., carriers of one Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ 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 are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ 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 heterozygotes, or are at risk of being heterozygotes. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible. • The father of an affected male will not have the disease 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 son and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ • 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 • All of their daughters, who will be heterozygotes. Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ • None of their sons. • Some individuals diagnosed with AD-EDMD have an affected parent. • A proband with AD-EDMD often has the disorder as the result of a • 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 AD-EDMD 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 appropriate evaluations (e.g., molecular genetic testing and cardiac evaluation) have been performed on the parents of the proband. (See • If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • If the • If the parents have not been tested for the • The parents of an affected individual are typically obligate heterozygotes (i.e., carriers of one • Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ • 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 are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ • 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 heterozygotes, or are at risk of being heterozygotes. ## Mode of Inheritance Emery-Dreifuss muscular dystrophy (EDMD) is inherited in an X-linked (XL-EDMD), an autosomal dominant (AD-EDMD), or, rarely, an autosomal recessive (AR-EDMD) manner. ## X-Linked Inheritance – Risk to Family Members The father of an affected male will not have the disease 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 son and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ 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 All of their daughters, who will be heterozygotes. Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ None of their sons. Note: Females heterozygous for an • The father of an affected male will not have the disease 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 son and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ • 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 • All of their daughters, who will be heterozygotes. Female heterozygotes are usually asymptomatic, but they are at risk of developing a cardiac disease, a progressive muscular dystrophy, or an EDMD phenotype [ • None of their sons. ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with AD-EDMD have an affected parent. A proband with AD-EDMD often has the disorder as the result of a 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 AD-EDMD 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 appropriate evaluations (e.g., molecular genetic testing and cardiac evaluation) have been performed on the parents of the proband. (See If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. If the If the parents have not been tested for the • Some individuals diagnosed with AD-EDMD have an affected parent. • A proband with AD-EDMD often has the disorder as the result of a • 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 AD-EDMD 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 appropriate evaluations (e.g., molecular genetic testing and cardiac evaluation) have been performed on the parents of the proband. (See • If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. • If the • If the parents have not been tested for the ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected individual are typically obligate heterozygotes (i.e., carriers of one Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ 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 are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ • The parents of an affected individual are typically obligate heterozygotes (i.e., carriers of one • Heterozygotes are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ • 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 are usually asymptomatic and are not at risk of developing the disorder. In rare cases, late-onset cardiac disease may occur [ ## 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 heterozygotes, or are at risk of being heterozygotes. • 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 heterozygotes, or are at risk of being heterozygotes. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for EDMD are possible. ## Resources Associazione Italiana Distrofia Muscolare di Emery Dreifuss Onlus Italy France Japan United Kingdom • • Associazione Italiana Distrofia Muscolare di Emery Dreifuss Onlus • Italy • • • • • France • • • • • Japan • • • • • • • United Kingdom • ## Molecular Genetics Emery-Dreifuss Muscular Dystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Emery-Dreifuss Muscular Dystrophy ( The genes Structural strain caused by mechanical stress present in skeletal muscle and cardiac muscle Modification of gene expression caused by abnormal chromatin organization associated with alteration of proliferation/differentiation and/or signaling pathways of muscle cells Interactions of these nuclear envelope proteins with chromatin- and nuclear matrix-associated proteins are of particular interest. Both emerin and lamin A/C interact with nuclear actin, a component of the chromatin remodeling complex associated with the nuclear matrix, suggesting that either chromatin arrangement or gene transcription or both could be impaired in the disease [ Emerin binds directly to lamins A/C and to BAF (OMIM FHL1 proteins belong to a protein family containing LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences comprising two zinc fingers in tandem, implicated in numerous interactions. Each of the two zinc fingers contains four highly conserved cysteines linking together one zinc ion [ The main isoform, FHL1A, is predominantly expressed in striated muscles [ The two other (less abundant) isoforms, FHL1B and FHL1C, are expressed in striated muscles [ Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals. Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [ Pathogenic variants associated with autosomal recessive (AR) disease generally occur at different residues from those responsible for autosomal dominant (AD) disease. As yet, variants cannot be predicted to cause AR or AD disease. Selected Variants listed in the table have been provided by the authors. See The promoter 1C2 located in the first intron of Transcription factors such as c-fos, pRb, and Lco1 have been identified as binding partners of Lamin A/C, suggesting possible deregulation of signaling pathways and alteration of proliferation/differentiation of muscle cells [ • Structural strain caused by mechanical stress present in skeletal muscle and cardiac muscle • Modification of gene expression caused by abnormal chromatin organization associated with alteration of proliferation/differentiation and/or signaling pathways of muscle cells • Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals. • Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [ ## Molecular Pathogenesis The genes Structural strain caused by mechanical stress present in skeletal muscle and cardiac muscle Modification of gene expression caused by abnormal chromatin organization associated with alteration of proliferation/differentiation and/or signaling pathways of muscle cells Interactions of these nuclear envelope proteins with chromatin- and nuclear matrix-associated proteins are of particular interest. Both emerin and lamin A/C interact with nuclear actin, a component of the chromatin remodeling complex associated with the nuclear matrix, suggesting that either chromatin arrangement or gene transcription or both could be impaired in the disease [ Emerin binds directly to lamins A/C and to BAF (OMIM FHL1 proteins belong to a protein family containing LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences comprising two zinc fingers in tandem, implicated in numerous interactions. Each of the two zinc fingers contains four highly conserved cysteines linking together one zinc ion [ The main isoform, FHL1A, is predominantly expressed in striated muscles [ The two other (less abundant) isoforms, FHL1B and FHL1C, are expressed in striated muscles [ Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals. Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [ Pathogenic variants associated with autosomal recessive (AR) disease generally occur at different residues from those responsible for autosomal dominant (AD) disease. As yet, variants cannot be predicted to cause AR or AD disease. Selected Variants listed in the table have been provided by the authors. See The promoter 1C2 located in the first intron of Transcription factors such as c-fos, pRb, and Lco1 have been identified as binding partners of Lamin A/C, suggesting possible deregulation of signaling pathways and alteration of proliferation/differentiation of muscle cells [ • Structural strain caused by mechanical stress present in skeletal muscle and cardiac muscle • Modification of gene expression caused by abnormal chromatin organization associated with alteration of proliferation/differentiation and/or signaling pathways of muscle cells • Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals. • Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [ ## Emerin binds directly to lamins A/C and to BAF (OMIM ## FHL1 proteins belong to a protein family containing LIM domains (Lin-11, Isl-1, Mec3), which are highly conserved sequences comprising two zinc fingers in tandem, implicated in numerous interactions. Each of the two zinc fingers contains four highly conserved cysteines linking together one zinc ion [ The main isoform, FHL1A, is predominantly expressed in striated muscles [ The two other (less abundant) isoforms, FHL1B and FHL1C, are expressed in striated muscles [ Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals. Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [ • Missense variants affect highly conserved cysteine residues important for the zinc finger conformation and lead to variable expression level of mutated protein in muscles of affected individuals. • Loss-of-function variants are expressed at a very low level. In myoblasts from affected individuals myotube formation was severely delayed [ ## Pathogenic variants associated with autosomal recessive (AR) disease generally occur at different residues from those responsible for autosomal dominant (AD) disease. As yet, variants cannot be predicted to cause AR or AD disease. Selected Variants listed in the table have been provided by the authors. See The promoter 1C2 located in the first intron of Transcription factors such as c-fos, pRb, and Lco1 have been identified as binding partners of Lamin A/C, suggesting possible deregulation of signaling pathways and alteration of proliferation/differentiation of muscle cells [ ## Chapter Notes Authors are coordinators (GB, FL, RBY) of the French networks for rare diseases on "EDMD and other nuclear envelope pathologies," network supported by AFM (Association Française contre les Myopathies, grant #10722 and #12325). GB and RBY have been members of the European consortium "Euro-Laminopathies" supported by an EU-FP7 grant (#018690) and are currently members of SOLVE-RD, an European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. GB, FL, RBY are supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, the Assistance Publique des Hôpitaux de Paris. Rabah Ben Yaou, MD (2004-present)Gisèle Bonne, PhD (2004-present)France Leturcq, MD (2004-present)Dominique Récan-Budiartha, MD; Hôpital Cochin (2004-2010) 15 August 2019 (ha) Comprehensive update posted live 25 November 2015 (me) Comprehensive update posted live 17 January 2013 (me) Comprehensive update posted live 24 August 2010 (cd) Revision: sequence analysis and prenatal testing for 15 June 2010 (me) Comprehensive update posted live 21 November 2007 (cd) Revision: LMNA deletion/duplication testing available clinically 26 April 2007 (me) Comprehensive update posted live 29 September 2004 (me) Review posted live 27 January 2004 (gb) Original submission • 15 August 2019 (ha) Comprehensive update posted live • 25 November 2015 (me) Comprehensive update posted live • 17 January 2013 (me) Comprehensive update posted live • 24 August 2010 (cd) Revision: sequence analysis and prenatal testing for • 15 June 2010 (me) Comprehensive update posted live • 21 November 2007 (cd) Revision: LMNA deletion/duplication testing available clinically • 26 April 2007 (me) Comprehensive update posted live • 29 September 2004 (me) Review posted live • 27 January 2004 (gb) Original submission ## Acknowledgments Authors are coordinators (GB, FL, RBY) of the French networks for rare diseases on "EDMD and other nuclear envelope pathologies," network supported by AFM (Association Française contre les Myopathies, grant #10722 and #12325). GB and RBY have been members of the European consortium "Euro-Laminopathies" supported by an EU-FP7 grant (#018690) and are currently members of SOLVE-RD, an European Union's Horizon 2020 research and innovation programme under grant agreement No. 779257. GB, FL, RBY are supported by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, the Assistance Publique des Hôpitaux de Paris. ## Author History Rabah Ben Yaou, MD (2004-present)Gisèle Bonne, PhD (2004-present)France Leturcq, MD (2004-present)Dominique Récan-Budiartha, MD; Hôpital Cochin (2004-2010) ## Revision History 15 August 2019 (ha) Comprehensive update posted live 25 November 2015 (me) Comprehensive update posted live 17 January 2013 (me) Comprehensive update posted live 24 August 2010 (cd) Revision: sequence analysis and prenatal testing for 15 June 2010 (me) Comprehensive update posted live 21 November 2007 (cd) Revision: LMNA deletion/duplication testing available clinically 26 April 2007 (me) Comprehensive update posted live 29 September 2004 (me) Review posted live 27 January 2004 (gb) Original submission • 15 August 2019 (ha) Comprehensive update posted live • 25 November 2015 (me) Comprehensive update posted live • 17 January 2013 (me) Comprehensive update posted live • 24 August 2010 (cd) Revision: sequence analysis and prenatal testing for • 15 June 2010 (me) Comprehensive update posted live • 21 November 2007 (cd) Revision: LMNA deletion/duplication testing available clinically • 26 April 2007 (me) Comprehensive update posted live • 29 September 2004 (me) Review posted live • 27 January 2004 (gb) Original submission ## References ## Literature Cited
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Brain 2009;132:3175-86", "G Novelli, A Muchir, F Sangiuolo, A Helbling-Leclerc, MR D'Apice, C Massart, F Capon, P Sbraccia, M Federici, R Lauro, C Tudisco, R Pallotta, G Scarano, B Dallapiccola, L Merlini, G Bonne. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.. Am J Hum Genet 2002;71:426-31", "G Quarta, P Syrris, M Ashworth, S Jenkins, K Zuborne Alapi, J Morgan, A Muir, A Pantazis, WJ McKenna, PM Elliott. Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy.. Eur Heart J. 2012;33:1128-36", "S Quijano-Roy, B Mbieleu, CG Bönnemann, PY Jeannet, J Colomer, NF Clarke, JM Cuisset, H Roper, L De Meirleir, A D'Amico, R Ben Yaou, A Nascimento, A Barois, L Demay, E Bertini, A Ferreiro, CA Sewry, NB Romero, M Ryan, F Muntoni, P Guicheney, P Richard, G Bonne, B Estournet. De novo LMNA mutations cause a new form of Congenital Muscular Dystrophy (L-CMD).. Ann Neurol 2008;64:177-86", "CM Quinzii, TH Vu, KC Min, K Tanji, S Barral, RP Grewal, A Kattah, P Camaño, D Otaegui, T Kunimatsu, DM Blake, KC Wilhelmsen, LP Rowland, AP Hays, E Bonilla, M Hirano. X-linked dominant scapuloperoneal myopathy is due to a mutation in the gene encoding four-and-a-half-LIM protein 1.. Am J Hum Genet. 2008;82:208-13", "M Raffaele Di Barletta, E Ricci, G Galluzzi, P Tonali, M Mora, L Morandi, A Romorini, T Voit, KH Orstavik, L Merlini, C Trevisan, V Biancalana, I Housmanowa-Petrusewicz, S Bione, R Ricotti, K Schwartz, G Bonne, D Toniolo. Different mutations in the LMNA gene cause autosomal dominant and autosomal recessive Emery-Dreifuss muscular dystrophy.. Am J Hum Genet 2000;66:1407-12", "J Rankin, M Auer-Grumbach, W Bagg, K Colclough, TD Nguyen, J Fenton-May, A Hattersley, J Hudson, P Jardine, D Josifova, C Longman, R McWilliam, K Owen, M Walker, M Wehnert, S Ellard. Extreme phenotypic diversity and onpenetrance in families with the LMNA gene mutation R644C.. Am J Med Genet A 2008;146A:1530-42", "L Redondo-Vergé, RB Yaou, M Fernández-Recio, L Dinca, P Richard, G Bonne. Cardioembolic stroke prompting diagnosis of LMNA-associated Emery-Dreifuss muscular dystrophy.. Muscle Nerve. 2011;44:587-9", "L Renou, S Stora, RB Yaou, M Volk, M Sinkovec, L Demay, P Richard, B Peterlin, G Bonne. Heart-hand syndrome of Slovenian type: a new kind of laminopathy.. J Med Genet. 2008;45:666-71", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "P Sabatelli, G Lattanzi, A Ognibene, M Columbaro, C Capanni, L Merlini, NM Maraldi, S Squarzoni. Nuclear alterations in autosomal-dominant Emery-Dreifuss muscular dystrophy.. Muscle Nerve 2001;24:826-9", "K Sakata, M Shimizu, H Ino, M Yamaguchi, H Terai, N Fujino, K Hayashi, T Kaneda, M Inoue, Y Oda, T Fujita, B Kaku, H Kanaya, H Mabuchi. High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene.. Circulation. 2005;111:3352-8", "T Sanna, A Dello Russo, D Toniolo, M Vytopil, G Pelargonio, G De Martino, E Ricci, G Silvestri, V Giglio, L Messano, E Zachara, F Bellocci. Cardiac features of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutations.. Eur Heart J 2003;24:2227-36", "J Scharner, CA Brown, M Bower, ST Iannaccone, IA Khatri, D Escolar, E Gordon, K Felice, CA Crowe, C Grosmann, MN Meriggioli, A Asamoah, O Gordon, VF Gnocchi, JA Ellis, JR Mendell, PS Zammit. Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations.. Hum Mutat. 2011;32:152-67", "J Schessl, Y Zou, MJ McGrath, BS Cowling, B Maiti, SS Chin, C Sewry, R Battini, Y Hu, DL Cottle, M Rosenblatt, L Spruce, A Ganguly, J Kirschner, AR Judkins, JA Golden, HH Goebel, F Muntoni, KM Flanigan, CA Mitchell, CG Bönnemann. Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy.. J Clin Invest. 2008;118:904-12", "P Sébillon, C Bouchier, LD Bidot, G Bonne, K Ahamed, P Charron, V Drouin-Garraud, A Millaire, G Desrumeaux, A Benaiche, JC Charniot, K Schwartz, E Villard, M Komajda. Expanding the phenotype of LMNA mutations in dilated cardiomyopathy and functional consequences of these mutations.. J Med Genet 2003;40:560-7", "CA Sewry, SC Brown, E Mercuri, G Bonne, L Feng, G Camici, GE Morris, F Muntoni. Skeletal muscle pathology in autosomal dominant Emery-Dreifuss muscular dystrophy with lamin A/C mutations.. Neuropathol Appl Neurobiol 2001;27:281-90", "M Sframeli, A Sarkozy, M Bertoli, G Astrea, J Hudson, M Scoto, R Mein, M Yau, R Phadke, L Feng, C Sewry, ANS Fen, C Longman, G McCullagh, V Straub, S Robb, A Manzur, K Bushby, F Muntoni. Congenital muscular dystrophies in the UK population: Clinical and molecular spectrum of a large cohort diagnosed over a 12-year period.. Neuromuscul Disord. 2017;27:793-803", "S Shackleton, DJ Lloyd, SN Jackson, R Evans, MF Niermeijer, BM Singh, H Schmidt, G Brabant, S Kumar, PN Durrington, S Gregory, S O'Rahilly, RC Trembath. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy.. Nat Genet 2000;24:153-6", "S Shalaby, YK Hayashi, K Goto, M Ogawa, I Nonaka, S Noguchi, I Nishino. Rigid spine syndrome caused by a novel mutation in four-and-a-half LIM domain 1 gene (FHL1).. Neuromuscul. Disord. 2008;18:959-61", "F Sheikh, A Raskin, PH Chu, S Lange, AA Domenighetti, M Zheng, X Liang, T Zhang, T Yajima, Y Gu, ND Dalton, SK Mahata, GW Dorn, JH Brown, KL Peterson, JH Omens, AD McCulloch, J Chen. An FHL1-containing complex within the cardiomyocyte sarcomere mediates hypertrophic biomechanical stress responses in mice.. J. Clin. Invest. 2008;118:3870-80", "K Small, ST Warren. Emerin deletions occurring on both Xq28 inversion backgrounds.. Hum Mol Genet 1998;7:135-9", "B Stallmeyer, M Koopmann, E Schulze-Bahr. Identification of novel mutations in LMNA associated with familial forms of dilated cardiomyopathy.. Genet Test Mol Biomarkers. 2012;16:543-9", "UA Talkop, I Talvik, M Sonajalg, H Sibul, A Kolk, A Piirsoo, R Warzok, K Wulff, MS Wehnert, T Talvik. Early onset of cardiomyopathy in two brothers with X-linked Emery-Dreifuss muscular dystrophy.. Neuromuscul Disord 2002;12:878-81", "Y Taniguchi, T Furukawa, T Tun, H Han, T Honjo. LIM protein KyoT2 negatively regulates transcription by association with the RBP-J DNA-binding protein.. Mol Cell Biol. 1998;18:644-54", "HR Tiffin, ZA Jenkins, MJ Gray, SR Cameron-Christie, J Eaton, S Aftimos, D Markie, SP Robertson. Dysregulation of FHL1 spliceforms due to an indel mutation produces an Emery-Dreifuss muscular dystrophy plus phenotype.. Neurogenetics. 2013;14:113-21", "S Ura, YK Hayashi, K Goto, MN Astejada, T Murakami, M Nagato, S Ohta, Y Daimon, H Takekawa, K Hirata, I Nonaka, S Noguchi, I Nishino. Limb-girdle muscular dystrophy due to emerin gene mutations.. Arch Neurol 2007;64:1038-41", "JH van Berlo, WG de Voogt, AJ van der Kooi, JP van Tintelen, G Bonne, RB Yaou, D Duboc, T Rossenbacker, H Heidbuchel, M de Visser, HJ Crijns, YM Pinto. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death?. J Mol Med 2005;83:79-83", "AJ van der Kooi, G Bonne, B Eymard, D Duboc, B Talim, M Van der Valk, P Reiss, P Richard, L Demay, L Merlini, K Schwartz, HF Busch, M de Visser. Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy.. Neurology 2002;59:620-3", "AJ van der Kooi, TM Ledderhof, WG de Voogt, CJ Res, G Bouwsma, D Troost, HF Busch, AE Becker, M de Visser. A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement.. Ann Neurol 1996;39:636-42", "H Van Esch, AK Agarwal, P Debeer, JP Fryns, A Garg. A homozygous mutation in the lamin A/C gene associated with a novel syndrome of arthropathy, tendinous calcinosis, and progeroid features.. J Clin Endocrinol Metab 2006;91:517-21", "S Vlcek, R Foisner. A-type lamin networks in light of laminopathic diseases.. 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Eur Arch Psychiatry Neurol Sci 1988;237:230-6", "HJ Worman, G Bonne. \"Laminopathies\": a wide spectrum of human diseases.. Exp Cell Res 2007;313:2121-33", "HJ Worman, LG Fong, A Muchir, SG Young. Laminopathies and the long strange trip from basic cell biology to therapy.. J Clin Invest 2009;119:1825-36", "K Wulff, JE Parrish, FH Herrmann, M Wehnert. Six novel mutations in the emerin gene causing X-linked Emery-Dreifuss muscular dystrophy.. Hum Mutat. 1997;9:526-30", "JR Yates, J Bagshaw, VM Aksmanovic, E Coomber, R McMahon, JL Whittaker, PJ Morrison, J Kendrick-Jones, JA Ellis. Genotype-phenotype analysis in X-linked Emery-Dreifuss muscular dystrophy and identification of a missense mutation associated with a milder phenotype.. Neuromuscul Disord 1999;9:159-65", "JR Yates, M Wehnert. The Emery-Dreifuss Muscular Dystrophy Mutation Database.. Neuromuscul Disord 1999;9:199", "H Yorifuji, Y Tadano, Y Tsuchiya, M Ogawa, K Goto, A Umetani, Y Asaka, K Arahata. Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane.. Neurogenetics 1997;1:135-40", "J Young, L Morbois-Trabut, B Couzinet, O Lascols, E Dion, V Béréziat, B Fève, I Richard, J Capeau, P Chanson, C. Vigouroux. Type A insulin resistance syndrome revealing a novel lamin A mutation.. Diabetes. 2005;54:1873-8" ]
29/9/2004
15/8/2019
24/8/2010
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eds-mc
eds-mc
[ "mcEDS", "Adducted Thumb-Clubfoot Syndrome (ATCS)", "Dündar Syndrome", "Ehlers-Danlos Syndrome, Kosho Type (EDS-KT)", "mcEDS", "Adducted Thumb-Clubfoot Syndrome (ATCS)", "Dündar Syndrome", "Ehlers-Danlos Syndrome, Kosho Type (EDS-KT)", "Carbohydrate sulfotransferase 14", "Dermatan-sulfate epimerase", "CHST14", "DSE", "Musculocontractural Ehlers-Danlos Syndrome" ]
Musculocontractural Ehlers-Danlos Syndrome
Tomoki Kosho, Tomomi Yamaguchi, Shuji Mizumoto, Roberto Mendoza-Londono
Summary Musculocontractural Ehlers-Danlos syndrome (mcEDS) is characterized by multiple congenital contractures, progressive foot and ankle deformities, hypermobility of the small joints, recurrent dislocations, spinal deformities, characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia), skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars), large subcutaneous hematoma, and ocular abnormalities (strabismus, refractive errors, and glaucoma). Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal. The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in Musculocontractural EDS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
## Diagnosis No consensus clinical diagnostic criteria for musculocontractural Ehlers-Danlos syndrome (mcEDS) have been published. Musculocontractural EDS Multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot) Characteristic craniofacial features, which are evident at birth or in early infancy (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia) Characteristic cutaneous features (including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling) Recurrent/chronic joint dislocations Pectus excavatum or flat sternum with loss of normal thoracic curve Spinal deformities (scoliosis, kyphoscoliosis) Characteristic finger morphology (tapered, slender, cylindrical) Progressive foot and ankle deformities (valgus deformity of the ankle, pes planus, pes cavus) Large subcutaneous hematomas Chronic constipation Colonic diverticula Pneumothorax/pneumohemothorax Nephrolithiasis/cystolithiasis Hydronephrosis Cryptorchidism in males Strabismus Refractive errors (myopia, astigmatism) Glaucoma / elevated intraocular pressure The diagnosis of mcEDS is Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of mcEDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Musculocontractural Ehlers-Danlos Syndrome mcEDS = musculocontractural Ehlers-Danlos 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, 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. Data derived from To date, no large intragenic deletions/duplications have been reported in individuals with mcEDS. • Multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot) • Characteristic craniofacial features, which are evident at birth or in early infancy (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia) • Characteristic cutaneous features (including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling) • Recurrent/chronic joint dislocations • Pectus excavatum or flat sternum with loss of normal thoracic curve • Spinal deformities (scoliosis, kyphoscoliosis) • Characteristic finger morphology (tapered, slender, cylindrical) • Progressive foot and ankle deformities (valgus deformity of the ankle, pes planus, pes cavus) • Large subcutaneous hematomas • Chronic constipation • Colonic diverticula • Pneumothorax/pneumohemothorax • Nephrolithiasis/cystolithiasis • Hydronephrosis • Cryptorchidism in males • Strabismus • Refractive errors (myopia, astigmatism) • Glaucoma / elevated intraocular pressure ## Suggestive Findings Musculocontractural EDS Multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot) Characteristic craniofacial features, which are evident at birth or in early infancy (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia) Characteristic cutaneous features (including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling) Recurrent/chronic joint dislocations Pectus excavatum or flat sternum with loss of normal thoracic curve Spinal deformities (scoliosis, kyphoscoliosis) Characteristic finger morphology (tapered, slender, cylindrical) Progressive foot and ankle deformities (valgus deformity of the ankle, pes planus, pes cavus) Large subcutaneous hematomas Chronic constipation Colonic diverticula Pneumothorax/pneumohemothorax Nephrolithiasis/cystolithiasis Hydronephrosis Cryptorchidism in males Strabismus Refractive errors (myopia, astigmatism) Glaucoma / elevated intraocular pressure • Multiple congenital contractures, characteristically adduction-flexion contractures and/or talipes equinovarus (clubfoot) • Characteristic craniofacial features, which are evident at birth or in early infancy (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia) • Characteristic cutaneous features (including skin hyperextensibility, easy bruisability, skin fragility with atrophic scars, increased palmar wrinkling) • Recurrent/chronic joint dislocations • Pectus excavatum or flat sternum with loss of normal thoracic curve • Spinal deformities (scoliosis, kyphoscoliosis) • Characteristic finger morphology (tapered, slender, cylindrical) • Progressive foot and ankle deformities (valgus deformity of the ankle, pes planus, pes cavus) • Large subcutaneous hematomas • Chronic constipation • Colonic diverticula • Pneumothorax/pneumohemothorax • Nephrolithiasis/cystolithiasis • Hydronephrosis • Cryptorchidism in males • Strabismus • Refractive errors (myopia, astigmatism) • Glaucoma / elevated intraocular pressure ## Establishing the Diagnosis The diagnosis of mcEDS is Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of mcEDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Musculocontractural Ehlers-Danlos Syndrome mcEDS = musculocontractural Ehlers-Danlos 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, 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. Data derived from To date, no large intragenic deletions/duplications have been reported in individuals with mcEDS. ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of mcEDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Musculocontractural Ehlers-Danlos Syndrome mcEDS = musculocontractural Ehlers-Danlos 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, 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. Data derived from To date, no large intragenic deletions/duplications have been reported in individuals with mcEDS. ## Clinical Characteristics Musculocontractural Ehlers-Danlos syndrome (mcEDS) is characterized by multiple congenital contractures, progressive foot and ankle deformities, hypermobility of the small joints, recurrent dislocations, spinal deformities, characteristic craniofacial features, skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars), large subcutaneous hematoma, and ocular abnormalities [ Musculocontractural Ehlers-Danlos Syndrome: Frequency of Select Features Combined data from two reported cohorts: According to a single institution-based survey including 12 individuals with mcEDS- According to a single institution-based survey including 12 individuals with mcEDS- Urologic manifestations (hydronephrosis, bladder dysfunction, recurrent urinary tract infection, nephrolithiasis) have occasionally been observed. Recurrent urinary tract infection was only reported in those with mcEDS- Structural brain abnormalities are reported in individuals with mcEDS- The clinical phenotypes of mcEDS- No clinically relevant genotype-phenotype correlations have been identified. To date, 70 individuals from 51 families have been identified with biallelic pathogenic variants in Prevalence of mcEDS- ## Clinical Description Musculocontractural Ehlers-Danlos syndrome (mcEDS) is characterized by multiple congenital contractures, progressive foot and ankle deformities, hypermobility of the small joints, recurrent dislocations, spinal deformities, characteristic craniofacial features, skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars), large subcutaneous hematoma, and ocular abnormalities [ Musculocontractural Ehlers-Danlos Syndrome: Frequency of Select Features Combined data from two reported cohorts: According to a single institution-based survey including 12 individuals with mcEDS- According to a single institution-based survey including 12 individuals with mcEDS- Urologic manifestations (hydronephrosis, bladder dysfunction, recurrent urinary tract infection, nephrolithiasis) have occasionally been observed. Recurrent urinary tract infection was only reported in those with mcEDS- Structural brain abnormalities are reported in individuals with mcEDS- ## Phenotype Correlations by Gene The clinical phenotypes of mcEDS- ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified. ## Prevalence To date, 70 individuals from 51 families have been identified with biallelic pathogenic variants in Prevalence of mcEDS- ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis In newborns and young infants with characteristic craniofacial features and multiple congenital contractures, the differential diagnosis of musculocontractural Ehlers-Danlos syndrome (mcEDS) includes arthrogryposis syndromes (e.g., Freeman-Sheldon syndrome) and some hereditary connective tissue disorders (e.g., Loeys-Dietz syndrome, early-onset Marfan syndrome, spondylodysplastic EDS, kyphoscoliosis EDS [ In individuals with joint hypermobility/dislocation, skin hyperextensibility, and easy bruisability, the differential diagnosis of mcEDS includes other types of EDS. Typically joint hypermobility in individuals with mcEDS is limited to small joints, whereas generalized joint hypermobility is a hallmark of Genes of Interest in the Differential Diagnosis of Musculocontractural Ehlers-Danlos Syndrome Craniofacial features Slender fingers Progressive cardiovascular lesions Absence of skin fragility, bruisability ↓ joint mobility, esp of hands (camptodactyly) & feet (clubfeet) in some persons Easy bruising Progressive cardiovascular lesions Absence of skin fragility Craniofacial features Hypotonia Inguinal or umbilical hernia Skeletal manifestations (pectus deformity, camptodactyly, scoliosis, & joint hypermobility) Atrophic scarring Easy bruising Skin hyperextensibility Soft, doughy skin Redundant, almost lax, skin Different craniofacial features Postnatal growth restriction Absence of congenital contractures Easy bruising Skin hyperextensibility Prematurely aged appearance Absence of congenital contractures Absence of characteristic craniofacial features Joint hypermobility (distal joints) Kyphoscoliosis ( Short stature Bowing of limbs Impaired cognitive function Atrophic scarring Easy bruising Skin hyperextensibility Recurrent joint subluxations/dislocations Congenital bilateral hip dislocation No other congenital contractures Different craniofacial features Atrophic scarring Easy bruising Skin hyperextensibility Cardiac valvular disease Absence of congenital contractures Absence of characteristic craniofacial features Atrophic scarring Easy bruising Chronic joint subluxations/dislocations Clubfoot Arterial, intestinal, &/or uterine fragility Absence of congenital contractures (other than clubfeet) Different craniofacial features Aged appearance of extremities Hypotonia Atrophic scarring & easy bruising in some persons Congenital contractures (up to 1/3 of affected persons) Skin hyperextensibility Kyphoscoliosis Myopathy Absence of characteristic craniofacial features Atrophic scarring Easy bruising Skin hyperextensibility Hypotonia Kyphoscoliosis Absence of congenital contractures Absence of characteristic craniofacial features Risk of aortic dilatation/dissection & rupture of medium-sized arteries Easy bruising Skin hyperextensibility Velvety skin Absence of congenital contractures Absence of characteristic craniofacial features Absence of atrophic scarring AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; ID = intellectual disability; mcEDS = musculocontractural Ehlers-Danlos syndrome; MOI = mode of inheritance Loeys-Dietz syndrome (LDS) caused by a pathogenic variant in Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. • Craniofacial features • Slender fingers • Progressive cardiovascular lesions • Absence of skin fragility, bruisability • ↓ joint mobility, esp of hands (camptodactyly) & feet (clubfeet) in some persons • Easy bruising • Progressive cardiovascular lesions • Absence of skin fragility • Craniofacial features • Hypotonia • Inguinal or umbilical hernia • Skeletal manifestations (pectus deformity, camptodactyly, scoliosis, & joint hypermobility) • Atrophic scarring • Easy bruising • Skin hyperextensibility • Soft, doughy skin • Redundant, almost lax, skin • Different craniofacial features • Postnatal growth restriction • Absence of congenital contractures • Easy bruising • Skin hyperextensibility • Prematurely aged appearance • Absence of congenital contractures • Absence of characteristic craniofacial features • Joint hypermobility (distal joints) • Kyphoscoliosis ( • Short stature • Bowing of limbs • Impaired cognitive function • Atrophic scarring • Easy bruising • Skin hyperextensibility • Recurrent joint subluxations/dislocations • Congenital bilateral hip dislocation • No other congenital contractures • Different craniofacial features • Atrophic scarring • Easy bruising • Skin hyperextensibility • Cardiac valvular disease • Absence of congenital contractures • Absence of characteristic craniofacial features • Atrophic scarring • Easy bruising • Chronic joint subluxations/dislocations • Clubfoot • Arterial, intestinal, &/or uterine fragility • Absence of congenital contractures (other than clubfeet) • Different craniofacial features • Aged appearance of extremities • Hypotonia • Atrophic scarring & easy bruising in some persons • Congenital contractures (up to 1/3 of affected persons) • Skin hyperextensibility • Kyphoscoliosis • Myopathy • Absence of characteristic craniofacial features • Atrophic scarring • Easy bruising • Skin hyperextensibility • Hypotonia • Kyphoscoliosis • Absence of congenital contractures • Absence of characteristic craniofacial features • Risk of aortic dilatation/dissection & rupture of medium-sized arteries • Easy bruising • Skin hyperextensibility • Velvety skin • Absence of congenital contractures • Absence of characteristic craniofacial features • Absence of atrophic scarring ## Management Health care guidelines for musculocontractural Ehlers-Danlos syndrome (mcEDS) have been proposed [ To establish the extent of disease and needs in an individual diagnosed with mcEDS, the evaluations summarized in Musculocontractural Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis Assessment for cryptorchidism in males Kidney US for hydronephrosis Assessment of tone & motor development Cranial US, followed by brain MRI as needed Community or online Social work involvement for parental support Home nursing referral ABR = auditory brain stem response; ASSR = auditory steady-state response; mcEDS = musculocontractural Ehlers-Danlos syndrome; MOI = mode of inheritance; US = ultrasound 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 Musculocontractural Ehlers-Danlos Syndrome: Treatment of Manifestations Braces Surgical correction as needed Braces Surgical correction Hygiene Topical or oral antibiotics if necessary Corrective lenses Surgical correction if necessary Prophylactic antibiotics Surgical correction of urologic abnormalities if necessary Compression & icing; surgical drainage if necessary Desmopressin (prophylactic, therapeutic) Tranexamic acid (prophylactic, therapeutic) To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Musculocontractural Ehlers-Danlos Syndrome: Recommended Surveillance In infancy (after treatment for clubfeet), every 3 mos In childhood, every 6 mos In adolescence & adulthood, annually & as needed Every 6-12 mos beginning in infancy More frequently in those w/progressive deformities Every 3 mos beginning in infancy Every 6 mos through childhood OAEs = otoacoustic emissions; US = ultrasound Avoid the following: Contact or competitive sports Upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure See To date, only one pregnancy and delivery was recognized in a woman with mcEDS- See Search • Assessment for cryptorchidism in males • Kidney US for hydronephrosis • Assessment of tone & motor development • Cranial US, followed by brain MRI as needed • Community or online • Social work involvement for parental support • Home nursing referral • Braces • Surgical correction as needed • Braces • Surgical correction • Hygiene • Topical or oral antibiotics if necessary • Corrective lenses • Surgical correction if necessary • Prophylactic antibiotics • Surgical correction of urologic abnormalities if necessary • Compression & icing; surgical drainage if necessary • Desmopressin (prophylactic, therapeutic) • Tranexamic acid (prophylactic, therapeutic) • In infancy (after treatment for clubfeet), every 3 mos • In childhood, every 6 mos • In adolescence & adulthood, annually & as needed • Every 6-12 mos beginning in infancy • More frequently in those w/progressive deformities • Every 3 mos beginning in infancy • Every 6 mos through childhood • Contact or competitive sports • Upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with mcEDS, the evaluations summarized in Musculocontractural Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis Assessment for cryptorchidism in males Kidney US for hydronephrosis Assessment of tone & motor development Cranial US, followed by brain MRI as needed Community or online Social work involvement for parental support Home nursing referral ABR = auditory brain stem response; ASSR = auditory steady-state response; mcEDS = musculocontractural Ehlers-Danlos syndrome; MOI = mode of inheritance; US = ultrasound Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Assessment for cryptorchidism in males • Kidney US for hydronephrosis • Assessment of tone & motor development • Cranial US, followed by brain MRI as needed • Community or online • 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 Musculocontractural Ehlers-Danlos Syndrome: Treatment of Manifestations Braces Surgical correction as needed Braces Surgical correction Hygiene Topical or oral antibiotics if necessary Corrective lenses Surgical correction if necessary Prophylactic antibiotics Surgical correction of urologic abnormalities if necessary Compression & icing; surgical drainage if necessary Desmopressin (prophylactic, therapeutic) Tranexamic acid (prophylactic, therapeutic) • Braces • Surgical correction as needed • Braces • Surgical correction • Hygiene • Topical or oral antibiotics if necessary • Corrective lenses • Surgical correction if necessary • Prophylactic antibiotics • Surgical correction of urologic abnormalities if necessary • Compression & icing; surgical drainage if necessary • Desmopressin (prophylactic, therapeutic) • Tranexamic acid (prophylactic, therapeutic) ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Musculocontractural Ehlers-Danlos Syndrome: Recommended Surveillance In infancy (after treatment for clubfeet), every 3 mos In childhood, every 6 mos In adolescence & adulthood, annually & as needed Every 6-12 mos beginning in infancy More frequently in those w/progressive deformities Every 3 mos beginning in infancy Every 6 mos through childhood OAEs = otoacoustic emissions; US = ultrasound • In infancy (after treatment for clubfeet), every 3 mos • In childhood, every 6 mos • In adolescence & adulthood, annually & as needed • Every 6-12 mos beginning in infancy • More frequently in those w/progressive deformities • Every 3 mos beginning in infancy • Every 6 mos through childhood ## Agents/Circumstances to Avoid Avoid the following: Contact or competitive sports Upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure • Contact or competitive sports • Upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure ## Evaluation of Relatives at Risk See ## Pregnancy Management To date, only one pregnancy and delivery was recognized in a woman with mcEDS- See ## Therapies Under Investigation Search ## Genetic Counseling Musculocontractural Ehlers-Danlos syndrome (mcEDS) is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for an mcEDS-related pathogenic variant. Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 mcEDS-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, 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 mcEDS, particularly if both partners are of the same ancestry. Once the mcEDS-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an mcEDS-related pathogenic variant. • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with mcEDS, particularly if both partners are of the same ancestry. ## Mode of Inheritance Musculocontractural Ehlers-Danlos syndrome (mcEDS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an mcEDS-related pathogenic variant. Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 an mcEDS-related pathogenic variant. • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 mcEDS-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, 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 mcEDS, particularly if both partners are of the same ancestry. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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 mcEDS, particularly if both partners are of the same ancestry. ## Prenatal Testing and Preimplantation Genetic Testing Once the mcEDS-related pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Japan • • United Kingdom • • • • • • Japan • • • • • ## Molecular Genetics Musculocontractural Ehlers-Danlos Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Musculocontractural Ehlers-Danlos Syndrome ( Skin fibroblasts from individuals with pathogenic variants in Pathogenic Variants Referenced in this Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Skin fibroblasts from individuals with pathogenic variants in Pathogenic Variants Referenced in this Variants listed in the table have been provided by the authors. ## Chapter Notes The Kosho Lab (Center for Medical Genetics Shinshu [CMGS] at Shinshu University Hospital, Department of Medical Genetics and Division of Clinical Sequencing, Shinshu University School of Medicine) performs integrated translational research on Ehlers-Danlos syndromes (EDS). CMGS has a strong reputation as an internationally recognized center of expertise for research, diagnostics, and clinical management related to a range of hereditary connective tissue disorders (HCTD), including, among others, EDS. At the Kosho Lab, PI Prof Tomoki Kosho, MD, PhD, and Associate Prof Tomomi Yamaguchi, PhD, lead studies in the following areas of interest: Unraveling the molecular basis of HCTD, with a specific focus on EDS, and studying their natural history and genotype-phenotype correlations Elucidating molecular and physiologic mechanisms underlying HCTD pathogenesis, using an integrated approach of in vivo and in vitro techniques, on tissue samples of humans, patient-derived induced pluripotent stem (iPS) cells, and animal models (mice). Tomoki Kosho ( Prof Kosho is also interested in hearing from clinicians treating families affected by mcEDS 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 Tomomi Yamaguchi ( The Kosho Lab leads variable international collaborative clinical and basic studies on HCTD with multiple institutes, including the lab in the Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, that Dr Shuji Mizumoto belongs to. Contact Dr Shuji Mizumoto ( Contact Dr Mendoza-Londono ( This work is supported by the endowed chair named "Division of Clinical Sequencing, Shinshu University School of Medicine," which is sponsored by BML, Inc and Life Technologies Japan Ltd, a subsidiary of Thermo Fisher Scientific Inc. The authors wish to thank the EDS Society and Japan Ehlers-Danlos Syndrome Fellowship Association (JEFA). 15 May 2025 (sw) Review posted live 27 November 2024 (tk) Original submission • Unraveling the molecular basis of HCTD, with a specific focus on EDS, and studying their natural history and genotype-phenotype correlations • Elucidating molecular and physiologic mechanisms underlying HCTD pathogenesis, using an integrated approach of in vivo and in vitro techniques, on tissue samples of humans, patient-derived induced pluripotent stem (iPS) cells, and animal models (mice). • 15 May 2025 (sw) Review posted live • 27 November 2024 (tk) Original submission ## Author Notes The Kosho Lab (Center for Medical Genetics Shinshu [CMGS] at Shinshu University Hospital, Department of Medical Genetics and Division of Clinical Sequencing, Shinshu University School of Medicine) performs integrated translational research on Ehlers-Danlos syndromes (EDS). CMGS has a strong reputation as an internationally recognized center of expertise for research, diagnostics, and clinical management related to a range of hereditary connective tissue disorders (HCTD), including, among others, EDS. At the Kosho Lab, PI Prof Tomoki Kosho, MD, PhD, and Associate Prof Tomomi Yamaguchi, PhD, lead studies in the following areas of interest: Unraveling the molecular basis of HCTD, with a specific focus on EDS, and studying their natural history and genotype-phenotype correlations Elucidating molecular and physiologic mechanisms underlying HCTD pathogenesis, using an integrated approach of in vivo and in vitro techniques, on tissue samples of humans, patient-derived induced pluripotent stem (iPS) cells, and animal models (mice). Tomoki Kosho ( Prof Kosho is also interested in hearing from clinicians treating families affected by mcEDS 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 Tomomi Yamaguchi ( The Kosho Lab leads variable international collaborative clinical and basic studies on HCTD with multiple institutes, including the lab in the Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, that Dr Shuji Mizumoto belongs to. Contact Dr Shuji Mizumoto ( Contact Dr Mendoza-Londono ( • Unraveling the molecular basis of HCTD, with a specific focus on EDS, and studying their natural history and genotype-phenotype correlations • Elucidating molecular and physiologic mechanisms underlying HCTD pathogenesis, using an integrated approach of in vivo and in vitro techniques, on tissue samples of humans, patient-derived induced pluripotent stem (iPS) cells, and animal models (mice). ## Acknowledgments This work is supported by the endowed chair named "Division of Clinical Sequencing, Shinshu University School of Medicine," which is sponsored by BML, Inc and Life Technologies Japan Ltd, a subsidiary of Thermo Fisher Scientific Inc. The authors wish to thank the EDS Society and Japan Ehlers-Danlos Syndrome Fellowship Association (JEFA). ## Revision History 15 May 2025 (sw) Review posted live 27 November 2024 (tk) Original submission • 15 May 2025 (sw) Review posted live • 27 November 2024 (tk) Original submission ## References ## Literature Cited Clinical photographs of hands of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st & 2nd row. Clinical photographs of three individuals with mcEDS- 3rd row. Clinical photographs of an individual with mcEDS- Clinical photographs of feet of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st & 2nd row. Clinical photographs of two individuals with mcEDS- 3rd row. Foot and toe deformities in an individual with mcEDS- Craniofacial features of individuals with musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st row. Composite images of 15 individuals with mcEDS- 2nd & 3rd row. Clinical photographs of four individuals with mcEDS- 4th row. Clinical photographs of an individual with mcEDS- Clinical photographs of skin manifestations of musculocontractural Ehlers-Danlos syndrome (mcEDS) 1st–3rd row. Clinical photographs of six individuals with mcEDS- 4th row. Clinical photographs of an individual with mcEDS-
[]
15/5/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eds-pd
eds-pd
[ "EDS Type VIII", "pEDS", "pEDS", "EDS Type VIII", "Complement C1r subcomponent", "Complement C1s subcomponent", "C1R", "C1S", "Periodontal Ehlers-Danlos Syndrome" ]
Periodontal Ehlers-Danlos Syndrome
Ines Kapferer-Seebacher, Fleur S van Dijk, Johannes Zschocke
Summary Periodontal Ehlers-Danlos syndrome (pEDS) is characterized by distinct oral manifestations. Periodontal tissue breakdown beginning in the teens results in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture. Since the first descriptions of pEDS in the 1970s, 148 individuals have been reported in the literature; however, future in-depth descriptions of non-oral manifestations in newly diagnosed individuals with a molecularly confirmed diagnosis of pEDS will be important to further define the clinical features. The diagnosis of pEDS is established in a proband with suggestive clinical findings and a heterozygous pathogenic gain-of-function variant in either Periodontal EDS is inherited in an autosomal dominant manner. Most individuals with pEDS have the disorder as the result of a
## Diagnosis Formal clinical diagnostic criteria for periodontal Ehlers-Danlos syndrome (pEDS) were established in the 2017 revised Ehlers-Danlos syndrome nosology [ Periodontal Ehlers-Danlos syndrome (pEDS) Severe periodontitis of early onset (childhood or adolescence) Generalized lack of attached gingiva ( Pretibial plaques (i.e., hemosiderin deposition) ( Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.) Easy bruising Prominent vasculature Joint hypermobility, mostly distal joints Hernias Marfanoid facial features Acrogeria Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) Increased rate of infections EITHER of the following major criteria: Severe and intractable periodontitis of early onset (childhood or adolescence) Lack of attached gingiva Plus BOTH of the following: At least two other major criteria One minor criterion Since the publication of the diagnostic criteria for pEDS [ Generalized lack of attached gingiva is the only clinical finding consistently present in affected children younger than age ten years. As such, the current combination of criteria will not be suitable to make a diagnosis in children. Other clinical manifestations apart from easy bruising and gum bleeding are mild or absent in early childhood. Lack of attached gingiva in combination with family history of a first-degree relative would be suggestive of a diagnosis of pEDS [ Dental screening includes an orthopantomogram. For periodontal diagnostics and treatment, panoramic radiographs may be supplemented by selected intra-oral radiographs such as vertical bite-wings or (a full-mouth series of) periapical radiographs. The diagnosis of periodontal Ehlers-Danlos syndrome Note: Identification of a heterozygous variant of uncertain significance in either 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 Periodontal Ehlers-Danlos Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Relevant variants include small in-frame intragenic deletions/insertions, missense variants, and potentially some in-frame splice site variants; exon or whole-gene deletions/duplications are not typically detected but (like nonsense and out-of-frame splice site variants) are not expected to cause pEDS. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis is not expected to detect variants that cause pEDS. • Severe periodontitis of early onset (childhood or adolescence) • Generalized lack of attached gingiva ( • Pretibial plaques (i.e., hemosiderin deposition) ( • Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.) • Easy bruising • Prominent vasculature • Joint hypermobility, mostly distal joints • Hernias • Marfanoid facial features • Acrogeria • Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) • Increased rate of infections • EITHER of the following major criteria: • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • Plus BOTH of the following: • At least two other major criteria • One minor criterion • At least two other major criteria • One minor criterion • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • At least two other major criteria • One minor criterion • Dental screening includes an orthopantomogram. • For periodontal diagnostics and treatment, panoramic radiographs may be supplemented by selected intra-oral radiographs such as vertical bite-wings or (a full-mouth series of) periapical radiographs. ## Suggestive Findings Periodontal Ehlers-Danlos syndrome (pEDS) Severe periodontitis of early onset (childhood or adolescence) Generalized lack of attached gingiva ( Pretibial plaques (i.e., hemosiderin deposition) ( Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.) Easy bruising Prominent vasculature Joint hypermobility, mostly distal joints Hernias Marfanoid facial features Acrogeria Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) Increased rate of infections EITHER of the following major criteria: Severe and intractable periodontitis of early onset (childhood or adolescence) Lack of attached gingiva Plus BOTH of the following: At least two other major criteria One minor criterion Since the publication of the diagnostic criteria for pEDS [ Generalized lack of attached gingiva is the only clinical finding consistently present in affected children younger than age ten years. As such, the current combination of criteria will not be suitable to make a diagnosis in children. Other clinical manifestations apart from easy bruising and gum bleeding are mild or absent in early childhood. Lack of attached gingiva in combination with family history of a first-degree relative would be suggestive of a diagnosis of pEDS [ Dental screening includes an orthopantomogram. For periodontal diagnostics and treatment, panoramic radiographs may be supplemented by selected intra-oral radiographs such as vertical bite-wings or (a full-mouth series of) periapical radiographs. • Severe periodontitis of early onset (childhood or adolescence) • Generalized lack of attached gingiva ( • Pretibial plaques (i.e., hemosiderin deposition) ( • Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.) • Easy bruising • Prominent vasculature • Joint hypermobility, mostly distal joints • Hernias • Marfanoid facial features • Acrogeria • Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) • Increased rate of infections • EITHER of the following major criteria: • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • Plus BOTH of the following: • At least two other major criteria • One minor criterion • At least two other major criteria • One minor criterion • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • At least two other major criteria • One minor criterion • Dental screening includes an orthopantomogram. • For periodontal diagnostics and treatment, panoramic radiographs may be supplemented by selected intra-oral radiographs such as vertical bite-wings or (a full-mouth series of) periapical radiographs. ## Clinical Findings Severe periodontitis of early onset (childhood or adolescence) Generalized lack of attached gingiva ( Pretibial plaques (i.e., hemosiderin deposition) ( Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.) Easy bruising Prominent vasculature Joint hypermobility, mostly distal joints Hernias Marfanoid facial features Acrogeria Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) Increased rate of infections EITHER of the following major criteria: Severe and intractable periodontitis of early onset (childhood or adolescence) Lack of attached gingiva Plus BOTH of the following: At least two other major criteria One minor criterion Since the publication of the diagnostic criteria for pEDS [ Generalized lack of attached gingiva is the only clinical finding consistently present in affected children younger than age ten years. As such, the current combination of criteria will not be suitable to make a diagnosis in children. Other clinical manifestations apart from easy bruising and gum bleeding are mild or absent in early childhood. Lack of attached gingiva in combination with family history of a first-degree relative would be suggestive of a diagnosis of pEDS [ • Severe periodontitis of early onset (childhood or adolescence) • Generalized lack of attached gingiva ( • Pretibial plaques (i.e., hemosiderin deposition) ( • Family history of a first-degree relative who meets diagnostic criteria (Absence of a known family history does not preclude the diagnosis.) • Easy bruising • Prominent vasculature • Joint hypermobility, mostly distal joints • Hernias • Marfanoid facial features • Acrogeria • Skin hyperextensibility and fragility, abnormal scarring (wide or atrophic) • Increased rate of infections • EITHER of the following major criteria: • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • Plus BOTH of the following: • At least two other major criteria • One minor criterion • At least two other major criteria • One minor criterion • Severe and intractable periodontitis of early onset (childhood or adolescence) • Lack of attached gingiva • At least two other major criteria • One minor criterion ## Imaging Findings Dental screening includes an orthopantomogram. For periodontal diagnostics and treatment, panoramic radiographs may be supplemented by selected intra-oral radiographs such as vertical bite-wings or (a full-mouth series of) periapical radiographs. • Dental screening includes an orthopantomogram. • For periodontal diagnostics and treatment, panoramic radiographs may be supplemented by selected intra-oral radiographs such as vertical bite-wings or (a full-mouth series of) periapical radiographs. ## Establishing the Diagnosis The diagnosis of periodontal Ehlers-Danlos syndrome Note: Identification of a heterozygous variant of uncertain significance in either 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 Periodontal Ehlers-Danlos Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Relevant variants include small in-frame intragenic deletions/insertions, missense variants, and potentially some in-frame splice site variants; exon or whole-gene deletions/duplications are not typically detected but (like nonsense and out-of-frame splice site variants) are not expected to cause pEDS. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis is not expected to detect variants that cause pEDS. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Periodontal Ehlers-Danlos Syndrome See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Relevant variants include small in-frame intragenic deletions/insertions, missense variants, and potentially some in-frame splice site variants; exon or whole-gene deletions/duplications are not typically detected but (like nonsense and out-of-frame splice site variants) are not expected to cause pEDS. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis is not expected to detect variants that cause pEDS. ## Clinical Characteristics Periodontal EDS (pEDS) is characterized by distinct oral manifestations. Early and severe breakdown of the tooth-supporting tissues (i.e., alveolar bone, periodontal ligament, root cementum, and gingival attachment) result in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture (see Since the first descriptions of pEDS in the 1970s [ Periodontal Ehlers-Danlos Syndrome: Frequency of Select Features Based on Periodontitis with early onset was reported in 98.4% of affected adults [ Median age of onset of periodontitis is reported to be 14 years (range: 2-35 years) [ Clinical investigations of 12 affected children (ages 8 to 13 years) revealed localized periodontal bone loss of up to 6 mm only in the oldest individual (age 13 years), an observation supporting the notion that onset of periodontitis is predominantly in adolescence [ Although most individuals report frequent gum bleeding when brushing their teeth, frequent gum bleeding (a sign of gingival inflammation) is difficult to evaluate as it is subjective and very frequent in the general population due to insufficient plaque control. In healthy individuals, the gums are classified as keratinized attached gingiva and non-keratinized movable mucosa. The keratinized attached gingiva is tightly and unmovably bound to the periosteum via collagen type I fibers as a thick band to provide mechanical protection. The non-keratinized oral mucosa is thin, more fragile, translucent, and only loosely connected to the periosteum. In pEDS, the thick band of gingiva is missing and the fragile mucosa extends to the gingival margin, causing tissue fragility and predisposing to gingival recession. The MRI pattern was suggestive of an underlying small-vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the paucity of neurologic features. Medical history revealed recurrent headaches or depression in single cases. Neurologic examination was unremarkable in all individuals except one who had mild cognitive decline, ataxia, and a history of one seizure. Other clinical manifestations of pEDS are mild or absent in affected children, although the parents of all affected children reported easy bruising and gum bleeding. Median age of onset of periodontitis was reported to be 14 years. Of note, a child with No genotype-phenotype correlations in pEDs have been identified. The penetrance in affected individuals identified to date is 100%. However, it is age-related: periodontitis may be absent in young individuals, particularly those with good dental hygiene [ Periodontal EDS was originally referred to as Ehlers Danlos syndrome type VIII [ There are no estimates of the prevalence of pEDS in any population. To date, 148 individuals with pEDS have been described in 34 case reports, seven pedigree analyses, and two cohort studies [ Due to the high prevalence of periodontitis in the general population [ ## Clinical Description Periodontal EDS (pEDS) is characterized by distinct oral manifestations. Early and severe breakdown of the tooth-supporting tissues (i.e., alveolar bone, periodontal ligament, root cementum, and gingival attachment) result in premature loss of teeth. Lack of attached gingiva and thin and fragile gums lead to gingival recession. Connective tissue abnormalities of pEDS typically include easy bruising, pretibial plaques, distal joint hypermobility, hoarse voice, and less commonly manifestations such as organ or vessel rupture (see Since the first descriptions of pEDS in the 1970s [ Periodontal Ehlers-Danlos Syndrome: Frequency of Select Features Based on Periodontitis with early onset was reported in 98.4% of affected adults [ Median age of onset of periodontitis is reported to be 14 years (range: 2-35 years) [ Clinical investigations of 12 affected children (ages 8 to 13 years) revealed localized periodontal bone loss of up to 6 mm only in the oldest individual (age 13 years), an observation supporting the notion that onset of periodontitis is predominantly in adolescence [ Although most individuals report frequent gum bleeding when brushing their teeth, frequent gum bleeding (a sign of gingival inflammation) is difficult to evaluate as it is subjective and very frequent in the general population due to insufficient plaque control. In healthy individuals, the gums are classified as keratinized attached gingiva and non-keratinized movable mucosa. The keratinized attached gingiva is tightly and unmovably bound to the periosteum via collagen type I fibers as a thick band to provide mechanical protection. The non-keratinized oral mucosa is thin, more fragile, translucent, and only loosely connected to the periosteum. In pEDS, the thick band of gingiva is missing and the fragile mucosa extends to the gingival margin, causing tissue fragility and predisposing to gingival recession. The MRI pattern was suggestive of an underlying small-vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the paucity of neurologic features. Medical history revealed recurrent headaches or depression in single cases. Neurologic examination was unremarkable in all individuals except one who had mild cognitive decline, ataxia, and a history of one seizure. Other clinical manifestations of pEDS are mild or absent in affected children, although the parents of all affected children reported easy bruising and gum bleeding. Median age of onset of periodontitis was reported to be 14 years. Of note, a child with ## Dental Findings Periodontitis with early onset was reported in 98.4% of affected adults [ Median age of onset of periodontitis is reported to be 14 years (range: 2-35 years) [ Clinical investigations of 12 affected children (ages 8 to 13 years) revealed localized periodontal bone loss of up to 6 mm only in the oldest individual (age 13 years), an observation supporting the notion that onset of periodontitis is predominantly in adolescence [ Although most individuals report frequent gum bleeding when brushing their teeth, frequent gum bleeding (a sign of gingival inflammation) is difficult to evaluate as it is subjective and very frequent in the general population due to insufficient plaque control. In healthy individuals, the gums are classified as keratinized attached gingiva and non-keratinized movable mucosa. The keratinized attached gingiva is tightly and unmovably bound to the periosteum via collagen type I fibers as a thick band to provide mechanical protection. The non-keratinized oral mucosa is thin, more fragile, translucent, and only loosely connected to the periosteum. In pEDS, the thick band of gingiva is missing and the fragile mucosa extends to the gingival margin, causing tissue fragility and predisposing to gingival recession. ## Ehlers-Danlos Syndrome Findings ## Other The MRI pattern was suggestive of an underlying small-vessel disease that is progressive with age. As observed in other leukoencephalopathies related to microangiopathies, the extent of the white matter changes was disproportionate to the paucity of neurologic features. Medical history revealed recurrent headaches or depression in single cases. Neurologic examination was unremarkable in all individuals except one who had mild cognitive decline, ataxia, and a history of one seizure. Other clinical manifestations of pEDS are mild or absent in affected children, although the parents of all affected children reported easy bruising and gum bleeding. Median age of onset of periodontitis was reported to be 14 years. Of note, a child with ## Genotype-Phenotype Correlations No genotype-phenotype correlations in pEDs have been identified. ## Penetrance The penetrance in affected individuals identified to date is 100%. However, it is age-related: periodontitis may be absent in young individuals, particularly those with good dental hygiene [ ## Nomenclature Periodontal EDS was originally referred to as Ehlers Danlos syndrome type VIII [ ## Prevalence There are no estimates of the prevalence of pEDS in any population. To date, 148 individuals with pEDS have been described in 34 case reports, seven pedigree analyses, and two cohort studies [ Due to the high prevalence of periodontitis in the general population [ ## Genetically Related (Allelic) Disorders Loss of complement complex 1 subunit proteins – inherited as autosomal recessive trait and including C1s deficiency (OMIM ## Differential Diagnosis Periodontal EDS (pEDS) must be distinguished from genetic disorders that include periodontitis and/or other features associated with pEDS and acquired periodontitis. The gingival phenotype as well as age of onset may be useful in differentiating pEDS from these conditions. Note: The current classification of periodontal diseases distinguishes "periodontitis as a complex genetic disorder" (i.e., "acquired periodontitis") from "periodontitis as a manifestation of systemic diseases" – which includes periodontal EDS. Genetic Disorders Associated with Oral Manifestations in the Differential Diagnosis of Periodontal Ehlers-Danlos Syndrome AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance; XL = X-linked In addition to the disorders summarized in Nonsyndromic aortopathy (See According to the current classification of periodontal and peri-implant diseases and conditions, "periodontitis" is distinguished from "necrotizing periodontal diseases" and "periodontitis as a manifestation of systemic disease," the latter including rare systemic disorders like pEDS [ In contrast to periodontitis as a manifestation of a rare disorder, periodontitis in general is a highly prevalent disease. In population-based studies periodontitis was diagnosed in up to 72.4% of individuals, with severe periodontitis (corresponding to stage III and IV) in up to 17.5% [ • Nonsyndromic aortopathy (See • • • ## Genetic Disorders Genetic Disorders Associated with Oral Manifestations in the Differential Diagnosis of Periodontal Ehlers-Danlos Syndrome AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance; XL = X-linked In addition to the disorders summarized in Nonsyndromic aortopathy (See According to the current classification of periodontal and peri-implant diseases and conditions, "periodontitis" is distinguished from "necrotizing periodontal diseases" and "periodontitis as a manifestation of systemic disease," the latter including rare systemic disorders like pEDS [ In contrast to periodontitis as a manifestation of a rare disorder, periodontitis in general is a highly prevalent disease. In population-based studies periodontitis was diagnosed in up to 72.4% of individuals, with severe periodontitis (corresponding to stage III and IV) in up to 17.5% [ • Nonsyndromic aortopathy (See • • • ## Management At this point no clinical practice guidelines for periodontal Ehlers-Danlos syndrome (pEDS) have been published. However, some recommendations exist [Authors, personal observation]. To establish the extent of disease and needs in an individual diagnosed with periodontal Ehlers-Danlos syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Periodontal Ehlers-Danlos Syndrome Use of community or Need for parental support. MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified advanced genetic nurse Periodontal breakdown with pEDS is most likely caused by a hyperinflammatory reaction [ Early severe periodontitis may be ameliorated with strict oral hygiene measures starting in early childhood. Professional tooth cleaning approximately every three months and frequent oral hygiene instructions to achieve livelong excellent personal oral hygiene appear to be essential. Soft toothbrushes are recommended because of sensitive gums. Treatment is individualized based on the clinical manifestations present. Given the characteristic features of early and severe periodontitis, all individuals should be regularly seen by a periodontist beginning in early childhood. Excellent oral hygiene is also a major element of the treatment of existing periodontitis. For example, affected individuals must be instructed frequently in order to achieve excellent personal oral hygiene with interdental cleaning devices and (electric) toothbrushes (see Dental implants are often used to replace lost teeth. With pEDS there appears to be a high risk of peri-implantitis and consequently implant failure [ Therefore, the primary objective in the oral treatment of pEDS is to help affected individuals retain their own teeth for as long as possible [ Treatment of Manifestations in Individuals with Periodontal Ehlers-Danlos Syndrome Surgical treatment of gingival recession in general is possible; however, no experience exists w/pEDS. Oral hygiene instructions for gentle cleaning (e.g., w/soft toothbrushes) recommended Advice re avoidance of high-impact sports For wounds that do not heal consult a dermatologist. There is some evidence in OT = occupational therapy; PT = physical therapy Recommended Surveillance for Individuals with Periodontal Ehlers-Danlos Syndrome OT = occupational therapist; PT = physical therapist Currently, evidence does not support a general recommendation that persons with pEDS avoid any specific activities/treatment/medications. However, this may vary on an individual basis; for example, in an individual with pEDS and arterial aneurysms, activities such as high-impact sports and weight lifting would be actively discouraged. 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 preventive dental hygiene and routine dental care and surveillance. See Search • Use of community or • Need for parental support. • Early severe periodontitis may be ameliorated with strict oral hygiene measures starting in early childhood. • Professional tooth cleaning approximately every three months and frequent oral hygiene instructions to achieve livelong excellent personal oral hygiene appear to be essential. • Soft toothbrushes are recommended because of sensitive gums. • Surgical treatment of gingival recession in general is possible; however, no experience exists w/pEDS. • Oral hygiene instructions for gentle cleaning (e.g., w/soft toothbrushes) recommended • Advice re avoidance of high-impact sports • For wounds that do not heal consult a dermatologist. • There is some evidence in ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with periodontal Ehlers-Danlos syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Periodontal Ehlers-Danlos Syndrome Use of community or Need for parental support. MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified advanced genetic nurse • Use of community or • Need for parental support. ## Preventive Measures Periodontal breakdown with pEDS is most likely caused by a hyperinflammatory reaction [ Early severe periodontitis may be ameliorated with strict oral hygiene measures starting in early childhood. Professional tooth cleaning approximately every three months and frequent oral hygiene instructions to achieve livelong excellent personal oral hygiene appear to be essential. Soft toothbrushes are recommended because of sensitive gums. • Early severe periodontitis may be ameliorated with strict oral hygiene measures starting in early childhood. • Professional tooth cleaning approximately every three months and frequent oral hygiene instructions to achieve livelong excellent personal oral hygiene appear to be essential. • Soft toothbrushes are recommended because of sensitive gums. ## Treatment of Manifestations Treatment is individualized based on the clinical manifestations present. Given the characteristic features of early and severe periodontitis, all individuals should be regularly seen by a periodontist beginning in early childhood. Excellent oral hygiene is also a major element of the treatment of existing periodontitis. For example, affected individuals must be instructed frequently in order to achieve excellent personal oral hygiene with interdental cleaning devices and (electric) toothbrushes (see Dental implants are often used to replace lost teeth. With pEDS there appears to be a high risk of peri-implantitis and consequently implant failure [ Therefore, the primary objective in the oral treatment of pEDS is to help affected individuals retain their own teeth for as long as possible [ Treatment of Manifestations in Individuals with Periodontal Ehlers-Danlos Syndrome Surgical treatment of gingival recession in general is possible; however, no experience exists w/pEDS. Oral hygiene instructions for gentle cleaning (e.g., w/soft toothbrushes) recommended Advice re avoidance of high-impact sports For wounds that do not heal consult a dermatologist. There is some evidence in OT = occupational therapy; PT = physical therapy • Surgical treatment of gingival recession in general is possible; however, no experience exists w/pEDS. • Oral hygiene instructions for gentle cleaning (e.g., w/soft toothbrushes) recommended • Advice re avoidance of high-impact sports • For wounds that do not heal consult a dermatologist. • There is some evidence in ## Surveillance Recommended Surveillance for Individuals with Periodontal Ehlers-Danlos Syndrome OT = occupational therapist; PT = physical therapist ## Agents/Circumstances to Avoid Currently, evidence does not support a general recommendation that persons with pEDS avoid any specific activities/treatment/medications. However, this may vary on an individual basis; for example, in an individual with pEDS and arterial aneurysms, activities such as high-impact sports and weight lifting would be actively discouraged. ## 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 preventive dental hygiene and routine dental care and surveillance. See ## Therapies Under Investigation Search ## Genetic Counseling Periodontal Ehlers-Danlos syndrome (pEDS) is inherited in an autosomal dominant manner. Most probands reported to date have pEDS as the result of a Some individuals with pEDS 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 confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with pEDS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. All sibs who inherit a pEDS-related pathogenic variant are expected to develop manifestations of pEDS, although the age of onset may vary between heterozygous family members (see If the proband has a known pEDS-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 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 pEDS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are technically 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 probands reported to date have pEDS as the result of a • Some individuals with pEDS 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 confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • 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 pEDS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • 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%. All sibs who inherit a pEDS-related pathogenic variant are expected to develop manifestations of pEDS, although the age of onset may vary between heterozygous family members (see • If the proband has a known pEDS-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 optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 Periodontal Ehlers-Danlos syndrome (pEDS) is inherited in an autosomal dominant manner. ## Risk to Family Members Most probands reported to date have pEDS as the result of a Some individuals with pEDS 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 confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with pEDS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. All sibs who inherit a pEDS-related pathogenic variant are expected to develop manifestations of pEDS, although the age of onset may vary between heterozygous family members (see If the proband has a known pEDS-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 probands reported to date have pEDS as the result of a • Some individuals with pEDS 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 confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • 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 pEDS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. • 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%. All sibs who inherit a pEDS-related pathogenic variant are expected to develop manifestations of pEDS, although the age of onset may vary between heterozygous family members (see • If the proband has a known pEDS-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 ## 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 pEDS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are technically 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 67, rue Jules Lecesne Le Havre 76600 France Postfach 1619 Germany • • United Kingdom • • • • • • • 67, rue Jules Lecesne • Le Havre 76600 • France • • Postfach 1619 • Germany • • • ## Molecular Genetics Periodontal Ehlers-Danlos Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Periodontal Ehlers-Danlos Syndrome ( Periodontal Ehlers-Danlos syndrome (pEDS) results from specific heterozygous variants in The central element in the pathogenesis of pEDS is the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that – independent of microbial triggers – can activate the classic complement cascade. This mechanism is triggered by specific gain-of-function variants [ Functional studies in transfected HEK cells and fibroblasts from affected individuals revealed that all 16 pEDS variants studied prevented normal integration into the C1 complex and caused abnormal extracellular C1r/C1s serine protease activation. Variants that remove C1r or C1s serine protease function – such as large genomic rearrangements, out-of-frame deletions or duplications, or nonsense variants – are not expected to cause pEDS. However, pEDS causation cannot be fully excluded for in-frame deletions or duplication. ## Molecular Pathogenesis Periodontal Ehlers-Danlos syndrome (pEDS) results from specific heterozygous variants in The central element in the pathogenesis of pEDS is the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that – independent of microbial triggers – can activate the classic complement cascade. This mechanism is triggered by specific gain-of-function variants [ Functional studies in transfected HEK cells and fibroblasts from affected individuals revealed that all 16 pEDS variants studied prevented normal integration into the C1 complex and caused abnormal extracellular C1r/C1s serine protease activation. Variants that remove C1r or C1s serine protease function – such as large genomic rearrangements, out-of-frame deletions or duplications, or nonsense variants – are not expected to cause pEDS. However, pEDS causation cannot be fully excluded for in-frame deletions or duplication. ## Chapter Notes Further information is available at the dedicated website The authors wish to thank the affected individuals and their families who supported the detailed clinical characterization of the condition. The assistance of the many collaborative partners listed in the various publications is gratefully acknowledged. 29 July 2021 (bp) Review posted live 5 May 2021 (jz) Original submission • 29 July 2021 (bp) Review posted live • 5 May 2021 (jz) Original submission ## Author Notes Further information is available at the dedicated website ## Acknowledgments The authors wish to thank the affected individuals and their families who supported the detailed clinical characterization of the condition. The assistance of the many collaborative partners listed in the various publications is gratefully acknowledged. ## Revision History 29 July 2021 (bp) Review posted live 5 May 2021 (jz) Original submission • 29 July 2021 (bp) Review posted live • 5 May 2021 (jz) Original submission ## References ## Literature Cited Generalized lack of attached gingiva is a major criterion of periodontal Ehlers-Danlos syndrome. A. In healthy individuals a band of thick and keratinized gingiva (*) provides mechanical protection. It is tightly and unmovably bound to the periosteum via collagen type I fibers. B. Due to the lack of attached gingiva with periodontal Ehlers-Danlos syndrome, the mucosa extends to the free gingival margin. The oral mucosa is non-keratinized and loosely connected to the periosteum. It is thinner and more fragile than in a healthy individual; it is also translucent such that blood vessels are clearly visible. Pretibial plaques have been described in 83% of individuals with periodontal EDS [
[ "JM Albandar. Aggressive and acute periodontal diseases.. Periodontol 2000 2014;65:7-12", "I Bally, F Dalonneau, A Chouquet, R Grobner, A Amberger, I Kapferer-Seebacher, H Stoiber, J Zschocke, NM Thielens, V Rossi, C Gaboriaud. Two different missense C1S mutations, associated to periodontal Ehlers-Danlos syndrome, lead to identical molecular outcomes.. Front Immunol. 2019;10:2962", "P Beighton, A De Paepe, B Steinmann, P Tsipouras, RJ Wenstrup. Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK).. Am J Med Genet. 1998;77:31-7", "JG Caton, G Armitage, T Berglundh, ILC Chapple, S Jepsen, KS Kornman, BL Mealey, PN Papapanou, M Sanz, MS Tonetti. A new classification scheme for periodontal and peri-implant diseases and conditions - Introduction and key changes from the 1999 classification.. J Periodontol. 2018;89:S1-S8", "MX Chen, YJ Zhong, QQ Dong, HM Wong, YF Wen. Global, regional, and national burden of severe periodontitis, 1990-2019: an analysis of the Global Burden of Disease Study 2019.. J Clin Periodontol. 2021", "U Cıkla, A Sadighi, A Bauer, MK Başkaya. Fatal ruptured blood blister-like aneurysm of middle cerebral artery associated with Ehlers-Danlos syndrome type VIII (periodontitis type).. J Neurol Surg Rep. 2014;75:e210-3", "J Cortés-Bretón Brinkmann, I García-Gil, DM Lobato-Peña, C Martínez-Mera, MJ Suárez-García, JM Martínez-González, M Rioboo. The key role of the dental practitioner in early diagnosis of periodontal Ehlers-Danlos syndromes: a rare case report of siblings.. Quintessence Int. 2021;52:166-74", "C Cunniff, L. Williamson-Kruse. Ehlers-Danlos syndrome, type VIII presenting with periodontitis and prolonged bleeding time.. Clin Dysmorphol. 1995;4:145-9", "E Demirkaya, Q Zhou, CK Smith, MJ Ombrello, N Deuitch, WL Tsai, P Hoffmann, EF Remmers, M Takeuchi, YH Park, J Chae, K Barut, D Simsek, A Adrovic, S Sahin, S Caliskan, SC Chandrasekharappa, SA Hasni, AK Ombrello, M Gadina, DL Kastner, MJ Kaplan, O Kasapcopur, I Aksentijevich. Brief report: deficiency of complement 1r subcomponent in early-onset systemic lupus erythematosus: the role of disease-modifying alleles in a monogenic disease.. Arthritis Rheumatol. 2017;69:1832-9", "M Frank, J Albuisson, B Ranque, L Golmard, JM Mazzella, L Bal-Theoleyre, AL Fauret, T Mirault, N Denarié, E Mousseaux, P Boutouyrie, JN Fiessinger, J Emmerich, E Messas, X Jeunemaitre. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome.. Eur J Hum Genet. 2015;23:1657-64", "M Germen, U Baser, CC Lacin, E Fıratlı, H İşsever, F Yalcin. Int J Environ Res Public Health. 2021;18:3459", "SM George, A Vandersteen, E Nigar, DJ Ferguson, EJ Topham, FM Pope. Two patients with Ehlers-Danlos syndrome type VIII with unexpected hoarseness.. Clin Exp Dermatol. 2016;41:771-4", "R Gröbner, I Kapferer-Seebacher, A Amberger, R Redolfi, F Dalonneau, E Bjorck, D Milnes, I Bally, V Rossi, N Thielens, H Stoiber, C Gaboriaud, J. Zschocke. C1R mutations trigger constitutive complement 1 activation in periodontal Ehlers-Danlos syndrome.. Front Immunol. 2019;10:2537", "JK Hartsfield, BG Kousseff. Phenotypic overlap of Ehlers-Danlos syndrome types IV and VIII.. Am J Med Genet. 1990;37:465-70", "I Kapferer-Seebacher, P Lundberg, F Malfait, J. Zschocke. Periodontal manifestations of Ehlers-Danlos syndromes: A systematic review.. J Clin Periodontol. 2017;44:1088-100", "I Kapferer-Seebacher, E Oakley-Hannibal, U Lepperdinger, D Johnson, N Ghali, AF Brady, GJ Sobey, J Zschocke, FS Van Dijk. Prospective clinical investigations of children with periodontal Ehlers–Danlos syndrome identify generalized lack of attached gingiva as a pathognomonic feature.. Genet Med. 2021;23:316-22", "I Kapferer-Seebacher, M Pepin, R Werner, TJ Aitman, A Nordgren, H Stoiber, N Thielens, C Gaboriaud, A Amberger, A Schossig, R Gruber, C Giunta, M Bamshad, E Bjorck, C Chen, D Chitayat, M Dorschner, M Schmitt-Egenolf, CJ Hale, D Hanna, HC Hennies, I Heiss-Kisielewsky, A Lindstrand, P Lundberg, AL Mitchell, DA Nickerson, E Reinstein, M Rohrbach, N Romani, M Schmuth, R Silver, F Taylan, A Vandersteen, J Vandrovcova, R Weerakkody, M Yang, FM Pope, PH Byers, J Zschocke. Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement.. Am J Hum Genet. 2016;99:1005-14", "I Kapferer-Seebacher, Q Waisfisz, S Boesch, M Bronk, P Van Tintelen, ER Gizewski, R Groebner, J Zschocke, MS Van Der Knaap. Periodontal Ehlers-Danlos syndrome is associated with leukoencephalopathy.. Neurogenetics. 2019;20:1-8", "AC Macedo, L Isaac. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway.. Front Immunol. 2016;7:55", "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", "F Malfait, S Symoens, J De Backer, T Hermanns-Lê, N Sakalihasan, CM Lapière, P Coucke, A De Paepe. Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood.. Hum Mutat. 2007;28:387-95", "L Nuytinck, M Freund, L Lagae, GE Pierard, T Hermanns-Le, A De Paepe. Classical Ehlers-Danlos syndrome caused by a mutation in type I collagen.. Am J Hum Genet. 2000;66:1398-402", "T Pitney, M Pitney. Phenotypic mimicry between periodontal and vascular Ehlers-Danlos variants resolved by molecular genetic testing.. Int J Dermatol. 2020;59:e387-e388", "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", "A Rinner, J Zschocke, A Schossig, R Gröbner, H Strobl, I Kapferer-Seebacher. High risk of peri-implant disease in periodontal Ehlers-Danlos Syndrome. A case series.. Clin Oral Implants Res. 2018;29:1101-6", "S Ronceray, J Miquel, A Lucas, GE Pierard, T Hermanns-Le, A De Paepe, A Dupuy. Ehlers-Danlos syndrome type VIII: a rare cause of leg ulcers in young patients.. Case Rep Dermatol Med. 2013;2013", "S Spranger, M Spranger, K Kirchhof, B. Steinmann. Ehlers-Danlos syndrome type VIII and leukodystrophy.. Am J Med Genet. 1996;66:239-40", "RE Stewart, DW Hollister, DL Rimoin. A new variant of Ehlers-Danlos syndrome: an autosomal dominant disorder of fragile skin, abnormal scarring, and generalized periodontitis.. Birth Defects Orig Artic Ser. 1977;13:85-93", "F Stock, M Hanisch, S Lechner, S Biskup, A Bohring, J Zschocke, I Kapferer-Seebacher. Prepubertal periodontitis in a patient with combined classical and periodontal Ehlers-Danlos syndrome.. Biomolecules 2021;11:149", "IH Stødle, A Verket, H Høvik, A Sen, OC Koldsland. Prevalence of periodontitis based on the 2017 classification in a Norwegian population. The HUNT Study.. J Clin Periodontol. 2021", "MS Tonetti, H Greenwell, KS Kornman. Staging and grading of periodontitis: Framework and proposal of a new classification and case definition.. J Periodontol. 2018;89:S159-S172", "J Wu, J Yang, J Zhao, JR Wu, X Zhang, WK Leung, WB Sun. A Chinese family with periodontal Ehlers-Danlos syndrome associated with missense mutation in the C1R gene.. J Clin Periodontol. 2018;45:1311-18" ]
29/7/2021
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eds
eds
[ "Classical Ehlers-Danlos Syndrome", "Ehlers-Danlos Syndrome, Classical Type", "cEDS", "Classical Ehlers-Danlos Syndrome", "Ehlers-Danlos Syndrome, Classical Type", "cEDS", "Ehlers-Danlos Syndrome, Classic Type, COL5A1-Related", "Ehlers-Danlos Syndrome, Classic Type, COL5A2-Related", "Collagen alpha-1(I) chain", "Collagen alpha-1(V) chain", "Collagen alpha-2(V) chain", "COL1A1", "COL5A1", "COL5A2", "Classic Ehlers-Danlos Syndrome" ]
Classic Ehlers-Danlos Syndrome
Fransiska Malfait, Sofie Symoens, Delfien Syx
Summary Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, atrophic scarring, and generalized joint hypermobility (GJH). The skin is soft, velvety, or doughy to the touch. In addition, the skin is hyperextensible, meaning that it extends easily and snaps back after release. The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Wound healing is poor, and stretching, thinning, and pigmentation of scars is characteristic, leading to the presence of atrophic and/or hemosiderotic scars. Easy bruising is also a hallmark of cEDS. GJH is present in most but not all affected individuals, evidenced by the presence of a Beighton score of five or greater, either on examination or historically. Joint instability complications may comprise sprains and dislocations/subluxations. Mild muscle hypotonia with delayed motor development, fatigue and muscle cramps, and some skeletal morphologic alterations (scoliosis, pectus deformities, genus/hallux valgus, pes planus) are regularly observed. While aortic root dilatation and mitral valve prolapse are seen in cEDS, they are rarely clinically significant. Arterial aneurysm and rupture have been reported in a few individuals with cEDS. The diagnosis of cEDS is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in Classic EDS is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with cEDS have an affected parent; approximately 50% of individuals diagnosed with cEDS have the disorder as the result of a
## Diagnosis There are no consensus clinical diagnostic criteria for classic Ehlers-Danlos syndrome (cEDS); diagnosis requires molecular testing. Classic EDS should be suspected in a proband with either of the following: OR Beighton Criteria for Joint Hypermobility A total score of ≥5 is considered positive for the presence of generalized joint hypermobility. Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations. The five-point questionnaire is as follows (adapted from Can you now (or could you ever) place your hands flat on the floor without bending your knees? Can you now (or could you ever) bend your thumb to touch your forearm? As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? Do you consider yourself "double-jointed"? Note: A "yes" answer to ≥2 questions suggests joint hypermobility with 80%-85% sensitivity and 80%-90% specificity. Easy bruising Soft, doughy skin Skin fragility (or traumatic splitting) Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees Subcutaneous spheroids: small, spherical hard bodies, frequently mobile, palpable on the forearms and shins. Spheroids may be calcified and detectable radiologically. Hernia (or history thereof) Epicanthal folds Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flat foot) Family history of a first-degree relative with a diagnosis of cEDS The diagnosis of cEDS 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: (1) Multigene targeted analysis implies that the coding regions for the genes, included in the multigene panel, are enriched. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by hypermobility, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Classic Ehlers-Danlos Syndrome cEDS = classic Ehlers-Danlos 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. In addition, in silico prediction software, such as ExomeDepth, is available for predicting deletions/duplications in large, comprehensive datasets (e.g., from exome sequencing). Large deletions in Data derived from the subscription-based professional view of Human Gene Mutation Database [ • OR • Beighton Criteria for Joint Hypermobility • A total score of ≥5 is considered positive for the presence of generalized joint hypermobility. • Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations. The five-point questionnaire is as follows (adapted from • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • Note: A "yes" answer to ≥2 questions suggests joint hypermobility with 80%-85% sensitivity and 80%-90% specificity. • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • Easy bruising • Soft, doughy skin • Skin fragility (or traumatic splitting) • Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees • Subcutaneous spheroids: small, spherical hard bodies, frequently mobile, palpable on the forearms and shins. Spheroids may be calcified and detectable radiologically. • Hernia (or history thereof) • Epicanthal folds • Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flat foot) • Family history of a first-degree relative with a diagnosis of cEDS ## Suggestive Findings Classic EDS should be suspected in a proband with either of the following: OR Beighton Criteria for Joint Hypermobility A total score of ≥5 is considered positive for the presence of generalized joint hypermobility. Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations. The five-point questionnaire is as follows (adapted from Can you now (or could you ever) place your hands flat on the floor without bending your knees? Can you now (or could you ever) bend your thumb to touch your forearm? As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? Do you consider yourself "double-jointed"? Note: A "yes" answer to ≥2 questions suggests joint hypermobility with 80%-85% sensitivity and 80%-90% specificity. Easy bruising Soft, doughy skin Skin fragility (or traumatic splitting) Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees Subcutaneous spheroids: small, spherical hard bodies, frequently mobile, palpable on the forearms and shins. Spheroids may be calcified and detectable radiologically. Hernia (or history thereof) Epicanthal folds Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flat foot) Family history of a first-degree relative with a diagnosis of cEDS • OR • Beighton Criteria for Joint Hypermobility • A total score of ≥5 is considered positive for the presence of generalized joint hypermobility. • Since laxity decreases with age, individuals with a Beighton score of <5 may be considered positive based on historical observations. The five-point questionnaire is as follows (adapted from • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • Note: A "yes" answer to ≥2 questions suggests joint hypermobility with 80%-85% sensitivity and 80%-90% specificity. • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • Easy bruising • Soft, doughy skin • Skin fragility (or traumatic splitting) • Molluscoid pseudotumors: fleshy, heaped-up lesions associated with scars over pressure points such as the elbows and knees • Subcutaneous spheroids: small, spherical hard bodies, frequently mobile, palpable on the forearms and shins. Spheroids may be calcified and detectable radiologically. • Hernia (or history thereof) • Epicanthal folds • Complications of joint hypermobility (e.g., sprains, dislocations/subluxations, pain, flexible flat foot) • Family history of a first-degree relative with a diagnosis of cEDS ## Establishing the Diagnosis The diagnosis of cEDS 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: (1) Multigene targeted analysis implies that the coding regions for the genes, included in the multigene panel, are enriched. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by hypermobility, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Classic Ehlers-Danlos Syndrome cEDS = classic Ehlers-Danlos 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. In addition, in silico prediction software, such as ExomeDepth, is available for predicting deletions/duplications in large, comprehensive datasets (e.g., from exome sequencing). Large deletions in Data derived from the subscription-based professional view of Human Gene Mutation Database [ ## Option 1 Note: (1) Multigene targeted analysis implies that the coding regions for the genes, included in the multigene panel, are enriched. (2) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (3) Some multigene panels may include genes not associated with the condition discussed in this For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by hypermobility, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Classic Ehlers-Danlos Syndrome cEDS = classic Ehlers-Danlos 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. In addition, in silico prediction software, such as ExomeDepth, is available for predicting deletions/duplications in large, comprehensive datasets (e.g., from exome sequencing). Large deletions in Data derived from the subscription-based professional view of Human Gene Mutation Database [ ## Other Testing ## Clinical Characteristics Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility. The skin is soft, velvety, or doughy to the touch. The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Skin fragility may cause dehiscence of sutured incisions in skin or mucosa. Wound healing is poor, and stretching, thinning, and pigmentation of scars is characteristic. Scars become wide, with a "cigarette-paper"-like (papyraceous) appearance, also referred to as atrophic and/or hemosiderotic scars. Other dermatologic features in cEDS: Molluscoid pseudotumors Subcutaneous spheroids Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing Elastosis perforans serpiginosa: characterized by skin-colored to erythematous keratotic papules, some enlarging outward in serpiginous or arcuate configurations, leaving slightly atrophic centers Acrocyanosis: painless constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur Chilblains: cold injuries, characterized by red, swollen skin that is tender and hot to the touch and may itch; can develop in less than two hours in skin exposed to cold Cervical insufficiency during pregnancy Inguinal and umbilical hernia Hiatal and incisional hernia Recurrent rectal prolapse in early childhood Other problems related to joint hypermobility are joint instability, foot deformities such as congenital clubfoot or pes planus, and temporomandibular joint dysfunction [ Mitral valve prolapse and (less frequently) tricuspid valve prolapse may occur. Stringent criteria should be used for the diagnosis of mitral valve prolapse. When it does occur, mitral valve prolapse tends to be of little clinical consequence [ Aortic root dilatation has been reported in individuals with cEDS [ Individuals with cEDS are at risk for spontaneous rupture of large arteries, although the prevalence of such complications is much lower than in those with vascular EDS. Premature rupture of the membranes and prematurity are reported to be twice as common in fetuses with cEDS born to healthy mothers, compared with fetuses without EDS born to a mother with cEDS. Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn. Intrauterine growth restriction may occur. Perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur. No genotype-phenotype correlations have emerged to date. Penetrance is presumably 100% in both males and females, but in some individuals the condition is very mild, and may be undiagnosed. As a result of the 1997 Villefranche conference on EDS [ The prevalence of cEDS has been estimated at 1:20,000 [ • Molluscoid pseudotumors • Subcutaneous spheroids • Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing • Elastosis perforans serpiginosa: characterized by skin-colored to erythematous keratotic papules, some enlarging outward in serpiginous or arcuate configurations, leaving slightly atrophic centers • Acrocyanosis: painless constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur • Chilblains: cold injuries, characterized by red, swollen skin that is tender and hot to the touch and may itch; can develop in less than two hours in skin exposed to cold • Cervical insufficiency during pregnancy • Inguinal and umbilical hernia • Hiatal and incisional hernia • Recurrent rectal prolapse in early childhood • Premature rupture of the membranes and prematurity are reported to be twice as common in fetuses with cEDS born to healthy mothers, compared with fetuses without EDS born to a mother with cEDS. • Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn. • Intrauterine growth restriction may occur. • Perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur. ## Clinical Description Classic Ehlers-Danlos syndrome (cEDS) is a heritable connective tissue disorder characterized by skin hyperextensibility, abnormal wound healing, and generalized joint hypermobility. The skin is soft, velvety, or doughy to the touch. The skin is fragile, as manifested by splitting of the dermis following relatively minor trauma, especially over pressure points (knees, elbows) and areas prone to trauma (shins, forehead, chin). Skin fragility may cause dehiscence of sutured incisions in skin or mucosa. Wound healing is poor, and stretching, thinning, and pigmentation of scars is characteristic. Scars become wide, with a "cigarette-paper"-like (papyraceous) appearance, also referred to as atrophic and/or hemosiderotic scars. Other dermatologic features in cEDS: Molluscoid pseudotumors Subcutaneous spheroids Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing Elastosis perforans serpiginosa: characterized by skin-colored to erythematous keratotic papules, some enlarging outward in serpiginous or arcuate configurations, leaving slightly atrophic centers Acrocyanosis: painless constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur Chilblains: cold injuries, characterized by red, swollen skin that is tender and hot to the touch and may itch; can develop in less than two hours in skin exposed to cold Cervical insufficiency during pregnancy Inguinal and umbilical hernia Hiatal and incisional hernia Recurrent rectal prolapse in early childhood Other problems related to joint hypermobility are joint instability, foot deformities such as congenital clubfoot or pes planus, and temporomandibular joint dysfunction [ Mitral valve prolapse and (less frequently) tricuspid valve prolapse may occur. Stringent criteria should be used for the diagnosis of mitral valve prolapse. When it does occur, mitral valve prolapse tends to be of little clinical consequence [ Aortic root dilatation has been reported in individuals with cEDS [ Individuals with cEDS are at risk for spontaneous rupture of large arteries, although the prevalence of such complications is much lower than in those with vascular EDS. Premature rupture of the membranes and prematurity are reported to be twice as common in fetuses with cEDS born to healthy mothers, compared with fetuses without EDS born to a mother with cEDS. Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn. Intrauterine growth restriction may occur. Perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur. • Molluscoid pseudotumors • Subcutaneous spheroids • Piezogenic papules: small, painful, reversible herniations of underlying adipose tissue globules through the fascia into the dermis, such as on medial and lateral aspects of the feet upon standing • Elastosis perforans serpiginosa: characterized by skin-colored to erythematous keratotic papules, some enlarging outward in serpiginous or arcuate configurations, leaving slightly atrophic centers • Acrocyanosis: painless constriction or narrowing of the small blood vessels in the skin (affecting mainly the hands) in which the affected areas turn blue and become cold and sweaty; localized swelling may also occur • Chilblains: cold injuries, characterized by red, swollen skin that is tender and hot to the touch and may itch; can develop in less than two hours in skin exposed to cold • Cervical insufficiency during pregnancy • Inguinal and umbilical hernia • Hiatal and incisional hernia • Recurrent rectal prolapse in early childhood • Premature rupture of the membranes and prematurity are reported to be twice as common in fetuses with cEDS born to healthy mothers, compared with fetuses without EDS born to a mother with cEDS. • Because of hypotonia, breech presentation is more frequent if the baby is affected and may lead to dislocation of the hips or shoulder of the newborn. • Intrauterine growth restriction may occur. • Perineal tearing, postpartum hemorrhage, pelvic prolapse, and incontinence following delivery may occur. ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations No genotype-phenotype correlations have emerged to date. ## Penetrance Penetrance is presumably 100% in both males and females, but in some individuals the condition is very mild, and may be undiagnosed. ## Nomenclature As a result of the 1997 Villefranche conference on EDS [ ## Prevalence The prevalence of cEDS has been estimated at 1:20,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes associated with germline pathogenic variants in Allelic Disorders EDS = Ehlers-Danlos syndrome; OI = osteogenesis imperfecta ## Differential Diagnosis Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation. Clinical overlap with classic EDS (cEDS) is seen with all other forms of EDS, in particular with hypermobile EDS (hEDS) and the EDS types listed in Hypermobile EDS is generally considered the least severe type of EDS, although significant complications, primarily musculoskeletal, can occur. Similar to cEDS, generalized joint hypermobility, mild atrophic scarring, mild skin hyperextensibility, and soft, velvety skin are seen in hEDS. Unlike cEDS, hEDS is not associated with truly papyraceous and/or hemosiderotic scars. The diagnosis of hEDS is based entirely on clinical evaluation and family history. The gene(s) in which pathogenic variants cause hEDS are unknown. Ehlers-Danlos Syndrome-Related Genes of Interest in the Differential Diagnosis of Classic Ehlers-Danlos Syndrome Atrophic scarring Easy bruising GJH Skin hyperextensibility Soft, doughy skin Extreme skin fragility (usually > than in cEDS) Redundant, almost lax, skin Unusual craniofacial features Postnatal growth restriction Atrophic scarring Easy bruising GJH Skin hyperextensibility Prematurely aged appearance Thinning of hair or (partial) alopecia Atrophic scarring Easy bruising GJH Skin hyperextensibility Atrophic scarring Easy bruising (Generalized) joint hypermobility Skin hyperextensibility Atrophic scarring Easy bruising GJH Skin hyperextensibility Doughy skin Gastrointestinal rupture Pneumothorax Severe hematoma formation, incl muscle hematoma Easy bruising GJH Skin hyperextensibility Congenital muscle hypotonia Muscle atrophy Congenital hearing impairment Atrophic scarring Easy bruising GJH Skin hyperextensibility Easy bruising GJH Skin hyperextensibilityy Velvety skin AD = autosomal dominant; AR = autosomal recessive; cEDS = classic Ehlers-Danlos syndrome; EDS = Ehlers-Danlos syndrome; GJH = generalized joint hypermobility; MOI = mode of inheritance Glutamic acid to lysine substitutions in • Atrophic scarring • Easy bruising • GJH • Skin hyperextensibility • Soft, doughy skin • Extreme skin fragility (usually > than in cEDS) • Redundant, almost lax, skin • Unusual craniofacial features • Postnatal growth restriction • Atrophic scarring • Easy bruising • GJH • Skin hyperextensibility • Prematurely aged appearance • Thinning of hair or (partial) alopecia • Atrophic scarring • Easy bruising • GJH • Skin hyperextensibility • Atrophic scarring • Easy bruising • (Generalized) joint hypermobility • Skin hyperextensibility • Atrophic scarring • Easy bruising • GJH • Skin hyperextensibility • Doughy skin • Gastrointestinal rupture • Pneumothorax • Severe hematoma formation, incl muscle hematoma • Easy bruising • GJH • Skin hyperextensibility • Congenital muscle hypotonia • Muscle atrophy • Congenital hearing impairment • Atrophic scarring • Easy bruising • GJH • Skin hyperextensibility • Easy bruising • GJH • Skin hyperextensibilityy • Velvety skin ## Management For a detailed review of complications and management of classic Ehlers-Danlos syndrome (cEDS), see To establish the extent of disease in an individual diagnosed with cEDS, the evaluations summarized in Classic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis Assessment for easy bruising &/or prolonged bleeding Eval of clotting factors (platelet count, aPTT, PT, thrombin time) if severe easy bruising is present cEDS = classic Ehlers-Danlos syndrome; MOI = mode of inheritance; aPTT = activated partial thromboplastin time; PT = prothrombin time 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 Classic Ehlers-Danlos Syndrome: Treatment of Manifestations Dermal wounds should be closed w/o tension, preferably in 2 layers. Deep stitches should be applied generously. Cutaneous stitches should be left in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. Very young children w/pronounced skin fragility can wear protective pads or bandages over the forehead, knees, & shins to avoid skin tears. Older children who are active can wear soccer pads or ski stockings w/shin padding during activities. Braces are useful to improve joint stability. Orthopedist, rheumatologist, or physical therapist referral for knee or ankle braces as needed Occupational therapist referral for ring splints (to stabilize interphalangeal joints) & wrist or wrist & thumb braces for small joint instability A soft neck collar, if tolerated, may help w/neck pain & headaches. Wheelchair or scooter as needed to decrease stress on lower-extremity joints Wheelchair customizations (e.g., lightweight, motorized, seat pads, specialized wheels, wheel grasps) as needed to accommodate pelvic & upper-extremity issues A waterbed, adjustable air mattress, or viscoelastic foam mattress (&/or pillow) may increase support for improved sleep quality & less pain. Those w/hypotonia, joint instability, & chronic pain may need to adapt lifestyle accordingly. Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement. Acetaminophen: 4,000 mg daily in 3-4 divided doses NSAIDs, as tolerated by upper GI symptoms, for arthralgia, myalgia, & secondary inflammatory conditions (e.g., bursitis, tendinitis, costochondritis, postdislocation pain) COX-2 inhibitors have similar efficacy to NSAIDS but may be better tolerated. Topical lidocaine (cream or patch) may be useful for localized pain. Topical capsaicin is of questionable utility but is safe. Tramadol w/acetaminophen & NSAID or COX-2 inhibitor before resorting to other opioids (Nausea is the most common side effect.) Opioids for myofascial pain & neuropathic pain; should be reserved after failing the above medications. Administer w/other analgesics to minimize total opioid requirements. Typically used chronically (or at least several months), the primary formulation should be long acting (e.g., sustained-release oxycodone or morphine or topical fentanyl patch) w/short-acting forms of the same drug as needed for breakthrough pain. Routine use of ≥2 daily doses of a short-acting form should prompt an increase in the long-acting dose or another adjustment to the pain regimen. Bruising is not a contraindication to NSAID therapy, but occasionally requires dose reduction or change to a COX-2 inhibitor. Those w/muscle hypotonia & joint instability w/chronic pain may have to adjust lifestyle & professional choices accordingly. Emotional support & behavioral & psychological therapy may help in developing acceptance & coping skills. Long-term chronic pain may result in the need for mental health services. All require gradual titration before reaching therapeutic levels. Gabapentin should be titrated as tolerated to at least 1,200 mg 3x per day before declaring failure, but dose is often limited by sedation &/or GI side effects. Pregabalin, titrated to at least 300 mg divided 2-3x/day, tends to be better tolerated than gabapentin. Limited by sedation; metaxalone may be least sedating Muscle relaxants may ↑ joint instability by ↓ muscle tone. No specific formulation or dosage is established as superior. Adverse effects (sedation, nausea, abdominal pain, & diarrhea) are more common w/oral rather than topical supplementation. Typical doses are nortriptyline (25-150 mg) or trazadone (50-300 mg) every evening. Constipation, a common side effect, can be managed w/fluids, fiber, stool softeners, & laxatives. For those w/diarrhea-predominant irritable bowel syndrome, the constipating effect may be therapeutic. Physiotherapeutic program for children w/hypotonia &/or delayed motor development Non-weight-bearing muscular exercise (e.g., swimming) to promote muscular development & coordination cEDS = classic Ehlers-Danlos syndrome; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Classic Ehlers-Danlos Syndrome: Recommended Surveillance Children: frequency of follow up per pediatric cardiologist Adults: no follow-up echocardiogram necessary aPTT = activated partial thromboplastin time; PT = prothrombin time Sports with heavy joint strain should be avoided (contact sports, fighting sports, football, running). 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 of the pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. See Because of the increased risk for skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended. Ascorbic acid (vitamin C) may reduce easy bruising. In general, 2 g per day is recommended for adults; however, no strict guidelines exist regarding recommended dose during the third trimester of pregnancy. Physiotherapist referral should be made to address pelvic instability and pain. Monitoring for intrauterine growth restriction and cervical insufficiency through cervical length screening can be valuable. Monitoring of pregnant women for preterm labor is warranted during the third trimester, when the risk for preterm premature rupture of the membranes is increased. For vaginal delivery, prompt episiotomy should be considered to prevent excessive perineal damage. Prophylactic desmopressin and tranexamic acid, along with postpartum oxytocin, should be considered in view of the increased risk for postpartum hemorrhage. Search • Assessment for easy bruising &/or prolonged bleeding • Eval of clotting factors (platelet count, aPTT, PT, thrombin time) if severe easy bruising is present • Dermal wounds should be closed w/o tension, preferably in 2 layers. • Deep stitches should be applied generously. • Cutaneous stitches should be left in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. • Very young children w/pronounced skin fragility can wear protective pads or bandages over the forehead, knees, & shins to avoid skin tears. • Older children who are active can wear soccer pads or ski stockings w/shin padding during activities. • Braces are useful to improve joint stability. • Orthopedist, rheumatologist, or physical therapist referral for knee or ankle braces as needed • Occupational therapist referral for ring splints (to stabilize interphalangeal joints) & wrist or wrist & thumb braces for small joint instability • A soft neck collar, if tolerated, may help w/neck pain & headaches. • Wheelchair or scooter as needed to decrease stress on lower-extremity joints • Wheelchair customizations (e.g., lightweight, motorized, seat pads, specialized wheels, wheel grasps) as needed to accommodate pelvic & upper-extremity issues • A waterbed, adjustable air mattress, or viscoelastic foam mattress (&/or pillow) may increase support for improved sleep quality & less pain. • Those w/hypotonia, joint instability, & chronic pain may need to adapt lifestyle accordingly. • Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement. • Acetaminophen: 4,000 mg daily in 3-4 divided doses • NSAIDs, as tolerated by upper GI symptoms, for arthralgia, myalgia, & secondary inflammatory conditions (e.g., bursitis, tendinitis, costochondritis, postdislocation pain) • COX-2 inhibitors have similar efficacy to NSAIDS but may be better tolerated. • Topical lidocaine (cream or patch) may be useful for localized pain. • Topical capsaicin is of questionable utility but is safe. • Tramadol w/acetaminophen & NSAID or COX-2 inhibitor before resorting to other opioids (Nausea is the most common side effect.) • Opioids for myofascial pain & neuropathic pain; should be reserved after failing the above medications. Administer w/other analgesics to minimize total opioid requirements. Typically used chronically (or at least several months), the primary formulation should be long acting (e.g., sustained-release oxycodone or morphine or topical fentanyl patch) w/short-acting forms of the same drug as needed for breakthrough pain. Routine use of ≥2 daily doses of a short-acting form should prompt an increase in the long-acting dose or another adjustment to the pain regimen. • Bruising is not a contraindication to NSAID therapy, but occasionally requires dose reduction or change to a COX-2 inhibitor. • Those w/muscle hypotonia & joint instability w/chronic pain may have to adjust lifestyle & professional choices accordingly. • Emotional support & behavioral & psychological therapy may help in developing acceptance & coping skills. • Long-term chronic pain may result in the need for mental health services. • All require gradual titration before reaching therapeutic levels. • Gabapentin should be titrated as tolerated to at least 1,200 mg 3x per day before declaring failure, but dose is often limited by sedation &/or GI side effects. • Pregabalin, titrated to at least 300 mg divided 2-3x/day, tends to be better tolerated than gabapentin. • Limited by sedation; metaxalone may be least sedating • Muscle relaxants may ↑ joint instability by ↓ muscle tone. • No specific formulation or dosage is established as superior. • Adverse effects (sedation, nausea, abdominal pain, & diarrhea) are more common w/oral rather than topical supplementation. • Typical doses are nortriptyline (25-150 mg) or trazadone (50-300 mg) every evening. • Constipation, a common side effect, can be managed w/fluids, fiber, stool softeners, & laxatives. • For those w/diarrhea-predominant irritable bowel syndrome, the constipating effect may be therapeutic. • Physiotherapeutic program for children w/hypotonia &/or delayed motor development • Non-weight-bearing muscular exercise (e.g., swimming) to promote muscular development & coordination • Children: frequency of follow up per pediatric cardiologist • Adults: no follow-up echocardiogram necessary ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with cEDS, the evaluations summarized in Classic Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis Assessment for easy bruising &/or prolonged bleeding Eval of clotting factors (platelet count, aPTT, PT, thrombin time) if severe easy bruising is present cEDS = classic Ehlers-Danlos syndrome; MOI = mode of inheritance; aPTT = activated partial thromboplastin time; PT = prothrombin time Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assessment for easy bruising &/or prolonged bleeding • Eval of clotting factors (platelet count, aPTT, PT, thrombin time) if severe easy bruising is present ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Classic Ehlers-Danlos Syndrome: Treatment of Manifestations Dermal wounds should be closed w/o tension, preferably in 2 layers. Deep stitches should be applied generously. Cutaneous stitches should be left in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. Very young children w/pronounced skin fragility can wear protective pads or bandages over the forehead, knees, & shins to avoid skin tears. Older children who are active can wear soccer pads or ski stockings w/shin padding during activities. Braces are useful to improve joint stability. Orthopedist, rheumatologist, or physical therapist referral for knee or ankle braces as needed Occupational therapist referral for ring splints (to stabilize interphalangeal joints) & wrist or wrist & thumb braces for small joint instability A soft neck collar, if tolerated, may help w/neck pain & headaches. Wheelchair or scooter as needed to decrease stress on lower-extremity joints Wheelchair customizations (e.g., lightweight, motorized, seat pads, specialized wheels, wheel grasps) as needed to accommodate pelvic & upper-extremity issues A waterbed, adjustable air mattress, or viscoelastic foam mattress (&/or pillow) may increase support for improved sleep quality & less pain. Those w/hypotonia, joint instability, & chronic pain may need to adapt lifestyle accordingly. Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement. Acetaminophen: 4,000 mg daily in 3-4 divided doses NSAIDs, as tolerated by upper GI symptoms, for arthralgia, myalgia, & secondary inflammatory conditions (e.g., bursitis, tendinitis, costochondritis, postdislocation pain) COX-2 inhibitors have similar efficacy to NSAIDS but may be better tolerated. Topical lidocaine (cream or patch) may be useful for localized pain. Topical capsaicin is of questionable utility but is safe. Tramadol w/acetaminophen & NSAID or COX-2 inhibitor before resorting to other opioids (Nausea is the most common side effect.) Opioids for myofascial pain & neuropathic pain; should be reserved after failing the above medications. Administer w/other analgesics to minimize total opioid requirements. Typically used chronically (or at least several months), the primary formulation should be long acting (e.g., sustained-release oxycodone or morphine or topical fentanyl patch) w/short-acting forms of the same drug as needed for breakthrough pain. Routine use of ≥2 daily doses of a short-acting form should prompt an increase in the long-acting dose or another adjustment to the pain regimen. Bruising is not a contraindication to NSAID therapy, but occasionally requires dose reduction or change to a COX-2 inhibitor. Those w/muscle hypotonia & joint instability w/chronic pain may have to adjust lifestyle & professional choices accordingly. Emotional support & behavioral & psychological therapy may help in developing acceptance & coping skills. Long-term chronic pain may result in the need for mental health services. All require gradual titration before reaching therapeutic levels. Gabapentin should be titrated as tolerated to at least 1,200 mg 3x per day before declaring failure, but dose is often limited by sedation &/or GI side effects. Pregabalin, titrated to at least 300 mg divided 2-3x/day, tends to be better tolerated than gabapentin. Limited by sedation; metaxalone may be least sedating Muscle relaxants may ↑ joint instability by ↓ muscle tone. No specific formulation or dosage is established as superior. Adverse effects (sedation, nausea, abdominal pain, & diarrhea) are more common w/oral rather than topical supplementation. Typical doses are nortriptyline (25-150 mg) or trazadone (50-300 mg) every evening. Constipation, a common side effect, can be managed w/fluids, fiber, stool softeners, & laxatives. For those w/diarrhea-predominant irritable bowel syndrome, the constipating effect may be therapeutic. Physiotherapeutic program for children w/hypotonia &/or delayed motor development Non-weight-bearing muscular exercise (e.g., swimming) to promote muscular development & coordination cEDS = classic Ehlers-Danlos syndrome; GI = gastrointestinal; NSAIDs = nonsteroidal anti-inflammatory drugs • Dermal wounds should be closed w/o tension, preferably in 2 layers. • Deep stitches should be applied generously. • Cutaneous stitches should be left in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. • Very young children w/pronounced skin fragility can wear protective pads or bandages over the forehead, knees, & shins to avoid skin tears. • Older children who are active can wear soccer pads or ski stockings w/shin padding during activities. • Braces are useful to improve joint stability. • Orthopedist, rheumatologist, or physical therapist referral for knee or ankle braces as needed • Occupational therapist referral for ring splints (to stabilize interphalangeal joints) & wrist or wrist & thumb braces for small joint instability • A soft neck collar, if tolerated, may help w/neck pain & headaches. • Wheelchair or scooter as needed to decrease stress on lower-extremity joints • Wheelchair customizations (e.g., lightweight, motorized, seat pads, specialized wheels, wheel grasps) as needed to accommodate pelvic & upper-extremity issues • A waterbed, adjustable air mattress, or viscoelastic foam mattress (&/or pillow) may increase support for improved sleep quality & less pain. • Those w/hypotonia, joint instability, & chronic pain may need to adapt lifestyle accordingly. • Note: Surgical stabilization of joints may lead to disappointing, or only temporary, improvement. • Acetaminophen: 4,000 mg daily in 3-4 divided doses • NSAIDs, as tolerated by upper GI symptoms, for arthralgia, myalgia, & secondary inflammatory conditions (e.g., bursitis, tendinitis, costochondritis, postdislocation pain) • COX-2 inhibitors have similar efficacy to NSAIDS but may be better tolerated. • Topical lidocaine (cream or patch) may be useful for localized pain. • Topical capsaicin is of questionable utility but is safe. • Tramadol w/acetaminophen & NSAID or COX-2 inhibitor before resorting to other opioids (Nausea is the most common side effect.) • Opioids for myofascial pain & neuropathic pain; should be reserved after failing the above medications. Administer w/other analgesics to minimize total opioid requirements. Typically used chronically (or at least several months), the primary formulation should be long acting (e.g., sustained-release oxycodone or morphine or topical fentanyl patch) w/short-acting forms of the same drug as needed for breakthrough pain. Routine use of ≥2 daily doses of a short-acting form should prompt an increase in the long-acting dose or another adjustment to the pain regimen. • Bruising is not a contraindication to NSAID therapy, but occasionally requires dose reduction or change to a COX-2 inhibitor. • Those w/muscle hypotonia & joint instability w/chronic pain may have to adjust lifestyle & professional choices accordingly. • Emotional support & behavioral & psychological therapy may help in developing acceptance & coping skills. • Long-term chronic pain may result in the need for mental health services. • All require gradual titration before reaching therapeutic levels. • Gabapentin should be titrated as tolerated to at least 1,200 mg 3x per day before declaring failure, but dose is often limited by sedation &/or GI side effects. • Pregabalin, titrated to at least 300 mg divided 2-3x/day, tends to be better tolerated than gabapentin. • Limited by sedation; metaxalone may be least sedating • Muscle relaxants may ↑ joint instability by ↓ muscle tone. • No specific formulation or dosage is established as superior. • Adverse effects (sedation, nausea, abdominal pain, & diarrhea) are more common w/oral rather than topical supplementation. • Typical doses are nortriptyline (25-150 mg) or trazadone (50-300 mg) every evening. • Constipation, a common side effect, can be managed w/fluids, fiber, stool softeners, & laxatives. • For those w/diarrhea-predominant irritable bowel syndrome, the constipating effect may be therapeutic. • Physiotherapeutic program for children w/hypotonia &/or delayed motor development • Non-weight-bearing muscular exercise (e.g., swimming) to promote muscular development & coordination ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Classic Ehlers-Danlos Syndrome: Recommended Surveillance Children: frequency of follow up per pediatric cardiologist Adults: no follow-up echocardiogram necessary aPTT = activated partial thromboplastin time; PT = prothrombin time • Children: frequency of follow up per pediatric cardiologist • Adults: no follow-up echocardiogram necessary ## Agents/Circumstances to Avoid Sports with heavy joint strain should be avoided (contact sports, fighting sports, football, running). ## 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 of the pathogenic variant in the family in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. See ## Pregnancy Management Because of the increased risk for skin lacerations, postpartum hemorrhages, and prolapse of the uterus and/or bladder, monitoring of women throughout pregnancy and in the postpartum period is recommended. Ascorbic acid (vitamin C) may reduce easy bruising. In general, 2 g per day is recommended for adults; however, no strict guidelines exist regarding recommended dose during the third trimester of pregnancy. Physiotherapist referral should be made to address pelvic instability and pain. Monitoring for intrauterine growth restriction and cervical insufficiency through cervical length screening can be valuable. Monitoring of pregnant women for preterm labor is warranted during the third trimester, when the risk for preterm premature rupture of the membranes is increased. For vaginal delivery, prompt episiotomy should be considered to prevent excessive perineal damage. Prophylactic desmopressin and tranexamic acid, along with postpartum oxytocin, should be considered in view of the increased risk for postpartum hemorrhage. ## Therapies Under Investigation Search ## Genetic Counseling Classic Ehlers-Danlos syndrome (cEDS) is inherited in an autosomal dominant manner. Approximately 50% of individuals diagnosed with cEDS have an affected parent. A proband with cEDS 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 both parents of the proband include: Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents 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 [ The family history of some individuals diagnosed with cEDS may appear to be negative because of failure to recognize the disorder in family members with very mild phenotypes. 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 known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed; the severity, specific manifestations, and progression of the disorder are variable and cannot be predicted in a sib who inherits a pathogenic variant. If the cEDS-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 slightly greater than that of the general population because of the possibility of parental germline mosaicism. Paternal mosaicism for a If the parents appear to be 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 a very mild phenotype in an undiagnosed heterozygous parent and 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 cEDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, the severity, specific manifestations, and progression of cEDS are variable and cannot be predicted based on family history or the presence of a pathogenic variant identified on prenatal 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 50% of individuals diagnosed with cEDS have an affected parent. • A proband with cEDS 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 both parents of the proband include: • Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); • Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents and inform recurrence risk assessment. • Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); • Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents 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 [ • 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 cEDS may appear to be negative because of failure to recognize the disorder in family members with very mild phenotypes. 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). • Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); • Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents and inform recurrence risk assessment. • 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 known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed; the severity, specific manifestations, and progression of the disorder are variable and cannot be predicted in a sib who inherits a pathogenic variant. • If the cEDS-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 slightly greater than that of the general population because of the possibility of parental germline mosaicism. Paternal mosaicism for a • If the parents appear to be 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 a very mild phenotype in an undiagnosed heterozygous parent and 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 Classic Ehlers-Danlos syndrome (cEDS) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 50% of individuals diagnosed with cEDS have an affected parent. A proband with cEDS 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 both parents of the proband include: Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents 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 [ The family history of some individuals diagnosed with cEDS may appear to be negative because of failure to recognize the disorder in family members with very mild phenotypes. 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 known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed; the severity, specific manifestations, and progression of the disorder are variable and cannot be predicted in a sib who inherits a pathogenic variant. If the cEDS-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 slightly greater than that of the general population because of the possibility of parental germline mosaicism. Paternal mosaicism for a If the parents appear to be 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 a very mild phenotype in an undiagnosed heterozygous parent and of parental germline mosaicism. • Approximately 50% of individuals diagnosed with cEDS have an affected parent. • A proband with cEDS 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 both parents of the proband include: • Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); • Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents and inform recurrence risk assessment. • Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); • Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents 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 [ • 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 cEDS may appear to be negative because of failure to recognize the disorder in family members with very mild phenotypes. 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). • Evaluation for manifestations of cEDS (i.e., physical examination of the skin with special attention to delayed wound healing, easy bruising, joint hypermobility or recurrent dislocations, and chronic articular pain); • Molecular genetic testing for the cEDS-related pathogenic variant identified in the proband to evaluate the genetic status of the parents and inform recurrence risk assessment. • 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 known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Intrafamilial phenotypic variability is observed; the severity, specific manifestations, and progression of the disorder are variable and cannot be predicted in a sib who inherits a pathogenic variant. • If the cEDS-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 slightly greater than that of the general population because of the possibility of parental germline mosaicism. Paternal mosaicism for a • If the parents appear to be 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 a very mild phenotype in an undiagnosed heterozygous parent and 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 cEDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. However, the severity, specific manifestations, and progression of cEDS are variable and cannot be predicted based on family history or the presence of a pathogenic variant identified on prenatal 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 • • United Kingdom • • United Kingdom • • • • • • • ## Molecular Genetics Classic Ehlers-Danlos Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Classic Ehlers-Danlos Syndrome ( Classic Ehlers-Danlos Syndrome: Gene-Specific Mechanism of Disease Causation Haploinsufficiency: diminished type V collagen caused by nonsense or frameshift variants may alter normal collagen fibrillogenesis [ Dominant-negative activity: the abnormal type V collagen interferes w/protein derived from the normal allele. Genes from Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. Genes from • Haploinsufficiency: diminished type V collagen caused by nonsense or frameshift variants may alter normal collagen fibrillogenesis [ • Dominant-negative activity: the abnormal type V collagen interferes w/protein derived from the normal allele. ## Molecular Pathogenesis Classic Ehlers-Danlos Syndrome: Gene-Specific Mechanism of Disease Causation Haploinsufficiency: diminished type V collagen caused by nonsense or frameshift variants may alter normal collagen fibrillogenesis [ Dominant-negative activity: the abnormal type V collagen interferes w/protein derived from the normal allele. Genes from Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. Genes from • Haploinsufficiency: diminished type V collagen caused by nonsense or frameshift variants may alter normal collagen fibrillogenesis [ • Dominant-negative activity: the abnormal type V collagen interferes w/protein derived from the normal allele. ## Chapter Notes The At the Malfait Lab, PI Prof Fransiska Malfait, MD, PhD, and Postdoctoral Fellow Delfien Syx, PhD, lead studies in the following areas of interest: Unraveling the molecular basis of hereditary CTD, with a special focus on EDS and other hypermobility-related disorders, and studying their natural history and genotype-phenotype correlations; Elucidating molecular and physiologic mechanisms underlying hereditary CTD pathogenesis, using an integrated approach of in vitro and in vivo techniques, on tissue samples of humans and animal models (zebra fish, mice); Studying prevalence, nature, and pathophysiologic mechanisms of pain in individuals with EDS and in relevant animal models. Fransiska Malfait ( Prof Malfait is also interested in hearing from clinicians treating families affected by EDS 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 Sofie Symoens ( This work is supported by the Research Foundation Flanders (12Q5920N to D.S.; 1842318N & 3G041519 to F.M.), Ghent University (GOA019-21 to F.M.), Association française des syndromes d'Ehlers-Danlos (AFSED), The Ehlers-Danlos Society, Zebrapad VZW. The authors wish to thank the International Consortium on the Ehlers-Danlos Syndromes for their contribution. Anne De Paepe, MD, PhD; Ghent University Hospital (2003-2024)Fransiska Malfait, MD, PhD (2003-present)Sofie Symoens, PhDDelfien Syx, PhDRichard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (2003-2024) 1 February 2024 (sw) Comprehensive update posted live 26 July 2018 (ha) Comprehensive update posted live 18 August 2011 (me) Comprehensive update posted live 24 July 2008 (me) Comprehensive update posted live 10 April 2006 (me) Comprehensive update posted live 29 October 2003 (ca) Review posted live 20 June 2003 (rw, ad) Original submission • Unraveling the molecular basis of hereditary CTD, with a special focus on EDS and other hypermobility-related disorders, and studying their natural history and genotype-phenotype correlations; • Elucidating molecular and physiologic mechanisms underlying hereditary CTD pathogenesis, using an integrated approach of in vitro and in vivo techniques, on tissue samples of humans and animal models (zebra fish, mice); • Studying prevalence, nature, and pathophysiologic mechanisms of pain in individuals with EDS and in relevant animal models. • 1 February 2024 (sw) Comprehensive update posted live • 26 July 2018 (ha) Comprehensive update posted live • 18 August 2011 (me) Comprehensive update posted live • 24 July 2008 (me) Comprehensive update posted live • 10 April 2006 (me) Comprehensive update posted live • 29 October 2003 (ca) Review posted live • 20 June 2003 (rw, ad) Original submission ## Author Notes The At the Malfait Lab, PI Prof Fransiska Malfait, MD, PhD, and Postdoctoral Fellow Delfien Syx, PhD, lead studies in the following areas of interest: Unraveling the molecular basis of hereditary CTD, with a special focus on EDS and other hypermobility-related disorders, and studying their natural history and genotype-phenotype correlations; Elucidating molecular and physiologic mechanisms underlying hereditary CTD pathogenesis, using an integrated approach of in vitro and in vivo techniques, on tissue samples of humans and animal models (zebra fish, mice); Studying prevalence, nature, and pathophysiologic mechanisms of pain in individuals with EDS and in relevant animal models. Fransiska Malfait ( Prof Malfait is also interested in hearing from clinicians treating families affected by EDS 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 Sofie Symoens ( • Unraveling the molecular basis of hereditary CTD, with a special focus on EDS and other hypermobility-related disorders, and studying their natural history and genotype-phenotype correlations; • Elucidating molecular and physiologic mechanisms underlying hereditary CTD pathogenesis, using an integrated approach of in vitro and in vivo techniques, on tissue samples of humans and animal models (zebra fish, mice); • Studying prevalence, nature, and pathophysiologic mechanisms of pain in individuals with EDS and in relevant animal models. ## Acknowledgments This work is supported by the Research Foundation Flanders (12Q5920N to D.S.; 1842318N & 3G041519 to F.M.), Ghent University (GOA019-21 to F.M.), Association française des syndromes d'Ehlers-Danlos (AFSED), The Ehlers-Danlos Society, Zebrapad VZW. The authors wish to thank the International Consortium on the Ehlers-Danlos Syndromes for their contribution. ## Author History Anne De Paepe, MD, PhD; Ghent University Hospital (2003-2024)Fransiska Malfait, MD, PhD (2003-present)Sofie Symoens, PhDDelfien Syx, PhDRichard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (2003-2024) ## Revision History 1 February 2024 (sw) Comprehensive update posted live 26 July 2018 (ha) Comprehensive update posted live 18 August 2011 (me) Comprehensive update posted live 24 July 2008 (me) Comprehensive update posted live 10 April 2006 (me) Comprehensive update posted live 29 October 2003 (ca) Review posted live 20 June 2003 (rw, ad) Original submission • 1 February 2024 (sw) Comprehensive update posted live • 26 July 2018 (ha) Comprehensive update posted live • 18 August 2011 (me) Comprehensive update posted live • 24 July 2008 (me) Comprehensive update posted live • 10 April 2006 (me) Comprehensive update posted live • 29 October 2003 (ca) Review posted live • 20 June 2003 (rw, ad) Original submission ## References Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175:27-39. [ Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26. [ • Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175:27-39. [ • Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26. [ ## Published Guidelines / Consensus Statements Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175:27-39. [ Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26. [ • Bowen JM, Sobey GJ, Burrows NP, Colombi M, Lavallee ME, Malfait F, Francomano CA. Ehlers-Danlos syndrome, classical type. Am J Med Genet C Semin Med Genet. 2017;175:27-39. [ • Malfait F, Francomano C, Byers P, Belmont J, Berglund B, Black J, Bloom L, Bowen JM, Brady AF, Burrows NP, Castori M, Cohen H, Colombi M, Demirdas S, De Backer J, De Paepe A, Fournel-Gigleux S, Frank M, Ghali N, Giunta C, Grahame R, Hakim A, Jeunemaitre X, Johnson D, Juul-Kristensen B, Kapferer-Seebacher I, Kazkaz H, Kosho T, Lavallee ME, Levy H, Mendoza-Londono R, Pepin M, Pope FM, Reinstein E, Robert L, Rohrbach M, Sanders L, Sobey GJ, Van Damme T, Vandersteen A, van Mourik C, Voermans N, Wheeldon N, Zschocke J, Tinkle B. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175:8-26. [ ## Literature Cited Skin hyperextensibility Widened atrophic scars Flexion of the thumb to forearm, illustrating joint hypermobility
[]
29/5/2007
1/2/2024
11/5/2010
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eds3
eds3
[ "Ehlers-Danlos Syndrome Hypermobility Type", "Ehlers-Danlos Syndrome Type III", "hEDS", "hEDS", "Ehlers-Danlos Syndrome Hypermobility Type", "Ehlers-Danlos Syndrome Type III", "Hypermobile Ehlers-Danlos Syndrome" ]
Hypermobile Ehlers-Danlos Syndrome
Alan Hakim
Summary Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, functional bowel disorders, cardiovascular autonomic dysfunction, swallow and phonation disorders, sleep disorders including apnea, migraine, entrapment and peripheral neuropathies, inflammation from mast cell activation disorders, anxiety disorders, and urogynecologic disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications. The diagnosis of hEDS is established in an adult proband based on 2017 international clinical diagnostic criteria. Currently, no underlying genetic, epigenetic, or metabolomic etiology has been identified for hEDS. Hypermobile EDS is inherited in an autosomal dominant manner with variable expression of signs and variable severity of symptoms among affected family members. Most individuals diagnosed with hEDS have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin manifestations despite the absence of serious complications. Each child of an individual with hEDS has a 50% chance of inheriting hEDS. Because the gene(s) and pathogenic variant(s) responsible for hEDS have not been identified, prenatal and preimplantation genetic testing are not possible.
## Diagnosis The diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS) were revised by the International Consortium on Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders in 2017 [ Hypermobile EDS should be suspected in adult probands (individuals who have reached biologic maturity) with the following clinical features [ Joint instability including subluxations and dislocations Musculoskeletal pain Soft, hyperextensible skin, with atypical stretchmarks and/or scarring Dental crowding and a high or narrow-arched palate Abdominal hernias Pelvic organ prolapse A marfanoid body habitus Mitral valve prolapse and/or aortic root dilatation Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. In addition, hEDS is associated with clinical manifestations that are not included in the published diagnostic criteria including [ Chronic fatigue Easy bruising Functional bowel disorders (gastroesophageal reflux, gastritis, early satiety, delayed gastric emptying, irritable bowel syndrome, constipation) Additional cardiovascular manifestations (autonomic dysfunction, Raynaud phenomenon, acrocyanosis) Reduced efficacy of local anesthetics Laryngeal and breathing disorders including apnea Neurologic complications (migraine, Chiari I malformation, cerebrospinal fluid leaks, craniocervical instability and associated cord and nerve root pathology, tethered cord, entrapment and peripheral neuropathy, small fiber neuropathy) Mast cell activation disorders and immune deficiency including primary immune deficiency Anxiety disorders Autism and attention-deficit/hyperactivity disorder Urogynecologic manifestations (dysmenorrhea, menorrhagia, interstitial cystitis, urinary incontinence, pelvic organ prolapse) The diagnosis of hEDS can be established in an adult proband based on clinical diagnostic criteria [ No underlying genetic etiology has been identified for hEDS, and thus molecular genetic testing cannot be used to establish the diagnosis. The clinical diagnosis of hEDS can be established in an adult proband (an individual who has reached biologic maturity) with all three of the following criteria: Generalized joint hypermobility with a Beighton score of: ≥5 for adolescents who have reached biologic majority and adults age ≤50 years ≥4 for those age >50 years Evidence of two of the following: systemic manifestations of a more generalized connective tissue disorder, family history, and musculoskeletal complications Exclusion of alternative diagnoses In individuals with acquired limitation of joint mobility, generalized joint hypermobility may be confirmed in an individual whose Beighton score is one point below the age-specific cutoff if there are two or more positive answers to the five-point questionnaire (5PQ) [ Can you now (or could you ever) place your hands flat on the floor without bending your knees? Can you now (or could you ever) bend your thumb to touch your forearm? As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? Do you consider yourself "double-jointed"? Note: In clinical practice, individuals with a history of joint hypermobility – suggested by a positive 5PQ (≥2 positive answers) – but scoring two or more points below the age-specific Beighton cutoff should be assessed further outside of the Beighton score (e.g., shoulders, hips, ankles, toes) for evidence of generalized joint hypermobility. In some individuals, joint hypermobility may be local or regional, and these individuals should be evaluated for hypermobility spectrum disorder [ Musculoskeletal pain in two or more limbs, recurring daily for at least three months Chronic widespread pain for at least three months Recurrent joint dislocations or frank joint instability, in the absence of trauma: Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times OR Medical confirmation of joint instability at two or more sites not related to trauma All the following must be met: Absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia, which should prompt consideration of other types of EDS (See Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses associated with joint hypermobility due to hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders, and skeletal dysplasias (See Other rheumatologic disorders may be the cause of musculoskeletal pain and inflammation (e.g., osteoarthritis, systemic lupus erythematosus, and rheumatoid arthritis); these disorders may coexist with hEDS. In individuals with a rheumatologic disorder, the diagnosis of hEDS requires that sufficient features in Criterion 2, Feature C are due to hEDS and not the co-occurring rheumatologic disorder. The etiology of hEDS is unknown; genetic heterogeneity is likely. There are currently no molecular genetic tests available to establish the diagnosis of hEDS. • Joint instability including subluxations and dislocations • Musculoskeletal pain • Soft, hyperextensible skin, with atypical stretchmarks and/or scarring • Dental crowding and a high or narrow-arched palate • Abdominal hernias • Pelvic organ prolapse • A marfanoid body habitus • Mitral valve prolapse and/or aortic root dilatation • Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. • Chronic fatigue • Easy bruising • Functional bowel disorders (gastroesophageal reflux, gastritis, early satiety, delayed gastric emptying, irritable bowel syndrome, constipation) • Additional cardiovascular manifestations (autonomic dysfunction, Raynaud phenomenon, acrocyanosis) • Reduced efficacy of local anesthetics • Laryngeal and breathing disorders including apnea • Neurologic complications (migraine, Chiari I malformation, cerebrospinal fluid leaks, craniocervical instability and associated cord and nerve root pathology, tethered cord, entrapment and peripheral neuropathy, small fiber neuropathy) • Mast cell activation disorders and immune deficiency including primary immune deficiency • Anxiety disorders • Autism and attention-deficit/hyperactivity disorder • Urogynecologic manifestations (dysmenorrhea, menorrhagia, interstitial cystitis, urinary incontinence, pelvic organ prolapse) • Generalized joint hypermobility with a Beighton score of: • ≥5 for adolescents who have reached biologic majority and adults age ≤50 years • ≥4 for those age >50 years • ≥5 for adolescents who have reached biologic majority and adults age ≤50 years • ≥4 for those age >50 years • Evidence of two of the following: systemic manifestations of a more generalized connective tissue disorder, family history, and musculoskeletal complications • Exclusion of alternative diagnoses • ≥5 for adolescents who have reached biologic majority and adults age ≤50 years • ≥4 for those age >50 years • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • • Musculoskeletal pain in two or more limbs, recurring daily for at least three months • Chronic widespread pain for at least three months • Recurrent joint dislocations or frank joint instability, in the absence of trauma: • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia, which should prompt consideration of other types of EDS (See • Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses associated with joint hypermobility due to hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders, and skeletal dysplasias (See • Other rheumatologic disorders may be the cause of musculoskeletal pain and inflammation (e.g., osteoarthritis, systemic lupus erythematosus, and rheumatoid arthritis); these disorders may coexist with hEDS. In individuals with a rheumatologic disorder, the diagnosis of hEDS requires that sufficient features in Criterion 2, Feature C are due to hEDS and not the co-occurring rheumatologic disorder. ## Suggestive Findings Hypermobile EDS should be suspected in adult probands (individuals who have reached biologic maturity) with the following clinical features [ Joint instability including subluxations and dislocations Musculoskeletal pain Soft, hyperextensible skin, with atypical stretchmarks and/or scarring Dental crowding and a high or narrow-arched palate Abdominal hernias Pelvic organ prolapse A marfanoid body habitus Mitral valve prolapse and/or aortic root dilatation Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. In addition, hEDS is associated with clinical manifestations that are not included in the published diagnostic criteria including [ Chronic fatigue Easy bruising Functional bowel disorders (gastroesophageal reflux, gastritis, early satiety, delayed gastric emptying, irritable bowel syndrome, constipation) Additional cardiovascular manifestations (autonomic dysfunction, Raynaud phenomenon, acrocyanosis) Reduced efficacy of local anesthetics Laryngeal and breathing disorders including apnea Neurologic complications (migraine, Chiari I malformation, cerebrospinal fluid leaks, craniocervical instability and associated cord and nerve root pathology, tethered cord, entrapment and peripheral neuropathy, small fiber neuropathy) Mast cell activation disorders and immune deficiency including primary immune deficiency Anxiety disorders Autism and attention-deficit/hyperactivity disorder Urogynecologic manifestations (dysmenorrhea, menorrhagia, interstitial cystitis, urinary incontinence, pelvic organ prolapse) • Joint instability including subluxations and dislocations • Musculoskeletal pain • Soft, hyperextensible skin, with atypical stretchmarks and/or scarring • Dental crowding and a high or narrow-arched palate • Abdominal hernias • Pelvic organ prolapse • A marfanoid body habitus • Mitral valve prolapse and/or aortic root dilatation • Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis. • Chronic fatigue • Easy bruising • Functional bowel disorders (gastroesophageal reflux, gastritis, early satiety, delayed gastric emptying, irritable bowel syndrome, constipation) • Additional cardiovascular manifestations (autonomic dysfunction, Raynaud phenomenon, acrocyanosis) • Reduced efficacy of local anesthetics • Laryngeal and breathing disorders including apnea • Neurologic complications (migraine, Chiari I malformation, cerebrospinal fluid leaks, craniocervical instability and associated cord and nerve root pathology, tethered cord, entrapment and peripheral neuropathy, small fiber neuropathy) • Mast cell activation disorders and immune deficiency including primary immune deficiency • Anxiety disorders • Autism and attention-deficit/hyperactivity disorder • Urogynecologic manifestations (dysmenorrhea, menorrhagia, interstitial cystitis, urinary incontinence, pelvic organ prolapse) ## Establishing the Diagnosis The diagnosis of hEDS can be established in an adult proband based on clinical diagnostic criteria [ No underlying genetic etiology has been identified for hEDS, and thus molecular genetic testing cannot be used to establish the diagnosis. The clinical diagnosis of hEDS can be established in an adult proband (an individual who has reached biologic maturity) with all three of the following criteria: Generalized joint hypermobility with a Beighton score of: ≥5 for adolescents who have reached biologic majority and adults age ≤50 years ≥4 for those age >50 years Evidence of two of the following: systemic manifestations of a more generalized connective tissue disorder, family history, and musculoskeletal complications Exclusion of alternative diagnoses In individuals with acquired limitation of joint mobility, generalized joint hypermobility may be confirmed in an individual whose Beighton score is one point below the age-specific cutoff if there are two or more positive answers to the five-point questionnaire (5PQ) [ Can you now (or could you ever) place your hands flat on the floor without bending your knees? Can you now (or could you ever) bend your thumb to touch your forearm? As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? Do you consider yourself "double-jointed"? Note: In clinical practice, individuals with a history of joint hypermobility – suggested by a positive 5PQ (≥2 positive answers) – but scoring two or more points below the age-specific Beighton cutoff should be assessed further outside of the Beighton score (e.g., shoulders, hips, ankles, toes) for evidence of generalized joint hypermobility. In some individuals, joint hypermobility may be local or regional, and these individuals should be evaluated for hypermobility spectrum disorder [ Musculoskeletal pain in two or more limbs, recurring daily for at least three months Chronic widespread pain for at least three months Recurrent joint dislocations or frank joint instability, in the absence of trauma: Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times OR Medical confirmation of joint instability at two or more sites not related to trauma All the following must be met: Absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia, which should prompt consideration of other types of EDS (See Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses associated with joint hypermobility due to hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders, and skeletal dysplasias (See Other rheumatologic disorders may be the cause of musculoskeletal pain and inflammation (e.g., osteoarthritis, systemic lupus erythematosus, and rheumatoid arthritis); these disorders may coexist with hEDS. In individuals with a rheumatologic disorder, the diagnosis of hEDS requires that sufficient features in Criterion 2, Feature C are due to hEDS and not the co-occurring rheumatologic disorder. The etiology of hEDS is unknown; genetic heterogeneity is likely. There are currently no molecular genetic tests available to establish the diagnosis of hEDS. • Generalized joint hypermobility with a Beighton score of: • ≥5 for adolescents who have reached biologic majority and adults age ≤50 years • ≥4 for those age >50 years • ≥5 for adolescents who have reached biologic majority and adults age ≤50 years • ≥4 for those age >50 years • Evidence of two of the following: systemic manifestations of a more generalized connective tissue disorder, family history, and musculoskeletal complications • Exclusion of alternative diagnoses • ≥5 for adolescents who have reached biologic majority and adults age ≤50 years • ≥4 for those age >50 years • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? • • Musculoskeletal pain in two or more limbs, recurring daily for at least three months • Chronic widespread pain for at least three months • Recurrent joint dislocations or frank joint instability, in the absence of trauma: • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia, which should prompt consideration of other types of EDS (See • Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses associated with joint hypermobility due to hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders, and skeletal dysplasias (See • Other rheumatologic disorders may be the cause of musculoskeletal pain and inflammation (e.g., osteoarthritis, systemic lupus erythematosus, and rheumatoid arthritis); these disorders may coexist with hEDS. In individuals with a rheumatologic disorder, the diagnosis of hEDS requires that sufficient features in Criterion 2, Feature C are due to hEDS and not the co-occurring rheumatologic disorder. ## Criterion 1 In individuals with acquired limitation of joint mobility, generalized joint hypermobility may be confirmed in an individual whose Beighton score is one point below the age-specific cutoff if there are two or more positive answers to the five-point questionnaire (5PQ) [ Can you now (or could you ever) place your hands flat on the floor without bending your knees? Can you now (or could you ever) bend your thumb to touch your forearm? As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? Do you consider yourself "double-jointed"? Note: In clinical practice, individuals with a history of joint hypermobility – suggested by a positive 5PQ (≥2 positive answers) – but scoring two or more points below the age-specific Beighton cutoff should be assessed further outside of the Beighton score (e.g., shoulders, hips, ankles, toes) for evidence of generalized joint hypermobility. In some individuals, joint hypermobility may be local or regional, and these individuals should be evaluated for hypermobility spectrum disorder [ • Can you now (or could you ever) place your hands flat on the floor without bending your knees? • Can you now (or could you ever) bend your thumb to touch your forearm? • As a child, did you amuse your friends by contorting your body into strange shapes or could you do the splits? • As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion? • Do you consider yourself "double-jointed"? ## Criterion 2 Musculoskeletal pain in two or more limbs, recurring daily for at least three months Chronic widespread pain for at least three months Recurrent joint dislocations or frank joint instability, in the absence of trauma: Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times OR Medical confirmation of joint instability at two or more sites not related to trauma • • Musculoskeletal pain in two or more limbs, recurring daily for at least three months • Chronic widespread pain for at least three months • Recurrent joint dislocations or frank joint instability, in the absence of trauma: • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma • Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times • OR • Medical confirmation of joint instability at two or more sites not related to trauma ## Criterion 3 All the following must be met: Absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia, which should prompt consideration of other types of EDS (See Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses associated with joint hypermobility due to hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders, and skeletal dysplasias (See Other rheumatologic disorders may be the cause of musculoskeletal pain and inflammation (e.g., osteoarthritis, systemic lupus erythematosus, and rheumatoid arthritis); these disorders may coexist with hEDS. In individuals with a rheumatologic disorder, the diagnosis of hEDS requires that sufficient features in Criterion 2, Feature C are due to hEDS and not the co-occurring rheumatologic disorder. • Absence of unusual skin, ocular, periodontal, vascular, or visceral organ tissue fragility or skeletal dysplasia, which should prompt consideration of other types of EDS (See • Exclusion (based on history, physical exam, and/or molecular genetic testing) of alternative diagnoses associated with joint hypermobility due to hypotonia and/or connective tissue laxity such as neuromuscular disorders, other heritable connective tissue disorders, and skeletal dysplasias (See • Other rheumatologic disorders may be the cause of musculoskeletal pain and inflammation (e.g., osteoarthritis, systemic lupus erythematosus, and rheumatoid arthritis); these disorders may coexist with hEDS. In individuals with a rheumatologic disorder, the diagnosis of hEDS requires that sufficient features in Criterion 2, Feature C are due to hEDS and not the co-occurring rheumatologic disorder. ## Molecular Genetic Testing The etiology of hEDS is unknown; genetic heterogeneity is likely. There are currently no molecular genetic tests available to establish the diagnosis of hEDS. ## Clinical Characteristics Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, swallow and phonation disorders, functional bowel disorders, cardiovascular autonomic dysfunction, migraine, entrapment and peripheral neuropathies and dystonia, urogynecologic disorders, anxiety disorders, and inflammation from mast cell activation disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications. Psychiatric manifestations in individuals with hEDS include depression, anxiety disorders, affective disorder, low self-confidence, negative thinking, hopelessness, and desperation. Fatigue and pain exacerbate the psychological dysfunction, and psychological distress exacerbates pain [ Several studies have reviewed the evidence for medical issues reported in childbearing women with hEDS, including those related to preconception (e.g., musculoskeletal health and medication use), antenatal (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum (e.g., birth choices, mobility in labor, anesthesia), and postpartum (e.g., wound healing, pelvic health, newborn/infant care adjustments) health [ The 1997 Villefranche criteria [ The terms "benign familial articular hypermobility syndrome" and "joint hypermobility syndrome" are no longer used [ The 2017 criteria were constructed with adults in mind. Many of these features arise over time and may not be present in childhood and adolescence. In addition, many of the clinical manifestations are common in younger individuals. A framework for the diagnosis in younger people was developed by A study of health care records in the Welsh population found an hEDS prevalence of approximately 1:3,100 [ ## Clinical Description Hypermobile Ehlers-Danlos syndrome (hEDS) is characterized by generalized joint hypermobility, joint instability, pain, soft and hyperextensible skin with atrophic scars and easy bruising, dental crowding, abdominal hernias, pelvic organ prolapse, marfanoid body habitus, mitral valve prolapse, and aortic root dilatation. Subluxations, dislocations, and soft tissue injury are common; they may occur spontaneously or with minimal trauma and can be acutely painful. Degenerative joint and chronic soft tissue disorders may arise due to repeated injury. Chronic pain, distinct from that associated with acute injury, is common and often neuropathic in nature. Chronic fatigue, swallow and phonation disorders, functional bowel disorders, cardiovascular autonomic dysfunction, migraine, entrapment and peripheral neuropathies and dystonia, urogynecologic disorders, anxiety disorders, and inflammation from mast cell activation disorders are common. Mitral valve prolapse and aortic root dilatation, when present, are typically of a mild degree with no increased risk of cardiac complications. Psychiatric manifestations in individuals with hEDS include depression, anxiety disorders, affective disorder, low self-confidence, negative thinking, hopelessness, and desperation. Fatigue and pain exacerbate the psychological dysfunction, and psychological distress exacerbates pain [ Several studies have reviewed the evidence for medical issues reported in childbearing women with hEDS, including those related to preconception (e.g., musculoskeletal health and medication use), antenatal (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum (e.g., birth choices, mobility in labor, anesthesia), and postpartum (e.g., wound healing, pelvic health, newborn/infant care adjustments) health [ ## Nomenclature The 1997 Villefranche criteria [ The terms "benign familial articular hypermobility syndrome" and "joint hypermobility syndrome" are no longer used [ The 2017 criteria were constructed with adults in mind. Many of these features arise over time and may not be present in childhood and adolescence. In addition, many of the clinical manifestations are common in younger individuals. A framework for the diagnosis in younger people was developed by ## Prevalence A study of health care records in the Welsh population found an hEDS prevalence of approximately 1:3,100 [ ## Differential Diagnosis EDS Types in the Differential Diagnosis of Hypermobile Ehlers-Danlos Syndrome Classic EDS is assoc w/skin & soft tissue fragility. Mild cEDS presentations – i.e., similar degrees of joint laxity, pain, pelvic prolapse, dyspareunia, & manifestations in the hematologic, gastrointestinal, cardiovascular, & ocular systems – may be mistaken for hEDS. The diagnosis may be revised from hEDS to cEDS if there is later development of more significant skin & soft tissue manifestations in the individual or a family member. Among persons w/all of the skin features of cEDS, incl dystrophic scarring, ~90% have an identifiable pathogenic variant in Joint laxity is predominantly in small joints in vEDS; generalized laxity is common in hEDS. Vascular EDS usually manifests as thin, translucent skin, fragility of skin & soft tissue, & atrophic scarring. Predisposition to spontaneous rupture of arteries &/or hollow organs or family history of unexplained sudden death is a hallmark of vEDS. Nonspecific venous & hematologic abnormalities incl varicose veins, hemorrhoids, easy bruising, & bleeding diathesis are not suggestive of vEDS. Kyphoscoliotic EDS is distinguished by more severe skin manifestations & other features (e.g., hypotonia, early-onset kyphoscoliosis, & ocular abnormality). Scoliosis in kEDS is usually more severe & of earlier onset than in other EDS types. Heterozygous AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; hEDS = hypermobile Ehlers-Danlos syndrome; MOI = mode of inheritance Ordered based on prevalence The proportion of cEDS attributed to pathogenic variants in Pathogenic variants in Described after the publication of the 2017 International Classification of EDS [ Described after the publication of the 2017 International Classification of EDS [ Most of the disorders in Disorders with Joint Laxity in the Differential Diagnosis of Hypermobile Ehlers-Danlos Syndrome Skeletal, ocular, cardiovascular, pulmonary, & skin/integument manifestations beyond those seen in hEDS. Joint hypermobility is common in the MASS phenotype (myopia, mitral valve prolapse, mild aortic root dilatation, striae, & minor skeletal manifestations of Marfan syndrome). Persons w/hEDS can have a marfanoid body habitus & resemble persons w/Marfan syndrome or a Marfan-related disorder. The most significant distinguishing feature is shawl scrotum, which may become less obvious in adulthood. Widow's peak, short upturned nose, & other dysmorphic features can be additional diagnostic clues. ID, which is not assoc w/any of the types of EDS, is sometimes present. Features incl vascular findings (cerebral, thoracic, & abdominal arterial aneurysms &/or dissections) & skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). The LDS presentation often mimics Marfan syndrome or vEDS, but prior to detection of the arterial abnormalities, persons may be misdiagnosed w/cEDS or hEDS. AD = autosomal dominant; AR = autosomal recessive; cEDS = classic Ehlers-Danlos syndrome; EDS = Ehlers-Danlos syndrome; hEDS = hypermobile Ehlers-Danlos syndrome; ID = intellectual disability; MOI = mode of inheritance; vEDS = vascular Ehlers-Danlos syndrome Stickler syndrome caused by pathogenic variants in M Many other • Classic EDS is assoc w/skin & soft tissue fragility. • Mild cEDS presentations – i.e., similar degrees of joint laxity, pain, pelvic prolapse, dyspareunia, & manifestations in the hematologic, gastrointestinal, cardiovascular, & ocular systems – may be mistaken for hEDS. The diagnosis may be revised from hEDS to cEDS if there is later development of more significant skin & soft tissue manifestations in the individual or a family member. • Among persons w/all of the skin features of cEDS, incl dystrophic scarring, ~90% have an identifiable pathogenic variant in • Joint laxity is predominantly in small joints in vEDS; generalized laxity is common in hEDS. • Vascular EDS usually manifests as thin, translucent skin, fragility of skin & soft tissue, & atrophic scarring. • Predisposition to spontaneous rupture of arteries &/or hollow organs or family history of unexplained sudden death is a hallmark of vEDS. • Nonspecific venous & hematologic abnormalities incl varicose veins, hemorrhoids, easy bruising, & bleeding diathesis are not suggestive of vEDS. • Kyphoscoliotic EDS is distinguished by more severe skin manifestations & other features (e.g., hypotonia, early-onset kyphoscoliosis, & ocular abnormality). • Scoliosis in kEDS is usually more severe & of earlier onset than in other EDS types. • Heterozygous • Skeletal, ocular, cardiovascular, pulmonary, & skin/integument manifestations beyond those seen in hEDS. Joint hypermobility is common in the MASS phenotype (myopia, mitral valve prolapse, mild aortic root dilatation, striae, & minor skeletal manifestations of Marfan syndrome). • Persons w/hEDS can have a marfanoid body habitus & resemble persons w/Marfan syndrome or a Marfan-related disorder. • The most significant distinguishing feature is shawl scrotum, which may become less obvious in adulthood. Widow's peak, short upturned nose, & other dysmorphic features can be additional diagnostic clues. • ID, which is not assoc w/any of the types of EDS, is sometimes present. • Features incl vascular findings (cerebral, thoracic, & abdominal arterial aneurysms &/or dissections) & skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus). • The LDS presentation often mimics Marfan syndrome or vEDS, but prior to detection of the arterial abnormalities, persons may be misdiagnosed w/cEDS or hEDS. • M • Many other ## Management Treatment recommendations for hypermobile Ehlers-Danlos syndrome (hEDS) have been published [ To establish the extent of disease and needs in an individual diagnosed with hEDS, the evaluations summarized in Hypermobile Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis Assess for joint manifestations, pain, & disability. Assess prior mechanical, pharmacologic, &/or surgical treatment of joint instability & pain. Imaging as needed for joint & tissue damage; may incl radiographs, CT, &/or MRI Flexion/extension/rotation studies to assess for craniocervical instability as needed Assess nature of pain & possible causes of pain & fatigue incl musculoskeletal, neuropathic, visceral, & mast cell activation disorder. Consider laboratory assessment for causes of fatigue: clotting disorders, assessment for autoimmune disorders (e.g., rheumatologic, endocrine, & gastrointestinal), micronutrient deficiencies, & mast cell activation disorders. Transit studies for those with slow gut transit (e.g., radiopaque marker method for upper & lower tract) Doppler ultrasound for vascular compression syndromes Assess for phonation & breathing difficulties, incl asthma-like symptoms & apnea. Thoracic cage, musculoskeletal, & diaphragmatic concerns may also be a cause of shortness of breath. Assess for sleep issues. ADHD = attention-deficit/hyperactivity disorder; hEDS = hypermobile Ehlers-Danlos syndrome; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Some individuals will have undergone orthopedic and orthognathic procedures prior to diagnosis. Anecdotally, a lack of awareness of the joint hypermobility and tissue fragility may lead to poorer surgical outcomes, but datasets of outcomes are lacking. Some will require surgical procedures if conservative therapies for hEDS fail or there are significant pathologies present (e.g., impingement disorders, dysplasias, and cord/nerve entrapment with neurologic deficit) [ Prolotherapy, in which saline and/or other irritants are injected in tendons or around joints to induce scar formation and increase stability, has been objectively shown to be safe and effective in one study [ Other vascular concerns, including significant aortic root dilatation and abdominal and pelvic vascular compression syndromes, require referral to a cardiovascular specialist. Rapid aortic root growth, an indication for intervention, is defined as ≥0.5 cm in one year. For TMJ dysfunction, intraoral devices/retainers may be helpful. Oral rest, local myofascial release, and muscle relaxant medications may be beneficial for acute flares. Surgical intervention may be required. Issues with swallow and phonation should be assessed by an otolaryngologist. A pulmonology, otolaryngology, or sleep specialist assessment is recommended for apnea. There are no specific surveillance guidelines for hEDS. Specific concerns should be followed up based on clinical need and standard protocols. See Hypermobile Ehlers-Danlos Syndrome: Recommended Surveillance Follow-up echocardiogram 1 yr after initial echocardiogram & if no change, follow-up echocardiogram in 5 yrs In those w/progressive aortic dilatation: continue annual echocardiography; if progressive dilatation stops, then echocardiogram every 3 yrs Assess for phonation & respiratory issues. Assess for sleep issues. ADHD = attention-deficit/hyperactivity disorder; DXA = dual-energy x-ray absorptiometry Since the risk of progression of aortic root dilatation has not yet been defined by longitudinal studies, surveillance should follow the American College of Cardiology / American Heart Association (ACC/AHA) guidelines for EDS [ High-impact activity may increase the risk for acute subluxation/dislocation and acute and chronic pain. Some sports, such as tackle football, may not be suitable but should be discussed on an individual basis. Most sports and activities are acceptable with appropriate precautions. Chiropractic adjustment and yoga are not contraindicated but must be performed in ways that avoid subluxations or dislocations. Joint hyperextension may not need to be avoided. In a randomized controlled trial of physical therapy among 26 children and adolescents with joint hypermobility and knee pain, those allowed to exercise into hyperextension had similar improvement in pain score and better improvement in psychosocial score compared to those restricted to neutral joint position [ Autonomic concerns, gastrointestinal disorders, and intolerances, for example, may preclude use of medications or their excipients (e.g., common analgesics in someone with slow gastrointestinal transit, vasodilator in a person with orthostatic intolerance). Topical agents and adhesives should be used cautiously in those with skin fragility and/or allergy. See Management of women with hEDS should include preconception assessment (e.g., musculoskeletal health and medication use), antenatal evaluation (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum planning (e.g., birth choices, mobility in labor, anesthesia), and postpartum care (e.g., wound healing, pelvic health, newborn/infant care). Musculoskeletal complications of hEDS including pain and joint instability may arise for the first time or worsen during pregnancy. In women with hEDS there is a higher incidence of preeclampsia, eclampsia, preterm rupture of membranes, preterm birth, antepartum hemorrhage, postpartum hemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder, precipitous labor, and delivery prior to arrival at planned place of birth [ Pregnant women with known aortic root dilatation should have an echocardiogram in each trimester. Echocardiography is not needed if the aortic root is normal prior to pregnancy. Search • Assess for joint manifestations, pain, & disability. • Assess prior mechanical, pharmacologic, &/or surgical treatment of joint instability & pain. • Imaging as needed for joint & tissue damage; may incl radiographs, CT, &/or MRI • Flexion/extension/rotation studies to assess for craniocervical instability as needed • Assess nature of pain & possible causes of pain & fatigue incl musculoskeletal, neuropathic, visceral, & mast cell activation disorder. • Consider laboratory assessment for causes of fatigue: clotting disorders, assessment for autoimmune disorders (e.g., rheumatologic, endocrine, & gastrointestinal), micronutrient deficiencies, & mast cell activation disorders. • Transit studies for those with slow gut transit (e.g., radiopaque marker method for upper & lower tract) • Doppler ultrasound for vascular compression syndromes • Assess for phonation & breathing difficulties, incl asthma-like symptoms & apnea. Thoracic cage, musculoskeletal, & diaphragmatic concerns may also be a cause of shortness of breath. • Assess for sleep issues. • Follow-up echocardiogram 1 yr after initial echocardiogram & if no change, follow-up echocardiogram in 5 yrs • In those w/progressive aortic dilatation: continue annual echocardiography; if progressive dilatation stops, then echocardiogram every 3 yrs • Assess for phonation & respiratory issues. • Assess for sleep issues. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hEDS, the evaluations summarized in Hypermobile Ehlers-Danlos Syndrome: Recommended Evaluations Following Initial Diagnosis Assess for joint manifestations, pain, & disability. Assess prior mechanical, pharmacologic, &/or surgical treatment of joint instability & pain. Imaging as needed for joint & tissue damage; may incl radiographs, CT, &/or MRI Flexion/extension/rotation studies to assess for craniocervical instability as needed Assess nature of pain & possible causes of pain & fatigue incl musculoskeletal, neuropathic, visceral, & mast cell activation disorder. Consider laboratory assessment for causes of fatigue: clotting disorders, assessment for autoimmune disorders (e.g., rheumatologic, endocrine, & gastrointestinal), micronutrient deficiencies, & mast cell activation disorders. Transit studies for those with slow gut transit (e.g., radiopaque marker method for upper & lower tract) Doppler ultrasound for vascular compression syndromes Assess for phonation & breathing difficulties, incl asthma-like symptoms & apnea. Thoracic cage, musculoskeletal, & diaphragmatic concerns may also be a cause of shortness of breath. Assess for sleep issues. ADHD = attention-deficit/hyperactivity disorder; hEDS = hypermobile Ehlers-Danlos syndrome; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Assess for joint manifestations, pain, & disability. • Assess prior mechanical, pharmacologic, &/or surgical treatment of joint instability & pain. • Imaging as needed for joint & tissue damage; may incl radiographs, CT, &/or MRI • Flexion/extension/rotation studies to assess for craniocervical instability as needed • Assess nature of pain & possible causes of pain & fatigue incl musculoskeletal, neuropathic, visceral, & mast cell activation disorder. • Consider laboratory assessment for causes of fatigue: clotting disorders, assessment for autoimmune disorders (e.g., rheumatologic, endocrine, & gastrointestinal), micronutrient deficiencies, & mast cell activation disorders. • Transit studies for those with slow gut transit (e.g., radiopaque marker method for upper & lower tract) • Doppler ultrasound for vascular compression syndromes • Assess for phonation & breathing difficulties, incl asthma-like symptoms & apnea. Thoracic cage, musculoskeletal, & diaphragmatic concerns may also be a cause of shortness of breath. • Assess for sleep issues. ## Treatment of Manifestations Some individuals will have undergone orthopedic and orthognathic procedures prior to diagnosis. Anecdotally, a lack of awareness of the joint hypermobility and tissue fragility may lead to poorer surgical outcomes, but datasets of outcomes are lacking. Some will require surgical procedures if conservative therapies for hEDS fail or there are significant pathologies present (e.g., impingement disorders, dysplasias, and cord/nerve entrapment with neurologic deficit) [ Prolotherapy, in which saline and/or other irritants are injected in tendons or around joints to induce scar formation and increase stability, has been objectively shown to be safe and effective in one study [ Other vascular concerns, including significant aortic root dilatation and abdominal and pelvic vascular compression syndromes, require referral to a cardiovascular specialist. Rapid aortic root growth, an indication for intervention, is defined as ≥0.5 cm in one year. For TMJ dysfunction, intraoral devices/retainers may be helpful. Oral rest, local myofascial release, and muscle relaxant medications may be beneficial for acute flares. Surgical intervention may be required. Issues with swallow and phonation should be assessed by an otolaryngologist. A pulmonology, otolaryngology, or sleep specialist assessment is recommended for apnea. ## Surveillance There are no specific surveillance guidelines for hEDS. Specific concerns should be followed up based on clinical need and standard protocols. See Hypermobile Ehlers-Danlos Syndrome: Recommended Surveillance Follow-up echocardiogram 1 yr after initial echocardiogram & if no change, follow-up echocardiogram in 5 yrs In those w/progressive aortic dilatation: continue annual echocardiography; if progressive dilatation stops, then echocardiogram every 3 yrs Assess for phonation & respiratory issues. Assess for sleep issues. ADHD = attention-deficit/hyperactivity disorder; DXA = dual-energy x-ray absorptiometry Since the risk of progression of aortic root dilatation has not yet been defined by longitudinal studies, surveillance should follow the American College of Cardiology / American Heart Association (ACC/AHA) guidelines for EDS [ • Follow-up echocardiogram 1 yr after initial echocardiogram & if no change, follow-up echocardiogram in 5 yrs • In those w/progressive aortic dilatation: continue annual echocardiography; if progressive dilatation stops, then echocardiogram every 3 yrs • Assess for phonation & respiratory issues. • Assess for sleep issues. ## Agents/Circumstances to Avoid High-impact activity may increase the risk for acute subluxation/dislocation and acute and chronic pain. Some sports, such as tackle football, may not be suitable but should be discussed on an individual basis. Most sports and activities are acceptable with appropriate precautions. Chiropractic adjustment and yoga are not contraindicated but must be performed in ways that avoid subluxations or dislocations. Joint hyperextension may not need to be avoided. In a randomized controlled trial of physical therapy among 26 children and adolescents with joint hypermobility and knee pain, those allowed to exercise into hyperextension had similar improvement in pain score and better improvement in psychosocial score compared to those restricted to neutral joint position [ Autonomic concerns, gastrointestinal disorders, and intolerances, for example, may preclude use of medications or their excipients (e.g., common analgesics in someone with slow gastrointestinal transit, vasodilator in a person with orthostatic intolerance). Topical agents and adhesives should be used cautiously in those with skin fragility and/or allergy. ## Evaluation of Relatives at Risk See ## Pregnancy Management Management of women with hEDS should include preconception assessment (e.g., musculoskeletal health and medication use), antenatal evaluation (e.g., joint instability, pelvic strength, hernias, and pain management), intrapartum planning (e.g., birth choices, mobility in labor, anesthesia), and postpartum care (e.g., wound healing, pelvic health, newborn/infant care). Musculoskeletal complications of hEDS including pain and joint instability may arise for the first time or worsen during pregnancy. In women with hEDS there is a higher incidence of preeclampsia, eclampsia, preterm rupture of membranes, preterm birth, antepartum hemorrhage, postpartum hemorrhage, hyperemesis gravidarum, shoulder dystocia, caesarean wound infection, postpartum psychosis, post-traumatic stress disorder, precipitous labor, and delivery prior to arrival at planned place of birth [ Pregnant women with known aortic root dilatation should have an echocardiogram in each trimester. Echocardiography is not needed if the aortic root is normal prior to pregnancy. ## Therapies Under Investigation Search ## Genetic Counseling Hypermobile Ehlers-Danlos syndrome (hEDS) is inherited in an autosomal dominant manner with variable expression of signs and variable severity of symptoms among affected family members. Most individuals diagnosed with hEDS are likely to have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin concerns despite the absence of serious complications. A proband with hEDS may be the only family member known to be affected. If a parent of the proband is affected, the risk to the sibs is 50%. If both parents are clinically unaffected, the risk to the sibs is likely to be low. Each child of an individual with hEDS has a 50% chance of inheriting hEDS. Because of marked clinical variability, it is difficult to predict severity among affected offspring. Because the gene(s) and pathogenic variant(s) responsible for hEDS have not been identified, prenatal and preimplantation genetic testing are not possible at this time. • Most individuals diagnosed with hEDS are likely to have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin concerns despite the absence of serious complications. • A proband with hEDS may be the only family member known to be affected. • If a parent of the proband is affected, the risk to the sibs is 50%. • If both parents are clinically unaffected, the risk to the sibs is likely to be low. • Each child of an individual with hEDS has a 50% chance of inheriting hEDS. • Because of marked clinical variability, it is difficult to predict severity among affected offspring. ## Mode of Inheritance Hypermobile Ehlers-Danlos syndrome (hEDS) is inherited in an autosomal dominant manner with variable expression of signs and variable severity of symptoms among affected family members. ## Risk to Family Members Most individuals diagnosed with hEDS are likely to have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin concerns despite the absence of serious complications. A proband with hEDS may be the only family member known to be affected. If a parent of the proband is affected, the risk to the sibs is 50%. If both parents are clinically unaffected, the risk to the sibs is likely to be low. Each child of an individual with hEDS has a 50% chance of inheriting hEDS. Because of marked clinical variability, it is difficult to predict severity among affected offspring. • Most individuals diagnosed with hEDS are likely to have an affected parent, although a detailed history and examination of the parents is often necessary to recognize that a parent has a current or prior history of joint laxity, easy bruising, and skin concerns despite the absence of serious complications. • A proband with hEDS may be the only family member known to be affected. • If a parent of the proband is affected, the risk to the sibs is 50%. • If both parents are clinically unaffected, the risk to the sibs is likely to be low. • Each child of an individual with hEDS has a 50% chance of inheriting hEDS. • Because of marked clinical variability, it is difficult to predict severity among affected offspring. ## Related Genetic Counseling Issues ## Prenatal Testing and Preimplantation Genetic Testing Because the gene(s) and pathogenic variant(s) responsible for hEDS have not been identified, prenatal and preimplantation genetic testing are not possible at this time. ## Resources United Kingdom United Kingdom • • United Kingdom • • • • • • United Kingdom • ## Molecular Genetics OMIM Entries for Hypermobile Ehlers-Danlos Syndrome ( No pathogenic variants in any genes have as yet been associated with hypermobile Ehlers-Danlos syndrome (hEDS). ## Molecular Pathogenesis No pathogenic variants in any genes have as yet been associated with hypermobile Ehlers-Danlos syndrome (hEDS). ## Chapter Notes Assoc Prof Dr Alan Hakim is an adult certified consultant in Medicine and Rheumatology based in the United Kingdom. Having practiced for more than 30 years in medicine, he has 28 years of experience in rheumatology and translational medicine and 23 years of experience in hypermobility-related disorders. In hospital and community clinical commissioning and administration, he has worked at divisional, director, executive, and board levels. He has project-managed multiple large-scale programs of work across the health sector in the UK. Dr Hakim has published widely in clinical research and education, including more than 100 original scientific and review papers, six books, and multiple chapters and online pages and webinars. He has also held several roles as a Principal and Chief Investigator in pharmaceutical studies related to rheumatic disorders and been awarded numerous major grants in support of his research. He is a Fellow of The Royal College of Physicians, London, UK; an Adjunct Associate Professor in Medicine at The School of Medicine, Penn State, USA; Honorary Consultant at UCLH, London; Chief Medical Officer, Director of Education, Director of Research, and Lead for EDS ECHO at The Ehlers-Danlos Society; and a member of the Steering Committee and Chair of the hEDS/HSD Working Group of the International Consortium on the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders. I first wish to thank all my patients for their insights, in good times and in bad, that they have shared with me over many years regarding living with Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders. Second, I wish to thank Dr Howard Levy, previous author of this review, for nominating me as his successor. Third, I may not have entered the field had I not undertaken research with Prof Tim Spector and Prof Alex MacGregor, and met with Prof Rodney Grahame some 25 years ago. I am grateful to them for helping me establish and develop a subspecialty clinical expertise and a clinical academic career. That in mind, I must thank the Arthritis Research Campaign for funding my initial research fellowship, and all the grant-awarding bodies and donors that have supported me since. Finally, in more recent years I have had the privilege of working with several charitable organizations. In my role as the CMO, Director of Education, and Director of Research at The Ehlers-Danlos Society, I work with a truly dedicated staff and volunteers and with the most incredible array of community and professional colleagues internationally from whom and with whom I continue to learn every day. Alan Hakim, BA, MBBChir, MA (2024-present)Howard P Levy, MD, PhD; Johns Hopkins University School of Medicine (2004-2024) 22 February 2024 (sw) Comprehensive update posted live 31 March 2016 (ha) Comprehensive update posted live 13 September 2012 (me) Comprehensive update posted live 27 April 2010 (me) Comprehensive update posted live 1 May 2007 (me) Comprehensive update posted live 22 October 2004 (me) Review posted live 1 June 2004 (hpl) Original submission • 22 February 2024 (sw) Comprehensive update posted live • 31 March 2016 (ha) Comprehensive update posted live • 13 September 2012 (me) Comprehensive update posted live • 27 April 2010 (me) Comprehensive update posted live • 1 May 2007 (me) Comprehensive update posted live • 22 October 2004 (me) Review posted live • 1 June 2004 (hpl) Original submission ## Author Notes Assoc Prof Dr Alan Hakim is an adult certified consultant in Medicine and Rheumatology based in the United Kingdom. Having practiced for more than 30 years in medicine, he has 28 years of experience in rheumatology and translational medicine and 23 years of experience in hypermobility-related disorders. In hospital and community clinical commissioning and administration, he has worked at divisional, director, executive, and board levels. He has project-managed multiple large-scale programs of work across the health sector in the UK. Dr Hakim has published widely in clinical research and education, including more than 100 original scientific and review papers, six books, and multiple chapters and online pages and webinars. He has also held several roles as a Principal and Chief Investigator in pharmaceutical studies related to rheumatic disorders and been awarded numerous major grants in support of his research. He is a Fellow of The Royal College of Physicians, London, UK; an Adjunct Associate Professor in Medicine at The School of Medicine, Penn State, USA; Honorary Consultant at UCLH, London; Chief Medical Officer, Director of Education, Director of Research, and Lead for EDS ECHO at The Ehlers-Danlos Society; and a member of the Steering Committee and Chair of the hEDS/HSD Working Group of the International Consortium on the Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders. ## Acknowledgments I first wish to thank all my patients for their insights, in good times and in bad, that they have shared with me over many years regarding living with Ehlers-Danlos syndromes (EDS) and hypermobility spectrum disorders. Second, I wish to thank Dr Howard Levy, previous author of this review, for nominating me as his successor. Third, I may not have entered the field had I not undertaken research with Prof Tim Spector and Prof Alex MacGregor, and met with Prof Rodney Grahame some 25 years ago. I am grateful to them for helping me establish and develop a subspecialty clinical expertise and a clinical academic career. That in mind, I must thank the Arthritis Research Campaign for funding my initial research fellowship, and all the grant-awarding bodies and donors that have supported me since. Finally, in more recent years I have had the privilege of working with several charitable organizations. In my role as the CMO, Director of Education, and Director of Research at The Ehlers-Danlos Society, I work with a truly dedicated staff and volunteers and with the most incredible array of community and professional colleagues internationally from whom and with whom I continue to learn every day. ## Author History Alan Hakim, BA, MBBChir, MA (2024-present)Howard P Levy, MD, PhD; Johns Hopkins University School of Medicine (2004-2024) ## Revision History 22 February 2024 (sw) Comprehensive update posted live 31 March 2016 (ha) Comprehensive update posted live 13 September 2012 (me) Comprehensive update posted live 27 April 2010 (me) Comprehensive update posted live 1 May 2007 (me) Comprehensive update posted live 22 October 2004 (me) Review posted live 1 June 2004 (hpl) Original submission • 22 February 2024 (sw) Comprehensive update posted live • 31 March 2016 (ha) Comprehensive update posted live • 13 September 2012 (me) Comprehensive update posted live • 27 April 2010 (me) Comprehensive update posted live • 1 May 2007 (me) Comprehensive update posted live • 22 October 2004 (me) Review posted live • 1 June 2004 (hpl) Original submission ## References ## Literature Cited
[]
22/10/2004
22/2/2024
21/6/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eds4
eds4
[ "EDS Type IV", "Ehlers-Danlos Syndrome, Vascular Type", "vEDS", "Ehlers-Danlos Syndrome, Vascular Type", "EDS Type IV", "vEDS", "Collagen alpha-1(III) chain", "COL3A1", "Vascular Ehlers-Danlos Syndrome" ]
Vascular Ehlers-Danlos Syndrome
Peter H Byers
Summary Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication. The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in Vascular EDS is an autosomal dominant disorder. About 50% of individuals diagnosed with vEDS have an affected parent; about 50% of affected individuals have the disorder as the result of a
## Diagnosis No consensus clinical diagnostic criteria for vascular Ehlers-Danlos syndrome (vEDS) have been published. When the diagnosis is suspected on clinical grounds, molecular diagnostic testing of Vascular EDS Arterial aneurysms, dissection, or rupture Intestinal rupture, most often in the sigmoid colon Uterine rupture during pregnancy Family history of vEDS Pneumothorax/hemopneumothorax Easy bruising (spontaneous or with minimal trauma) Thin, translucent skin (especially noticeable on the chest/abdomen) Carotid-cavernous sinus fistula Talipes equinovarus (clubfoot) Facial appearance that includes thin vermilion of the lips, micrognathia, narrow nose, protuberant eyes Acrogeria (an aged appearance to the extremities, particularly the hands) Hypermobility of small joints Tendon/muscle rupture Early-onset varicose veins Chronic joint subluxations/dislocations Congenital dislocation of the hips The diagnosis of vEDS 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 vEDS, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype overlaps those of many other inherited connective tissue disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Vascular Ehlers-Danlos 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 PH Byers, personal observation Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The low frequency of genomic deletions is consistent with the failure to detect a deletion in 155 specimens submitted for Analysis of type III procollagen synthesized by cultured cells can identify abnormalities in synthesis and mobility of type III collagen chains. Alterations in mobility may result from substitutions for glycines in the triple helical domain because they lead to slow folding and increased post-translational modification, or as the result of deletions or duplication or splice site alterations. Use of cultured fibroblasts is used now almost exclusively to characterize the outcome of splice site alterations identified by DNA sequence analysis. • Arterial aneurysms, dissection, or rupture • Intestinal rupture, most often in the sigmoid colon • Uterine rupture during pregnancy • Family history of vEDS • Pneumothorax/hemopneumothorax • Easy bruising (spontaneous or with minimal trauma) • Thin, translucent skin (especially noticeable on the chest/abdomen) • Carotid-cavernous sinus fistula • Talipes equinovarus (clubfoot) • Facial appearance that includes thin vermilion of the lips, micrognathia, narrow nose, protuberant eyes • Acrogeria (an aged appearance to the extremities, particularly the hands) • Hypermobility of small joints • Tendon/muscle rupture • Early-onset varicose veins • Chronic joint subluxations/dislocations • Congenital dislocation of the hips • For an introduction to multigene panels click ## Suggestive Findings Vascular EDS Arterial aneurysms, dissection, or rupture Intestinal rupture, most often in the sigmoid colon Uterine rupture during pregnancy Family history of vEDS Pneumothorax/hemopneumothorax Easy bruising (spontaneous or with minimal trauma) Thin, translucent skin (especially noticeable on the chest/abdomen) Carotid-cavernous sinus fistula Talipes equinovarus (clubfoot) Facial appearance that includes thin vermilion of the lips, micrognathia, narrow nose, protuberant eyes Acrogeria (an aged appearance to the extremities, particularly the hands) Hypermobility of small joints Tendon/muscle rupture Early-onset varicose veins Chronic joint subluxations/dislocations Congenital dislocation of the hips • Arterial aneurysms, dissection, or rupture • Intestinal rupture, most often in the sigmoid colon • Uterine rupture during pregnancy • Family history of vEDS • Pneumothorax/hemopneumothorax • Easy bruising (spontaneous or with minimal trauma) • Thin, translucent skin (especially noticeable on the chest/abdomen) • Carotid-cavernous sinus fistula • Talipes equinovarus (clubfoot) • Facial appearance that includes thin vermilion of the lips, micrognathia, narrow nose, protuberant eyes • Acrogeria (an aged appearance to the extremities, particularly the hands) • Hypermobility of small joints • Tendon/muscle rupture • Early-onset varicose veins • Chronic joint subluxations/dislocations • Congenital dislocation of the hips ## Establishing the Diagnosis The diagnosis of vEDS 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 vEDS, molecular genetic testing approaches can include For an introduction to multigene panels click When the phenotype overlaps those of many other inherited connective tissue disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Vascular Ehlers-Danlos 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 PH Byers, personal observation Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The low frequency of genomic deletions is consistent with the failure to detect a deletion in 155 specimens submitted for Analysis of type III procollagen synthesized by cultured cells can identify abnormalities in synthesis and mobility of type III collagen chains. Alterations in mobility may result from substitutions for glycines in the triple helical domain because they lead to slow folding and increased post-translational modification, or as the result of deletions or duplication or splice site alterations. Use of cultured fibroblasts is used now almost exclusively to characterize the outcome of splice site alterations identified by DNA sequence analysis. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of vEDS, 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 overlaps those of many other inherited connective tissue disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Vascular Ehlers-Danlos 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 PH Byers, personal observation Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The low frequency of genomic deletions is consistent with the failure to detect a deletion in 155 specimens submitted for Analysis of type III procollagen synthesized by cultured cells can identify abnormalities in synthesis and mobility of type III collagen chains. Alterations in mobility may result from substitutions for glycines in the triple helical domain because they lead to slow folding and increased post-translational modification, or as the result of deletions or duplication or splice site alterations. Use of cultured fibroblasts is used now almost exclusively to characterize the outcome of splice site alterations identified by DNA sequence analysis. ## Clinical Characteristics The most comprehensive descriptions of clinical features and natural history derive from two types of studies of individuals with vascular Ehlers-Danlos syndrome (vEDS): a cross-sectional and retrospective view obtained at the time of diagnostic testing [ The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history [ Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing. Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – were most often present in those ascertained without a major complication. At birth, clubfoot (unilateral or bilateral) was noted in 8% of children with vEDS. Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). The clinical presentation depends on the location of the arterial event. Unexplained acute pain warrants immediate medical attention. Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. Venous varicosities also occur. Most GI perforations occur in the sigmoid colon. Ruptures of the small bowel and stomach have been reported, though infrequently. Iatrogenic perforation during colonoscopy has also been reported [ Bowel rupture is rarely lethal (3%) [ Surgical intervention for bowel rupture is often necessary and usually lifesaving, although treatment with antibiotics and fluid support has been used successfully [PH Byers, personal observation]. The successful surgical approach to perforation repair in vEDS includes partial colectomy, colostomy and creation of a Hartman pouch, and reversal after several months. Reports of primary repair are few. Complications during and following surgery are related to tissue and vessel friability, which result in recurrent arterial or bowel tears, fistulae, poor wound healing, and suture dehiscence. Individuals who survive a first complication may experience recurrent rupture. The timing and site of repeat rupture cannot be predicted by the first event. Recurrent perforation may lead to colonic resection. Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. Hemoptysis can be severe and recurrent, even life-threatening [ Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [ Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [ Carotid-cavernous sinus fistulas typically present with sudden onset of blurred vision, diplopia due to 6th nerve palsy, ocular pain, proptosis, and chemosis, and almost always requires rapid intervention to save vision. It affects as many as 10% of individuals with vEDS with a preponderance among females [ More than 600 unique Among the 1,200 individuals with vEDS described by In families identified on the basis of clinical complications, penetrance of the vEDS phenotype appears to be close to 100% in adults with a missense or exon-skipping alteration; the age at which the pathogenic variant becomes penetrant may vary. The following terms for vEDS have been used: "Status dysvascularis" was introduced by Georg Sack in 1936; the term was never used extensively. "Familial acrogeria," introduced by Heinrich Gottron in 1940, probably included some individuals with vEDS. "Sack-Barabas syndrome" or the "Sack-Barabas type of Ehlers-Danlos syndrome" was used after "Ehlers Danlos syndrome type IV" was introduced by Beighton in his 1979 review of classification following its inclusion as the fourth entry in his 1969 review. "Vascular Ehlers Danlos syndrome" was adopted with the 1998 revision of the EDS classification and in the 2017 extension and revision. There are no good estimates of the prevalence of vEDS in any population. More than 2,000 affected individuals in the United States have been identified on the basis of biochemical and genetic testing and analysis of family pedigrees [PH Byers, personal observation], leading to a minimum prevalence estimate of 1:150,000. The decreased frequency of certain classes of pathogenic variants suggests that the overall prevalence of individuals with pathogenic variants in Because many families with vEDS are identified only after a severe complication or death, it is likely that individuals/families with pathogenic variants in • Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing. • Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. • Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – were most often present in those ascertained without a major complication. • At birth, clubfoot (unilateral or bilateral) was noted in 8% of children with vEDS. • Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. • Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. • The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). • The clinical presentation depends on the location of the arterial event. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. • Venous varicosities also occur. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Most GI perforations occur in the sigmoid colon. • Ruptures of the small bowel and stomach have been reported, though infrequently. • Iatrogenic perforation during colonoscopy has also been reported [ • Bowel rupture is rarely lethal (3%) [ • Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. • Hemoptysis can be severe and recurrent, even life-threatening [ • Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [ • Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [ • "Status dysvascularis" was introduced by Georg Sack in 1936; the term was never used extensively. • "Familial acrogeria," introduced by Heinrich Gottron in 1940, probably included some individuals with vEDS. • "Sack-Barabas syndrome" or the "Sack-Barabas type of Ehlers-Danlos syndrome" was used after • "Ehlers Danlos syndrome type IV" was introduced by Beighton in his 1979 review of classification following its inclusion as the fourth entry in his 1969 review. • "Vascular Ehlers Danlos syndrome" was adopted with the 1998 revision of the EDS classification and in the 2017 extension and revision. ## Clinical Description The most comprehensive descriptions of clinical features and natural history derive from two types of studies of individuals with vascular Ehlers-Danlos syndrome (vEDS): a cross-sectional and retrospective view obtained at the time of diagnostic testing [ The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history [ Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing. Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – were most often present in those ascertained without a major complication. At birth, clubfoot (unilateral or bilateral) was noted in 8% of children with vEDS. Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). The clinical presentation depends on the location of the arterial event. Unexplained acute pain warrants immediate medical attention. Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. Venous varicosities also occur. Most GI perforations occur in the sigmoid colon. Ruptures of the small bowel and stomach have been reported, though infrequently. Iatrogenic perforation during colonoscopy has also been reported [ Bowel rupture is rarely lethal (3%) [ Surgical intervention for bowel rupture is often necessary and usually lifesaving, although treatment with antibiotics and fluid support has been used successfully [PH Byers, personal observation]. The successful surgical approach to perforation repair in vEDS includes partial colectomy, colostomy and creation of a Hartman pouch, and reversal after several months. Reports of primary repair are few. Complications during and following surgery are related to tissue and vessel friability, which result in recurrent arterial or bowel tears, fistulae, poor wound healing, and suture dehiscence. Individuals who survive a first complication may experience recurrent rupture. The timing and site of repeat rupture cannot be predicted by the first event. Recurrent perforation may lead to colonic resection. Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. Hemoptysis can be severe and recurrent, even life-threatening [ Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [ Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [ Carotid-cavernous sinus fistulas typically present with sudden onset of blurred vision, diplopia due to 6th nerve palsy, ocular pain, proptosis, and chemosis, and almost always requires rapid intervention to save vision. It affects as many as 10% of individuals with vEDS with a preponderance among females [ • Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing. • Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. • Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – were most often present in those ascertained without a major complication. • At birth, clubfoot (unilateral or bilateral) was noted in 8% of children with vEDS. • Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. • Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. • The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). • The clinical presentation depends on the location of the arterial event. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. • Venous varicosities also occur. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Most GI perforations occur in the sigmoid colon. • Ruptures of the small bowel and stomach have been reported, though infrequently. • Iatrogenic perforation during colonoscopy has also been reported [ • Bowel rupture is rarely lethal (3%) [ • Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. • Hemoptysis can be severe and recurrent, even life-threatening [ • Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [ • Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [ ## Children The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history [ Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing. Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – were most often present in those ascertained without a major complication. At birth, clubfoot (unilateral or bilateral) was noted in 8% of children with vEDS. Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Approximately 15% of these individuals had experienced a major complication of vEDS by the time of testing. • Of the 121 children tested in the absence of a positive family history, 65 presented with a major complication at an average age of 11 years. • Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – were most often present in those ascertained without a major complication. • At birth, clubfoot (unilateral or bilateral) was noted in 8% of children with vEDS. • Hip dislocation, limb deficiency, and amniotic bands appeared in approximately 1% of affected infants. • Death that occurred in the first two decades of life almost always resulted from spontaneous artery rupture or dissection. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. • Artery rupture, 60% of which involved the aorta, was responsible for all deaths in young males. • Death before age 20 years occurred in a 3:1 ratio of males to females. This difference was not noted in the French cohort study because ascertainment was restricted to adults. ## Adults Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). The clinical presentation depends on the location of the arterial event. Unexplained acute pain warrants immediate medical attention. Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. Venous varicosities also occur. Most GI perforations occur in the sigmoid colon. Ruptures of the small bowel and stomach have been reported, though infrequently. Iatrogenic perforation during colonoscopy has also been reported [ Bowel rupture is rarely lethal (3%) [ Surgical intervention for bowel rupture is often necessary and usually lifesaving, although treatment with antibiotics and fluid support has been used successfully [PH Byers, personal observation]. The successful surgical approach to perforation repair in vEDS includes partial colectomy, colostomy and creation of a Hartman pouch, and reversal after several months. Reports of primary repair are few. Complications during and following surgery are related to tissue and vessel friability, which result in recurrent arterial or bowel tears, fistulae, poor wound healing, and suture dehiscence. Individuals who survive a first complication may experience recurrent rupture. The timing and site of repeat rupture cannot be predicted by the first event. Recurrent perforation may lead to colonic resection. Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. Hemoptysis can be severe and recurrent, even life-threatening [ Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [ Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [ Carotid-cavernous sinus fistulas typically present with sudden onset of blurred vision, diplopia due to 6th nerve palsy, ocular pain, proptosis, and chemosis, and almost always requires rapid intervention to save vision. It affects as many as 10% of individuals with vEDS with a preponderance among females [ • Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, or may occur spontaneously. • The sites of arterial rupture are the thorax and abdomen (66%), head and neck (17%), and extremities (17%). • The clinical presentation depends on the location of the arterial event. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Ruptures of the chordae tendinae or ventricle of the heart are rare cardiovascular complications. • Venous varicosities also occur. • Unexplained acute pain warrants immediate medical attention. • Chest pain or symptoms of "heart attack" were described in 80% of the 26 individuals with vEDS later identified to have experienced a coronary artery dissection. • Most GI perforations occur in the sigmoid colon. • Ruptures of the small bowel and stomach have been reported, though infrequently. • Iatrogenic perforation during colonoscopy has also been reported [ • Bowel rupture is rarely lethal (3%) [ • Hemothorax and hemopneumothorax have been reported, often in association with pulmonary blebs, cystic lesions, and hemorrhagic or fibrous nodules. • Hemoptysis can be severe and recurrent, even life-threatening [ • Pathologic evaluation may demonstrate acute hematoma, fibrous nodules, vascular disruption, intraluminal and interstitial hemosiderosis, and emphysematous changes [ • Successful lung transplantation was reported in one individual with severe pulmonary complications of vEDS [ ## Genotype-Phenotype Correlations More than 600 unique Among the 1,200 individuals with vEDS described by ## Penetrance In families identified on the basis of clinical complications, penetrance of the vEDS phenotype appears to be close to 100% in adults with a missense or exon-skipping alteration; the age at which the pathogenic variant becomes penetrant may vary. ## Nomenclature The following terms for vEDS have been used: "Status dysvascularis" was introduced by Georg Sack in 1936; the term was never used extensively. "Familial acrogeria," introduced by Heinrich Gottron in 1940, probably included some individuals with vEDS. "Sack-Barabas syndrome" or the "Sack-Barabas type of Ehlers-Danlos syndrome" was used after "Ehlers Danlos syndrome type IV" was introduced by Beighton in his 1979 review of classification following its inclusion as the fourth entry in his 1969 review. "Vascular Ehlers Danlos syndrome" was adopted with the 1998 revision of the EDS classification and in the 2017 extension and revision. • "Status dysvascularis" was introduced by Georg Sack in 1936; the term was never used extensively. • "Familial acrogeria," introduced by Heinrich Gottron in 1940, probably included some individuals with vEDS. • "Sack-Barabas syndrome" or the "Sack-Barabas type of Ehlers-Danlos syndrome" was used after • "Ehlers Danlos syndrome type IV" was introduced by Beighton in his 1979 review of classification following its inclusion as the fourth entry in his 1969 review. • "Vascular Ehlers Danlos syndrome" was adopted with the 1998 revision of the EDS classification and in the 2017 extension and revision. ## Prevalence There are no good estimates of the prevalence of vEDS in any population. More than 2,000 affected individuals in the United States have been identified on the basis of biochemical and genetic testing and analysis of family pedigrees [PH Byers, personal observation], leading to a minimum prevalence estimate of 1:150,000. The decreased frequency of certain classes of pathogenic variants suggests that the overall prevalence of individuals with pathogenic variants in Because many families with vEDS are identified only after a severe complication or death, it is likely that individuals/families with pathogenic variants in ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Other forms of Ehlers-Danlos syndrome (EDS) should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies or molecular analysis of Disorders to Consider in the Differential Diagnosis of vEDS Generally late onset Bilateral renal cysts & cysts in other organs Abdominal wall hernias Kidney manifestations: hypertension, kidney pain, & kidney insufficiency Rare Features of classic EDS + early periodontal friability, recession, & tooth loss White matter alterations in brain Skin staining, particularly shins Arterial aneurysm & rupture have been reported in a few persons (although cEDS is typically not assoc w/blood vessel, bowel, or organ rupture). Pathogenic variants in Soft, doughy, stretchy skin Abnormal scars Significant large-joint hypermobility Progressive scoliosis Hypotonia Ocular fragility in minority of persons w/ Sensorineural deafness w/ Vascular findings (cerebral, thoracic, & abdominal arterial aneurysms &/or dissections) Aggressive arterial aneurysms & high incidence of pregnancy-related complications Thin, translucent skin & easy bruising Skeletal manifestations Craniofacial anomalies Predisposition to allergic disease AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance; vEDS = vascular Ehlers-Danlos syndrome Pathogenic variants in Loeys-Dietz syndrome (LDS) caused by a pathogenic variant in Familial forms of arterial aneurysm have been linked to multiple genes (see • Generally late onset • Bilateral renal cysts & cysts in other organs • Abdominal wall hernias • Kidney manifestations: hypertension, kidney pain, & kidney insufficiency • Rare • Features of classic EDS + early periodontal friability, recession, & tooth loss • White matter alterations in brain • Skin staining, particularly shins • Arterial aneurysm & rupture have been reported in a few persons (although cEDS is typically not assoc w/blood vessel, bowel, or organ rupture). • Pathogenic variants in • Soft, doughy, stretchy skin • Abnormal scars • Significant large-joint hypermobility • Progressive scoliosis • Hypotonia • Ocular fragility in minority of persons w/ • Sensorineural deafness w/ • Vascular findings (cerebral, thoracic, & abdominal arterial aneurysms &/or dissections) • Aggressive arterial aneurysms & high incidence of pregnancy-related complications • Thin, translucent skin & easy bruising • Skeletal manifestations • Craniofacial anomalies • Predisposition to allergic disease ## Management There has been a gradual transition in the approach to both surveillance and intervention prior to arterial events in individuals with vascular Ehlers-Danlos syndrome (vEDS). This shift appears to reflect increased recognition of the diagnosis of vEDS both at the time of an event and before, the creation of centers of excellence and experience for vEDS both in the United States and in other countries, and differences in surgical techniques and approaches with a move away from open intervention and increased use of endovascular approaches. Nonetheless, there is still no consensus regarding the appropriate extent of evaluation at the time of initial diagnosis. To establish the extent of disease and needs in an individual diagnosed with vEDS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) provide a baseline with which to evaluate progression. Because of the risk for asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [ Because no specific gastrointestinal (GI) findings are known to precede or predict bowel rupture, invasive GI evaluation is of no benefit. Consultation with a clinical geneticist and/or genetic counselor is recommended. Following diagnosis, the most crucial aspect of management is the creation of an organized care team (see Review of lifestyle with the affected individual and emphasis of the importance of minimizing collision activities and sports is recommended. The most crucial aspect of management is the creation of an organized care team that includes a primary care physician, vascular surgeon, and general surgeon, as well as cardiologist and pulmonologist depending on initial evaluation. A geneticist is often valuable for integration of care. This team is responsible for the organization of ordinary and extraordinary care. In addition, individuals with vEDS should carry documentation of their genetic diagnosis, such as a MedicAlert Affected individuals should be instructed to seek immediate medical attention for sudden, unexplained pain. Surgical intervention may be lifesaving in the face of bowel rupture, arterial rupture, or organ rupture (e.g., the uterus in pregnancy). When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [ In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vEDS and its associated tissue fragility [ There are no guidelines to direct recommendations for elective repair in individuals with aneurysm(s) and vEDS. A decision about the timing and approach of an elective vascular procedure or the use of endovascular approaches is typically based on an individualized risk-versus-benefit assessment. Reports of successful endovascular approaches are growing. A retrospective review of open versus endovascular repair of splenic artery aneurysm and dissection strongly favors the endovascular approach, with fewer complications and deaths [ Prompt surgical intervention of bowel rupture is usually essential to limit the extent of infection and facilitate early restoration of bowel continuity. Death from bowel rupture is uncommon because intervention is generally effective. Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery. The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial or total colectomy at the time of the initial event to reduce the risk of recurrent bowel rupture [ Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [ The use of surveillance of the arterial vasculature assumes that effective interventions will decrease the risk of arterial dissection or rupture and prolong life. At a time when an open surgical approach was the only option, the benefit of surveillance could not be established. As endovascular approaches to management of aneurysms and dissection become more available, earlier intervention is considered and surveillance may have greater benefit. There are, however, no published data assessing the efficacy of screening strategies in identifying the regions in the arterial vasculature at highest risk; conversely, there are examples in which regions of concern in the arterial vasculature failed to progress and arterial rupture occurred at other, more distant sites. Thus, the benefit of controlled studies cannot be overemphasized. If undertaken, noninvasive imaging such as ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast is preferred to identify aneurysms, dissections, and vascular ruptures [ Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops, thus reducing the risk for vascular stress and injury. It is appropriate to evaluate first-degree relatives of an affected individual in order to identify as early as possible those who could benefit from surveillance, awareness of treatment for potential complications, and appropriate restriction of high-risk physical activities. Evaluation usually starts with clinical assessment and, even in the absence of clinical signs, progresses to molecular genetic testing for the known familial pathogenic variant. Molecular genetic testing if the pathogenic variant in the family is known; In the unusual circumstance in which clinical evaluation strongly suggests the diagnosis but it has not been confirmed by genetic analysis, the first step would be to review the genetic testing in the proband and determine if it is complete or should be extended to a more detailed evaluation or to analysis of other genes. If a genetic diagnosis remains elusive, then evaluation for complications seen in the proband can drive the assessment. See Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality. The most extensive study, which included evaluation of more than 500 pregnancies in 253 women [ Increasingly, the practice is to plan delivery by cesarean section at 36-38 weeks' gestation to avoid the extensive tissue injury that can accompany vaginal delivery. This procedure can be associated with an increased risk of hemorrhage and inadvertent damage to nearby abdominal organs. Thought should be given to stratifying intervention by consideration of the underlying When the diagnosis is known in the mother, the maternal risks should be discussed and all options considered, preferably in the pre-pregnancy decision-making period. The decision to proceed with pregnancy should involve enlarging the care team to include a high-risk obstetric service. Plans for early delivery should include the presence of the vascular surgeon and potentially the general surgeon. It is essential to educate the pregnant woman and her family regarding possible complications and the need for close monitoring. A clinical trial in France to determine if addition of an angiotensin receptor blocker to celiprolol decreases arterial complications and extends life expectancy is currently under way ( Search • Because of the risk for asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [ • Because no specific gastrointestinal (GI) findings are known to precede or predict bowel rupture, invasive GI evaluation is of no benefit. • Consultation with a clinical geneticist and/or genetic counselor is recommended. • Following diagnosis, the most crucial aspect of management is the creation of an organized care team (see • Review of lifestyle with the affected individual and emphasis of the importance of minimizing collision activities and sports is recommended. • When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [ • In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vEDS and its associated tissue fragility [ • A decision about the timing and approach of an elective vascular procedure or the use of endovascular approaches is typically based on an individualized risk-versus-benefit assessment. • Reports of successful endovascular approaches are growing. A retrospective review of open versus endovascular repair of splenic artery aneurysm and dissection strongly favors the endovascular approach, with fewer complications and deaths [ • Death from bowel rupture is uncommon because intervention is generally effective. • Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery. • The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial or total colectomy at the time of the initial event to reduce the risk of recurrent bowel rupture [ • Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [ • Molecular genetic testing if the pathogenic variant in the family is known; • In the unusual circumstance in which clinical evaluation strongly suggests the diagnosis but it has not been confirmed by genetic analysis, the first step would be to review the genetic testing in the proband and determine if it is complete or should be extended to a more detailed evaluation or to analysis of other genes. If a genetic diagnosis remains elusive, then evaluation for complications seen in the proband can drive the assessment. ## Evaluations Following Initial Diagnosis There has been a gradual transition in the approach to both surveillance and intervention prior to arterial events in individuals with vascular Ehlers-Danlos syndrome (vEDS). This shift appears to reflect increased recognition of the diagnosis of vEDS both at the time of an event and before, the creation of centers of excellence and experience for vEDS both in the United States and in other countries, and differences in surgical techniques and approaches with a move away from open intervention and increased use of endovascular approaches. Nonetheless, there is still no consensus regarding the appropriate extent of evaluation at the time of initial diagnosis. To establish the extent of disease and needs in an individual diagnosed with vEDS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) provide a baseline with which to evaluate progression. Because of the risk for asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [ Because no specific gastrointestinal (GI) findings are known to precede or predict bowel rupture, invasive GI evaluation is of no benefit. Consultation with a clinical geneticist and/or genetic counselor is recommended. Following diagnosis, the most crucial aspect of management is the creation of an organized care team (see Review of lifestyle with the affected individual and emphasis of the importance of minimizing collision activities and sports is recommended. • Because of the risk for asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [ • Because no specific gastrointestinal (GI) findings are known to precede or predict bowel rupture, invasive GI evaluation is of no benefit. • Consultation with a clinical geneticist and/or genetic counselor is recommended. • Following diagnosis, the most crucial aspect of management is the creation of an organized care team (see • Review of lifestyle with the affected individual and emphasis of the importance of minimizing collision activities and sports is recommended. ## Treatment of Manifestations The most crucial aspect of management is the creation of an organized care team that includes a primary care physician, vascular surgeon, and general surgeon, as well as cardiologist and pulmonologist depending on initial evaluation. A geneticist is often valuable for integration of care. This team is responsible for the organization of ordinary and extraordinary care. In addition, individuals with vEDS should carry documentation of their genetic diagnosis, such as a MedicAlert Affected individuals should be instructed to seek immediate medical attention for sudden, unexplained pain. Surgical intervention may be lifesaving in the face of bowel rupture, arterial rupture, or organ rupture (e.g., the uterus in pregnancy). When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [ In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vEDS and its associated tissue fragility [ There are no guidelines to direct recommendations for elective repair in individuals with aneurysm(s) and vEDS. A decision about the timing and approach of an elective vascular procedure or the use of endovascular approaches is typically based on an individualized risk-versus-benefit assessment. Reports of successful endovascular approaches are growing. A retrospective review of open versus endovascular repair of splenic artery aneurysm and dissection strongly favors the endovascular approach, with fewer complications and deaths [ Prompt surgical intervention of bowel rupture is usually essential to limit the extent of infection and facilitate early restoration of bowel continuity. Death from bowel rupture is uncommon because intervention is generally effective. Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery. The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial or total colectomy at the time of the initial event to reduce the risk of recurrent bowel rupture [ Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [ • When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [ • In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vEDS and its associated tissue fragility [ • A decision about the timing and approach of an elective vascular procedure or the use of endovascular approaches is typically based on an individualized risk-versus-benefit assessment. • Reports of successful endovascular approaches are growing. A retrospective review of open versus endovascular repair of splenic artery aneurysm and dissection strongly favors the endovascular approach, with fewer complications and deaths [ • Death from bowel rupture is uncommon because intervention is generally effective. • Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery. • The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial or total colectomy at the time of the initial event to reduce the risk of recurrent bowel rupture [ • Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [ ## Surveillance The use of surveillance of the arterial vasculature assumes that effective interventions will decrease the risk of arterial dissection or rupture and prolong life. At a time when an open surgical approach was the only option, the benefit of surveillance could not be established. As endovascular approaches to management of aneurysms and dissection become more available, earlier intervention is considered and surveillance may have greater benefit. There are, however, no published data assessing the efficacy of screening strategies in identifying the regions in the arterial vasculature at highest risk; conversely, there are examples in which regions of concern in the arterial vasculature failed to progress and arterial rupture occurred at other, more distant sites. Thus, the benefit of controlled studies cannot be overemphasized. If undertaken, noninvasive imaging such as ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast is preferred to identify aneurysms, dissections, and vascular ruptures [ Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops, thus reducing the risk for vascular stress and injury. ## Agents/Circumstances to Avoid ## Evaluation of Relatives at Risk It is appropriate to evaluate first-degree relatives of an affected individual in order to identify as early as possible those who could benefit from surveillance, awareness of treatment for potential complications, and appropriate restriction of high-risk physical activities. Evaluation usually starts with clinical assessment and, even in the absence of clinical signs, progresses to molecular genetic testing for the known familial pathogenic variant. Molecular genetic testing if the pathogenic variant in the family is known; In the unusual circumstance in which clinical evaluation strongly suggests the diagnosis but it has not been confirmed by genetic analysis, the first step would be to review the genetic testing in the proband and determine if it is complete or should be extended to a more detailed evaluation or to analysis of other genes. If a genetic diagnosis remains elusive, then evaluation for complications seen in the proband can drive the assessment. See • Molecular genetic testing if the pathogenic variant in the family is known; • In the unusual circumstance in which clinical evaluation strongly suggests the diagnosis but it has not been confirmed by genetic analysis, the first step would be to review the genetic testing in the proband and determine if it is complete or should be extended to a more detailed evaluation or to analysis of other genes. If a genetic diagnosis remains elusive, then evaluation for complications seen in the proband can drive the assessment. ## Pregnancy Management Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality. The most extensive study, which included evaluation of more than 500 pregnancies in 253 women [ Increasingly, the practice is to plan delivery by cesarean section at 36-38 weeks' gestation to avoid the extensive tissue injury that can accompany vaginal delivery. This procedure can be associated with an increased risk of hemorrhage and inadvertent damage to nearby abdominal organs. Thought should be given to stratifying intervention by consideration of the underlying When the diagnosis is known in the mother, the maternal risks should be discussed and all options considered, preferably in the pre-pregnancy decision-making period. The decision to proceed with pregnancy should involve enlarging the care team to include a high-risk obstetric service. Plans for early delivery should include the presence of the vascular surgeon and potentially the general surgeon. It is essential to educate the pregnant woman and her family regarding possible complications and the need for close monitoring. ## Therapies Under Investigation A clinical trial in France to determine if addition of an angiotensin receptor blocker to celiprolol decreases arterial complications and extends life expectancy is currently under way ( Search ## Genetic Counseling Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disorder; about half of affected individuals have an affected parent and about half of affected individuals have the disorder as the result of a Note: Biallelic About 50% of individuals diagnosed with vEDS have an affected parent. An individual with vEDS 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 (if the proband has a known Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, late onset of the disease in an affected parent, or parental mosaicism [ If the proband has a known The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently If a parent of the proband is affected and/or is known to have the If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for vEDS because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. Each child of an individual with vEDS has a 50% chance of inheriting the In the rare occurrence in which an individual has biallelic 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. Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality (see The benefits of testing individuals younger than age 18 years for vEDS include: (1) elimination of concern for those children who do not have the familial pathogenic variant; (2) awareness of and preparedness for potential complications; and (3) restriction of high-impact sports and high-risk activities for those with the pathogenic variant. Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years [ In a family with an established diagnosis of vEDS it is appropriate to consider testing symptomatic individuals regardless of age. 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 vEDS have an affected parent. • An individual with vEDS 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 (if the proband has a known • Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, late onset of the disease in an affected parent, or parental mosaicism [ • If the proband has a known • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently • If a parent of the proband is affected and/or is known to have the • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for vEDS because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • Each child of an individual with vEDS has a 50% chance of inheriting the • In the rare occurrence in which an individual has biallelic • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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. • Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality (see • The benefits of testing individuals younger than age 18 years for vEDS include: (1) elimination of concern for those children who do not have the familial pathogenic variant; (2) awareness of and preparedness for potential complications; and (3) restriction of high-impact sports and high-risk activities for those with the pathogenic variant. • Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years [ ## Mode of Inheritance Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disorder; about half of affected individuals have an affected parent and about half of affected individuals have the disorder as the result of a Note: Biallelic ## Risk to Family Members About 50% of individuals diagnosed with vEDS have an affected parent. An individual with vEDS 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 (if the proband has a known Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, late onset of the disease in an affected parent, or parental mosaicism [ If the proband has a known The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently If a parent of the proband is affected and/or is known to have the If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for vEDS because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. Each child of an individual with vEDS has a 50% chance of inheriting the In the rare occurrence in which an individual has biallelic • About 50% of individuals diagnosed with vEDS have an affected parent. • An individual with vEDS 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 (if the proband has a known • Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, late onset of the disease in an affected parent, or parental mosaicism [ • If the proband has a known • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently • If a parent of the proband is affected and/or is known to have the • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for vEDS because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism. • Each child of an individual with vEDS has a 50% chance of inheriting the • In the rare occurrence in which an individual has biallelic ## 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. Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality (see The benefits of testing individuals younger than age 18 years for vEDS include: (1) elimination of concern for those children who do not have the familial pathogenic variant; (2) awareness of and preparedness for potential complications; and (3) restriction of high-impact sports and high-risk activities for those with the pathogenic variant. Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years [ In a family with an established diagnosis of vEDS it is appropriate to consider testing 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. • Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality (see • The benefits of testing individuals younger than age 18 years for vEDS include: (1) elimination of concern for those children who do not have the familial pathogenic variant; (2) awareness of and preparedness for potential complications; and (3) restriction of high-impact sports and high-risk activities for those with the pathogenic variant. • Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years [ ## 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 United Kingdom • • United Kingdom • • • • • United Kingdom • • United Kingdom • • • • • • • • • ## Molecular Genetics Vascular Ehlers-Danlos Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Vascular Ehlers-Danlos Syndrome ( More than 1,500 The majority of identified pathogenic variants result in single-amino-acid substitutions for glycines in the Gly-X-Y repeats of the triple helical region of the type III procollagen molecule. The phenotypic effects of these variants vary according to the nature of the substituting residues. Single nucleotide changes in glycine codons can result in substitutions by valine, alanine, aspartic acid, glutamic acid, arginine, serine, cysteine, or phenylalanine with different expected rates and different observed rates. Phenotypes as measured by both longevity and clinical features are generally milder with smaller amino acid substitution. About one quarter of reported pathogenic variants occur at splice sites, most resulting in exon skipping. A smaller number of splice site variants lead to the use of cryptic splice sites with partial-exon exclusion or intron inclusion and/or mRNA instability. The majority of exon-skipping splice site variants have been identified at the 5' donor site, with very few found at the 3' splice site. Several partial-gene deletions have been reported as well. Less common are variants that create premature termination codons predicted to result in Note: At least two classes of Substitutions of glycine in the triple helical domain by alanine Null variants Thus, some pathogenic variants in • Substitutions of glycine in the triple helical domain by alanine • Null variants ## Molecular Pathogenesis More than 1,500 The majority of identified pathogenic variants result in single-amino-acid substitutions for glycines in the Gly-X-Y repeats of the triple helical region of the type III procollagen molecule. The phenotypic effects of these variants vary according to the nature of the substituting residues. Single nucleotide changes in glycine codons can result in substitutions by valine, alanine, aspartic acid, glutamic acid, arginine, serine, cysteine, or phenylalanine with different expected rates and different observed rates. Phenotypes as measured by both longevity and clinical features are generally milder with smaller amino acid substitution. About one quarter of reported pathogenic variants occur at splice sites, most resulting in exon skipping. A smaller number of splice site variants lead to the use of cryptic splice sites with partial-exon exclusion or intron inclusion and/or mRNA instability. The majority of exon-skipping splice site variants have been identified at the 5' donor site, with very few found at the 3' splice site. Several partial-gene deletions have been reported as well. Less common are variants that create premature termination codons predicted to result in Note: At least two classes of Substitutions of glycine in the triple helical domain by alanine Null variants Thus, some pathogenic variants in • Substitutions of glycine in the triple helical domain by alanine • Null variants ## Chapter Notes Collagen Diagnostic Laboratory Peter H Byers, MD, and Ulrike Schwarze, MD, along with Dru Leistritz, are actively involved in clinical research regarding individuals with different forms of Ehlers-Danlos syndrome, osteogenesis imperfecta, and genetic aortopathies. They would be happy to communicate with persons who have any questions regarding diagnosis of these conditions or other considerations. Contact Dr Byers or Dr Schwarze to inquire about review of variants of uncertain significance in genes studied at the Collagen Diagnostic Laboratory. We are grateful to the Freudmann Fund, private contributions from a number of families, and to the OI Foundation, the Ehlers-Danlos Society, and the Marfan Foundation for enthusiastic support of the work to support the individual in those organization affected by the conditions. Peter H Byers, MD (1999-present)Mitzi L Murray, MD, MA; University of Washington (2015-2019)Melanie G Pepin, MS, CGC; University of Washington (1999-2019) 10 April 2025 (sw) Comprehensive update posted live 21 February 2019 (ha) Comprehensive update posted live 19 November 2015 (me) Comprehensive update posted live 3 May 2011 (me) Comprehensive update posted live 7 June 2006 (me) Comprehensive update posted live 14 April 2004 (me) Comprehensive update posted live 15 April 2002 (me) Comprehensive update posted live 2 September 1999 (me) Review posted live 6 April 1999 (mp) Original submission • 10 April 2025 (sw) Comprehensive update posted live • 21 February 2019 (ha) Comprehensive update posted live • 19 November 2015 (me) Comprehensive update posted live • 3 May 2011 (me) Comprehensive update posted live • 7 June 2006 (me) Comprehensive update posted live • 14 April 2004 (me) Comprehensive update posted live • 15 April 2002 (me) Comprehensive update posted live • 2 September 1999 (me) Review posted live • 6 April 1999 (mp) Original submission ## Author Notes Collagen Diagnostic Laboratory Peter H Byers, MD, and Ulrike Schwarze, MD, along with Dru Leistritz, are actively involved in clinical research regarding individuals with different forms of Ehlers-Danlos syndrome, osteogenesis imperfecta, and genetic aortopathies. They would be happy to communicate with persons who have any questions regarding diagnosis of these conditions or other considerations. Contact Dr Byers or Dr Schwarze to inquire about review of variants of uncertain significance in genes studied at the Collagen Diagnostic Laboratory. ## Acknowledgments We are grateful to the Freudmann Fund, private contributions from a number of families, and to the OI Foundation, the Ehlers-Danlos Society, and the Marfan Foundation for enthusiastic support of the work to support the individual in those organization affected by the conditions. ## Author History Peter H Byers, MD (1999-present)Mitzi L Murray, MD, MA; University of Washington (2015-2019)Melanie G Pepin, MS, CGC; University of Washington (1999-2019) ## Revision History 10 April 2025 (sw) Comprehensive update posted live 21 February 2019 (ha) Comprehensive update posted live 19 November 2015 (me) Comprehensive update posted live 3 May 2011 (me) Comprehensive update posted live 7 June 2006 (me) Comprehensive update posted live 14 April 2004 (me) Comprehensive update posted live 15 April 2002 (me) Comprehensive update posted live 2 September 1999 (me) Review posted live 6 April 1999 (mp) Original submission • 10 April 2025 (sw) Comprehensive update posted live • 21 February 2019 (ha) Comprehensive update posted live • 19 November 2015 (me) Comprehensive update posted live • 3 May 2011 (me) Comprehensive update posted live • 7 June 2006 (me) Comprehensive update posted live • 14 April 2004 (me) Comprehensive update posted live • 15 April 2002 (me) Comprehensive update posted live • 2 September 1999 (me) Review posted live • 6 April 1999 (mp) Original submission ## References ## Literature Cited
[]
2/9/1999
10/4/2025
25/1/2005
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eds6
eds6
[ "Ehlers-Danlos Syndrome Type VIA (EDS VIA)", "Lysyl-Hydroxylase 1 Deficiency", "PLOD1-kEDS", "Ehlers-Danlos Syndrome Type VIA (EDS VIA),", "Lysyl-Hydroxylase 1 Deficiency", "PLOD1-kEDS", "Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1", "PLOD1", "PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome" ]
Marianne Rohrbach, Cecilia Giunta
Summary The diagnosis of
## Diagnosis Congenital muscular hypotonia Congenital or early-onset kyphoscoliosis (progressive or nonprogressive) Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) Skin hyperextensibility Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) Rupture/aneurysm of a medium-sized artery Osteopenia/osteoporosis Blue sclerae, scleral and ocular fragility/rupture Hernia (umbilical or inguinal) Pectus deformity Marfanoid habitus Talipes equinovarus Refractive errors (myopia, hypermetropia) Microcornea Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS Either of the following: Generalized joint hypermobility Three minor criteria 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 Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited generalized connective tissue disorders, 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. • Congenital muscular hypotonia • Congenital or early-onset kyphoscoliosis (progressive or nonprogressive) • Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) • Skin hyperextensibility • Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) • Rupture/aneurysm of a medium-sized artery • Osteopenia/osteoporosis • Blue sclerae, scleral and ocular fragility/rupture • Hernia (umbilical or inguinal) • Pectus deformity • Marfanoid habitus • Talipes equinovarus • Refractive errors (myopia, hypermetropia) • Microcornea • Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS • Either of the following: • Generalized joint hypermobility • Three minor criteria • Generalized joint hypermobility • Three minor criteria • Generalized joint hypermobility • Three minor criteria • For an introduction to multigene panels click ## Suggestive Findings Congenital muscular hypotonia Congenital or early-onset kyphoscoliosis (progressive or nonprogressive) Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) Skin hyperextensibility Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) Rupture/aneurysm of a medium-sized artery Osteopenia/osteoporosis Blue sclerae, scleral and ocular fragility/rupture Hernia (umbilical or inguinal) Pectus deformity Marfanoid habitus Talipes equinovarus Refractive errors (myopia, hypermetropia) Microcornea Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS Either of the following: Generalized joint hypermobility Three minor criteria 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. • Congenital muscular hypotonia • Congenital or early-onset kyphoscoliosis (progressive or nonprogressive) • Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) • Skin hyperextensibility • Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) • Rupture/aneurysm of a medium-sized artery • Osteopenia/osteoporosis • Blue sclerae, scleral and ocular fragility/rupture • Hernia (umbilical or inguinal) • Pectus deformity • Marfanoid habitus • Talipes equinovarus • Refractive errors (myopia, hypermetropia) • Microcornea • Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS • Either of the following: • Generalized joint hypermobility • Three minor criteria • Generalized joint hypermobility • Three minor criteria • Generalized joint hypermobility • Three minor criteria ## Clinical Features Congenital muscular hypotonia Congenital or early-onset kyphoscoliosis (progressive or nonprogressive) Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) Skin hyperextensibility Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) Rupture/aneurysm of a medium-sized artery Osteopenia/osteoporosis Blue sclerae, scleral and ocular fragility/rupture Hernia (umbilical or inguinal) Pectus deformity Marfanoid habitus Talipes equinovarus Refractive errors (myopia, hypermetropia) Microcornea Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS Either of the following: Generalized joint hypermobility Three minor criteria • Congenital muscular hypotonia • Congenital or early-onset kyphoscoliosis (progressive or nonprogressive) • Generalized joint hypermobility with dislocations/subluxations (shoulders, hips, and knees in particular) • Skin hyperextensibility • Skin fragility (easy bruising, friable skin, poor wound healing, widened atrophic scarring) • Rupture/aneurysm of a medium-sized artery • Osteopenia/osteoporosis • Blue sclerae, scleral and ocular fragility/rupture • Hernia (umbilical or inguinal) • Pectus deformity • Marfanoid habitus • Talipes equinovarus • Refractive errors (myopia, hypermetropia) • Microcornea • Congenital muscular hypotonia AND congenital or early-onset kyphoscoliosis; PLUS • Either of the following: • Generalized joint hypermobility • Three minor criteria • Generalized joint hypermobility • Three minor criteria • Generalized joint hypermobility • Three minor criteria ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited generalized connective tissue disorders, 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. • 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 generalized connective tissue disorders, 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. ## Additional Confirmatory Testing ## Clinical Characteristics Mild-to-moderate gross motor delay is common. Walking nearly always occurs before age two years. Loss of motor milestones does not occur. Fine motor skills can be affected as well due to weakness and/or joint laxity. Intellect is unaffected. Thoracic (kypho)scoliosis is also common in the neonate. Kyphoscoliosis appears during infancy and becomes moderate to severe in childhood. Clubfoot (talipes equinovarus) deformities are present at birth in approximately 25% of affected individuals. Pectus deformity is also present with similar frequency. Osteopenia/osteoporosis occurs in 25% of affected individuals, but its clinical significance is currently unknown. A marfanoid habitus is often striking, including pectus deformity (~25%), long limbs, and arachnodactyly. No clinically relevant genotype-phenotype correlations have been reported to date. Penetrance for Kyphoscoliotic EDS (or EDS, kyphoscoliotic form) was initially referred to as EDS, oculoscoliotic form after its first description by Prior to the development of the 1998 Villefranche classification, kEDS was known as Ehlers-Danlos syndrome type VI (EDS VI) or Ehlers-Danlos syndrome type VIA (EDS VIA). In 2017, the International EDS Consortium proposed a revised EDS classification system. The new nomenclature for EDS, kyphoscoliotic form is kyphoscoliotic EDS, or kEDS [ Prevalence does not vary by race or ethnicity, although many of the reported and unreported individuals originated from Turkey, the Middle East, and Greece [ ## Clinical Description Mild-to-moderate gross motor delay is common. Walking nearly always occurs before age two years. Loss of motor milestones does not occur. Fine motor skills can be affected as well due to weakness and/or joint laxity. Intellect is unaffected. Thoracic (kypho)scoliosis is also common in the neonate. Kyphoscoliosis appears during infancy and becomes moderate to severe in childhood. Clubfoot (talipes equinovarus) deformities are present at birth in approximately 25% of affected individuals. Pectus deformity is also present with similar frequency. Osteopenia/osteoporosis occurs in 25% of affected individuals, but its clinical significance is currently unknown. A marfanoid habitus is often striking, including pectus deformity (~25%), long limbs, and arachnodactyly. ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been reported to date. ## Penetrance Penetrance for ## Nomenclature Kyphoscoliotic EDS (or EDS, kyphoscoliotic form) was initially referred to as EDS, oculoscoliotic form after its first description by Prior to the development of the 1998 Villefranche classification, kEDS was known as Ehlers-Danlos syndrome type VI (EDS VI) or Ehlers-Danlos syndrome type VIA (EDS VIA). In 2017, the International EDS Consortium proposed a revised EDS classification system. The new nomenclature for EDS, kyphoscoliotic form is kyphoscoliotic EDS, or kEDS [ ## Prevalence Prevalence does not vary by race or ethnicity, although many of the reported and unreported individuals originated from Turkey, the Middle East, and Greece [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Selected Genes of Interest in the Differential Diagnosis of Atrophic scarring, easy bruising Joint hypermobility Skin hyperextensibility Prematurely aged appearance Thinning of hair or (partial) alopecia Joint hypermobility Poor wound healing Hypotonia Skin hyperextensibility Progeroid characteristics Vertebral dysplasia w/moderate short stature & characteristic features of the hands (thenar atrophy, short metacarpals & phalanges, inability to adduct thumbs) Blue sclerae Marfanoid habitus Generalized joint hypermobility Scoliosis Skin hyperextensibility Easy bruising; atrophic scarring Hypotonia Refractive errors Characteristic facies Adducted thumbs & feet Gastrointestinal & genitourinary manifestations Intestinal rupture Uterine rupture during pregnancy Atrophic scarring, easy bruising Joint hypermobility Skin hyperextensibility Absence of congenital muscular hypotonia Scoliosis rather than kyphoscoliosis Congenital muscular hypotonia Congenital/early-onset kyphoscoliosis Generalized joint hypermobility Myopathy Hearing loss Easy bruising Joint hypermobility Skin hyperextensibility, velvety skin Corneal disorder Skin hyperelasticity Joint hypermobility Thinning of cornea w/risk of rupture Deafness (mixed conductive & sensorineural) AD = autosomal dominant; AR = autosomal recessive; EDS = Ehlers-Danlos syndrome; MOI = mode of inheritance Pathogenic variants in Vascular EDS is almost always inherited in an autosomal dominant manner, but rare examples of biallelic inheritance have been reported. The proportion of cEDS attributed to pathogenic variants in • Atrophic scarring, easy bruising • Joint hypermobility • Skin hyperextensibility • Prematurely aged appearance • Thinning of hair or (partial) alopecia • Joint hypermobility • Poor wound healing • Hypotonia • Skin hyperextensibility • Progeroid characteristics • Vertebral dysplasia w/moderate short stature & characteristic features of the hands (thenar atrophy, short metacarpals & phalanges, inability to adduct thumbs) • Blue sclerae • Marfanoid habitus • Generalized joint hypermobility • Scoliosis • Skin hyperextensibility • Easy bruising; atrophic scarring • Hypotonia • Refractive errors • Characteristic facies • Adducted thumbs & feet • Gastrointestinal & genitourinary manifestations • Intestinal rupture • Uterine rupture during pregnancy • Atrophic scarring, easy bruising • Joint hypermobility • Skin hyperextensibility • Absence of congenital muscular hypotonia • Scoliosis rather than kyphoscoliosis • Congenital muscular hypotonia • Congenital/early-onset kyphoscoliosis • Generalized joint hypermobility • Myopathy • Hearing loss • Easy bruising • Joint hypermobility • Skin hyperextensibility, velvety skin • Corneal disorder • Skin hyperelasticity • Joint hypermobility • Thinning of cornea w/risk of rupture • Deafness (mixed conductive & sensorineural) ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with MOI = mode of inheritance; MRA = magnetic resonance angiogram; Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for PT for older children, adolescents, & adults to strengthen large muscle groups, particularly at the shoulder girdle, & to prevent recurrent shoulder dislocation Swimming is recommended. Referral to orthopedic surgeon for mgmt of kyphoscoliosis Bracing may be required to support unstable joints. Due to skin fragility, protective pads over knees, shins, & elbows may prevent lacerations, particularly in children. Use of helmets for active sports Close dermal wounds w/o tension, preferably in 2 layers. Apply deep stitches generously. Leave cutaneous stitches in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. Treatment per cardiologist Vigilant observation & control of blood pressure can ↓ risk of arterial rupture. Those w/aortic dilatation may require treatment w/beta-blockers to prevent further expansion. Those w/mitral valve prolapse should follow standard AHA guidelines for antimicrobial prophylaxis. Corrective lenses for myopia &/or astigmatism Laser treatment of retina in those w/imminent detachment AHA = American Heart Association; EDS = Ehlers-Danlos syndrome; To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Assessment w/cardiologist Echocardiogram MRA = magnetic resonance angiogram; PT = physical therapy In children with significant joint hyperextensibility, sports that place stress on the joints (e.g., gymnastics, long-distance running) should be avoided. High-impact sports (collision sports), heavy lifting, and weight training with extreme lifting should be avoided. Arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury. It is appropriate to clarify the genetic status of 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 both Measurement of cross-links in urine for markedly increased ratio of deoxypyridinoline to pyridinoline by high-performance liquid chromatography if only one or no pathogenic variant in See Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries [ Search • PT for older children, adolescents, & adults to strengthen large muscle groups, particularly at the shoulder girdle, & to prevent recurrent shoulder dislocation • Swimming is recommended. • Referral to orthopedic surgeon for mgmt of kyphoscoliosis • Bracing may be required to support unstable joints. • Due to skin fragility, protective pads over knees, shins, & elbows may prevent lacerations, particularly in children. • Use of helmets for active sports • Close dermal wounds w/o tension, preferably in 2 layers. • Apply deep stitches generously. • Leave cutaneous stitches in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. • Treatment per cardiologist • Vigilant observation & control of blood pressure can ↓ risk of arterial rupture. • Those w/aortic dilatation may require treatment w/beta-blockers to prevent further expansion. • Those w/mitral valve prolapse should follow standard AHA guidelines for antimicrobial prophylaxis. • Corrective lenses for myopia &/or astigmatism • Laser treatment of retina in those w/imminent detachment • Assessment w/cardiologist • Echocardiogram • Molecular genetic testing if both • Measurement of cross-links in urine for markedly increased ratio of deoxypyridinoline to pyridinoline by high-performance liquid chromatography if only one or no pathogenic variant in ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MOI = mode of inheritance; MRA = magnetic resonance angiogram; Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations There is no cure for PT for older children, adolescents, & adults to strengthen large muscle groups, particularly at the shoulder girdle, & to prevent recurrent shoulder dislocation Swimming is recommended. Referral to orthopedic surgeon for mgmt of kyphoscoliosis Bracing may be required to support unstable joints. Due to skin fragility, protective pads over knees, shins, & elbows may prevent lacerations, particularly in children. Use of helmets for active sports Close dermal wounds w/o tension, preferably in 2 layers. Apply deep stitches generously. Leave cutaneous stitches in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. Treatment per cardiologist Vigilant observation & control of blood pressure can ↓ risk of arterial rupture. Those w/aortic dilatation may require treatment w/beta-blockers to prevent further expansion. Those w/mitral valve prolapse should follow standard AHA guidelines for antimicrobial prophylaxis. Corrective lenses for myopia &/or astigmatism Laser treatment of retina in those w/imminent detachment AHA = American Heart Association; EDS = Ehlers-Danlos syndrome; • PT for older children, adolescents, & adults to strengthen large muscle groups, particularly at the shoulder girdle, & to prevent recurrent shoulder dislocation • Swimming is recommended. • Referral to orthopedic surgeon for mgmt of kyphoscoliosis • Bracing may be required to support unstable joints. • Due to skin fragility, protective pads over knees, shins, & elbows may prevent lacerations, particularly in children. • Use of helmets for active sports • Close dermal wounds w/o tension, preferably in 2 layers. • Apply deep stitches generously. • Leave cutaneous stitches in place twice as long as usual, & additional fixation of adjacent skin w/adhesive tape can help prevent stretching of the scar. • Treatment per cardiologist • Vigilant observation & control of blood pressure can ↓ risk of arterial rupture. • Those w/aortic dilatation may require treatment w/beta-blockers to prevent further expansion. • Those w/mitral valve prolapse should follow standard AHA guidelines for antimicrobial prophylaxis. • Corrective lenses for myopia &/or astigmatism • Laser treatment of retina in those w/imminent detachment ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Assessment w/cardiologist Echocardiogram MRA = magnetic resonance angiogram; PT = physical therapy • Assessment w/cardiologist • Echocardiogram ## Agents/Circumstances to Avoid In children with significant joint hyperextensibility, sports that place stress on the joints (e.g., gymnastics, long-distance running) should be avoided. High-impact sports (collision sports), heavy lifting, and weight training with extreme lifting should be avoided. Arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of 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 both Measurement of cross-links in urine for markedly increased ratio of deoxypyridinoline to pyridinoline by high-performance liquid chromatography if only one or no pathogenic variant in See • Molecular genetic testing if both • Measurement of cross-links in urine for markedly increased ratio of deoxypyridinoline to pyridinoline by high-performance liquid chromatography if only one or no pathogenic variant in ## Pregnancy Management Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries [ ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are presumed to be heterozygous for a If both 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, are carriers, or are at risk of being carriers. Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries (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 • If both • 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, are carriers, or are at risk of being carriers. • Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries (see ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for a If both 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 • If both • 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 ## 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. Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries (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. • Affected pregnant women may be at increased risk for miscarriage, premature rupture of membranes, and rupture of arteries (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 United Kingdom United Kingdom • • United Kingdom • • United Kingdom • • • • • • • ## Molecular Genetics PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome ( Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. ## Chapter Notes Cecilia Giunta, PhD (2024-present)Marianne Rohrbach, MD, PhD (2024-present)Beat Steinmann, MD; University Children's Hospital Zurich (2008-2024)Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (1999-2008)Heather N Yeowell, PhD; Duke University Medical Center (2005-2024) 13 June 2024 (sw) Comprehensive update posted live 12 April 2018 (ha) Comprehensive update posted live 24 January 2013 (me) Comprehensive update posted live 19 February 2008 (me) Comprehensive update posted live 12 July 2005 (me) Comprehensive update posted live 12 March 2003 (me) Comprehensive update posted live 2 February 2000 (me) Review posted live 7 April 1999 (rw) Original submission • 13 June 2024 (sw) Comprehensive update posted live • 12 April 2018 (ha) Comprehensive update posted live • 24 January 2013 (me) Comprehensive update posted live • 19 February 2008 (me) Comprehensive update posted live • 12 July 2005 (me) Comprehensive update posted live • 12 March 2003 (me) Comprehensive update posted live • 2 February 2000 (me) Review posted live • 7 April 1999 (rw) Original submission ## Author Notes ## Author History Cecilia Giunta, PhD (2024-present)Marianne Rohrbach, MD, PhD (2024-present)Beat Steinmann, MD; University Children's Hospital Zurich (2008-2024)Richard Wenstrup, MD; Cincinnati Children's Hospital Medical Center (1999-2008)Heather N Yeowell, PhD; Duke University Medical Center (2005-2024) ## Revision History 13 June 2024 (sw) Comprehensive update posted live 12 April 2018 (ha) Comprehensive update posted live 24 January 2013 (me) Comprehensive update posted live 19 February 2008 (me) Comprehensive update posted live 12 July 2005 (me) Comprehensive update posted live 12 March 2003 (me) Comprehensive update posted live 2 February 2000 (me) Review posted live 7 April 1999 (rw) Original submission • 13 June 2024 (sw) Comprehensive update posted live • 12 April 2018 (ha) Comprehensive update posted live • 24 January 2013 (me) Comprehensive update posted live • 19 February 2008 (me) Comprehensive update posted live • 12 July 2005 (me) Comprehensive update posted live • 12 March 2003 (me) Comprehensive update posted live • 2 February 2000 (me) Review posted live • 7 April 1999 (rw) Original submission ## References ## Literature Cited
[]
2/2/2000
13/6/2024
18/10/2018
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ee
ee
[ "ETHE1 Deficiency", "ETHE1 Deficiency", "Persulfide dioxygenase ETHE1, mitochondrial", "ETHE1", "Ethylmalonic Encephalopathy" ]
Ethylmalonic Encephalopathy
Ivano Di Meo, Costanza Lamperti, Valeria Tiranti
Summary Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder characterized by developmental delay / mild-to-severe intellectual disability; generalized infantile hypotonia that evolves into hypertonia, spasticity, and (in some instances) dystonia; generalized tonic-clonic seizures; and generalized microvascular damage (diffuse and spontaneous relapsing petechial purpura, hemorrhagic suffusions of mucosal surfaces, and chronic hemorrhagic diarrhea). Infants sometimes have frequent vomiting and loss of social interaction. Speech is delayed and in some instances absent. Swallowing difficulties and failure to thrive are common. Children may be unable to walk without support and may be wheelchair bound. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of children die in the first decade. The diagnosis of EE is suggested by clinical findings and the laboratory findings of increased blood lactate levels, C4- and C5-acylcarnitine esters, plasma thiosulphate, and urinary ethylmalonic acid. The diagnosis is established by identification of biallelic pathogenic variants in EE 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. No individuals diagnosed with EE have been known to reproduce. Once the
## Diagnosis Ethylmalonic encephalopathy (EE) Global neurologic impairment Early-onset progressive psychomotor regression Seizures Dystonia Diffuse microvasculature injury Petechiae and/or purpura Orthostatic acrocyanosis Hemorrhagic suffusions of mucosal surfaces Chronic hemorrhagic diarrhea Increased blood lactate levels (normal range: 6-22 mg/dL) Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [ Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [ Increased plasma thiosulphate (normal range: <4 μmol/L) Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [ * More data are needed to define the range of C4/C5 acylcarnitine elevation in individuals with molecularly proven EE. Symmetric patchy T Atypical neuroradiologic patterns were also reported [ The diagnosis of ethylmalonic encephalopathy Molecular Genetic Testing Used in Ethylmalonic Encephalopathy 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. Deletion of exon 4 and deletion of exons 1 to 7 have been detected frequently [ • Global neurologic impairment • Early-onset progressive psychomotor regression • Seizures • Dystonia • Early-onset progressive psychomotor regression • Seizures • Dystonia • Diffuse microvasculature injury • Petechiae and/or purpura • Orthostatic acrocyanosis • Hemorrhagic suffusions of mucosal surfaces • Chronic hemorrhagic diarrhea • Petechiae and/or purpura • Orthostatic acrocyanosis • Hemorrhagic suffusions of mucosal surfaces • Chronic hemorrhagic diarrhea • Early-onset progressive psychomotor regression • Seizures • Dystonia • Petechiae and/or purpura • Orthostatic acrocyanosis • Hemorrhagic suffusions of mucosal surfaces • Chronic hemorrhagic diarrhea • Increased blood lactate levels (normal range: 6-22 mg/dL) • Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [ • Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [ • Increased plasma thiosulphate (normal range: <4 μmol/L) • Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [ • Symmetric patchy T • Atypical neuroradiologic patterns were also reported [ ## Suggestive Findings Ethylmalonic encephalopathy (EE) Global neurologic impairment Early-onset progressive psychomotor regression Seizures Dystonia Diffuse microvasculature injury Petechiae and/or purpura Orthostatic acrocyanosis Hemorrhagic suffusions of mucosal surfaces Chronic hemorrhagic diarrhea Increased blood lactate levels (normal range: 6-22 mg/dL) Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [ Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [ Increased plasma thiosulphate (normal range: <4 μmol/L) Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [ * More data are needed to define the range of C4/C5 acylcarnitine elevation in individuals with molecularly proven EE. Symmetric patchy T Atypical neuroradiologic patterns were also reported [ • Global neurologic impairment • Early-onset progressive psychomotor regression • Seizures • Dystonia • Early-onset progressive psychomotor regression • Seizures • Dystonia • Diffuse microvasculature injury • Petechiae and/or purpura • Orthostatic acrocyanosis • Hemorrhagic suffusions of mucosal surfaces • Chronic hemorrhagic diarrhea • Petechiae and/or purpura • Orthostatic acrocyanosis • Hemorrhagic suffusions of mucosal surfaces • Chronic hemorrhagic diarrhea • Early-onset progressive psychomotor regression • Seizures • Dystonia • Petechiae and/or purpura • Orthostatic acrocyanosis • Hemorrhagic suffusions of mucosal surfaces • Chronic hemorrhagic diarrhea • Increased blood lactate levels (normal range: 6-22 mg/dL) • Increased blood C4-acylcarnitine esters (normal range: <0.9 μmol/L) [ • Increased blood C5-acylcarnitine esters (normal range: <0.3 μmol/L) [ • Increased plasma thiosulphate (normal range: <4 μmol/L) • Increased urinary ethylmalonic acid (normal range: <10 μmol/mmol creatinine) evaluated on spot urine [ • Symmetric patchy T • Atypical neuroradiologic patterns were also reported [ ## Establishing the Diagnosis The diagnosis of ethylmalonic encephalopathy Molecular Genetic Testing Used in Ethylmalonic Encephalopathy 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. Deletion of exon 4 and deletion of exons 1 to 7 have been detected frequently [ ## Clinical Characteristics Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder, typically characterized by the following major manifestations: developmental delay, progressive neurologic involvement, seizures, and vascular damage. Findings usually appear in the first years of life, in some instances during metabolic stress such as infection or fever. Affected infants typically have severe neck, trunk, and limb hypotonia and loss of head control, sometimes associated with frequent vomiting and loss of social interaction. In addition, chronic diarrhea and failure to thrive are common. Atypical findings have also been reported [ Dystonia, an extrapyramidal finding, generally involves the limbs and trunk. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of patients die in the early years, although some are still alive in the second decade of life. Distal orthostatic acrocyanosis with edema of the extremities is often visible. Hemorrhagic suffusions of mucosal surfaces and chronic hemorrhagic diarrhea are common manifestations. Of two affected individuals reported by In one individual with a molecularly confirmed diagnosis, the clinical findings suggested a connective tissue disorder (vascular fragility, joint hyperextensibility, and delayed motor development with normal cognitive development); urinary excretion of ethylmalonic acid was not abnormally increased during intercritical phases [ One individual who had the typical findings of EE also had hydronephrosis, undescended testes, mild tricuspid regurgitation, and mild dilatation of the pulmonary artery [ Monochorial twins had severe axial hypotonia without petechiae, orthostatic acrocyanosis, or chronic diarrhea. Other clinical findings differed markedly: one twin had an episode of coma at age three years followed by spastic quadriparesis and loss of language; the other had pyramidal involvement (mainly limited to the lower extremities) and spoke two languages [ No genotype-phenotype correlations are known to be associated with The prevalence of ethylmalonic encephalopathy is unknown. More than 80 individuals with features consistent with EE and a molecularly confirmed diagnosis have been reported [ To date, families with EE have been from (or could be traced to) different regions of the Mediterranean basin or the Arabian Peninsula; parental consanguinity is common. ## Clinical Description Ethylmalonic encephalopathy (EE) is a severe, early-onset, progressive disorder, typically characterized by the following major manifestations: developmental delay, progressive neurologic involvement, seizures, and vascular damage. Findings usually appear in the first years of life, in some instances during metabolic stress such as infection or fever. Affected infants typically have severe neck, trunk, and limb hypotonia and loss of head control, sometimes associated with frequent vomiting and loss of social interaction. In addition, chronic diarrhea and failure to thrive are common. Atypical findings have also been reported [ Dystonia, an extrapyramidal finding, generally involves the limbs and trunk. Neurologic deterioration accelerates following intercurrent infectious illness, and the majority of patients die in the early years, although some are still alive in the second decade of life. Distal orthostatic acrocyanosis with edema of the extremities is often visible. Hemorrhagic suffusions of mucosal surfaces and chronic hemorrhagic diarrhea are common manifestations. Of two affected individuals reported by In one individual with a molecularly confirmed diagnosis, the clinical findings suggested a connective tissue disorder (vascular fragility, joint hyperextensibility, and delayed motor development with normal cognitive development); urinary excretion of ethylmalonic acid was not abnormally increased during intercritical phases [ One individual who had the typical findings of EE also had hydronephrosis, undescended testes, mild tricuspid regurgitation, and mild dilatation of the pulmonary artery [ Monochorial twins had severe axial hypotonia without petechiae, orthostatic acrocyanosis, or chronic diarrhea. Other clinical findings differed markedly: one twin had an episode of coma at age three years followed by spastic quadriparesis and loss of language; the other had pyramidal involvement (mainly limited to the lower extremities) and spoke two languages [ ## Individuals with Atypical Findings Of two affected individuals reported by In one individual with a molecularly confirmed diagnosis, the clinical findings suggested a connective tissue disorder (vascular fragility, joint hyperextensibility, and delayed motor development with normal cognitive development); urinary excretion of ethylmalonic acid was not abnormally increased during intercritical phases [ One individual who had the typical findings of EE also had hydronephrosis, undescended testes, mild tricuspid regurgitation, and mild dilatation of the pulmonary artery [ Monochorial twins had severe axial hypotonia without petechiae, orthostatic acrocyanosis, or chronic diarrhea. Other clinical findings differed markedly: one twin had an episode of coma at age three years followed by spastic quadriparesis and loss of language; the other had pyramidal involvement (mainly limited to the lower extremities) and spoke two languages [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known to be associated with ## Prevalence The prevalence of ethylmalonic encephalopathy is unknown. More than 80 individuals with features consistent with EE and a molecularly confirmed diagnosis have been reported [ To date, families with EE have been from (or could be traced to) different regions of the Mediterranean basin or the Arabian Peninsula; parental consanguinity is common. ## Genetically Related (Allelic) Disorders At present, no phenotypes other than those discussed in this ## Differential Diagnosis Ethylmalonic acid is a dicarboxylic organic acid produced by the carboxylation of butyrate. Ethylmalonic encephalopathy (EE) should be included in the differential diagnosis of other forms of persistent ethylmalonic aciduria, including the following: Defects of beta-oxidation of fatty acids with similar clinical findings (e.g., vomiting, diarrhea, difficulty with feeding, and developmental delay) such as Defects of the mitochondrial electron-transfer flavoprotein pathway or Some forms of respiratory chain deficiency Of note, brain vascular lesions appear to be a specific neuropathologic feature of EE, not seen in other forms of ethylmalonic aciduria or in disorders caused by primary respiratory chain defects such as • Defects of beta-oxidation of fatty acids with similar clinical findings (e.g., vomiting, diarrhea, difficulty with feeding, and developmental delay) such as • Defects of the mitochondrial electron-transfer flavoprotein pathway or • Some forms of respiratory chain deficiency ## Management To establish the extent of disease and needs in an individual diagnosed with ethylmalonic encephalopathy (EE), the recommended evaluations following diagnosis (if not performed as part of the evaluation that led to the diagnosis) are as summarized in Recommended Evaluations Following Initial Diagnosis of Ethylmalonic Encephalopathy (EE) Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, orthopedic, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes ethylmalonic encephalopathy. Treatment is primarily supportive including anti-spastic medications, muscle relaxants, and anti-seizure medication. Physical therapy early in the disease course can help prevent contractures. Treatment of Manifestations in Individuals with Ethylmalonic Encephalopathy Off-label compassionate use of N-acetylcysteine (NAC) in combination with metronidazole may be considered as they are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE [ N-acetylcysteine (NAC), a cell-permeable precursor of glutathione, is abundant in mitochondria where it can act as one of the physiologic acceptors of the sulfur atom of hydrogen sulfide (H Metronidazole is widely used to combat infections caused by anaerobic bacteria, and can reduce the sulfide-producing bacterial load in the large intestine. 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). Consider use of durable medical equipment 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, Botox All affected individuals should receive routine immunizations; as well as annual immunizations for influenza. Physicians must pay particular attention to the prevention of infections that could be fatal. Surveillance should be individualized based on symptoms and organs affected. Recommended Surveillance for Individuals with Ethylmalonic Encephalopathy See While clearance of circulating sulfide by a transplanted liver could be beneficial, to date only one instance of liver transplantation in EE has been reported [ Possible future treatments include AAV-mediated gene therapy [ Search • N-acetylcysteine (NAC), a cell-permeable precursor of glutathione, is abundant in mitochondria where it can act as one of the physiologic acceptors of the sulfur atom of hydrogen sulfide (H • Metronidazole is widely used to combat infections caused by anaerobic bacteria, and can reduce the sulfide-producing bacterial load in the large intestine. • 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). • Consider use of durable medical equipment 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, Botox ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ethylmalonic encephalopathy (EE), the recommended evaluations following diagnosis (if not performed as part of the evaluation that led to the diagnosis) are as summarized in Recommended Evaluations Following Initial Diagnosis of Ethylmalonic Encephalopathy (EE) ## Treatment of Manifestations Multi-specialty care that includes child neurology, pediatrics, clinical genetics, nutrition, gastroenterology, orthopedic, pain management, and physical therapy can help with timely detection and treatment of the multiorgan dysfunction that characterizes ethylmalonic encephalopathy. Treatment is primarily supportive including anti-spastic medications, muscle relaxants, and anti-seizure medication. Physical therapy early in the disease course can help prevent contractures. Treatment of Manifestations in Individuals with Ethylmalonic Encephalopathy Off-label compassionate use of N-acetylcysteine (NAC) in combination with metronidazole may be considered as they are the only drugs known to slow disease progression and improve the metabolic abnormalities of EE [ N-acetylcysteine (NAC), a cell-permeable precursor of glutathione, is abundant in mitochondria where it can act as one of the physiologic acceptors of the sulfur atom of hydrogen sulfide (H Metronidazole is widely used to combat infections caused by anaerobic bacteria, and can reduce the sulfide-producing bacterial load in the large intestine. 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). Consider use of durable medical equipment 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, Botox • N-acetylcysteine (NAC), a cell-permeable precursor of glutathione, is abundant in mitochondria where it can act as one of the physiologic acceptors of the sulfur atom of hydrogen sulfide (H • Metronidazole is widely used to combat infections caused by anaerobic bacteria, and can reduce the sulfide-producing bacterial load in the large intestine. • 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). • Consider use of durable medical equipment 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, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures). Consider use of durable medical equipment 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, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures). • Consider use of durable medical equipment 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, Botox ## Prevention of Secondary Complications All affected individuals should receive routine immunizations; as well as annual immunizations for influenza. Physicians must pay particular attention to the prevention of infections that could be fatal. ## Surveillance Surveillance should be individualized based on symptoms and organs affected. Recommended Surveillance for Individuals with Ethylmalonic Encephalopathy ## Evaluation of Relatives at Risk See ## Therapies Under Investigation While clearance of circulating sulfide by a transplanted liver could be beneficial, to date only one instance of liver transplantation in EE has been reported [ Possible future treatments include AAV-mediated gene therapy [ Search ## Genetic Counseling Ethylmalonic encephalopathy 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 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 Ethylmalonic encephalopathy 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 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 Italy • • • • United Kingdom • • • • Italy • ## Molecular Genetics Ethylmalonic Encephalopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ethylmalonic Encephalopathy ( Deletion of exon 4 and deletion of the entire gene are the most frequent large deletions [ Select Variants listed in the table have been provided by the authors. HGVS nomenclature: Originally reported with designation that does not conform to current naming conventions ## Chapter Notes 21 September 2017 (bp) Review posted live 23 August 2016 (vt) Original submission • 21 September 2017 (bp) Review posted live • 23 August 2016 (vt) Original submission ## Revision History 21 September 2017 (bp) Review posted live 23 August 2016 (vt) Original submission • 21 September 2017 (bp) Review posted live • 23 August 2016 (vt) Original submission ## References ## Literature Cited
[ "AB Burlina, C Dionisi-Vici, MJ Bennett, KM Gibson, S Servidei, E Bertini, DE Hale, E Schmidt-Sommerfeld, G Sabetta, F Zacchello. A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts.. J Pediatr. 1994;124:79-86", "I Di Meo, A Auricchio, C Lamperti, A Burlina, C Viscomi, M. Zeviani. Effective AAV-mediated gene therapy in a mouse model of ethylmalonic encephalopathy.. EMBO Mol Med 2012;4:1008-14", "I Di Meo, C Lamperti, V Tiranti. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches.. EMBO Mol Med 2015;7:1257-66", "C Dionisi-Vici, D Diodato, G Torre, S Picca, R Pariante, S Giuseppe Picardo, I Di Meo, C Rizzo, V Tiranti, M Zeviani. De GoyetJde V. Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease.. Brain 2016;139:1045-51", "M Di Rocco, U Caruso, E Briem, A Rossi, AE Allegri, D Buzzi, V Tiranti. A case of ethylmalonic encephalopathy with atypical clinical and biochemical presentation.. Mol Genet Metab. 2006;89:395-7", "A Drousiotou, I DiMeo, R Mineri, T Georgiou, G Stylianidou, V. Tiranti. Ethylmalonic encephalopathy: application of improved biochemical and molecular diagnostic approaches.. Clin Genet 2011;79:385-90", "C Giordano, C Viscomi, M Orlandi, P Papoff, A Spalice, A Burlina, I Di Meo, V Tiranti, V Leuzzi, G d'Amati. Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy.. J Inherit Metab Dis 2012;35:451-8", "GS Gorman, PF Chinnery, S DiMauro, M Hirano, Y Koga, R McFarland, A Suomalainen, DR Thorburn, M Zeviani, DM Turnbull. Mitochondrial diseases.. Nat Rev Dis Primers. 2016;2:16080", "S Grosso, R Mostardini, MA Farnetani, M Molinelli, R Berardi, C Dionisi-Vici, C Rizzo, G Morgese, P Balestri. Ethylmalonic encephalopathy: further clinical and neuroradiological characterization.. J Neurol. 2002;249:1446-50", "S Grosso, P Balestri, R Mostardini, A Federico, N De Stefano. Brain mitochondrial impairment in ethylmalonic encephalopathy.. J Neurol. 2004;251:755-6", "LC Heberle, AA Al Tawari, DG Ramadan, JK Ibrahim. Ethylmalonic encephalopathy: report of two cases.. Brain Dev. 2006;28:329-31", "M Kılıç, Ö Dedeoğlu, R Göçmen, S Kesici, D. Yüksel. Successful treatment of a patient with ethylmalonic encephalopathy by intravenous N-acetylcysteine.. Metabolic Brain Disease 2017;32:293-6", "D McHugh. Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.. Genet Med. 2011;13:230-54", "B Merinero, C Pérez-Cerdá, P Ruiz Sala, I Ferrer, MJ García, M Martínez Pardo, A Belanger-Quintana, JL de la Mota, E Martin-Hernández, C Vianey-Saban, C Bischoff, N Gregersen, M Ugarte. Persistent increase of plasma butyryl/isobutyrylcarnitine concentrations as marker of SCAD defect and ethylmalonic encephalopathy.. J Inherit Metab Dis. 2006;29:685", "R Mineri, M Rimoldi, AB Burlina, S Koskull, C Perletti, B Heese, U von Döbeln, P Mereghetti, I Di Meo, F Invernizzi, M Zeviani, G Uziel, V Tiranti. Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy.. J Med Genet. 2008;45:473-8", "N Pigeon, PM Campeau, D Cyr, B Lemieux, JT Clarke. Clinical heterogeneity in ethylmalonic encephalopathy.. J Child Neurol. 2009;24:991-6", "V Tiranti, E Briem, E Lamantea, R Mineri, E Papaleo, L De Gioia, F Forlani, P Rinaldo, P Dickson, B Abu-Libdeh, L Cindro-Heberle, M Owaidha, RM Jack, E Christensen, A Burlina, M Zeviani. ETHE1 mutations are specific to ethylmalonic encephalopathy.. J Med Genet. 2006;43:340-6", "V Tiranti, P D'Adamo, E Briem, G Ferrari, R Mineri, E Lamantea. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.. Am J Hum Genet 2004;74:239-52", "V Tiranti, M. Zeviani. Altered sulfide (H(2)S) metabolism in ethylmalonic encephalopathy.. Cold Spring Harb Perspect Biol 2013;5", "C Viscomi, AB Burlina, I Dweikat, M Savoiardo, C Lamperti, T Hildebrandt, V Tiranti, M Zeviani. Combined treatment with oral metronidazole and N-ace-tylcysteine is effective in ethylmalonic encephalopathy.. Nat Med 2010;16:869-71", "DI Zafeiriou, P Augoustides-Savvopoulou, D Haas, J Smet, P Triantafyllou, E Vargiami, M Tamiolaki, N Gombakis, R van Coster, AC Sewell, C Vianey-Saban, N Gregersen. Ethylmalonic encephalopathy: clinical and biochemical observations.. Neuropediatrics. 2007;38:78-82" ]
21/9/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eed-og
eed-og
[ "Polycomb protein EED", "EED", "EED-Related Overgrowth" ]
Ana Sequerra Amram Cohen, William Thomas Gibson
Summary The diagnosis of
## Diagnosis Overgrowth manifesting as: Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. Macrocephaly (z score ≥2 for age) Large hands and feet (length z score ≥2 for age) Intellectual disability, developmental delay Delay of gross motor skills Delay of fine motor skills Delay of speech acquisition Delay of social development Intellectual disability (by clinical assessment and/or formal testing) Advanced bone age (bone age z score ≥2 for chronologic age) Abnormalities of the cervical spine are uncommon but significant when present. Metaphyses may be widened, flared, and/or abnormally lucent. Skeletal surveys have variously revealed flattened glenoid fossae, humeral heads, femoral heads, and flattened acetabulum. Other findings include small iliac wings and coxa valga or congenital dislocation of the hips, as well as asymmetric limb lengths (1 individual) and flaring of the distal clavicles and distal ribs (1 individual). Osteopenia has been documented on skeletal survey; however, to date no increased risk of fractures has been documented. 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 disorders of overgrowth with intellectual disability (OGID) can be indistinguishable, children with the distinctive findings described in When the phenotype of a child with a disorder of OGID does not strongly suggest a specific diagnosis, molecular genetic testing approaches can include use of a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click When the phenotypic findings suggest the diagnosis 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 missense, nonsense, and splice site variants and small 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. • Overgrowth manifesting as: • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) • Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. • Macrocephaly (z score ≥2 for age) • Large hands and feet (length z score ≥2 for age) • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) • Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. • Macrocephaly (z score ≥2 for age) • Large hands and feet (length z score ≥2 for age) • Intellectual disability, developmental delay • Delay of gross motor skills • Delay of fine motor skills • Delay of speech acquisition • Delay of social development • Intellectual disability (by clinical assessment and/or formal testing) • Delay of gross motor skills • Delay of fine motor skills • Delay of speech acquisition • Delay of social development • Intellectual disability (by clinical assessment and/or formal testing) • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) • Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. • Macrocephaly (z score ≥2 for age) • Large hands and feet (length z score ≥2 for age) • Delay of gross motor skills • Delay of fine motor skills • Delay of speech acquisition • Delay of social development • Intellectual disability (by clinical assessment and/or formal testing) • Advanced bone age (bone age z score ≥2 for chronologic age) • Abnormalities of the cervical spine are uncommon but significant when present. • Metaphyses may be widened, flared, and/or abnormally lucent. • Skeletal surveys have variously revealed flattened glenoid fossae, humeral heads, femoral heads, and flattened acetabulum. Other findings include small iliac wings and coxa valga or congenital dislocation of the hips, as well as asymmetric limb lengths (1 individual) and flaring of the distal clavicles and distal ribs (1 individual). • Osteopenia has been documented on skeletal survey; however, to date no increased risk of fractures has been documented. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Overgrowth manifesting as: Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. Macrocephaly (z score ≥2 for age) Large hands and feet (length z score ≥2 for age) Intellectual disability, developmental delay Delay of gross motor skills Delay of fine motor skills Delay of speech acquisition Delay of social development Intellectual disability (by clinical assessment and/or formal testing) Advanced bone age (bone age z score ≥2 for chronologic age) Abnormalities of the cervical spine are uncommon but significant when present. Metaphyses may be widened, flared, and/or abnormally lucent. Skeletal surveys have variously revealed flattened glenoid fossae, humeral heads, femoral heads, and flattened acetabulum. Other findings include small iliac wings and coxa valga or congenital dislocation of the hips, as well as asymmetric limb lengths (1 individual) and flaring of the distal clavicles and distal ribs (1 individual). Osteopenia has been documented on skeletal survey; however, to date no increased risk of fractures has been documented. • Overgrowth manifesting as: • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) • Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. • Macrocephaly (z score ≥2 for age) • Large hands and feet (length z score ≥2 for age) • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) • Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. • Macrocephaly (z score ≥2 for age) • Large hands and feet (length z score ≥2 for age) • Intellectual disability, developmental delay • Delay of gross motor skills • Delay of fine motor skills • Delay of speech acquisition • Delay of social development • Intellectual disability (by clinical assessment and/or formal testing) • Delay of gross motor skills • Delay of fine motor skills • Delay of speech acquisition • Delay of social development • Intellectual disability (by clinical assessment and/or formal testing) • Tall stature (z score ≥2 for age, equivalent to standard deviation ≥2 above the mean) • Note: An adult of normal stature who had relatively tall stature and/or advanced bone age in childhood or adolescence could meet criteria for overgrowth. • Macrocephaly (z score ≥2 for age) • Large hands and feet (length z score ≥2 for age) • Delay of gross motor skills • Delay of fine motor skills • Delay of speech acquisition • Delay of social development • Intellectual disability (by clinical assessment and/or formal testing) • Advanced bone age (bone age z score ≥2 for chronologic age) • Abnormalities of the cervical spine are uncommon but significant when present. • Metaphyses may be widened, flared, and/or abnormally lucent. • Skeletal surveys have variously revealed flattened glenoid fossae, humeral heads, femoral heads, and flattened acetabulum. Other findings include small iliac wings and coxa valga or congenital dislocation of the hips, as well as asymmetric limb lengths (1 individual) and flaring of the distal clavicles and distal ribs (1 individual). • Osteopenia has been documented on skeletal survey; however, to date no increased risk of fractures has been documented. ## 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 disorders of overgrowth with intellectual disability (OGID) can be indistinguishable, children with the distinctive findings described in When the phenotype of a child with a disorder of OGID does not strongly suggest a specific diagnosis, molecular genetic testing approaches can include use of a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click When the phenotypic findings suggest the diagnosis 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 missense, nonsense, and splice site variants and small 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 • For an introduction to comprehensive genomic testing click ## Scenario 1 When the phenotype of a child with a disorder of OGID does not strongly suggest a specific diagnosis, molecular genetic testing approaches can include use of a For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Scenario 2 When the phenotypic findings suggest the diagnosis 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 missense, nonsense, and splice site variants and small 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 ASD = atrial septal defect; PDA = patent ductus arteriosus; VSD = ventricular septal defect The 19 affected individuals known to date have been reported in the following publications: Birth weight ranges from appropriate to large for gestational age, with weights ranging from 3,550 g (male, 38 weeks' gestation [ Birth length typically ranges from 52 cm (z score = 0.5) to 57 cm (z score = 3.0). Birth head circumference ranges from 35 cm (z score = 0) to 37.2 cm (z score = 2.0). Growth parameter z scores in adults using World Health Organization curves vary from 1.85 to 3.1 in height and 1.46 to 3.9 in head circumference. The two adults reported by Intellectual disability, present in all individuals reported to date, may be mild [ Two affected individuals had relatively sociable, friendly personalities; a third was somewhat hyperactive and lacking inhibition, with occasional aggression toward peers at school. In one individual who had had more detailed testing, specific weaknesses were noted in problem solving and memory, whereas visual memory was a relative strength. Characteristic craniofacial features that are more evident in infancy and childhood and tend to become less evident with age (see Bilateral cleft palate has been reported in one individual, and bifid uvula has been reported in another. Scoliosis and/or kyphoscoliosis of the thoracic spine have been reported frequently. Hypermobility of the small joints of the hands, recurrent patellar subluxation, and dislocation have also been described; with reported skin fragility (poor wound healing, fragile nails), these suggest more generalized laxity of connective tissue. Stenosis of the cervical spine has been reported in three individuals, one of whom required laminectomy and arthrodesis; another had associated myelopathy at the level of the third cervical vertebra. Laminectomy and fusion have also been required in a fourth individual, in the context of atlantoaxial instability with C1-C2 instability. Lumbar spinal stenosis or spondylolisthesis has also been reported in two individuals. Osteopenia, reported in two individuals, was a secondary finding on bone age radiographs or skeletal survey. Epilepsy has been reported in six individuals; one of them had seizures associated with hyperinsulinemic hypoglycemia (see Cerebral imaging has shown nonspecific enlargement of the ventricles, white matter volume loss, an arachnoid cyst, a cyst of the septum pellucidum that required surgical decompression, and a pituitary microadenoma in one individual each. Thinning or shortening of the corpus callosum has been described in two individuals. Cerebral imaging has also been normal in several individuals. Multiple pigmented nevi (3 individuals) Soft, doughy skin with increased elasticity (1 individual) Small nails (2 individuals) Fragile fingernails and toenails (1 individual) Poor wound healing with hyperpigmentation and keloid overgrowth of a surgical scar (1 individual) One female had nephromegaly and a duplicated collecting system. The following were reported in one individual each: Ptosis requiring surgical correction Early-onset cataracts (age 30 years) Chororetinal degeneration Bilateral hypoacusis of 50 dB (frequencies not specified) (1 individual) Mild-to-moderate conductive hearing loss (1 individual) Neonatal hyperinsulinemic hypoglycemia; treated by glucose infusion and resolved at 21 days (1 individual) Childhood-onset hyperinsulinemic hypoglycemia; treated with octreotide (1 individual). Calcification of one of the adrenal glands with hypocortisolism (1 individual) Gastrostomy tube feeds in infancy, later requiring partial bowel resection for obstruction (the latter possibly associated with anticholinergic medications) (1 individual) Chronic constipation (1 individual) Intestinal malrotation and Hirschsprung disease (1 individual) With only 19 probands reported to date, data are insufficient to consider genotype-phenotype correlations. Because most germline To date, 19 individuals have been reported with • Multiple pigmented nevi (3 individuals) • Soft, doughy skin with increased elasticity (1 individual) • Small nails (2 individuals) • Fragile fingernails and toenails (1 individual) • Poor wound healing with hyperpigmentation and keloid overgrowth of a surgical scar (1 individual) • Ptosis requiring surgical correction • Early-onset cataracts (age 30 years) • Chororetinal degeneration • Bilateral hypoacusis of 50 dB (frequencies not specified) (1 individual) • Mild-to-moderate conductive hearing loss (1 individual) • Neonatal hyperinsulinemic hypoglycemia; treated by glucose infusion and resolved at 21 days (1 individual) • Childhood-onset hyperinsulinemic hypoglycemia; treated with octreotide (1 individual). • Calcification of one of the adrenal glands with hypocortisolism (1 individual) • Gastrostomy tube feeds in infancy, later requiring partial bowel resection for obstruction (the latter possibly associated with anticholinergic medications) (1 individual) • Chronic constipation (1 individual) • Intestinal malrotation and Hirschsprung disease (1 individual) ## Clinical Description ASD = atrial septal defect; PDA = patent ductus arteriosus; VSD = ventricular septal defect The 19 affected individuals known to date have been reported in the following publications: Birth weight ranges from appropriate to large for gestational age, with weights ranging from 3,550 g (male, 38 weeks' gestation [ Birth length typically ranges from 52 cm (z score = 0.5) to 57 cm (z score = 3.0). Birth head circumference ranges from 35 cm (z score = 0) to 37.2 cm (z score = 2.0). Growth parameter z scores in adults using World Health Organization curves vary from 1.85 to 3.1 in height and 1.46 to 3.9 in head circumference. The two adults reported by Intellectual disability, present in all individuals reported to date, may be mild [ Two affected individuals had relatively sociable, friendly personalities; a third was somewhat hyperactive and lacking inhibition, with occasional aggression toward peers at school. In one individual who had had more detailed testing, specific weaknesses were noted in problem solving and memory, whereas visual memory was a relative strength. Characteristic craniofacial features that are more evident in infancy and childhood and tend to become less evident with age (see Bilateral cleft palate has been reported in one individual, and bifid uvula has been reported in another. Scoliosis and/or kyphoscoliosis of the thoracic spine have been reported frequently. Hypermobility of the small joints of the hands, recurrent patellar subluxation, and dislocation have also been described; with reported skin fragility (poor wound healing, fragile nails), these suggest more generalized laxity of connective tissue. Stenosis of the cervical spine has been reported in three individuals, one of whom required laminectomy and arthrodesis; another had associated myelopathy at the level of the third cervical vertebra. Laminectomy and fusion have also been required in a fourth individual, in the context of atlantoaxial instability with C1-C2 instability. Lumbar spinal stenosis or spondylolisthesis has also been reported in two individuals. Osteopenia, reported in two individuals, was a secondary finding on bone age radiographs or skeletal survey. Epilepsy has been reported in six individuals; one of them had seizures associated with hyperinsulinemic hypoglycemia (see Cerebral imaging has shown nonspecific enlargement of the ventricles, white matter volume loss, an arachnoid cyst, a cyst of the septum pellucidum that required surgical decompression, and a pituitary microadenoma in one individual each. Thinning or shortening of the corpus callosum has been described in two individuals. Cerebral imaging has also been normal in several individuals. Multiple pigmented nevi (3 individuals) Soft, doughy skin with increased elasticity (1 individual) Small nails (2 individuals) Fragile fingernails and toenails (1 individual) Poor wound healing with hyperpigmentation and keloid overgrowth of a surgical scar (1 individual) One female had nephromegaly and a duplicated collecting system. The following were reported in one individual each: Ptosis requiring surgical correction Early-onset cataracts (age 30 years) Chororetinal degeneration Bilateral hypoacusis of 50 dB (frequencies not specified) (1 individual) Mild-to-moderate conductive hearing loss (1 individual) Neonatal hyperinsulinemic hypoglycemia; treated by glucose infusion and resolved at 21 days (1 individual) Childhood-onset hyperinsulinemic hypoglycemia; treated with octreotide (1 individual). Calcification of one of the adrenal glands with hypocortisolism (1 individual) Gastrostomy tube feeds in infancy, later requiring partial bowel resection for obstruction (the latter possibly associated with anticholinergic medications) (1 individual) Chronic constipation (1 individual) Intestinal malrotation and Hirschsprung disease (1 individual) • Multiple pigmented nevi (3 individuals) • Soft, doughy skin with increased elasticity (1 individual) • Small nails (2 individuals) • Fragile fingernails and toenails (1 individual) • Poor wound healing with hyperpigmentation and keloid overgrowth of a surgical scar (1 individual) • Ptosis requiring surgical correction • Early-onset cataracts (age 30 years) • Chororetinal degeneration • Bilateral hypoacusis of 50 dB (frequencies not specified) (1 individual) • Mild-to-moderate conductive hearing loss (1 individual) • Neonatal hyperinsulinemic hypoglycemia; treated by glucose infusion and resolved at 21 days (1 individual) • Childhood-onset hyperinsulinemic hypoglycemia; treated with octreotide (1 individual). • Calcification of one of the adrenal glands with hypocortisolism (1 individual) • Gastrostomy tube feeds in infancy, later requiring partial bowel resection for obstruction (the latter possibly associated with anticholinergic medications) (1 individual) • Chronic constipation (1 individual) • Intestinal malrotation and Hirschsprung disease (1 individual) ## Genotype-Phenotype Correlations With only 19 probands reported to date, data are insufficient to consider genotype-phenotype correlations. ## Penetrance Because most germline ## Prevalence To date, 19 individuals have been reported with ## Genetically Related (Allelic) Disorders Additional individuals with pathogenic variants in Though to date malignant peripheral nerve sheath tumors (MPNSTs) have not been reported in individuals with ## Cancer and Benign Tumors Though to date malignant peripheral nerve sheath tumors (MPNSTs) have not been reported in individuals with ## Differential Diagnosis Significant overlap in findings is observed between Additional disorders of interest in the differential diagnosis of Disorders with Macrocephaly and Intellectual Disability of Interest in the Differential Diagnosis of Macrosomia Craniofacial dysmorphism similar to Advanced bone age Hematologic malignancies occur at a slightly ↑ frequency. Less frequent cervical spine anomalies Macrosomia Craniofacial dysmorphism similar to Advanced bone age Postnatal overgrowth Craniofacial dysmorphism similar to Advanced bone age Prenatal overgrowth apparently less severe Postnatal overgrowth apparently more severe Macrosomia Neonatal hypoglycemia Umbilical hernia ↑ risk for variety of tumors, in particular Wilms tumor & hepatoblastoma Organomegaly Macroglossia Macrosomia Craniofacial dysmorphism may be similar to Craniofacial dysmorphism in adulthood is distinct from Dilatation of aortic root is more common in Tall stature in childhood Scoliosis Camptodactyly Dilatation of aortic root is more common in Marfan syndrome. Lack of intellectual disability Scoliosis Kyphosis Camptodactyly "Crumpled" ears True joint contractures are rare in Hypertelorism & macrocephaly are more common in Macrosomia Macrocephaly Hernias Vertebral fusion Scoliosis Large hands Postaxial polydactyly Significant risk of embryonal tumors Camptodactyly Kyphoscoliosis Macrosomia Craniofacial dysmorphism Advanced bone age 1 person w/rib osteosarcoma & another w/Wilms tumor have been reported (overall prevalence of malignancy of ~2%). Less frequent cervical spine anomalies Macrocephaly Intellectual disability Cancer predisposition Mucocutaneous lesions AD = autosomal dominant; MOI = mode of inheritance; PV = pathogenic variant; XL = X-linked A constitutional epigenetic or genomic alteration leading to an abnormal methylation pattern at 11p15.5, a copy number variant of chromosome 11p15.5, or a heterozygous Recurrence risk depends on the genetic mechanism in the proband that underlies the abnormal expression of imprinted genes in the Beckwith-Wiedemann syndrome critical region. Contiguous deletions of • Macrosomia • Craniofacial dysmorphism similar to • Advanced bone age • Hematologic malignancies occur at a slightly ↑ frequency. • Less frequent cervical spine anomalies • Macrosomia • Craniofacial dysmorphism similar to • Advanced bone age • Postnatal overgrowth • Craniofacial dysmorphism similar to • Advanced bone age • Prenatal overgrowth apparently less severe • Postnatal overgrowth apparently more severe • Macrosomia • Neonatal hypoglycemia • Umbilical hernia • ↑ risk for variety of tumors, in particular Wilms tumor & hepatoblastoma • Organomegaly • Macroglossia • Macrosomia • Craniofacial dysmorphism may be similar to • Craniofacial dysmorphism in adulthood is distinct from • Dilatation of aortic root is more common in • Tall stature in childhood • Scoliosis • Camptodactyly • Dilatation of aortic root is more common in Marfan syndrome. • Lack of intellectual disability • Scoliosis • Kyphosis • Camptodactyly • "Crumpled" ears • True joint contractures are rare in • Hypertelorism & macrocephaly are more common in • Macrosomia • Macrocephaly • Hernias • Vertebral fusion • Scoliosis • Large hands • Postaxial polydactyly • Significant risk of embryonal tumors • Camptodactyly • Kyphoscoliosis • Macrosomia • Craniofacial dysmorphism • Advanced bone age • 1 person w/rib osteosarcoma & another w/Wilms tumor have been reported (overall prevalence of malignancy of ~2%). • Less frequent cervical spine anomalies • Macrocephaly • Intellectual disability • Cancer predisposition • Mucocutaneous lesions ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Refer to neurologist for seizure disorder mgmt. Rule out hyperinsulinism. If lethargy &/or poor feeding If seizures occur, measure glucose & insulin simultaneously. MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment is symptomatic; no therapy specific to the disorder is available. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Mgmt by cleft/craniofacial team Surgical correction of cleft palate Orthodontic interventions to correct retrognathia (overbite) as needed ASM = antiseizure medication; 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. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 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. Autism or other major behavior problems have not been reported to date in To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Though to date data are insufficient to recommend routine imaging of the cervical spine to screen for atlantoaxial instability or spinal canal stenosis, practitioners should have a low threshold for imaging when signs and symptoms are consistent with cord impingement, such as gait deterioration (particularly when of rapid onset). Elective cervical spine imaging should be considered when activities involve possible sudden movement of the neck and/or head and neck (e.g., contact sports, amusement park thrill rides). Hyperinsulinemic hypoglycemia was confirmed in two individuals (1 as a neonate); infants showing evidence of poor neonatal adaptation should have their serum glucose measured, and insulin levels measured if circulating glucose is low. Although malignant peripheral nerve sheath tumors (MPNSTs) have not been reported to date in individuals with In one individual, neurologic compromise resulting from neck motion during gymnastics required surgical intervention. Caution is advised for activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks). Side effects of pharmacologic agents that inhibit the activity of polycomb repressive complex 2 (PRC2) (which includes the polycomb protein EED, encoded by See Search • Refer to neurologist for seizure disorder mgmt. • Rule out hyperinsulinism. • If lethargy &/or poor feeding • If seizures occur, measure glucose & insulin simultaneously. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Mgmt by cleft/craniofacial team • Surgical correction of cleft palate • Orthodontic interventions to correct retrognathia (overbite) as needed • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 Refer to neurologist for seizure disorder mgmt. Rule out hyperinsulinism. If lethargy &/or poor feeding If seizures occur, measure glucose & insulin simultaneously. MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Refer to neurologist for seizure disorder mgmt. • Rule out hyperinsulinism. • If lethargy &/or poor feeding • If seizures occur, measure glucose & insulin simultaneously. ## Treatment of Manifestations Treatment is symptomatic; no therapy specific to the disorder is available. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Mgmt by cleft/craniofacial team Surgical correction of cleft palate Orthodontic interventions to correct retrognathia (overbite) as needed ASM = antiseizure medication; 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. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 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. Autism or other major behavior problems have not been reported to date in • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Mgmt by cleft/craniofacial team • Surgical correction of cleft palate • Orthodontic interventions to correct retrognathia (overbite) as needed • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 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. Autism or other major behavior problems have not been reported to date in ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Though to date data are insufficient to recommend routine imaging of the cervical spine to screen for atlantoaxial instability or spinal canal stenosis, practitioners should have a low threshold for imaging when signs and symptoms are consistent with cord impingement, such as gait deterioration (particularly when of rapid onset). Elective cervical spine imaging should be considered when activities involve possible sudden movement of the neck and/or head and neck (e.g., contact sports, amusement park thrill rides). Hyperinsulinemic hypoglycemia was confirmed in two individuals (1 as a neonate); infants showing evidence of poor neonatal adaptation should have their serum glucose measured, and insulin levels measured if circulating glucose is low. Although malignant peripheral nerve sheath tumors (MPNSTs) have not been reported to date in individuals with ## Agents/Circumstances to Avoid In one individual, neurologic compromise resulting from neck motion during gymnastics required surgical intervention. Caution is advised for activities that involve rapid neck motion and/or possible trauma to the head and neck region (e.g., contact sports or thrill rides at amusement parks). Side effects of pharmacologic agents that inhibit the activity of polycomb repressive complex 2 (PRC2) (which includes the polycomb protein EED, encoded by ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most probands reported to date with Some individuals diagnosed with If a parent of an individual with an identified If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 a family member has a confirmed molecular diagnosis of 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 probands reported to date with • Some individuals diagnosed with • If a parent of an individual with an identified • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. • 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 • The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 reported to date with Some individuals diagnosed with If a parent of an individual with an identified If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. 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 • Most probands reported to date with • Some individuals diagnosed with • If a parent of an individual with an identified • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * If the 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. Subtle features such as tall stature, larger-than-normal head circumference, mild facial dysmorphisms, and a history of mild developmental delay may not be obvious unless sought specifically during the parental assessment. • 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 ## 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 a family member has a confirmed molecular diagnosis of Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Canada Joint venture between TBRS Community and the Malan Syndrome Foundation Canada • • United Kingdom • • • • • • • • • Canada • • • Joint venture between TBRS Community and the Malan Syndrome Foundation • • • Canada • ## Molecular Genetics EED-Related Overgrowth: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EED-Related Overgrowth ( There are seven WD40 domains, though whether these domains have redundant or distinct functions is not yet known. The C-terminal domain of EED binds specifically to trimethylated H3K27 (i.e., H3K27me3) histone tails, and this function is thought to be necessary for the propagation of H3K27me3 marks to daughter cells that initially lack sufficient H3K27 marks after mitosis. In so doing, EED is believed to provide the epigenetic reader function of the PRC2 complex’s epigenetic reader-writer function. In general, PRC2 is a key chromatin modifier involved in the maintenance of transcriptional silencing. PRC2-mediated trimethylation of H3K27 is thought to correlate with transcriptional repression of local DNA. Correct propagation of H3K27me3 marks is in turn thought necessary in order for repressive domains to persist in the newly synthesized chromatin [ In an ex vivo assay, a lymphoblastoid cell line derived from a Japanese individual with Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis There are seven WD40 domains, though whether these domains have redundant or distinct functions is not yet known. The C-terminal domain of EED binds specifically to trimethylated H3K27 (i.e., H3K27me3) histone tails, and this function is thought to be necessary for the propagation of H3K27me3 marks to daughter cells that initially lack sufficient H3K27 marks after mitosis. In so doing, EED is believed to provide the epigenetic reader function of the PRC2 complex’s epigenetic reader-writer function. In general, PRC2 is a key chromatin modifier involved in the maintenance of transcriptional silencing. PRC2-mediated trimethylation of H3K27 is thought to correlate with transcriptional repression of local DNA. Correct propagation of H3K27me3 marks is in turn thought necessary in order for repressive domains to persist in the newly synthesized chromatin [ In an ex vivo assay, a lymphoblastoid cell line derived from a Japanese individual with Variants listed in the table have been provided by the authors. ## Chapter Notes Dr William T Gibson's clinical and laboratory research focuses on Cohen-Gibson syndrome, Weaver syndrome, and similar rare disorders, including rare genetic versions of common, complex diseases. Dr Gibson ( Dr Gibson is also interested in hearing from clinicians treating families affected by childhood overgrowth and intellectual disability 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 Gibson to inquire about review of We gratefully acknowledge the patients and their families who have generously participated in the research described and referenced here. We also gratefully acknowledge the contributions of Professor Steven JM Jones and Dr Yaoqing Shen for helpful discussions of Dr Gibson gratefully acknowledges both research salary support and laboratory support provided by the British Columbia Children's Hospital Foundation through the BC Children's Hospital Research Institute's IGAP Intramural Salary Award program, as well as various Childhood Diseases Theme and Diabetes Theme funding programs. Dr Gibson is also grateful for the operating funds provided competitively through various programs run by the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), Genome Canada, and Genome British Columbia. Dr Cohen would like to thank the generous gifts to Children's Mercy Research Institute and the Genomic Answers for Kids program at Children's Mercy Kansas City. 8 May 2025 (sw) Comprehensive updated posted live 11 April 2019 (bp) Review posted live 8 April 2018 (wtg) Original submission • 8 May 2025 (sw) Comprehensive updated posted live • 11 April 2019 (bp) Review posted live • 8 April 2018 (wtg) Original submission ## Author Notes Dr William T Gibson's clinical and laboratory research focuses on Cohen-Gibson syndrome, Weaver syndrome, and similar rare disorders, including rare genetic versions of common, complex diseases. Dr Gibson ( Dr Gibson is also interested in hearing from clinicians treating families affected by childhood overgrowth and intellectual disability 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 Gibson to inquire about review of ## Acknowledgments We gratefully acknowledge the patients and their families who have generously participated in the research described and referenced here. We also gratefully acknowledge the contributions of Professor Steven JM Jones and Dr Yaoqing Shen for helpful discussions of Dr Gibson gratefully acknowledges both research salary support and laboratory support provided by the British Columbia Children's Hospital Foundation through the BC Children's Hospital Research Institute's IGAP Intramural Salary Award program, as well as various Childhood Diseases Theme and Diabetes Theme funding programs. Dr Gibson is also grateful for the operating funds provided competitively through various programs run by the Canadian Institutes of Health Research (CIHR), the Canada Foundation for Innovation (CFI), Genome Canada, and Genome British Columbia. Dr Cohen would like to thank the generous gifts to Children's Mercy Research Institute and the Genomic Answers for Kids program at Children's Mercy Kansas City. ## Revision History 8 May 2025 (sw) Comprehensive updated posted live 11 April 2019 (bp) Review posted live 8 April 2018 (wtg) Original submission • 8 May 2025 (sw) Comprehensive updated posted live • 11 April 2019 (bp) Review posted live • 8 April 2018 (wtg) Original submission ## References ## Literature Cited Photographs of a male with Note round face with prominent forehead, hypertelorism, and depressed nasal bridge (A-F); large ears (C, G, H, I, K); prominent philtrum (A, B, C, J); prominent crease between the lower lip and chin (A, C, E, H, I, J); retrognathia (A, B, C, K); multiple pigmented nevi (J, K, L, M); overall body habitus (L, M); and large hands and feet (N, O, P). Published with permission.
[]
11/4/2019
8/5/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
efemp2-cutis-laxa
efemp2-cutis-laxa
[ "Autosomal Recessive Cutis Laxa Type 1B (ARCL1B)", "Autosomal Recessive Cutis Laxa Type 1B (ARCL1B)", "EGF-containing fibulin-like extracellular matrix protein 2", "EFEMP2", "EFEMP2-Related Cutis Laxa" ]
Bart Loeys, Anne De Paepe, Zsolt Urban
Summary The diagnosis of
## Diagnosis The diagnosis of Arterial and aortic tortuosity Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. Aortic stenosis. The isthmus aorta in particular is often stenotic. Stenosis and dilatation of pulmonary arteries Pulmonary hypertension Hemorrhagic stroke Retrognathia Widely spaced eyes High palate Long philtrum Sagging cheeks Dysplastic ears Other evidence of a Joint laxity or contractures Arachnodactyly Pectus excavatum Inguinal hernias Hypotonia Bone fragility 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 the phenotype of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of 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. • • Arterial and aortic tortuosity • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. • Aortic stenosis. The isthmus aorta in particular is often stenotic. • Stenosis and dilatation of pulmonary arteries • Pulmonary hypertension • Hemorrhagic stroke • Arterial and aortic tortuosity • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. • Aortic stenosis. The isthmus aorta in particular is often stenotic. • Stenosis and dilatation of pulmonary arteries • Pulmonary hypertension • Hemorrhagic stroke • • Retrognathia • Widely spaced eyes • High palate • Long philtrum • Sagging cheeks • Dysplastic ears • Retrognathia • Widely spaced eyes • High palate • Long philtrum • Sagging cheeks • Dysplastic ears • Other evidence of a • Joint laxity or contractures • Arachnodactyly • Pectus excavatum • Inguinal hernias • Hypotonia • Bone fragility • Joint laxity or contractures • Arachnodactyly • Pectus excavatum • Inguinal hernias • Hypotonia • Bone fragility • Arterial and aortic tortuosity • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. • Aortic stenosis. The isthmus aorta in particular is often stenotic. • Stenosis and dilatation of pulmonary arteries • Pulmonary hypertension • Hemorrhagic stroke • Retrognathia • Widely spaced eyes • High palate • Long philtrum • Sagging cheeks • Dysplastic ears • Joint laxity or contractures • Arachnodactyly • Pectus excavatum • Inguinal hernias • Hypotonia • Bone fragility • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click ## Suggestive Findings The diagnosis of Arterial and aortic tortuosity Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. Aortic stenosis. The isthmus aorta in particular is often stenotic. Stenosis and dilatation of pulmonary arteries Pulmonary hypertension Hemorrhagic stroke Retrognathia Widely spaced eyes High palate Long philtrum Sagging cheeks Dysplastic ears Other evidence of a Joint laxity or contractures Arachnodactyly Pectus excavatum Inguinal hernias Hypotonia Bone fragility • • Arterial and aortic tortuosity • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. • Aortic stenosis. The isthmus aorta in particular is often stenotic. • Stenosis and dilatation of pulmonary arteries • Pulmonary hypertension • Hemorrhagic stroke • Arterial and aortic tortuosity • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. • Aortic stenosis. The isthmus aorta in particular is often stenotic. • Stenosis and dilatation of pulmonary arteries • Pulmonary hypertension • Hemorrhagic stroke • • Retrognathia • Widely spaced eyes • High palate • Long philtrum • Sagging cheeks • Dysplastic ears • Retrognathia • Widely spaced eyes • High palate • Long philtrum • Sagging cheeks • Dysplastic ears • Other evidence of a • Joint laxity or contractures • Arachnodactyly • Pectus excavatum • Inguinal hernias • Hypotonia • Bone fragility • Joint laxity or contractures • Arachnodactyly • Pectus excavatum • Inguinal hernias • Hypotonia • Bone fragility • Arterial and aortic tortuosity • Aortic and arterial aneurysms. The ascending aorta and aortic arch are typically most dilated. • Aortic stenosis. The isthmus aorta in particular is often stenotic. • Stenosis and dilatation of pulmonary arteries • Pulmonary hypertension • Hemorrhagic stroke • Retrognathia • Widely spaced eyes • High palate • Long philtrum • Sagging cheeks • Dysplastic ears • Joint laxity or contractures • Arachnodactyly • Pectus excavatum • Inguinal hernias • Hypotonia • Bone fragility ## 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 the phenotype of Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of 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 • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, 49 individuals have been identified with a pathogenic variant in Based on Survival analysis comparing four individuals with at least one truncating Very few reliable estimates of the prevalence of cutis laxa exist. The prevalence at birth for all types of cutis laxa is 1:4,000,000 according to the Rhone-Alps Eurocat Registry [E Robert, personal observation]. ## Clinical Description To date, 49 individuals have been identified with a pathogenic variant in Based on ## Genotype-Phenotype Correlations Survival analysis comparing four individuals with at least one truncating ## Prevalence Very few reliable estimates of the prevalence of cutis laxa exist. The prevalence at birth for all types of cutis laxa is 1:4,000,000 according to the Rhone-Alps Eurocat Registry [E Robert, personal observation]. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of AD = autosomal dominant; ADCL = autosomal dominant cutis laxa; AR = autosomal recessive; ARCL = autosomal recessive cutis laxa; CL = cutis laxa; CV = cardiovascular; DD = developmental delay; GI = gastrointestinal; GU = genitourinary; ID = intellectual development; MOI = mode of inheritance; URDS = Urban-Rifkin-Davis syndrome Single case report of emphysema in arterial tortuosity syndrome reported by ## 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 MOI = mode of inheritance; MRA = magnetic resonance angiography Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with Based on experience in related disorders (e.g., Surgical repair of large aortic aneurysms (at risk for dissection) should be considered. Aortic aneurysm replacement has been performed successfully. PT = physical therapy Recommended Surveillance for Individuals with MRA = magnetic resonance angiography Avoid the following: Sun tanning, which can damage skin Cigarette smoking, which can worsen emphysema It is appropriate to clarify the genetic status of older and younger sibs of an affected individual in order to identify as early as possible those who should undergo regular cardiovascular and pulmonary See Search • Based on experience in related disorders (e.g., • Surgical repair of large aortic aneurysms (at risk for dissection) should be considered. • Aortic aneurysm replacement has been performed successfully. • Sun tanning, which can damage skin • Cigarette smoking, which can worsen emphysema ## 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 MOI = mode of inheritance; MRA = magnetic resonance angiography Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ## Treatment of Manifestations Treatment of Manifestations in Individuals with Based on experience in related disorders (e.g., Surgical repair of large aortic aneurysms (at risk for dissection) should be considered. Aortic aneurysm replacement has been performed successfully. PT = physical therapy • Based on experience in related disorders (e.g., • Surgical repair of large aortic aneurysms (at risk for dissection) should be considered. • Aortic aneurysm replacement has been performed successfully. ## Surveillance Recommended Surveillance for Individuals with MRA = magnetic resonance angiography ## Agents/Circumstances to Avoid Avoid the following: Sun tanning, which can damage skin Cigarette smoking, which can worsen emphysema • Sun tanning, which can damage skin • Cigarette smoking, which can worsen emphysema ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of older and younger sibs of an affected individual in order to identify as early as possible those who should undergo regular cardiovascular and pulmonary 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 In general, similar clinical manifestations are observed in sibs with 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., 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 • In general, similar clinical manifestations are observed in sibs with • 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., 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 In general, similar clinical manifestations are observed in sibs with 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 • In general, similar clinical manifestations are observed in sibs with • 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 New Zealand • • New Zealand • • • ## Molecular Genetics EFEMP2-Related Cutis Laxa: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EFEMP2-Related Cutis Laxa ( Different mechanisms have been suggested for the pathogenetic consequences of Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Different mechanisms have been suggested for the pathogenetic consequences of Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Bart Loeys, MD, PhD Anne De Paepe, MD, PhD Zsolt Urban, PhD This work was funded in part by the University of Antwerp (GOA, Methusalem-OEC grant "Genomed" FFB190208), the Fund for Scientific Research, Flanders (FWO, Belgium, G.0356.17, G.0447.20), the Dutch Heart Foundation (2013T093), and the Marfan Foundation. Dr Loeys, senior clinical investigator of the Fund for Scientific Research, Flanders, holds a consolidator grant from the European Research Council (Genomia – ERC-COG-2017-771945) and is a member of European Reference Network on rare vascular disorders (VASCERN). 15 June 2023 (aa) Revision: added 22 October 2020 (ha) Comprehensive update posted live 23 July 2015 (me) Comprehensive update posted live 12 May 2011 (me) Review posted live 9 July 2010 (bl) Original submission • 15 June 2023 (aa) Revision: added • 22 October 2020 (ha) Comprehensive update posted live • 23 July 2015 (me) Comprehensive update posted live • 12 May 2011 (me) Review posted live • 9 July 2010 (bl) Original submission ## Author Notes Bart Loeys, MD, PhD Anne De Paepe, MD, PhD Zsolt Urban, PhD ## Acknowledgments This work was funded in part by the University of Antwerp (GOA, Methusalem-OEC grant "Genomed" FFB190208), the Fund for Scientific Research, Flanders (FWO, Belgium, G.0356.17, G.0447.20), the Dutch Heart Foundation (2013T093), and the Marfan Foundation. Dr Loeys, senior clinical investigator of the Fund for Scientific Research, Flanders, holds a consolidator grant from the European Research Council (Genomia – ERC-COG-2017-771945) and is a member of European Reference Network on rare vascular disorders (VASCERN). ## Revision History 15 June 2023 (aa) Revision: added 22 October 2020 (ha) Comprehensive update posted live 23 July 2015 (me) Comprehensive update posted live 12 May 2011 (me) Review posted live 9 July 2010 (bl) Original submission • 15 June 2023 (aa) Revision: added • 22 October 2020 (ha) Comprehensive update posted live • 23 July 2015 (me) Comprehensive update posted live • 12 May 2011 (me) Review posted live • 9 July 2010 (bl) Original submission ## References ## Literature Cited
[ "CS Adamo, A Beyens, A Schiavinato, DR Keene, SF Tufa, M Mörgelin, J Brinckmann, T Sasaki, A Niehoff, M Dreiner, L Pottie, L Muiño-Mosquera, EY Gulec, A Gezdirici, P Braghetta, P Bonaldo, R Wagener, M Paulsson, H Bornaun, R De Rycke, M De Bruyne, F Baeke, WP Devine, B Gangaram, A Tam, M Balasubramanian, S Ellard, S Moore, S Symoens, J Shen, S Cole, U Schwarze, KW Holmes, SJ Hayflick, W Wiszniewski, S Nampoothiri, EC Davis, LY Sakai, G Sengle, B Callewaert. EMILIN1 deficiency causes arterial tortuosity with osteopenia and connects impaired elastogenesis with defective collagen fibrillogenesis.. Am J Hum Genet. 2022;109:2230-52", "ZN Al-Hassnan, AR Almesned, S Tulbah, A Hakami, A Al-Omrani, A Al Sehly, S Mohammed, S Majid, B Meyer, M Al-Fayyadh. Recessively inherited severe aortic aneurysm caused by mutated EFEMP2.. Am J Cardiol. 2012;109:1677-80", "M Dasouki, D Markova, R Garola, T Sasaki, NL Charbonneau, LY Sakai, ML Chu. Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa.. Am J Med Genet A. 2007;143A:2635-41", "LK Erickson, JM Opitz, H Zhou. Lethal osteogenesis imperfecta-like condition with cutis laxa and arterial tortuosity in MZ twins due to a homozygous fibulin-4 mutation.. Pediatr Dev Pathol. 2012;15:137-41", "C Hebson, K Coleman, M Clabby, D Sallee, S Shankar, B Loeys, L Van Laer, B Kogon. Severe aortopathy due to fibulin-4 deficiency: molecular insights, surgical strategy, and a review of the literature.. Eur J Pediatr. 2014;173:671-5", "M Hibino, Y Sakai, W Kato, K Tanaka, K Tajima, T Yokoyama, M Iwasa, H Morisaki, T Tsuzuki, A Usui. Ascending aortic aneurysm in a child with fibulin-4 deficiency.. Ann Thorac Surg. 2018;105:e59-e61", "J Hoyer, C Kraus, G Hammersen, JP Geppert, A Rauch. Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation.. Clin Genet 2009;76:276-81", "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", "V Hucthagowder, N Sausgruber, KH Kim, B Angle, LY Marmorstein, Z Urban. Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome.. Am J Hum Genet 2006;78:1075-80", "M Iascone, ME Sana, L Pezzoli, P Bianchi, D Marchetti, G Fasolini, Y Sadou, A Locatelli, F Fabiani, G Mangili, P Ferrazzi. Extensive arterial tortuosity and severe aortic dilation in a newborn with an EFEMP2 mutation.. Circulation. 2012;126:2764-8", "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", "M Kappanayil, S Nampoothiri, R Kannan, M Renard, P Coucke, F Malfait, S Menon, HK Ravindran, R Kurup, M Faiyaz-Ul-Haque, K Kumar, A De Paepe. Characterization of a distinct lethal arteriopathy syndrome in twenty-two infants associated with an identical, novel mutation in FBLN4 gene, confirms fibulin-4 as a critical determinant of human vascular elastogenesis.. Orphanet J Rare Dis. 2012;7:61", "P Letard, D Schepers, J Albuisson, P Bruneval, E Spaggiari, G Van de Beek, S Khung-Savatovsky, N Belarbi, Y Capri, AL Delezoide, B Loeys, F Guimiot. Severe phenotype of cutis laxa type 1b with antenatal signs due to a novel homozygous nonsense mutation in EFEMP2.. Mol Syndromol. 2018;9:190-6", "TF Mauger, CL Mundy, TD Oostra, PJ Patel. Keratoglobus with ARCL1B (EFEMP2 gene) cutis laxa.. Am J Ophthalmol Case Rep. 2019;15", "CL Papke, H Yanagisawa. Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies.. Matrix Biol. 2014;37:142-9", "M Renard, T Holm, R Veith, BL Callewaert, LC Adès, O Baspinar, A Pickart, M Dasouki, J Hoyer, A Rauch, P Trapane, MG Earing, PJ Coucke, LY Sakai, HC Dietz, AM De Paepe, BL Loeys. Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency.. Eur J Hum Genet. 2010;18:895-901", "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", "T Sasaki, FG Hanisch, R Deutzmann, LY Sakai, T Sakuma, T Miyamoto, T Yamamoto, E Hannappel, ML Chu, H Lanig, K von der Mark. Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa.. Matrix Biol. 2016;56:132-49", "SL Sawyer, F Dicke, A Kirton, T Rajapkse, IM Rebeyka, B McInnes, JS Parboosingh, FP Bernier. Longer term survival of a child with autosomal recessive cutis laxa due to a mutation in FBLN4.. Am J Med Genet A. 2013;161A:1148-53", "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", "Y Takahashi, K Fujii, A Yoshida, H Morisaki, Y Kohno, T Morisaki. Artery tortuosity syndrome exhibiting early-onset emphysema with novel compound heterozygous SLC2A10 mutations.. Am J Med Genet A. 2013;161A:856-9", "AT Yetman, J Hammel, JN Sanmann, LJ Starr. Valve-sparing root and total arch replacement for cutis laxa aortopathy.. World J Pediatr Congenit Heart Surg. 2019;10:376-9" ]
12/5/2011
22/10/2020
15/6/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
el-hattab-alkuraya
el-hattab-alkuraya
[ "WDR45B-Related Neurodevelopmental Disorder", "WDR45B-Related Neurodevelopmental Disorder", "WD repeat domain phosphoinositide-interacting protein 3", "WDR45B", "El-Hattab-Alkuraya Syndrome" ]
El-Hattab-Alkuraya Syndrome
Mohammed Almannai, Dana Marafi, Ayman W El-Hattab
Summary El-Hattab-Alkuraya syndrome is characterized by microcephaly (often early onset and progressive); severe-to-profound developmental delay; refractory and early-onset seizures; spastic quadriplegia with axial hypotonia; and growth deficiency with poor weight gain and short stature. Characteristic findings on brain imaging include cerebral atrophy that is disproportionately most prominent in the frontal lobes; The diagnosis of El-Hattab-Alkuraya syndrome is established in a proband by identification of biallelic pathogenic variants in El-Hattab-Alkuraya syndrome is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
## Diagnosis El-Hattab-Alkuraya syndrome Progressive microcephaly Developmental delay Early-onset, refractory seizures Spastic quadriplegia Growth deficiency (poor weight gain, short stature) Cerebral atrophy with disproportionate atrophy of the frontal lobes Brain stem volume loss with flattening of the belly of the pons Symmetric under-opercularization The diagnosis of El-Hattab-Alkuraya 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 comprehensive genomic testing click For an introduction to multigene panels click Molecular Genetic Testing Used in El-Hattab-Alkuraya 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 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 microcephaly • Developmental delay • Early-onset, refractory seizures • Spastic quadriplegia • Growth deficiency (poor weight gain, short stature) • Cerebral atrophy with disproportionate atrophy of the frontal lobes • Brain stem volume loss with flattening of the belly of the pons • Symmetric under-opercularization • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Suggestive Findings El-Hattab-Alkuraya syndrome Progressive microcephaly Developmental delay Early-onset, refractory seizures Spastic quadriplegia Growth deficiency (poor weight gain, short stature) Cerebral atrophy with disproportionate atrophy of the frontal lobes Brain stem volume loss with flattening of the belly of the pons Symmetric under-opercularization • Progressive microcephaly • Developmental delay • Early-onset, refractory seizures • Spastic quadriplegia • Growth deficiency (poor weight gain, short stature) • Cerebral atrophy with disproportionate atrophy of the frontal lobes • Brain stem volume loss with flattening of the belly of the pons • Symmetric under-opercularization ## Establishing the Diagnosis The diagnosis of El-Hattab-Alkuraya 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 comprehensive genomic testing click For an introduction to multigene panels click Molecular Genetic Testing Used in El-Hattab-Alkuraya 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 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 comprehensive genomic testing click • For an introduction to multigene panels click ## Clinical Characteristics El-Hattab-Alkuraya syndrome is characterized by congenital and progressive microcephaly, developmental delay, seizures, spastic quadriplegia, associated brain imaging findings, and progressive neurologic involvement with significant morbidity and mortality. To date, 22 individuals with biallelic pathogenic variants in El-Hattab-Alkuraya Syndrome: Frequency of Select Features Average age at the time of evaluation was 6.5 years (range 7 months – 14 years) Denominator reflects the number of persons assessed for the feature. Common Cerebral atrophy with disproportionate atrophy of the frontal lobe Giant cisterna magna Corpus callosum thinning Brain stem volume loss with flattening of the belly of the pons Symmetric under-opercularization Dysplastic hippocampi Cerebellar atrophy Cervical spine atrophy The number of affected individuals is insufficient to establish genotype-phenotype correlations. However, two sibs homozygous for missense variant El-Hattab-Alkuraya syndrome may also be referred to as The exact prevalence is unknown, but El-Hattab-Alkuraya syndrome appears to be rare, with only 22 individuals reported to date. Most affected individuals are of Arab ancestry. • Cerebral atrophy with disproportionate atrophy of the frontal lobe • Giant cisterna magna • Corpus callosum thinning • Brain stem volume loss with flattening of the belly of the pons • Symmetric under-opercularization • Dysplastic hippocampi • Cerebellar atrophy • Cervical spine atrophy ## Clinical Description El-Hattab-Alkuraya syndrome is characterized by congenital and progressive microcephaly, developmental delay, seizures, spastic quadriplegia, associated brain imaging findings, and progressive neurologic involvement with significant morbidity and mortality. To date, 22 individuals with biallelic pathogenic variants in El-Hattab-Alkuraya Syndrome: Frequency of Select Features Average age at the time of evaluation was 6.5 years (range 7 months – 14 years) Denominator reflects the number of persons assessed for the feature. Common Cerebral atrophy with disproportionate atrophy of the frontal lobe Giant cisterna magna Corpus callosum thinning Brain stem volume loss with flattening of the belly of the pons Symmetric under-opercularization Dysplastic hippocampi Cerebellar atrophy Cervical spine atrophy • Cerebral atrophy with disproportionate atrophy of the frontal lobe • Giant cisterna magna • Corpus callosum thinning • Brain stem volume loss with flattening of the belly of the pons • Symmetric under-opercularization • Dysplastic hippocampi • Cerebellar atrophy • Cervical spine atrophy ## Genotype-Phenotype Correlations The number of affected individuals is insufficient to establish genotype-phenotype correlations. However, two sibs homozygous for missense variant ## Nomenclature El-Hattab-Alkuraya syndrome may also be referred to as ## Prevalence The exact prevalence is unknown, but El-Hattab-Alkuraya syndrome appears to be rare, with only 22 individuals reported to date. Most affected individuals are of Arab ancestry. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Because the phenotypic features associated with El-Hattab-Alkuraya 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 ## Management To establish the extent of disease and needs in an individual diagnosed with El-Hattab-Alkuraya syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with El-Hattab-Alkuraya Syndrome To incl brain MRI to evaluate extent of disorder EEG To incl motor, adaptive, cognitive, & speech/language eval Assess needs for speech, OT, PT. Eval for early intervention / special education Nutritional eval Swallowing assessment for feeding difficulties Community or Social work involvement for parental support; Home nursing referral. 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 El-Hattab-Alkuraya Syndrome Feeding therapy Nasogastric tube or gastrostomy tube are frequently needed due to feeding difficulties & poor weight gain. ASM = anti-seizure medication 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 in Recommended Surveillance for Individuals with El-Hattab-Alkuraya Syndrome Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, & mvmt disorders. See Search • To incl brain MRI to evaluate extent of disorder • EEG • To incl motor, adaptive, cognitive, & speech/language eval • Assess needs for speech, OT, PT. • Eval for early intervention / special education • Nutritional eval • Swallowing assessment for feeding difficulties • Community or • Social work involvement for parental support; • Home nursing referral. • Feeding therapy • Nasogastric tube or gastrostomy tube are frequently needed due to feeding difficulties & poor weight gain. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, & mvmt disorders. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with El-Hattab-Alkuraya syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with El-Hattab-Alkuraya Syndrome To incl brain MRI to evaluate extent of disorder EEG To incl motor, adaptive, cognitive, & speech/language eval Assess needs for speech, OT, PT. Eval for early intervention / special education Nutritional eval Swallowing assessment for feeding difficulties Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI to evaluate extent of disorder • EEG • To incl motor, adaptive, cognitive, & speech/language eval • Assess needs for speech, OT, PT. • Eval for early intervention / special education • Nutritional eval • Swallowing assessment for feeding difficulties • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with El-Hattab-Alkuraya Syndrome Feeding therapy Nasogastric tube or gastrostomy tube are frequently needed due to feeding difficulties & poor weight gain. ASM = anti-seizure medication 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. • Feeding therapy • Nasogastric tube or gastrostomy tube are frequently needed due to feeding difficulties & poor weight gain. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 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 El-Hattab-Alkuraya Syndrome Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, & mvmt disorders. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, & mvmt disorders. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling El-Hattab-Alkuraya 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 El-Hattab-Alkuraya 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 Canada Canada • • • • • • Canada • • • • • Canada • • • • • ## Molecular Genetics El-Hattab-Alkuraya Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for El-Hattab-Alkuraya 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 29 September 2022 (sw) Review posted live 5 August 2022 (ma) Original submission • 29 September 2022 (sw) Review posted live • 5 August 2022 (ma) Original submission ## Revision History 29 September 2022 (sw) Review posted live 5 August 2022 (ma) Original submission • 29 September 2022 (sw) Review posted live • 5 August 2022 (ma) Original submission ## References ## Literature Cited
[ "M Almannai, D Marafi, GMH Abdel-Salam, MS Zaki, R Duan, D Calame, I Herman, F Levesque, HM Elbendary, I Hegazy, WK Chung, H Kavus, K Saeidi, R Maroofian, A AlHashim, A Al-Otaibi, A Al Madhi, HM Abou Al-Seood, A Alasmari, H Houlden, JG Gleeson, JV Hunter, JE Posey, JR Lupski, AW El-Hattab. El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: further delineation of the phenotype and genotype.. Clin Genet. 2022;101:530-40", "S Anazi, S Maddirevula, E Faqeih, H Alsedairy, F Alzahrani, HE Shamseldin, N Patel, M Hashem, N Ibrahim, F Abdulwahab, N Ewida, HS Alsaif, H Al Sharif, W Alamoudi, A Kentab, FA Bashiri, M Alnaser, AH AlWadei, M Alfadhel, W Eyaid, A Hashem, A Al Asmari, MM Saleh, A AlSaman, KA Alhasan, M Alsughayir, M Al Shammari, A Mahmoud, ZN Al-Hassnan, M Al-Husain, R Osama Khalil, N Abd El Meguid, A Masri, R Ali, T Ben-Omran, P El Fishway, A Hashish, A Ercan Sencicek, M State, AM Alazami, MA Salih, N Altassan, ST Arold, M Abouelhoda, SM Wakil, D Monies, R Shaheen, FS Alkuraya. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield.. Mol Psychiatry. 2017;22:615-24", "D Bakula, AJ Müller, T Zuleger, Z Takacs, M Franz-Wachtel, AK Thost, D Brigger, MP Tschan, T Frickey, H Robenek, B Macek, T Proikas-Cezanne. WIPI3 and WIPI4 β-propellers are scaffolds for LKB1-AMPK-TSC signalling circuits in the control of autophagy.. Nat Commun. 2017;8:15637", "LG Biesecker, MP Adam, FS Alkuraya, AR Amemiya, MJ Bamshad, AE Beck, JT Bennett, LM Bird, JC Carey, B Chung, RD Clark, TC Cox, C Curry, MBP Dinulos, WB Dobyns, PF Giampietro, KM Girisha, IA Glass, JM Graham, KW Gripp, CR Haldeman-Englert, BD Hall, AM Innes, JM Kalish, KM Keppler-Noreuil, K Kosaki, BA Kozel, GM Mirzaa, JJ Mulvihill, MJM Nowaczyk, RA Pagon, K Retterer, AF Rope, PA Sanchez-Lara, LH Seaver, JT Shieh, AM Slavotinek, AK Sobering, CA Stevens, DA Stevenson, TY Tan, WH Tan, AC Tsai, DD Weaver, MS Williams, E Zackai, YA Zarate. A dyadic approach to the delineation of diagnostic entities in clinical genomics.. Am J Hum Genet. 2021;108:8-15", "H Jónsson, P Sulem, B Kehr, S Kristmundsdottir, F Zink, E Hjartarson, MT Hardarson, KE Hjorleifsson, HP Eggertsson, SA Gudjonsson, LD Ward, GA Arnadottir, EA Helgason, H Helgason, A Gylfason, A Jonasdottir, A Jonasdottir, T Rafnar, M Frigge, SN Stacey, O Th Magnusson, U Thorsteinsdottir, G Masson, A Kong, BV Halldorsson, A Helgason, DF Gudbjartsson, K Stefansson. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.. Nature. 2017;549:519-22", "H 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", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "J Suleiman, D Allingham-Hawkins, M Hashem, HE Shamseldin, FS Alkuraya, AW El-Hattab. WDR45B-related intellectual disability, spastic quadriplegia, epilepsy, and cerebral hypoplasia: a consistent neurodevelopmental syndrome.. Clin Genet. 2018;93:360-4" ]
29/9/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
eln-cutis-laxa
eln-cutis-laxa
[ "Autosomal Dominant Cutis Laxa Type 1 (ADCL1)", "Autosomal Dominant Cutis Laxa Type 1 (ADCL1)", "Elastin", "ELN", "ELN-Related Cutis Laxa" ]
Bert L Callewaert, Zsolt Urban
Summary The diagnosis of
## Diagnosis No consensus clinical diagnostic criteria for Inguinal hernia, with increased risk at all ages Joint hyperlaxity Aortic root dilatation Emphysema Ptosis (eyelid drooping that can be caused by skin laxity) Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( Note: The skin is hyperextensible if it can be stretched more than a standardized cutoff in three of the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbows, and knees. 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 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 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 [ Percentage should include deep intronic sequencing, as Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 one family with a complex intragenic • • Inguinal hernia, with increased risk at all ages • Joint hyperlaxity • Inguinal hernia, with increased risk at all ages • Joint hyperlaxity • Aortic root dilatation • Emphysema • Ptosis (eyelid drooping that can be caused by skin laxity) • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( • Aortic root dilatation • Emphysema • Ptosis (eyelid drooping that can be caused by skin laxity) • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( • Inguinal hernia, with increased risk at all ages • Joint hyperlaxity • Aortic root dilatation • Emphysema • Ptosis (eyelid drooping that can be caused by skin laxity) • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Inguinal hernia, with increased risk at all ages Joint hyperlaxity Aortic root dilatation Emphysema Ptosis (eyelid drooping that can be caused by skin laxity) Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( Note: The skin is hyperextensible if it can be stretched more than a standardized cutoff in three of the following areas: 1.5 cm for the distal part of the forearms and the dorsum of the hands; 3 cm for neck, elbows, and knees. • • Inguinal hernia, with increased risk at all ages • Joint hyperlaxity • Inguinal hernia, with increased risk at all ages • Joint hyperlaxity • Aortic root dilatation • Emphysema • Ptosis (eyelid drooping that can be caused by skin laxity) • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( • Aortic root dilatation • Emphysema • Ptosis (eyelid drooping that can be caused by skin laxity) • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( • Inguinal hernia, with increased risk at all ages • Joint hyperlaxity • Aortic root dilatation • Emphysema • Ptosis (eyelid drooping that can be caused by skin laxity) • Facial characteristics that may become more prominent with age: large ears, convex nasal ridge, long philtrum, aged appearance ( ## 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 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 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 [ Percentage should include deep intronic sequencing, as Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 one family with a complex intragenic • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, more than 46 individuals from 23 families have been identified with a pathogenic variant in COPD = chronic obstructive pulmonary disease Nevertheless, all affected individuals have an aged appearance (see Aortic aneurysms are amenable to surgery and there is no evidence of vascular fragility during surgery [ Aortic dissection has been reported in multiple families as early as in the third decade [ Severe emphysema requiring lung transplantation has been observed in the context of concomitant excessive use of tobacco [ A splice site variant was reported in exon 25 of No genotype-phenotype correlations have been identified in individuals with While affected individuals have been mostly of European descent, individuals of other ethnicities have been reported, and there is no evidence to suspect ethnic preponderance. ## Clinical Description To date, more than 46 individuals from 23 families have been identified with a pathogenic variant in COPD = chronic obstructive pulmonary disease Nevertheless, all affected individuals have an aged appearance (see Aortic aneurysms are amenable to surgery and there is no evidence of vascular fragility during surgery [ Aortic dissection has been reported in multiple families as early as in the third decade [ Severe emphysema requiring lung transplantation has been observed in the context of concomitant excessive use of tobacco [ A splice site variant was reported in exon 25 of ## Findings in Nearly All Individuals Nevertheless, all affected individuals have an aged appearance (see ## Common Findings Aortic aneurysms are amenable to surgery and there is no evidence of vascular fragility during surgery [ Aortic dissection has been reported in multiple families as early as in the third decade [ Severe emphysema requiring lung transplantation has been observed in the context of concomitant excessive use of tobacco [ ## Infrequent Findings ## Other Observations A splice site variant was reported in exon 25 of ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified in individuals with ## Penetrance ## Prevalence While affected individuals have been mostly of European descent, individuals of other ethnicities have been reported, and there is no evidence to suspect ethnic preponderance. ## Genetically Related (Allelic) Disorders Pathogenic variants in This differs from the variants causing An ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of ADCL = autosomal dominant cutis laxa; ARCL = autosomal recessive cutis laxa; CDG = congenital disorder of glycosylation; DD = developmental delay; ID = intellectual disability; MACS = The term "neurometabolic cutis laxa" has been suggested for a group of diseases related to inborn errors of metabolism. These disorders combine cutis laxa and skeletal defects with neurometabolic findings and result from pathogenic variants causing aberrant intracellular processing of extracellular matrix proteins as well as other proteins necessary for neurometabolic homeostasis. Known genetic defects involved in neurometabolic cutis laxa include: Aberrant glycosylation due to reduced acidification of the secretory vesicles (caused by defects in subunits of the v-ATPase transporter, including Defects in transporters for cofactors necessary for enzymes in the glycosylation pathway ( Defects in proteins involved in retrograde Golgi-to-ER transport ( Defects in enzymes involved in mitochondrial processes that include proline synthesis ( Defects in enzymes involved in the synthesis of reducing equivalents to protect the cell from reactive oxygen species ( Defects in phosphatidylserine synthesis ( Note: For simplicity and clarity, not all of the growing list of genes involved in neurometabolic cutis laxa have been included in • Aberrant glycosylation due to reduced acidification of the secretory vesicles (caused by defects in subunits of the v-ATPase transporter, including • Defects in transporters for cofactors necessary for enzymes in the glycosylation pathway ( • Defects in proteins involved in retrograde Golgi-to-ER transport ( • Defects in enzymes involved in mitochondrial processes that include proline synthesis ( • Defects in enzymes involved in the synthesis of reducing equivalents to protect the cell from reactive oxygen species ( • Defects in phosphatidylserine synthesis ( ## Neurometabolic Cutis Laxa The term "neurometabolic cutis laxa" has been suggested for a group of diseases related to inborn errors of metabolism. These disorders combine cutis laxa and skeletal defects with neurometabolic findings and result from pathogenic variants causing aberrant intracellular processing of extracellular matrix proteins as well as other proteins necessary for neurometabolic homeostasis. Known genetic defects involved in neurometabolic cutis laxa include: Aberrant glycosylation due to reduced acidification of the secretory vesicles (caused by defects in subunits of the v-ATPase transporter, including Defects in transporters for cofactors necessary for enzymes in the glycosylation pathway ( Defects in proteins involved in retrograde Golgi-to-ER transport ( Defects in enzymes involved in mitochondrial processes that include proline synthesis ( Defects in enzymes involved in the synthesis of reducing equivalents to protect the cell from reactive oxygen species ( Defects in phosphatidylserine synthesis ( Note: For simplicity and clarity, not all of the growing list of genes involved in neurometabolic cutis laxa have been included in • Aberrant glycosylation due to reduced acidification of the secretory vesicles (caused by defects in subunits of the v-ATPase transporter, including • Defects in transporters for cofactors necessary for enzymes in the glycosylation pathway ( • Defects in proteins involved in retrograde Golgi-to-ER transport ( • Defects in enzymes involved in mitochondrial processes that include proline synthesis ( • Defects in enzymes involved in the synthesis of reducing equivalents to protect the cell from reactive oxygen species ( • Defects in phosphatidylserine synthesis ( ## 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 Aortic valve morphology Diameter of aortic root & ascending aorta To evaluate arterial tortuosity To enable visualization of ascending aorta when echocardiography is inadequate Baseline testing at age 15 yrs To identify joint hyperlaxity & joint instability/subluxations To evaluate general posture Community or Social work involvement for parental support. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Supportive Treatment of Manifestations in Individuals with Best thresholds for aortic repair are not established. In general, criteria for Effectiveness of beta-blocking agents or angiotensin receptor antagonists in slowing aortic root dilatation has not been evaluated, but (as w/other connective tissue disorders) these are likely beneficial. For beta-blocking agents, caution is appropriate in persons w/ (reversible) obstructive airway disease, & cardio-selective beta-blocking agents may be preferred. Education on complete bladder emptying when voiding Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections PT to strengthen pelvic floor to help prevent prolapse of pelvic organs Catheterization if significant urinary residual after voiding PT Pain medications in case of acute aggravation of pain Lifestyle recommendations Non-weight-bearing exercise such as cycling & swimming Skin laxity often recurs. Cosmetic interventions are currently not encouraged. PT = physical therapy Recommended Surveillance for Individuals with Baseline testing at age 7 yrs Repeat if there is shortness of breath or decline in peak flow measurement. Baseline testing at age 5 yrs Repeat every 6 mos. Ultrasound of urinary tract Voiding cystography Although the risk for arterial aneurysms beyond the ascending aorta is likely low, given the small number of individuals reported with Avoid the following: Positive pressure ventilation unless needed to treat life-threatening conditions. No data exist on the potential risk of continuous positive airway pressure (CPAP) for the treatment of sleep apnea. Close follow up is warranted when CPAP is started. Contracting respiratory infections Tobacco smoking, which can result in rapid, severe loss of lung function in persons with Isometric exercise (which causes an increase in blood pressure) Contact sports. The increased risk for joint injury or pain related to contact sports should be discussed. In case of arterial aneurysms reaching diameters necessitating surgery, blunt trauma should be prevented as much as possible (similar to Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually. See At least 21 pregnancies have been reported in affected females. No perinatal complications for the affected mother or the neonate were reported [ Per guidelines used for women with Additionally, pulmonary evaluation and follow up are warranted before and during pregnancy. Pregnancy may aggravate respiratory symptoms as a result of reduced lung volume, resulting in increased respiratory effort in the third trimester. Uterine prolapse may occur [ Affected women who anticipate pregnancy or become pregnant and are taking a beta-blocker should continue it during pregnancy; however, some other classes of medications, such as angiotensin receptor-blocking agents, are teratogenic and should be discontinued or changed to beta-blocking agents, given the increased risk for teratogenicity (i.e., increased risk for fetal loss, oligohydramnios, and abnormal fetal development) typically related to second- and third-trimester exposure. Women who are planning a pregnancy or who become pregnant while taking an angiotensin receptor blocker can be transitioned to a beta-blocker. See Search • Aortic valve morphology • Diameter of aortic root & ascending aorta • To evaluate arterial tortuosity • To enable visualization of ascending aorta when echocardiography is inadequate • Baseline testing at age 15 yrs • To identify joint hyperlaxity & joint instability/subluxations • To evaluate general posture • Community or • Social work involvement for parental support. • Best thresholds for aortic repair are not established. In general, criteria for • Effectiveness of beta-blocking agents or angiotensin receptor antagonists in slowing aortic root dilatation has not been evaluated, but (as w/other connective tissue disorders) these are likely beneficial. • For beta-blocking agents, caution is appropriate in persons w/ (reversible) obstructive airway disease, & cardio-selective beta-blocking agents may be preferred. • Education on complete bladder emptying when voiding • Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections • PT to strengthen pelvic floor to help prevent prolapse of pelvic organs • Catheterization if significant urinary residual after voiding • PT • Pain medications in case of acute aggravation of pain • Lifestyle recommendations • Non-weight-bearing exercise such as cycling & swimming • Skin laxity often recurs. • Cosmetic interventions are currently not encouraged. • Baseline testing at age 7 yrs • Repeat if there is shortness of breath or decline in peak flow measurement. • Baseline testing at age 5 yrs • Repeat every 6 mos. • Ultrasound of urinary tract • Voiding cystography • Positive pressure ventilation unless needed to treat life-threatening conditions. No data exist on the potential risk of continuous positive airway pressure (CPAP) for the treatment of sleep apnea. Close follow up is warranted when CPAP is started. • Contracting respiratory infections • Tobacco smoking, which can result in rapid, severe loss of lung function in persons with • Isometric exercise (which causes an increase in blood pressure) • Contact sports. The increased risk for joint injury or pain related to contact sports should be discussed. In case of arterial aneurysms reaching diameters necessitating surgery, blunt trauma should be prevented as much as possible (similar to • Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually. ## 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 Aortic valve morphology Diameter of aortic root & ascending aorta To evaluate arterial tortuosity To enable visualization of ascending aorta when echocardiography is inadequate Baseline testing at age 15 yrs To identify joint hyperlaxity & joint instability/subluxations To evaluate general posture Community or Social work involvement for parental support. MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Aortic valve morphology • Diameter of aortic root & ascending aorta • To evaluate arterial tortuosity • To enable visualization of ascending aorta when echocardiography is inadequate • Baseline testing at age 15 yrs • To identify joint hyperlaxity & joint instability/subluxations • To evaluate general posture • Community or • Social work involvement for parental support. ## Treatment of Manifestations There is no cure for Supportive Treatment of Manifestations in Individuals with Best thresholds for aortic repair are not established. In general, criteria for Effectiveness of beta-blocking agents or angiotensin receptor antagonists in slowing aortic root dilatation has not been evaluated, but (as w/other connective tissue disorders) these are likely beneficial. For beta-blocking agents, caution is appropriate in persons w/ (reversible) obstructive airway disease, & cardio-selective beta-blocking agents may be preferred. Education on complete bladder emptying when voiding Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections PT to strengthen pelvic floor to help prevent prolapse of pelvic organs Catheterization if significant urinary residual after voiding PT Pain medications in case of acute aggravation of pain Lifestyle recommendations Non-weight-bearing exercise such as cycling & swimming Skin laxity often recurs. Cosmetic interventions are currently not encouraged. PT = physical therapy • Best thresholds for aortic repair are not established. In general, criteria for • Effectiveness of beta-blocking agents or angiotensin receptor antagonists in slowing aortic root dilatation has not been evaluated, but (as w/other connective tissue disorders) these are likely beneficial. • For beta-blocking agents, caution is appropriate in persons w/ (reversible) obstructive airway disease, & cardio-selective beta-blocking agents may be preferred. • Education on complete bladder emptying when voiding • Antibiotic prophylaxis in case of incomplete voiding & recurrent urinary tract infections • PT to strengthen pelvic floor to help prevent prolapse of pelvic organs • Catheterization if significant urinary residual after voiding • PT • Pain medications in case of acute aggravation of pain • Lifestyle recommendations • Non-weight-bearing exercise such as cycling & swimming • Skin laxity often recurs. • Cosmetic interventions are currently not encouraged. ## Surveillance Recommended Surveillance for Individuals with Baseline testing at age 7 yrs Repeat if there is shortness of breath or decline in peak flow measurement. Baseline testing at age 5 yrs Repeat every 6 mos. Ultrasound of urinary tract Voiding cystography Although the risk for arterial aneurysms beyond the ascending aorta is likely low, given the small number of individuals reported with • Baseline testing at age 7 yrs • Repeat if there is shortness of breath or decline in peak flow measurement. • Baseline testing at age 5 yrs • Repeat every 6 mos. • Ultrasound of urinary tract • Voiding cystography ## Agents/Circumstances to Avoid Avoid the following: Positive pressure ventilation unless needed to treat life-threatening conditions. No data exist on the potential risk of continuous positive airway pressure (CPAP) for the treatment of sleep apnea. Close follow up is warranted when CPAP is started. Contracting respiratory infections Tobacco smoking, which can result in rapid, severe loss of lung function in persons with Isometric exercise (which causes an increase in blood pressure) Contact sports. The increased risk for joint injury or pain related to contact sports should be discussed. In case of arterial aneurysms reaching diameters necessitating surgery, blunt trauma should be prevented as much as possible (similar to Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually. • Positive pressure ventilation unless needed to treat life-threatening conditions. No data exist on the potential risk of continuous positive airway pressure (CPAP) for the treatment of sleep apnea. Close follow up is warranted when CPAP is started. • Contracting respiratory infections • Tobacco smoking, which can result in rapid, severe loss of lung function in persons with • Isometric exercise (which causes an increase in blood pressure) • Contact sports. The increased risk for joint injury or pain related to contact sports should be discussed. In case of arterial aneurysms reaching diameters necessitating surgery, blunt trauma should be prevented as much as possible (similar to • Sunbathing or tanning, to preserve residual skin elasticity. Vitamin D supplementation should be considered in this context, and monitored annually. ## Evaluation of Relatives at Risk See ## Pregnancy Management At least 21 pregnancies have been reported in affected females. No perinatal complications for the affected mother or the neonate were reported [ Per guidelines used for women with Additionally, pulmonary evaluation and follow up are warranted before and during pregnancy. Pregnancy may aggravate respiratory symptoms as a result of reduced lung volume, resulting in increased respiratory effort in the third trimester. Uterine prolapse may occur [ Affected women who anticipate pregnancy or become pregnant and are taking a beta-blocker should continue it during pregnancy; however, some other classes of medications, such as angiotensin receptor-blocking agents, are teratogenic and should be discontinued or changed to beta-blocking agents, given the increased risk for teratogenicity (i.e., increased risk for fetal loss, oligohydramnios, and abnormal fetal development) typically related to second- and third-trimester exposure. Women who are planning a pregnancy or who become pregnant while taking an angiotensin receptor blocker can be transitioned to a beta-blocker. See ## Therapies Under Investigation Search ## Genetic Counseling About one third of individuals diagnosed with About two thirds 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. Thus far, germline mosaicism has not been reported in 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%. A sib who inherits a pathogenic variant is expected to have manifestations of the disorder; however, intrafamilial clinical variability is observed in 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 most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • About one third of individuals diagnosed with • About two thirds 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. Thus far, germline mosaicism has not been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Thus far, germline mosaicism has not been reported in • 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. Thus far, germline mosaicism has not been reported in • 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%. • A sib who inherits a pathogenic variant is expected to have manifestations of the disorder; however, intrafamilial clinical variability is observed in • 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 About one third of individuals diagnosed with About two thirds 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. Thus far, germline mosaicism has not been reported in 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%. A sib who inherits a pathogenic variant is expected to have manifestations of the disorder; however, intrafamilial clinical variability is observed in If the If the parents have not been tested for the • About one third of individuals diagnosed with • About two thirds 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. Thus far, germline mosaicism has not been reported in • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Thus far, germline mosaicism has not been reported in • 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. Thus far, germline mosaicism has not been reported in • 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%. • A sib who inherits a pathogenic variant is expected to have manifestations of the disorder; however, intrafamilial clinical variability is observed in • 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 most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources New Zealand France • • New Zealand • • • • • • France • ## Molecular Genetics ELN-Related Cutis Laxa: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ELN-Related Cutis Laxa ( Although other mechanisms of A more complex gene duplication/triplication was reported in one family by Molecular testing should include analysis for deep intronic variants. One reported intronic splice variant ( Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions This nucleotide change affects the nucleotide immediately upstream of the donor splice site of intron 25 and is predicted to affect splicing. ## Molecular Pathogenesis Although other mechanisms of A more complex gene duplication/triplication was reported in one family by Molecular testing should include analysis for deep intronic variants. One reported intronic splice variant ( Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions This nucleotide change affects the nucleotide immediately upstream of the donor splice site of intron 25 and is predicted to affect splicing. ## Chapter Notes Dr Callewaert is actively involved in clinical research regarding individuals with Contact Dr Callewaert to inquire about the interpretation of Dr Callewaert is also interested in hearing from clinicians treating families affected by cutis laxa in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Email: Website: For more information, go to the Bert Callewaert is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders. Zsolt Urban is funded by a National Institutes of Health grant HL090648. 29 September 2022 (bp) Review posted live 25 January 2022 (bc) Original submission • 29 September 2022 (bp) Review posted live • 25 January 2022 (bc) Original submission ## Author Notes Dr Callewaert is actively involved in clinical research regarding individuals with Contact Dr Callewaert to inquire about the interpretation of Dr Callewaert is also interested in hearing from clinicians treating families affected by cutis laxa in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders. Email: Website: For more information, go to the ## Acknowledgments Bert Callewaert is a Senior Clinical Investigator of the Fund for Scientific Research-Flanders. Zsolt Urban is funded by a National Institutes of Health grant HL090648. ## Revision History 29 September 2022 (bp) Review posted live 25 January 2022 (bc) Original submission • 29 September 2022 (bp) Review posted live • 25 January 2022 (bc) Original submission ## References ## Literature Cited Findings in individuals with A, B, C. Girl age six years with generalized cutis laxa and typical facial features (convex nasal ridge, sagging cheeks, large ears, long philtrum, and increased folds of the perioral skin). Posture shows hyperlordosis. D. Man age 39 years with hyperextensible skin without obvious skin folds E. Boy age 18 months with generalized skin redundancy causing excessive skin folds
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29/9/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
emanuel
emanuel
[ "Supernumerary der(22)t(11;22) Syndrome", "Supernumerary der(22)t(11;22) Syndrome", "Emanuel Syndrome" ]
Emanuel Syndrome
Beverly S Emanuel, Elaine H Zackai, Livija Medne
Summary Emanuel syndrome is characterized by pre- and postnatal growth deficiency, microcephaly, hypotonia, severe developmental delays, ear anomalies, preauricular tags or pits, cleft or high-arched palate, congenital heart defects, kidney abnormalities, and genital abnormalities in males. The diagnosis of Emanuel syndrome is established in a proband by detection of a duplication of 22q10-22q11 and duplication of 11q23-qter on a supernumerary derivative chromosome 22 [der(22)]. In more than 99% of cases, one of the parents of a proband with Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. In most cases, a carrier parent has inherited the t(11;22) from a parent. When one of the parents of a proband is a carrier of the balanced t(11;22), possible outcomes of future pregnancies of the proband's parents include: normal chromosomes, supernumerary der(22) syndrome, balanced t(11;22) carrier, and spontaneous abortion as a result of supernumerary der(22) or another meiotic malsegregant. Risks vary depending on whether the mother or father of a proband is the balanced translocation carrier. Prenatal testing for a pregnancy at increased risk is possible if the chromosome abnormality has been confirmed in the family.
## Diagnosis Emanuel syndrome Severe intellectual disability Microcephaly Failure to thrive Preauricular tag or pit Ear anomalies Cleft or high-arched palate Micrognathia Kidney abnormalities Congenital heart defects Genital abnormalities in males The diagnosis of Emanuel syndrome Most commonly: 47,XX,+der(22)t(11;22)(q23;q11) in females 47,XY,+der(22)t(11;22)(q23;q11) in males Rarely: a balanced (11;22) translocation as well as the supernumerary derivative chromosome. Parental karyotypes should be performed next to determine whether one parent is a carrier of the balanced translocation, t(11;22). In the rare instance in which one of the parents is not a balanced translocation carrier, A Note: Chromosomal microarray cannot currently detect balanced translocations, in which there is no net gain or loss of genetic material. Molecular Genetic Testing Used in Emanuel Syndrome FISH testing using probes such as N25 or TUPLE1 mapping to 22q11.2 and using 11q subtelomeric probe. In the rare instance in which one of the parents is not a balanced translocation carrier, commercially available FISH probes for the 22q11.2 deletion and for the telomere of 11q can identify the supernumerary chromosome in the karyotype as being derived from chromosomes 11 and 22. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. Note: A limited karyotype or FISH is necessary to determine mechanism of the abnormality. • Severe intellectual disability • Microcephaly • Failure to thrive • Preauricular tag or pit • Ear anomalies • Cleft or high-arched palate • Micrognathia • Kidney abnormalities • Congenital heart defects • Genital abnormalities in males • Most commonly: • 47,XX,+der(22)t(11;22)(q23;q11) in females • 47,XY,+der(22)t(11;22)(q23;q11) in males • 47,XX,+der(22)t(11;22)(q23;q11) in females • 47,XY,+der(22)t(11;22)(q23;q11) in males • Rarely: a balanced (11;22) translocation as well as the supernumerary derivative chromosome. • 47,XX,+der(22)t(11;22)(q23;q11) in females • 47,XY,+der(22)t(11;22)(q23;q11) in males • Parental karyotypes should be performed next to determine whether one parent is a carrier of the balanced translocation, t(11;22). • In the rare instance in which one of the parents is not a balanced translocation carrier, • A ## Suggestive Findings Emanuel syndrome Severe intellectual disability Microcephaly Failure to thrive Preauricular tag or pit Ear anomalies Cleft or high-arched palate Micrognathia Kidney abnormalities Congenital heart defects Genital abnormalities in males • Severe intellectual disability • Microcephaly • Failure to thrive • Preauricular tag or pit • Ear anomalies • Cleft or high-arched palate • Micrognathia • Kidney abnormalities • Congenital heart defects • Genital abnormalities in males ## Establishing the Diagnosis The diagnosis of Emanuel syndrome Most commonly: 47,XX,+der(22)t(11;22)(q23;q11) in females 47,XY,+der(22)t(11;22)(q23;q11) in males Rarely: a balanced (11;22) translocation as well as the supernumerary derivative chromosome. Parental karyotypes should be performed next to determine whether one parent is a carrier of the balanced translocation, t(11;22). In the rare instance in which one of the parents is not a balanced translocation carrier, A Note: Chromosomal microarray cannot currently detect balanced translocations, in which there is no net gain or loss of genetic material. Molecular Genetic Testing Used in Emanuel Syndrome FISH testing using probes such as N25 or TUPLE1 mapping to 22q11.2 and using 11q subtelomeric probe. In the rare instance in which one of the parents is not a balanced translocation carrier, commercially available FISH probes for the 22q11.2 deletion and for the telomere of 11q can identify the supernumerary chromosome in the karyotype as being derived from chromosomes 11 and 22. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. Note: A limited karyotype or FISH is necessary to determine mechanism of the abnormality. • Most commonly: • 47,XX,+der(22)t(11;22)(q23;q11) in females • 47,XY,+der(22)t(11;22)(q23;q11) in males • 47,XX,+der(22)t(11;22)(q23;q11) in females • 47,XY,+der(22)t(11;22)(q23;q11) in males • Rarely: a balanced (11;22) translocation as well as the supernumerary derivative chromosome. • 47,XX,+der(22)t(11;22)(q23;q11) in females • 47,XY,+der(22)t(11;22)(q23;q11) in males • Parental karyotypes should be performed next to determine whether one parent is a carrier of the balanced translocation, t(11;22). • In the rare instance in which one of the parents is not a balanced translocation carrier, • A ## Option 1 Parental karyotypes should be performed next to determine whether one parent is a carrier of the balanced translocation, t(11;22). In the rare instance in which one of the parents is not a balanced translocation carrier, • Parental karyotypes should be performed next to determine whether one parent is a carrier of the balanced translocation, t(11;22). • In the rare instance in which one of the parents is not a balanced translocation carrier, ## Option 2 A Note: Chromosomal microarray cannot currently detect balanced translocations, in which there is no net gain or loss of genetic material. Molecular Genetic Testing Used in Emanuel Syndrome FISH testing using probes such as N25 or TUPLE1 mapping to 22q11.2 and using 11q subtelomeric probe. In the rare instance in which one of the parents is not a balanced translocation carrier, commercially available FISH probes for the 22q11.2 deletion and for the telomere of 11q can identify the supernumerary chromosome in the karyotype as being derived from chromosomes 11 and 22. Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. Note: A limited karyotype or FISH is necessary to determine mechanism of the abnormality. • A ## Clinical Characteristics Well over 400 individuals with supernumerary der(22) have been identified by support groups and by report. Significant mortality is associated with life-threatening congenital malformations such as congenital heart defects, diaphragmatic hernia, or renal insufficiency. The highest mortality rate is in the first months of life. With improved palliative care and time, survival chances improve and survival into adulthood has been documented. Affected children are usually identified in the newborn period as the offspring of balanced (11;22) translocation carriers. The external ear auricle is typically malformed and preauricular ear pits and/or tags are characteristic. Severe microtia with atresia of the external auditory canal and deafness have been reported. Hearing loss is uncommon, but milder forms may be underestimated because of the difficulties associated with accurate hearing evaluation in individuals with severe developmental delay. Cleft palate is seen in approximately 50% of affected individuals. Angular mouth pits or clefts, cleft maxilla, laryngomalacia, and branchial sinuses have been reported. Bifid uvula is also associated. Anal atresia with or without fistula is seen in about 20% of affected individuals. Anal stenosis without complete atresia is observed as well. Inguinal hernias are uncommon but well documented. Biliary atresia, Hirschsprung disease, abnormal liver lobation, extrahepatic biliary ducts, absent gallbladder, and polysplenia have been observed occasionally. Poor weight gain is common. While specific feeding problems are often not described, gastroesophageal reflux and difficulties with suck and swallow are common. Curvature of the spine is most likely a secondary complication of severe hypotonia and resulting motor delays. Sacral dimple is common. Congenital hip dislocation or subluxation is common. Arachnodactyly and tapering fingers are characteristic. Clubfoot and joint contractures can be congenital or develop later in life. Other, less frequently observed skeletal malformations include 13 pairs of ribs, hypoplastic clavicles, cubitus valgus, radioulnar synostosis, and 4-5 syndactyly of the toes. Lumbar myelomeningocele has been reported once. Delayed bone age is mentioned in a few reports. The incidence of structural brain abnormalities is not known as brain imaging is not required to establish the diagnosis. Reported malformations have included Dandy-Walker malformation, agenesis of the corpus callosum, arrhinencephaly, and absent olfactory bulbs and tracts. Seizures are reported in a few affected individuals and abnormal EEGs without clinical seizures in another small subset. All individuals with Emanuel syndrome have the supernumerary der(22), which results from almost identical breakpoints on both 11q23 and 22q11. The breakpoints differ by only a few nucleotides [ Penetrance is complete in individuals with the supernumerary der(22). Older case reports published prior to G banding described this chromosome abnormality as "partial trisomy 22" or "partial trisomy 11." Supernumerary der(22) is a rare chromosome disorder; its prevalence is unknown. The prevalence of balanced t(11;22) carriers in the general population is unknown. ## Clinical Description Well over 400 individuals with supernumerary der(22) have been identified by support groups and by report. Significant mortality is associated with life-threatening congenital malformations such as congenital heart defects, diaphragmatic hernia, or renal insufficiency. The highest mortality rate is in the first months of life. With improved palliative care and time, survival chances improve and survival into adulthood has been documented. Affected children are usually identified in the newborn period as the offspring of balanced (11;22) translocation carriers. The external ear auricle is typically malformed and preauricular ear pits and/or tags are characteristic. Severe microtia with atresia of the external auditory canal and deafness have been reported. Hearing loss is uncommon, but milder forms may be underestimated because of the difficulties associated with accurate hearing evaluation in individuals with severe developmental delay. Cleft palate is seen in approximately 50% of affected individuals. Angular mouth pits or clefts, cleft maxilla, laryngomalacia, and branchial sinuses have been reported. Bifid uvula is also associated. Anal atresia with or without fistula is seen in about 20% of affected individuals. Anal stenosis without complete atresia is observed as well. Inguinal hernias are uncommon but well documented. Biliary atresia, Hirschsprung disease, abnormal liver lobation, extrahepatic biliary ducts, absent gallbladder, and polysplenia have been observed occasionally. Poor weight gain is common. While specific feeding problems are often not described, gastroesophageal reflux and difficulties with suck and swallow are common. Curvature of the spine is most likely a secondary complication of severe hypotonia and resulting motor delays. Sacral dimple is common. Congenital hip dislocation or subluxation is common. Arachnodactyly and tapering fingers are characteristic. Clubfoot and joint contractures can be congenital or develop later in life. Other, less frequently observed skeletal malformations include 13 pairs of ribs, hypoplastic clavicles, cubitus valgus, radioulnar synostosis, and 4-5 syndactyly of the toes. Lumbar myelomeningocele has been reported once. Delayed bone age is mentioned in a few reports. The incidence of structural brain abnormalities is not known as brain imaging is not required to establish the diagnosis. Reported malformations have included Dandy-Walker malformation, agenesis of the corpus callosum, arrhinencephaly, and absent olfactory bulbs and tracts. Seizures are reported in a few affected individuals and abnormal EEGs without clinical seizures in another small subset. ## Genotype-Phenotype Correlations All individuals with Emanuel syndrome have the supernumerary der(22), which results from almost identical breakpoints on both 11q23 and 22q11. The breakpoints differ by only a few nucleotides [ ## Penetrance Penetrance is complete in individuals with the supernumerary der(22). ## Nomenclature Older case reports published prior to G banding described this chromosome abnormality as "partial trisomy 22" or "partial trisomy 11." ## Prevalence Supernumerary der(22) is a rare chromosome disorder; its prevalence is unknown. The prevalence of balanced t(11;22) carriers in the general population is unknown. ## Genetically Related Disorders No phenotypes other than those discussed in this Female carriers of a balanced t(11;22) have been reported in some studies to be at a somewhat increased risk for premenopausal breast cancer; however, results have not been consistent [ ## Differential Diagnosis Clinical features that overlap with Emanuel syndrome can be seen in the syndromes listed below. Chromosome analysis always confirms the diagnosis of Emanuel syndrome and rules out other diagnoses. Pallister-Killian syndrome (OMIM Wolf-Hirschhorn syndrome (OMIM Other chromosome abnormalities • • • Pallister-Killian syndrome (OMIM • • Wolf-Hirschhorn syndrome (OMIM • Other chromosome abnormalities ## Management No current guidelines to evaluate the clinical manifestations that contribute to morbidity and mortality have been published. The following measures ‒ based on the literature and the authors' experience ‒ are recommended (if they have not already been completed) to establish the extent of disease and needs in an individual diagnosed with Emanuel syndrome: Palatal evaluation for cleft palate Cardiac evaluation with an echocardiogram to screen for cardiac defects. Atrial septal defects are the most common defects and may not be detected by auscultation alone. Renal ultrasound examination to evaluate for structural kidney anomalies; if indicated, vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux Gastrointestinal evaluation with appropriate radiologic studies for structural anomalies of the gastrointestinal (GI) tract, in particular anal stenosis or diaphragmatic abnormalities, gastroesophageal reflux Feeding and swallowing assessment Orthopedic evaluation with appropriate radiologic studies for hip dysplasia as well as joint contractures, clubfoot, curvature of the spine, and radioulnar synostosis Otolaryngology (ENT) evaluation for stenosis or atresia of ear canals Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing (See Ophthalmologic evaluation including dilated fundoscopic examination to assess visual acuity and to evaluate for strabismus Urologic evaluation in males with cryptorchidism and/or micropenis Evaluation by a developmental pediatrician and therapists to develop educational/therapeutic intervention with emphasis on communication skills Consultation with a clinical geneticist and/or genetic counselor for evaluation for genetic counseling and to identify at-risk relatives (The +der(22) is almost always inherited from a carrier parent.) Depending on the age and extent of systemic involvement of the individual with Emanuel syndrome, evaluations involving health care providers from multiple specialties are necessary. In some individuals, palliative care is appropriate when there are severe structural defects and/or renal failure. Standard management of gastroesophageal reflux; supplementary formulas and consideration of enteral feeds if there is failure to thrive Surgical correction for anal atresia (or stenosis if indicated) and inguinal hernias Standard interventions for: Cardiac defects Cleft palate Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. Hearing loss Cryptorchidism and/or micropenis Refractive errors, strabismus, or other ophthalmologic issues Seizures, if present Ongoing physical, occupational, and speech therapies to optimize developmental outcome Alternative communication methods to facilitate communication as verbal skills are often very limited Care during sedation and/or operative procedures should be provided by a pediatric anesthesiologist as small airways, various palatal abnormalities, and laryngomalacia can be seen in children with Emanuel syndrome. The following are appropriate: Follow up as needed based on the extent of systemic involvement in the affected individual Regular assessment of developmental progress to guide therapeutic interventions and educational modalities Periodic reevaluation by a clinical geneticist to apprise the family of new developments and/or recommendations See Search Patients and their families should be informed regarding natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources. • Palatal evaluation for cleft palate • Cardiac evaluation with an echocardiogram to screen for cardiac defects. Atrial septal defects are the most common defects and may not be detected by auscultation alone. • Renal ultrasound examination to evaluate for structural kidney anomalies; if indicated, vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux • Gastrointestinal evaluation with appropriate radiologic studies for structural anomalies of the gastrointestinal (GI) tract, in particular anal stenosis or diaphragmatic abnormalities, gastroesophageal reflux • Feeding and swallowing assessment • Orthopedic evaluation with appropriate radiologic studies for hip dysplasia as well as joint contractures, clubfoot, curvature of the spine, and radioulnar synostosis • Otolaryngology (ENT) evaluation for stenosis or atresia of ear canals • Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing (See • Ophthalmologic evaluation including dilated fundoscopic examination to assess visual acuity and to evaluate for strabismus • Urologic evaluation in males with cryptorchidism and/or micropenis • Evaluation by a developmental pediatrician and therapists to develop educational/therapeutic intervention with emphasis on communication skills • Consultation with a clinical geneticist and/or genetic counselor for evaluation for genetic counseling and to identify at-risk relatives (The +der(22) is almost always inherited from a carrier parent.) • Standard management of gastroesophageal reflux; supplementary formulas and consideration of enteral feeds if there is failure to thrive • Surgical correction for anal atresia (or stenosis if indicated) and inguinal hernias • Standard interventions for: • Cardiac defects • Cleft palate • Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. • Hearing loss • Cryptorchidism and/or micropenis • Refractive errors, strabismus, or other ophthalmologic issues • Seizures, if present • Cardiac defects • Cleft palate • Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. • Hearing loss • Cryptorchidism and/or micropenis • Refractive errors, strabismus, or other ophthalmologic issues • Seizures, if present • Ongoing physical, occupational, and speech therapies to optimize developmental outcome • Alternative communication methods to facilitate communication as verbal skills are often very limited • Cardiac defects • Cleft palate • Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. • Hearing loss • Cryptorchidism and/or micropenis • Refractive errors, strabismus, or other ophthalmologic issues • Seizures, if present • Follow up as needed based on the extent of systemic involvement in the affected individual • Regular assessment of developmental progress to guide therapeutic interventions and educational modalities • Periodic reevaluation by a clinical geneticist to apprise the family of new developments and/or recommendations ## Evaluations Following Initial Diagnosis No current guidelines to evaluate the clinical manifestations that contribute to morbidity and mortality have been published. The following measures ‒ based on the literature and the authors' experience ‒ are recommended (if they have not already been completed) to establish the extent of disease and needs in an individual diagnosed with Emanuel syndrome: Palatal evaluation for cleft palate Cardiac evaluation with an echocardiogram to screen for cardiac defects. Atrial septal defects are the most common defects and may not be detected by auscultation alone. Renal ultrasound examination to evaluate for structural kidney anomalies; if indicated, vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux Gastrointestinal evaluation with appropriate radiologic studies for structural anomalies of the gastrointestinal (GI) tract, in particular anal stenosis or diaphragmatic abnormalities, gastroesophageal reflux Feeding and swallowing assessment Orthopedic evaluation with appropriate radiologic studies for hip dysplasia as well as joint contractures, clubfoot, curvature of the spine, and radioulnar synostosis Otolaryngology (ENT) evaluation for stenosis or atresia of ear canals Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing (See Ophthalmologic evaluation including dilated fundoscopic examination to assess visual acuity and to evaluate for strabismus Urologic evaluation in males with cryptorchidism and/or micropenis Evaluation by a developmental pediatrician and therapists to develop educational/therapeutic intervention with emphasis on communication skills Consultation with a clinical geneticist and/or genetic counselor for evaluation for genetic counseling and to identify at-risk relatives (The +der(22) is almost always inherited from a carrier parent.) • Palatal evaluation for cleft palate • Cardiac evaluation with an echocardiogram to screen for cardiac defects. Atrial septal defects are the most common defects and may not be detected by auscultation alone. • Renal ultrasound examination to evaluate for structural kidney anomalies; if indicated, vesicoureterogram (VCUG) to evaluate for vesicoureteral reflux • Gastrointestinal evaluation with appropriate radiologic studies for structural anomalies of the gastrointestinal (GI) tract, in particular anal stenosis or diaphragmatic abnormalities, gastroesophageal reflux • Feeding and swallowing assessment • Orthopedic evaluation with appropriate radiologic studies for hip dysplasia as well as joint contractures, clubfoot, curvature of the spine, and radioulnar synostosis • Otolaryngology (ENT) evaluation for stenosis or atresia of ear canals • Audiology evaluation with auditory brain stem response testing and otoacoustic emission testing (See • Ophthalmologic evaluation including dilated fundoscopic examination to assess visual acuity and to evaluate for strabismus • Urologic evaluation in males with cryptorchidism and/or micropenis • Evaluation by a developmental pediatrician and therapists to develop educational/therapeutic intervention with emphasis on communication skills • Consultation with a clinical geneticist and/or genetic counselor for evaluation for genetic counseling and to identify at-risk relatives (The +der(22) is almost always inherited from a carrier parent.) ## Treatment of Manifestations Depending on the age and extent of systemic involvement of the individual with Emanuel syndrome, evaluations involving health care providers from multiple specialties are necessary. In some individuals, palliative care is appropriate when there are severe structural defects and/or renal failure. Standard management of gastroesophageal reflux; supplementary formulas and consideration of enteral feeds if there is failure to thrive Surgical correction for anal atresia (or stenosis if indicated) and inguinal hernias Standard interventions for: Cardiac defects Cleft palate Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. Hearing loss Cryptorchidism and/or micropenis Refractive errors, strabismus, or other ophthalmologic issues Seizures, if present Ongoing physical, occupational, and speech therapies to optimize developmental outcome Alternative communication methods to facilitate communication as verbal skills are often very limited • Standard management of gastroesophageal reflux; supplementary formulas and consideration of enteral feeds if there is failure to thrive • Surgical correction for anal atresia (or stenosis if indicated) and inguinal hernias • Standard interventions for: • Cardiac defects • Cleft palate • Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. • Hearing loss • Cryptorchidism and/or micropenis • Refractive errors, strabismus, or other ophthalmologic issues • Seizures, if present • Cardiac defects • Cleft palate • Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. • Hearing loss • Cryptorchidism and/or micropenis • Refractive errors, strabismus, or other ophthalmologic issues • Seizures, if present • Ongoing physical, occupational, and speech therapies to optimize developmental outcome • Alternative communication methods to facilitate communication as verbal skills are often very limited • Cardiac defects • Cleft palate • Hip dysplasia and other skeletal complications. Assistive devices such as walkers are often required for ambulation. • Hearing loss • Cryptorchidism and/or micropenis • Refractive errors, strabismus, or other ophthalmologic issues • Seizures, if present ## Prevention of Secondary Complications Care during sedation and/or operative procedures should be provided by a pediatric anesthesiologist as small airways, various palatal abnormalities, and laryngomalacia can be seen in children with Emanuel syndrome. ## Surveillance The following are appropriate: Follow up as needed based on the extent of systemic involvement in the affected individual Regular assessment of developmental progress to guide therapeutic interventions and educational modalities Periodic reevaluation by a clinical geneticist to apprise the family of new developments and/or recommendations • Follow up as needed based on the extent of systemic involvement in the affected individual • Regular assessment of developmental progress to guide therapeutic interventions and educational modalities • Periodic reevaluation by a clinical geneticist to apprise the family of new developments and/or recommendations ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other Patients and their families should be informed regarding natural history, treatment, mode of inheritance, genetic risks to other family members, and consumer-oriented resources. ## Genetic Counseling Emanuel syndrome is an inherited chromosome abnormality. It is the result of 3:1 meiotic segregation of the balanced translocation t(11;22)(q23;q11). This rearrangement is the only known recurrent, non-Robertsonian translocation in humans. Evaluation of the parents by chromosome analysis to detect the balanced t(11:22) is recommended. In more than 99% of cases, one of the parents of a proband with Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. There is a single case report of supernumerary der(22) arising from Statistically, the mother of a proband with supernumerary der(22) is more likely than the father to be a carrier of the balanced t(11;22). In most cases, a carrier parent has inherited the t(11;22) from a parent. Sibs of a proband who have no findings of Emanuel syndrome: Are not at risk for Emanuel syndrome; Have almost no chance of having a different unbalanced chromosome abnormality; Have an estimated 50% chance of having a balanced translocation; Have an estimated 50% chance of having normal chromosomes. Sibs of a proband who have findings of Emanuel syndrome (e.g., severe developmental delays, poor growth, and multiple congenital anomalies) almost always have supernumerary der(22). When one of the parents of a proband is a carrier of the balanced t(11;22), possible outcomes of future pregnancies of the parents include the following: Normal chromosomes Supernumerary der(22) syndrome Balanced t(11;22) carrier Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant In any given pregnancy, the exact chance of each of the above four pregnancy outcomes occurring is not known. Furthermore, risks vary depending on whether the mother or father of a proband is the balanced translocation carrier [ The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. The risk to other family members depends on the status of the proband's parents: if a parent has the balanced t(11:22), members of the parent's family may also have the balanced translocation or Emanuel syndrome. For those identified as carriers, the risk would be the same as described above for parents who carry a balanced t(11;22). Chromosome analysis should be offered to at-risk family members. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are or are at risk of being balanced translocation carriers. Once the supernumerary der(22) has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. • Evaluation of the parents by chromosome analysis to detect the balanced t(11:22) is recommended. • In more than 99% of cases, one of the parents of a proband with Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. There is a single case report of supernumerary der(22) arising from • Statistically, the mother of a proband with supernumerary der(22) is more likely than the father to be a carrier of the balanced t(11;22). • In most cases, a carrier parent has inherited the t(11;22) from a parent. • Sibs of a proband who have no findings of Emanuel syndrome: • Are not at risk for Emanuel syndrome; • Have almost no chance of having a different unbalanced chromosome abnormality; • Have an estimated 50% chance of having a balanced translocation; • Have an estimated 50% chance of having normal chromosomes. • Are not at risk for Emanuel syndrome; • Have almost no chance of having a different unbalanced chromosome abnormality; • Have an estimated 50% chance of having a balanced translocation; • Have an estimated 50% chance of having normal chromosomes. • Sibs of a proband who have findings of Emanuel syndrome (e.g., severe developmental delays, poor growth, and multiple congenital anomalies) almost always have supernumerary der(22). • When one of the parents of a proband is a carrier of the balanced t(11;22), possible outcomes of future pregnancies of the parents include the following: • Normal chromosomes • Supernumerary der(22) syndrome • Balanced t(11;22) carrier • Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant • Normal chromosomes • Supernumerary der(22) syndrome • Balanced t(11;22) carrier • Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant • In any given pregnancy, the exact chance of each of the above four pregnancy outcomes occurring is not known. Furthermore, risks vary depending on whether the mother or father of a proband is the balanced translocation carrier [ • The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). • The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. • The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. • The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). • The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. • The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. • Are not at risk for Emanuel syndrome; • Have almost no chance of having a different unbalanced chromosome abnormality; • Have an estimated 50% chance of having a balanced translocation; • Have an estimated 50% chance of having normal chromosomes. • Normal chromosomes • Supernumerary der(22) syndrome • Balanced t(11;22) carrier • Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant • The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). • The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. • The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. • The risk to other family members depends on the status of the proband's parents: if a parent has the balanced t(11:22), members of the parent's family may also have the balanced translocation or Emanuel syndrome. For those identified as carriers, the risk would be the same as described above for parents who carry a balanced t(11;22). • Chromosome analysis should be offered to at-risk family members. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are or are at risk of being balanced translocation carriers. ## Mode of Inheritance Emanuel syndrome is an inherited chromosome abnormality. It is the result of 3:1 meiotic segregation of the balanced translocation t(11;22)(q23;q11). This rearrangement is the only known recurrent, non-Robertsonian translocation in humans. ## Risk to Family Members Evaluation of the parents by chromosome analysis to detect the balanced t(11:22) is recommended. In more than 99% of cases, one of the parents of a proband with Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. There is a single case report of supernumerary der(22) arising from Statistically, the mother of a proband with supernumerary der(22) is more likely than the father to be a carrier of the balanced t(11;22). In most cases, a carrier parent has inherited the t(11;22) from a parent. Sibs of a proband who have no findings of Emanuel syndrome: Are not at risk for Emanuel syndrome; Have almost no chance of having a different unbalanced chromosome abnormality; Have an estimated 50% chance of having a balanced translocation; Have an estimated 50% chance of having normal chromosomes. Sibs of a proband who have findings of Emanuel syndrome (e.g., severe developmental delays, poor growth, and multiple congenital anomalies) almost always have supernumerary der(22). When one of the parents of a proband is a carrier of the balanced t(11;22), possible outcomes of future pregnancies of the parents include the following: Normal chromosomes Supernumerary der(22) syndrome Balanced t(11;22) carrier Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant In any given pregnancy, the exact chance of each of the above four pregnancy outcomes occurring is not known. Furthermore, risks vary depending on whether the mother or father of a proband is the balanced translocation carrier [ The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. The risk to other family members depends on the status of the proband's parents: if a parent has the balanced t(11:22), members of the parent's family may also have the balanced translocation or Emanuel syndrome. For those identified as carriers, the risk would be the same as described above for parents who carry a balanced t(11;22). Chromosome analysis should be offered to at-risk family members. • Evaluation of the parents by chromosome analysis to detect the balanced t(11:22) is recommended. • In more than 99% of cases, one of the parents of a proband with Emanuel syndrome is a balanced carrier of a t(11;22)(q23;q11.2) and is phenotypically normal. There is a single case report of supernumerary der(22) arising from • Statistically, the mother of a proband with supernumerary der(22) is more likely than the father to be a carrier of the balanced t(11;22). • In most cases, a carrier parent has inherited the t(11;22) from a parent. • Sibs of a proband who have no findings of Emanuel syndrome: • Are not at risk for Emanuel syndrome; • Have almost no chance of having a different unbalanced chromosome abnormality; • Have an estimated 50% chance of having a balanced translocation; • Have an estimated 50% chance of having normal chromosomes. • Are not at risk for Emanuel syndrome; • Have almost no chance of having a different unbalanced chromosome abnormality; • Have an estimated 50% chance of having a balanced translocation; • Have an estimated 50% chance of having normal chromosomes. • Sibs of a proband who have findings of Emanuel syndrome (e.g., severe developmental delays, poor growth, and multiple congenital anomalies) almost always have supernumerary der(22). • When one of the parents of a proband is a carrier of the balanced t(11;22), possible outcomes of future pregnancies of the parents include the following: • Normal chromosomes • Supernumerary der(22) syndrome • Balanced t(11;22) carrier • Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant • Normal chromosomes • Supernumerary der(22) syndrome • Balanced t(11;22) carrier • Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant • In any given pregnancy, the exact chance of each of the above four pregnancy outcomes occurring is not known. Furthermore, risks vary depending on whether the mother or father of a proband is the balanced translocation carrier [ • The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). • The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. • The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. • The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). • The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. • The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. • Are not at risk for Emanuel syndrome; • Have almost no chance of having a different unbalanced chromosome abnormality; • Have an estimated 50% chance of having a balanced translocation; • Have an estimated 50% chance of having normal chromosomes. • Normal chromosomes • Supernumerary der(22) syndrome • Balanced t(11;22) carrier • Spontaneous abortion with supernumerary der(22) or another meiotic malsegregant • The risk of having a live-born infant with supernumerary der(22) is higher if the mother carries a balanced t(11;22) than if the father carries a balanced t(11;22). • The overall risk of having a live-born infant with supernumerary der(22) when a parent carries a balanced t(11;22) is estimated at between 1.8% and 5.6%. • The overall risk of having a spontaneous abortion with supernumerary der(22) or another meiotic malsegregant when a parent carries a balanced t(11;22) is estimated at between 23% and 37%. • The risk to other family members depends on the status of the proband's parents: if a parent has the balanced t(11:22), members of the parent's family may also have the balanced translocation or Emanuel syndrome. For those identified as carriers, the risk would be the same as described above for parents who carry a balanced t(11;22). • Chromosome analysis should be offered to at-risk family members. ## 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 or are at risk of being balanced translocation 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 or are at risk of being balanced translocation carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the supernumerary der(22) has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. ## Resources • • • • ## Molecular Genetics OMIM Entries for Emanuel Syndrome ( Molecular pathogenesis is not known as Emanuel syndrome results from duplicated genomic segments of chromosomes 11q and 22q, which include a significant number of genes. ## Molecular Pathogenesis Molecular pathogenesis is not known as Emanuel syndrome results from duplicated genomic segments of chromosomes 11q and 22q, which include a significant number of genes. ## Chapter Notes Web: We would like to thank Stephanie St Pierre, all the families, and Chromosome 22 Central for their support of our research efforts. 31 August 2017 (sw) Comprehensive update posted live 5 February 2015 (me) Comprehensive update posted live 11 May 2010 (me) Comprehensive update posted live 20 April 2007 (me) Review posted live 8 January 2007 (bse) Original submission • 31 August 2017 (sw) Comprehensive update posted live • 5 February 2015 (me) Comprehensive update posted live • 11 May 2010 (me) Comprehensive update posted live • 20 April 2007 (me) Review posted live • 8 January 2007 (bse) Original submission ## Author Notes Web: ## Acknowledgments We would like to thank Stephanie St Pierre, all the families, and Chromosome 22 Central for their support of our research efforts. ## Revision History 31 August 2017 (sw) Comprehensive update posted live 5 February 2015 (me) Comprehensive update posted live 11 May 2010 (me) Comprehensive update posted live 20 April 2007 (me) Review posted live 8 January 2007 (bse) Original submission • 31 August 2017 (sw) Comprehensive update posted live • 5 February 2015 (me) Comprehensive update posted live • 11 May 2010 (me) Comprehensive update posted live • 20 April 2007 (me) Review posted live • 8 January 2007 (bse) Original submission ## References ## Literature Cited A. Karyotype and schematic ideogram showing the supernumerary derivative chromosome 22, which results in trisomy of chromosome 11q23-qter and 22q cen-q11 B. Karyotype and schematic ideogram showing a balanced translocation carrier Four individuals with Emanuel syndrome. Note the round face, deeply set, round eyes, and prominent forehead in children A (age ~6 months) and B (age 3 years). Note the coarsening of facial features over time in individual D; photos are taken at age one year (D-1) and ten years (D-2). Facial features are significantly similar in the two older individuals, C (age 17 years) and D-2.
[ "MT Carter, NJ Barrowman, SA St Pierre, BS Emanuel, KM Boycott. Risk of breast cancer not increased in translocation 11;22 carriers: analysis of 80 pedigrees.. Am J Med Genet A. 2010;152A:212-4", "M Fraccaro, J Lindsten, CE Ford, L Iselius. The 11q;22q translocation: a European collaborative analysis of 43 cases.. Hum Genet 1980;56:21-51", "V Jobanputra, WK Chung, AM Hacker, BS Emanuel, D Warburton. A unique case of der(11)t(11;22),-22 arising from 3:1 segregation of a maternal t(11;22) in a family with co-segregation of the translocation and breast cancer.. Prenat Diagn 2005;25:683-6", "H Kurahashi, BS Emanuel. Long AT-rich palindromes and the constitutional t(11;22) breakpoint.. Hum Mol Genet 2001;10:2605-17", "H Kurahashi, TH Shaikh, P Hu, BA Roe, BS Emanuel, ML Budarf. Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22).. Hum Mol Genet 2000;9:1665-70", "TH Shaikh, ML Budarf, L Celle, EH Zackai, BS Emanuel. Clustered 11q23 and 22q11 breakpoints and 3:1 meiotic malsegregation in multiple unrelated t(11;22) families.. Am J Hum Genet 1999;65:1595-607", "I Wieland, P Muschke, M Volleth, A Ropke, AF Pelz, M Stumm, P Wieacker. High incidence of familial breast cancer segregates with constitutional t(11;22)(q23;q11).. Genes Chromosomes Cancer 2006;45:945-9", "EH Zackai, BS Emanuel. Site-specific reciprocal translocation, t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction.. Am J Med Genet 1980;7:507-21" ]
20/4/2007
31/8/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
emc10-ndd
emc10-ndd
[ "ER membrane protein complex subunit 10", "EMC10", "EMC10-Related Neurodevelopmental Disorder" ]
Muhammad Umair, Majid Alfadhel
Summary The diagnosis of
## Diagnosis Moderate-to-severe developmental delay Mild-to-severe intellectual disability Behavioral abnormalities and impaired social skills Seizures: multifocal, generalized tonic–clonic, and/or febrile Poor weight gain and growth deficiency Microcephaly (in some individuals) Upper limb anomalies: cubitus valgus, arachnodactyly, and fifth finger clinodactyly 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 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 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. To date, no large intragenic deletions/duplications have been reported in individuals with • Moderate-to-severe developmental delay • Mild-to-severe intellectual disability • Behavioral abnormalities and impaired social skills • Seizures: multifocal, generalized tonic–clonic, and/or febrile • Poor weight gain and growth deficiency • Microcephaly (in some individuals) • Upper limb anomalies: cubitus valgus, arachnodactyly, and fifth finger clinodactyly • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Moderate-to-severe developmental delay Mild-to-severe intellectual disability Behavioral abnormalities and impaired social skills Seizures: multifocal, generalized tonic–clonic, and/or febrile Poor weight gain and growth deficiency Microcephaly (in some individuals) Upper limb anomalies: cubitus valgus, arachnodactyly, and fifth finger clinodactyly • Moderate-to-severe developmental delay • Mild-to-severe intellectual disability • Behavioral abnormalities and impaired social skills • Seizures: multifocal, generalized tonic–clonic, and/or febrile • Poor weight gain and growth deficiency • Microcephaly (in some individuals) • Upper limb anomalies: cubitus valgus, arachnodactyly, and fifth finger clinodactyly ## 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 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 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. To date, no large intragenic deletions/duplications have been reported in individuals with • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics No genotype-phenotype correlations have been identified. The prevalence of this rare genetic disorder is unknown. To date, the clinical phenotype in 30 individuals from 15 different families has been reported [ ## Clinical Description ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence The prevalence of this rare genetic disorder is unknown. To date, the clinical phenotype in 30 individuals from 15 different families has been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The phenotypic features associated with • • • ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl brain MRI if not performed at time of diagnosis EEG if seizures are suspected Measurement of growth parameters Eval of nutritional status Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; Medical geneticist, certified genetic counselor, certified advanced genetic nurse 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 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. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 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. 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 ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl brain MRI if not performed at time of diagnosis • EEG if seizures are suspected • Measurement of growth parameters • Eval of nutritional status • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • 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 ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl brain MRI if not performed at time of diagnosis EEG if seizures are suspected Measurement of growth parameters Eval of nutritional status Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; 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) • To incl brain MRI if not performed at time of diagnosis • EEG if seizures are suspected • Measurement of growth parameters • Eval of nutritional status • Community or • Social work involvement for parental support; • Home nursing referral. ## 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 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. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 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. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • 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. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. 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. • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## 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. ## 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 ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 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 carriers or are at risk of being carriers. ## Mode of Inheritance ## 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics EMC10-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EMC10-Related Neurodevelopmental Disorder ( The endoplasmic reticulum membrane protein complex (EMC) protein family was first identified in yeast as a multiprotein transmembrane complex composed of ten subunits, where it was thought to be responsible for eliminating misfolded membrane proteins [ In an in vitro study, endoplasmic reticulum membrane protein complex subunit 10 (EMC10) was suggested as a potential therapeutic target for malignant glioblastoma after being found to exert cell proliferation inhibition, invasion, angiogenesis in endothelial cells, and cell migration in glioma cell lines [ ## Molecular Pathogenesis The endoplasmic reticulum membrane protein complex (EMC) protein family was first identified in yeast as a multiprotein transmembrane complex composed of ten subunits, where it was thought to be responsible for eliminating misfolded membrane proteins [ In an in vitro study, endoplasmic reticulum membrane protein complex subunit 10 (EMC10) was suggested as a potential therapeutic target for malignant glioblastoma after being found to exert cell proliferation inhibition, invasion, angiogenesis in endothelial cells, and cell migration in glioma cell lines [ ## Chapter Notes Dr Muhammad Umair ( Contact Dr Muhammad Umair ( Dr Muhammad Umair ( We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition. We are grateful to the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA). 15 June 2023 (sw) Review posted live 15 February 2023 (mu) Original submission • 15 June 2023 (sw) Review posted live • 15 February 2023 (mu) Original submission ## Author Notes Dr Muhammad Umair ( Contact Dr Muhammad Umair ( Dr Muhammad Umair ( ## Acknowledgments We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition. We are grateful to the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA). ## Revision History 15 June 2023 (sw) Review posted live 15 February 2023 (mu) Original submission • 15 June 2023 (sw) Review posted live • 15 February 2023 (mu) Original submission ## References ## Literature Cited
[ "E Haddad-Eid, N Gur, S Eid, T Pilowsky-Peleg, R Straussberg. The phenotype of homozygous EMC10 variant: a new syndrome with intellectual disability and language impairment.. Eur J Paediatr Neurol. 2022;37:56-61", "MC Jonikas, SR Collins, V Denic, E Oh, EM Quan, V Schmid, J Weibezahn, B Schwappach, P Walter, JS Weissman, M Schuldiner. Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum.. Science. 2009;323:1693-7", "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", "KS Junes-Gill, CE Lawrence, CJ Wheeler, R Cordner, TG Gill, V Mar, L Shiri, LA Basile. Human hematopoietic signal peptide-containing secreted 1 (hHSS1) modulates genes and pathways in glioma: implications for the regulation of tumorigenicity and angiogenesis.. BMC Cancer. 2014;14:920", "R Kaiyrzhanov, C Rocca, M Suri, S Gulieva, MS Zaki, NZ Henig, K Siquier, U Guliyeva, SM Mounir, D Marom, A Allahverdiyeva, H Megahed, H van Bokhoven, V Cantagrel, A Rad, A Pourkeramti, B Dehghani, DD Shao, K Markus-Bustani, E Sofrin-Drucker, N Orenstein, K Salayev, F Arrigoni, H Houlden, R Maroofian. Biallelic loss of EMC10 leads to mild to severe intellectual disability.. Ann Clin Transl Neurol. 2022;9:1080-9", "S Lahiri, JT Chao, S Tavassoli, AK Wong, V Choudhary, BP Young, CJ Loewen, WA Prinz. A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phospholipid transfer from the ER to mitochondria.. PLoS Biol. 2014;12", "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", "DD Shao, R Straussberg, H Ahmed, A Khan, S Tian, RS Hill, RS Smith, AJ Majmundar, N Ameziane, JE Neil, E Yang, A Al Tenaiji, SS Jamuar, TM Schlaeger, M Al-Saffar, I Hovel, A Al-Shamsi, L Basel-Salmon, AZ Amir, LM Rento, JY Lim, I Ganesan, S Shril, G Evrony, AJ Barkovich, P Bauer, F Hildebrandt, M Dong, G Borck, C Beetz, L Al-Gazali, W Eyaid, CA Walsh. A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features.. Genet Med. 2021;23:1158-62", "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", "M Umair, M Ballow, A Asiri, Y Alyafee, A Al Tuwaijri, KM Alhamoudi, T Aloraini, M Abdelhakim, AT Althagafi, S Kafkas, L Alsubaie, MT Alrifai, R Hoehndorf, A Alfares, M Alfadhel. EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay.. Clin Genet. 2020;98:555-61", "L Xiong, L Zhang, Y Yang, N Li, W Lai, F Wang, X Zhu, T. Wang. ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in drosophila and mice.. Cell Death Differ. 2020;27:646-61", "B Xu, PK Hsu, KL Stark, M Karayiorgou, JA Gogos. Derepression of a neuronal inhibitor due to miRNA dysregulation in a schizophrenia-related microdeletion.. Cell. 2013;152:262-75", "Y Zhou, F Wu, M Zhang, Z Xiong, Q Yin, Y Ru, H Shi, J Li, S Mao, Y Li, X Cao, R Hu, CW Liew, Q Ding, X Wang, Y Zhang. EMC10 governs male fertility via maintaining sperm ion balance.. J Mol Cell Biol. 2018;10:503-14" ]
15/6/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
entpd1-ndd
entpd1-ndd
[ "Autosomal Recessive Spastic Paraplegia 64", "HSP-ENTPD1", "Spastic Paraplegia 64 (SPG64)", "HSP-ENTPD1", "Spastic Paraplegia 64 (SPG64)", "Autosomal Recessive Spastic Paraplegia 64", "Ectonucleoside triphosphate diphosphohydrolase 1", "ENTPD1", "ENTPD1-Related Neurodevelopmental Disorder" ]
Daniel Calame, Isabella Herman
Summary Other neuromuscular findings can include abnormal deep tendon reflexes, weakness, neuropathy, epilepsy, dysarthria, and dysphagia. Behavior abnormalities and neurocognitive regression are common. Life span does not appear to be shortened. The diagnosis of
## Diagnosis Developmental delay / intellectual disability Abnormal reflexes (hyperreflexia, hyporeflexia, and/or areflexia with gait impairment by age five years) Behavioral concerns (attention-deficit/hyperactivity disorder, aggression, autistic features) Neurocognitive regression not attributed to progressive spastic paraplegia Other findings included thinning of the corpus callosum and cerebellar atrophy; it is unclear if the cerebellar atrophy is static or progressive (see 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 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Although no intragenic deletions or duplications have been identified to date, given that loss of function is a mechanism of disease causation, identification of an intragenic deletion or duplication may warrant further investigation and clinical correlation. • Developmental delay / intellectual disability • Abnormal reflexes (hyperreflexia, hyporeflexia, and/or areflexia with gait impairment by age five years) • Behavioral concerns (attention-deficit/hyperactivity disorder, aggression, autistic features) • Neurocognitive regression not attributed to progressive spastic paraplegia ## Suggestive Findings Developmental delay / intellectual disability Abnormal reflexes (hyperreflexia, hyporeflexia, and/or areflexia with gait impairment by age five years) Behavioral concerns (attention-deficit/hyperactivity disorder, aggression, autistic features) Neurocognitive regression not attributed to progressive spastic paraplegia Other findings included thinning of the corpus callosum and cerebellar atrophy; it is unclear if the cerebellar atrophy is static or progressive (see • Developmental delay / intellectual disability • Abnormal reflexes (hyperreflexia, hyporeflexia, and/or areflexia with gait impairment by age five years) • Behavioral concerns (attention-deficit/hyperactivity disorder, aggression, autistic features) • Neurocognitive regression not attributed to progressive spastic paraplegia ## 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 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Although no intragenic deletions or duplications have been identified to date, given that loss of function is a mechanism of disease causation, identification of an intragenic deletion or duplication may warrant further investigation and clinical correlation. ## 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ Although no intragenic deletions or duplications have been identified to date, given that loss of function is a mechanism of disease causation, identification of an intragenic deletion or duplication may warrant further investigation and clinical correlation. ## Clinical Characteristics To date, 40 individuals from 22 families have been identified with biallelic All individuals reported to date had onset younger than age five years. All individuals had developmental delay and intellectual disability, and progressive spastic paraplegia with gait impairment as well as abnormal deep tendon reflexes (hypereflexia, hyporeflexia, and/or areflexia). Additional neuromuscular findings can include weakness, neuropathy, and epilepsy. Other common findings are dysarthria, behavior abnormalities, and neurocognitive regression. Less commonly observed clinical findings include scoliosis and cataracts. At the time of this writing, Because limited clinical details are available for some reported individuals included in this table, the denominator represents the total number of individuals in whom the corresponding finding was reported. Speech and language development are variable. Some individuals never achieve independent expressive language, whereas others communicate expressively with dysarthric speech. Ability to engage in activities of daily living varies and depends on the level of intellectual disability, with some individuals requiring around-the-clock care. Electromyography / nerve conduction studies revealed findings consistent with motor axonal neuropathy. Pes cavus can be evident early in the disease course and has been reported in young children. No genotype-phenotype correlations have been identified. Pure HSP is characterized by progressive spastic paraplegia with gait impairment, corticospinal tract axonopathy, and axonal length-dependent neuropathy [ Complex HSP, the HSP category that encompasses Affected individuals have been reported throughout the world. However, it appears that this disorder is more common in populations with elevated rates of consanguinity. Additionally, the following recurrent The variants c The variants • Pes cavus can be evident early in the disease course and has been reported in young children. • Pure HSP is characterized by progressive spastic paraplegia with gait impairment, corticospinal tract axonopathy, and axonal length-dependent neuropathy [ • Complex HSP, the HSP category that encompasses • The variants c • The variants ## Clinical Description To date, 40 individuals from 22 families have been identified with biallelic All individuals reported to date had onset younger than age five years. All individuals had developmental delay and intellectual disability, and progressive spastic paraplegia with gait impairment as well as abnormal deep tendon reflexes (hypereflexia, hyporeflexia, and/or areflexia). Additional neuromuscular findings can include weakness, neuropathy, and epilepsy. Other common findings are dysarthria, behavior abnormalities, and neurocognitive regression. Less commonly observed clinical findings include scoliosis and cataracts. At the time of this writing, Because limited clinical details are available for some reported individuals included in this table, the denominator represents the total number of individuals in whom the corresponding finding was reported. Speech and language development are variable. Some individuals never achieve independent expressive language, whereas others communicate expressively with dysarthric speech. Ability to engage in activities of daily living varies and depends on the level of intellectual disability, with some individuals requiring around-the-clock care. Electromyography / nerve conduction studies revealed findings consistent with motor axonal neuropathy. Pes cavus can be evident early in the disease course and has been reported in young children. • Pes cavus can be evident early in the disease course and has been reported in young children. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Nomenclature Pure HSP is characterized by progressive spastic paraplegia with gait impairment, corticospinal tract axonopathy, and axonal length-dependent neuropathy [ Complex HSP, the HSP category that encompasses • Pure HSP is characterized by progressive spastic paraplegia with gait impairment, corticospinal tract axonopathy, and axonal length-dependent neuropathy [ • Complex HSP, the HSP category that encompasses ## Prevalence Affected individuals have been reported throughout the world. However, it appears that this disorder is more common in populations with elevated rates of consanguinity. Additionally, the following recurrent The variants c The variants • The variants c • The variants ## Genetically Related (Allelic) Disorders As of the writing of this chapter, no phenotypes other than those discussed in this ## Differential Diagnosis Selected Genes of Interest in the Differential Diagnosis of Cataracts Gastroesophageal reflux Motor neuronopathy Dysarthria Ataxia Cognitive impairment Cataracts Motor neuropathy Dysarthria Ataxia Cognitive impairment Congenital ichthyosis Macular dystrophy Leukodystrophy Seizures White matter abnormalities in brain Seizures Short stature Thin corpus callosum White matter changes Seizures Variable neurocognitive symptoms Brain abnormalities Seizures Variable neurocognitive findings Urinary incontinence Parkinsonism Dystonia Thin corpus callosum Leukodystrophy Severe DD in infantile onset Brain abnormalities DD Amyotrophy Dysarthria Ataxia DD Dystonia Dysarthria Amyotrophy DD Amyotrophy Contractures Weakness Gait abnormalities Amyotrophy Weakness Gait abnormalities Severe DD Dystonia Polyneuropathy Calcification of basal ganglia DD/ID Neuropathy Brain abnormalities Ataxia Polyneuropathy Extrapyramidal signs MRI signs of leukodystrophy White matter abnormalities Neuropathy Severe DD Optic atrophy Thin corpus callosum Leukodystrophy DD/ID Brain abnormalities Cataracts Feeding difficulties Encephalopathy Seizures Delayed myelination Abnormal T Cataracts Seizures White matter abnormalities Abnormal signal intensity in posterior limb of internal capsule Spastic ataxia Polyneuropathy Spasticity Gait abnormalities Neuropathy Severe DD Tremor Agenesis of corpus callosum Hypomyelination DD/ID Brain abnormalities Ataxia Adult-onset dementia & parkinsonism Polyneuropathy Akinetic mutism seen in advanced cases Dysarthria Ataxia Optic atrophy Supranuclear palsy Mitochondrial abnormalities on skeletal muscle biopsy Gait abnormalities Dysarthria Obesity Nystagmus Dysarthria Gait abnormalities ID Brain abnormalities Dysarthria ID Gait abnormalities Brain abnormalities Central apnea Severe DD Microcephaly Dysmorphic features Abnormal reflexes DD/ID Dysmorphic features Abnormal reflexes DD Optic atrophy Ataxia Central retinal degeneration Polyneuropathy DD/ID Abnormal gait Neuropathy AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; NDD = neurodevelopmental; SPG = spastic paraplegia See • Cataracts • Gastroesophageal reflux • Motor neuronopathy • Dysarthria • Ataxia • Cognitive impairment • Cataracts • Motor neuropathy • Dysarthria • Ataxia • Cognitive impairment • Congenital ichthyosis • Macular dystrophy • Leukodystrophy • Seizures • White matter abnormalities in brain • Seizures • Short stature • Thin corpus callosum • White matter changes • Seizures • Variable neurocognitive symptoms • Brain abnormalities • Seizures • Variable neurocognitive findings • Urinary incontinence • Parkinsonism • Dystonia • Thin corpus callosum • Leukodystrophy • Severe DD in infantile onset • Brain abnormalities • DD • Amyotrophy • Dysarthria • Ataxia • DD • Dystonia • Dysarthria • Amyotrophy • DD • Amyotrophy • Contractures • Weakness • Gait abnormalities • Amyotrophy • Weakness • Gait abnormalities • Severe DD • Dystonia • Polyneuropathy • Calcification of basal ganglia • DD/ID • Neuropathy • Brain abnormalities • Ataxia • Polyneuropathy • Extrapyramidal signs • MRI signs of leukodystrophy • White matter abnormalities • Neuropathy • Severe DD • Optic atrophy • Thin corpus callosum • Leukodystrophy • DD/ID • Brain abnormalities • Cataracts • Feeding difficulties • Encephalopathy • Seizures • Delayed myelination • Abnormal T • Cataracts • Seizures • White matter abnormalities • Abnormal signal intensity in posterior limb of internal capsule • Spastic ataxia • Polyneuropathy • Spasticity • Gait abnormalities • Neuropathy • Severe DD • Tremor • Agenesis of corpus callosum • Hypomyelination • DD/ID • Brain abnormalities • Ataxia • Adult-onset dementia & parkinsonism • Polyneuropathy • Akinetic mutism seen in advanced cases • Dysarthria • Ataxia • Optic atrophy • Supranuclear palsy • Mitochondrial abnormalities on skeletal muscle biopsy • Gait abnormalities • Dysarthria • Obesity • Nystagmus • Dysarthria • Gait abnormalities • ID • Brain abnormalities • Dysarthria • ID • Gait abnormalities • Brain abnormalities • Central apnea • Severe DD • Microcephaly • Dysmorphic features • Abnormal reflexes • DD/ID • Dysmorphic features • Abnormal reflexes • DD • Optic atrophy • Ataxia • Central retinal degeneration • Polyneuropathy • DD/ID • Abnormal gait • Neuropathy ## 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 baseline brain MRI (if not already performed) Consider EMG/NCS To incl assessment of strength, gait, deep tendon reflexes, spasticity Gross motor & fine motor skills Contractures, scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve or maintain gross motor skills) &/or OT (to improve or maintain fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; MOI = mode of inheritance; NCS = nerve conduction studies Brain MRI is essential for comparison in the event of neurocognitive regression. EMG/NCS may help identify and/or determine the severity of neuropathy, especially in individuals with impaired cognition who cannot report their symptoms or follow directions during a complicated neurologic examination. Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Incl stretching to help avoid contractures & falls Consider need for positioning & mobility devices, disability parking placard. Many ASMs may be effective; suggest use of broad-spectrum ASM (e.g., valproic acid). 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 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. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in New manifestations such as seizures & neurocognitive regression; Changes in existing issues w/tone & neurocognitive regression. While mild-to-moderate physical activity is highly recommended, affected individuals should avoid activity that significantly worsens their symptoms (e.g., worsening weakness, muscle cramps). See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To incl baseline brain MRI (if not already performed) • Consider EMG/NCS • To incl assessment of strength, gait, deep tendon reflexes, spasticity • Gross motor & fine motor skills • Contractures, scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve or maintain gross motor skills) &/or OT (to improve or maintain fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. • Incl stretching to help avoid contractures & falls • Consider need for positioning & mobility devices, disability parking placard. • Many ASMs may be effective; suggest use of broad-spectrum ASM (e.g., valproic acid). • 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 • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • New manifestations such as seizures & neurocognitive regression; • Changes in existing issues w/tone & neurocognitive regression. ## 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 baseline brain MRI (if not already performed) Consider EMG/NCS To incl assessment of strength, gait, deep tendon reflexes, spasticity Gross motor & fine motor skills Contractures, scoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve or maintain gross motor skills) &/or OT (to improve or maintain fine motor skills) Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; MOI = mode of inheritance; NCS = nerve conduction studies Brain MRI is essential for comparison in the event of neurocognitive regression. EMG/NCS may help identify and/or determine the severity of neuropathy, especially in individuals with impaired cognition who cannot report their symptoms or follow directions during a complicated neurologic examination. 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 baseline brain MRI (if not already performed) • Consider EMG/NCS • To incl assessment of strength, gait, deep tendon reflexes, spasticity • Gross motor & fine motor skills • Contractures, scoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve or maintain gross motor skills) &/or OT (to improve or maintain fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Incl stretching to help avoid contractures & falls Consider need for positioning & mobility devices, disability parking placard. Many ASMs may be effective; suggest use of broad-spectrum ASM (e.g., valproic acid). 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 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. • Incl stretching to help avoid contractures & falls • Consider need for positioning & mobility devices, disability parking placard. • Many ASMs may be effective; suggest use of broad-spectrum ASM (e.g., valproic acid). • 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 • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 New manifestations such as seizures & neurocognitive regression; Changes in existing issues w/tone & neurocognitive regression. • New manifestations such as seizures & neurocognitive regression; • Changes in existing issues w/tone & neurocognitive regression. ## Agents/Circumstances to Avoid While mild-to-moderate physical activity is highly recommended, affected individuals should avoid activity that significantly worsens their symptoms (e.g., worsening weakness, muscle cramps). ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling 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 resulted in the artifactual 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 Intrafamilial variability has been reported 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 individuals known to be carriers, particularly if consanguinity is likely and/or if both partners are of the same ethnic background (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 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 resulted in the artifactual 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 resulted in the artifactual 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 resulted in the artifactual 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 • Intrafamilial variability has been reported 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 carriers or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals known to be carriers, particularly if consanguinity is likely and/or if both partners are of the same ethnic background (see ## Mode of Inheritance ## 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 resulted in the artifactual 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 Intrafamilial variability has been reported 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 • 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 resulted in the artifactual 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 resulted in the artifactual 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 resulted in the artifactual 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 • Intrafamilial variability has been reported 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 individuals known to be carriers, particularly if consanguinity is likely and/or if both partners are of the same ethnic background (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 individuals known to be carriers, particularly if consanguinity is likely and/or if both partners are of the same ethnic background (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 Australia Tom Wahlig Stiftung Germany • • • • • • Australia • • • • • • • • • Tom Wahlig Stiftung • Germany • ## Molecular Genetics ENTPD1-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ENTPD1-Related Neurodevelopmental Disorder ( Anti-CD39/ENTPD1 flow cytometry of peripheral blood mononuclear cells ATP or ADPase assays using lymphoblastoid cell lines Anti-CD39/ENTPD1 immunohistochemistry of sural nerve biopsy 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 ( • Anti-CD39/ENTPD1 flow cytometry of peripheral blood mononuclear cells • ATP or ADPase assays using lymphoblastoid cell lines • Anti-CD39/ENTPD1 immunohistochemistry of sural nerve biopsy ## Molecular Pathogenesis Anti-CD39/ENTPD1 flow cytometry of peripheral blood mononuclear cells ATP or ADPase assays using lymphoblastoid cell lines Anti-CD39/ENTPD1 immunohistochemistry of sural nerve biopsy 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 ( • Anti-CD39/ENTPD1 flow cytometry of peripheral blood mononuclear cells • ATP or ADPase assays using lymphoblastoid cell lines • Anti-CD39/ENTPD1 immunohistochemistry of sural nerve biopsy ## Chapter Notes Daniel Calame, MD, PhD ([email protected]), and Isabella Herman, MD, PhD ([email protected]), are actively involved in basic, translational, and clinical research regarding individuals with Dr Calame and Dr Herman are also interested in hearing from clinicians treating families affected by disorders associated with progressive or non-progressive spastic paraplegia or abnormal neurodevelopment 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 Calame and Dr Herman to inquire about review of We wish to acknowledge all patients with 1 June 2023 (bp) Review posted live 14 November 2022 (dc) Original submission • 1 June 2023 (bp) Review posted live • 14 November 2022 (dc) Original submission ## Author Notes Daniel Calame, MD, PhD ([email protected]), and Isabella Herman, MD, PhD ([email protected]), are actively involved in basic, translational, and clinical research regarding individuals with Dr Calame and Dr Herman are also interested in hearing from clinicians treating families affected by disorders associated with progressive or non-progressive spastic paraplegia or abnormal neurodevelopment 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 Calame and Dr Herman to inquire about review of ## Acknowledgments We wish to acknowledge all patients with ## Revision History 1 June 2023 (bp) Review posted live 14 November 2022 (dc) Original submission • 1 June 2023 (bp) Review posted live • 14 November 2022 (dc) Original submission ## References ## Literature Cited Individuals with biallelic pathogenic Reprinted with permission from A. Sagittal T B, C. Sagittal T D. Sagittal T E. Sagittal T F. Sagittal (1) and axial (2) T G. Sagittal T
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Nomenclature of genetic movement disorders: recommendations of the International Parkinson and Movement Disorder Society Task Force - an update.. Mov Disord. 2022;37:905-35", "J Mamelona, N Crapoulet, A. Marrero. A new case of spastic paraplegia type 64 due to a missense mutation in the ENTPD1 gene.. Hum Genome Var. 2019;6:5", "A Nardi-Schreiber, G Sapir, A Gamliel, O Kakhlon, J Sosna, JM Gomori, V Meiner, A Lossos, R Katz-Brull. Defective ATP breakdown activity related to an ENTPD1 gene mutation demonstrated using (31)P NMR spectroscopy.. Chem Commun (Camb) 2017;53:9121-4", "G Novarino, AG Fenstermaker, MS Zaki, M Hofree, JL Silhavy, AD Heiberg, M Abdellateef, B Rosti, E Scott, L Mansour, A Masri, H Kayserili, JY Al-Aama, GMH Abdel-Salam, A Karminejad, M Kara, B Kara, B Bozorgmehri, T Ben-Omran, F Mojahedi, IG El Din Mahmoud, N Bouslam, A Bouhouche, A Benomar, S Hanein, L Raymond, S Forlani, M Mascaro, L Selim, N Shehata, N Al-Allawi, PS Bindu, M Azam, M Gunel, A Caglayan, K Bilguvar, A Tolun, MY Issa, J Schroth, EG Spencer, RO Rosti, N Akizu, KK Vaux, A Johansen, AA Koh, H Megahed, A Durr, A Brice, G Stevanin, SB Gabriel, T Ideker, JG Gleeson. Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders.. Science. 2014;343:506-11", "A Ölmez, GO Çetin, K Karaer. Early onset disease, anarthria, areflexia, and dystonia can be the distinctive features of SPG64, a very rare form of hereditary spastic paraplegias.. Am J Med Genet A. 2022;188:2712-7", "E Panza, JM Escamilla-Honrubia, C Marco-Marín, N Gougeard, G De Michele, VB Morra, R Liguori, L Salviati, MA Donati, R Cusano, T Pippucci, R Ravazzolo, AH Németh, S Smithson, S Davies, JA Hurst, D Bordo, V Rubio, M Seri. ALDH18A1 gene mutations cause dominant spastic paraplegia SPG9: loss of function effect and plausibility of a dominant negative mechanism.. Brain. 2016;139", "M Pashaei, A Davarzani, R Hajati, B Zamani, S Nafissi, F Larti, Y Nilipour, M Rohani, A Alavi. Description of clinical features and genetic analysis of one ultra-rare (SPG64) and two common forms (SPG5A and SPG15) of hereditary spastic paraplegia families.. J Neurogenet. 2021;35:84-94", "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 Saffari, M Kellner, C Jordan, H Rosengarten, A Mo, B Zhang, O Strelko, S Neuser, MY Davis, N Yoshikura, N Futamura, T Takeuchi, S Nabatame, H Ishiura, S Tsuji, HS Aldeen, E Cali, C Rocca, H Houlden, S Efthymiou, B Assmann, G Yoon, BA Trombetta, P Kivisäkk, F Eichler, H Nan, Y Takiyama, A Tessa, FM Santorelli, M Sahin, C Blackstone, E Yang, R Schüle, D Ebrahimi-Fakhari. The clinical and molecular spectrum of ZFYVE26-associated hereditary spastic paraplegia: SPG15.. Brain. 2023;146:2003-15", "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", "L Travaglini, C Aiello, F Stregapede, A D'Amico, V Alesi, A Ciolfi, A Bruselles, M Catteruccia, S Pizzi, G Zanni, S Loddo, S Barresi, G Vasco, M Tartaglia, E Bertini, F Nicita. The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes.. Neurogenetics. 2018;19:111-21" ]
1/6/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
epb42-spherocytosis
epb42-spherocytosis
[ "Protein 4.2", "EPB42", "EPB42-Related Hereditary Spherocytosis" ]
Theodosia A Kalfa, Amber H Begtrup
Summary Typical laboratory findings in EPB42-HS include anemia (decreased hemoglobin [Hgb] level) and reticulocytosis (increased percentage of reticulocytes), with high mean corpuscular Hgb concentration, presence of spherocytes in the peripheral blood smear, significantly decreased or absent haptoglobin, mildly increased osmotic fragility in osmotic fragility assay, increased O The diagnosis of EPB42-HS is established by identification of biallelic pathogenic variants in EPB42-HS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
## Diagnosis Pallor and/or fatigue due to anemia, which is usually of mild-to-moderate severity Jaundice Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction Splenomegaly Cholelithiasis in the second or third decade of life Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity Decreased Hgb level (See Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). Increased percent of reticulocytes as well as increased absolute reticulocyte count (See Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. Note: DAT should always be evaluated in a person with newly diagnosed hemolytic anemia to evaluate for an acute immune-mediated (acquired) hemolytic anemia. Note: The term "spherocyte" refers to the sphere-shaped red blood cells (with a decreased surface-to-volume ratio) that characterize the red blood cell membrane skeleton disorders (see Severity of Hereditary Spherocytosis Hgb = hemoglobin Based on table by Normal values may vary somewhat depending on age and sex. Absolute reticulocyte count = 45-90 x 10 The diagnosis of EPB42-HS Molecular genetic 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 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 only gross deletion reported to date is a deletion of 32 base pairs [ • Pallor and/or fatigue due to anemia, which is usually of mild-to-moderate severity • Jaundice • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis • In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis • In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction • Splenomegaly • Cholelithiasis in the second or third decade of life • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis • In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction • Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. • Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. • • Note: DAT should always be evaluated in a person with newly diagnosed hemolytic anemia to evaluate for an acute immune-mediated (acquired) hemolytic anemia. • Note: The term "spherocyte" refers to the sphere-shaped red blood cells (with a decreased surface-to-volume ratio) that characterize the red blood cell membrane skeleton disorders (see • Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • For an introduction to multigene panels click ## Suggestive Findings Pallor and/or fatigue due to anemia, which is usually of mild-to-moderate severity Jaundice Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction Splenomegaly Cholelithiasis in the second or third decade of life Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity Decreased Hgb level (See Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). Increased percent of reticulocytes as well as increased absolute reticulocyte count (See Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. Note: DAT should always be evaluated in a person with newly diagnosed hemolytic anemia to evaluate for an acute immune-mediated (acquired) hemolytic anemia. Note: The term "spherocyte" refers to the sphere-shaped red blood cells (with a decreased surface-to-volume ratio) that characterize the red blood cell membrane skeleton disorders (see Severity of Hereditary Spherocytosis Hgb = hemoglobin Based on table by Normal values may vary somewhat depending on age and sex. Absolute reticulocyte count = 45-90 x 10 • Pallor and/or fatigue due to anemia, which is usually of mild-to-moderate severity • Jaundice • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis • In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis • In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction • Splenomegaly • Cholelithiasis in the second or third decade of life • Usually intermittent and caused by unconjugated hyperbilirubinemia resulting from exacerbated hemolysis • In rare instances, caused by conjugated hyperbilirubinemia resulting from biliary obstruction • Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. • Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. • • Note: DAT should always be evaluated in a person with newly diagnosed hemolytic anemia to evaluate for an acute immune-mediated (acquired) hemolytic anemia. • Note: The term "spherocyte" refers to the sphere-shaped red blood cells (with a decreased surface-to-volume ratio) that characterize the red blood cell membrane skeleton disorders (see • Chronic, nonimmune hemolytic anemia (decreased hemoglobin [Hgb] with reticulocytosis), usually of mild-to-moderate severity • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). • High mean corpuscular Hgb concentration. Normal values are typically 31-37 g/dL. Values in individuals with hereditary spherocytosis are usually 35.5-37.5 g/dL. • Decreased Hgb level (See • Note: Hgb values in EPB42-HS may also vary depending on the clinical status of the affected individual (baseline or during a hemolytic or aplastic crisis). • Increased percent of reticulocytes as well as increased absolute reticulocyte count (See • Note: Percent of reticulocytes may vary (depending on baseline or crisis status) from 2.5% to greater than 10% (or even normal or low when in aplastic crisis). ## Establishing the Diagnosis The diagnosis of EPB42-HS Molecular genetic 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 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 only gross deletion reported to date is a deletion of 32 base pairs [ • For an introduction to multigene panels click ## Clinical Characteristics Children with Toddlers with hereditary spherocytosis are occasionally found to have age-related iron deficiency anemia; however, the anemia fails to completely resolve with iron supplementation and reticulocytosis persists [ As with all forms of mild or moderate hereditary spherocytosis (see EPB42-HS, if not recognized during infancy or early childhood, may be diagnosed later in life as a mild (hemoglobin [Hgb] = 11-15 g/dL) to moderate (Hgb = 8-11.5 g/dL) chronic hemolytic anemia (see Homozygosity for Homozygosity for Compound heterozygosity for One individual homozygous for the null Hereditary spherocytosis is the most common inherited anemia in individuals of northern European ancestry and is present worldwide, with a prevalence of 1:1,000-1:2,500 [ EPB42-HS is responsible for 40%-50% of hereditary spherocytosis in Japan, where the carrier frequency of In other populations, EPB42-HS accounts for 5% or less of hereditary spherocytosis [ ## Clinical Description Children with Toddlers with hereditary spherocytosis are occasionally found to have age-related iron deficiency anemia; however, the anemia fails to completely resolve with iron supplementation and reticulocytosis persists [ As with all forms of mild or moderate hereditary spherocytosis (see EPB42-HS, if not recognized during infancy or early childhood, may be diagnosed later in life as a mild (hemoglobin [Hgb] = 11-15 g/dL) to moderate (Hgb = 8-11.5 g/dL) chronic hemolytic anemia (see ## Genotype-Phenotype Correlations Homozygosity for Homozygosity for Compound heterozygosity for One individual homozygous for the null ## Prevalence Hereditary spherocytosis is the most common inherited anemia in individuals of northern European ancestry and is present worldwide, with a prevalence of 1:1,000-1:2,500 [ EPB42-HS is responsible for 40%-50% of hereditary spherocytosis in Japan, where the carrier frequency of In other populations, EPB42-HS accounts for 5% or less of hereditary spherocytosis [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The Complete blood count and reticulocyte count; Blood smear review; Direct and indirect anti-globulin test (DAT and IAT, traditionally called direct and indirect Coombs, respectively) to evaluate for autoimmune (or, in an infant, alloimmune) hemolytic anemia; Hemoglobin electrophoresis; G6PD enzyme activity (especially in males). Osmotic fragility testing and/or ektacytometry can identify erythrocyte membrane disorders. For the individual with Genes Associated With Hereditary Spherocytosis AD = autosomal dominant; AR = autosomal recessive; HS = hereditary spherocytosis; MOI = mode of inheritance Defined in Significant decrease or absence of erythrocyte membrane protein 4.2 in erythrocytes of persons with HS may also be secondary to biallelic Other Causes of Hereditary Hemolytic Anemia AD = autosomal dominant; AR = autosomal recessive; EPB42-HS = See Some erythrocyte enzyme disorders (e.g., triose phosphate isomerase deficiency [OMIM CDA I (caused by pathogenic variants in • Complete blood count and reticulocyte count; • Blood smear review; • Direct and indirect anti-globulin test (DAT and IAT, traditionally called direct and indirect Coombs, respectively) to evaluate for autoimmune (or, in an infant, alloimmune) hemolytic anemia; • Hemoglobin electrophoresis; • G6PD enzyme activity (especially in males). ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Hemoglobin Reticulocyte count Transfusion history EPB42-HS = Medical geneticist, certified genetic counselor, certified advanced genetic nurse Detailed management guidelines for hereditary spherocytosis have been published [ Treatment of Manifestations in Individuals with Folic acid supplementation (400 µg 1x/d until age 1 yr; 1 mg 1x/d thereafter) Red blood cell transfusion as needed for hemolytic or aplastic crisis Routine immunizations (incl annual influenza vaccine) to prevent infections & precipitation of hemolytic or aplastic crisis Supplemental iron only in those w/confirmed iron deficiency Carefully monitor iron status w/ferritin & transferrin or TIBC saturation. Discontinue iron therapy after iron stores are repleted to avoid iron overload. 23-valent pneumococcal polysaccharide vaccine (PPSV23) for Meningococcal conjugate vaccine for Prevnar-13 A 2-dose primary series of MenACWY given 8-12 wks apart Prevnar-13 3 yrs after primary series if 2-dose primary series was given between ages 2-6 yrs Every 5 yrs if 2-dose primary series or booster dose was given at age 7 yrs or older In those w/signs/symptoms of cholelithiasis In those w/history of cholelithiasis undergoing splenectomy Consider in asymptomatic persons when cholelithiasis is identified on screening ultrasound to prevent complications incl obstructive jaundice &/or pancreatitis. EPB42-HS = Recommended Surveillance for Individuals with Monitor in neonates during 1st wk of life. Monitor every 2-5 yrs later in life. If persistently ↑, consider possibility of concurrent Gilbert syndrome, which ↑s risk for early development of cholelithiasis. At least annually in those requiring frequent transfusions In those on chelation, monitor ferritin values every 3-4 mos. Any preparations containing iron should be avoided except in those with iron deficiency documented with appropriate studies (see Contact sports are not advisable in those with splenomegaly; of note, acute or excessive splenomegaly is a greater risk than chronic mild splenomegaly. It is appropriate to evaluate apparently asymptomatic older and younger sibs 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 include: Laboratory evaluation of the phenotype (complete blood count and reticulocyte count, blood smear, osmotic fragility, or ektacytometry); Molecular genetic testing for the Neonates require monitoring of serum bilirubin concentration during the first week of life so that treatment for hyperbilirubinemia can be instituted promptly to avoid complications such as kernicterus. Infants require monitoring in the first two to four months of life for significant anemia, which may require red blood cell transfusion. Initiation of folate supplementation should be considered in individuals with chronic hemolytic anemia with significant reticulocytosis. See Folic acid supplementation (800-1,000 µg daily) is recommended in pregnant women with EPB42-HS. Monitoring for exacerbation of anemia with complete blood count and reticulocyte count is recommended in pregnant women, as hemolytic crisis and persistent anemia have been reported during pregnancy in women with hemolytic anemia, especially in women who have not undergone splenectomy [ Search • Hemoglobin • Reticulocyte count • Transfusion history • Folic acid supplementation (400 µg 1x/d until age 1 yr; 1 mg 1x/d thereafter) • Red blood cell transfusion as needed for hemolytic or aplastic crisis • Routine immunizations (incl annual influenza vaccine) to prevent infections & precipitation of hemolytic or aplastic crisis • Supplemental iron only in those w/confirmed iron deficiency • Carefully monitor iron status w/ferritin & transferrin or TIBC saturation. • Discontinue iron therapy after iron stores are repleted to avoid iron overload. • 23-valent pneumococcal polysaccharide vaccine (PPSV23) for • Meningococcal conjugate vaccine for • Prevnar-13 • A 2-dose primary series of MenACWY given 8-12 wks apart • Prevnar-13 • 3 yrs after primary series if 2-dose primary series was given between ages 2-6 yrs • Every 5 yrs if 2-dose primary series or booster dose was given at age 7 yrs or older • In those w/signs/symptoms of cholelithiasis • In those w/history of cholelithiasis undergoing splenectomy • Consider in asymptomatic persons when cholelithiasis is identified on screening ultrasound to prevent complications incl obstructive jaundice &/or pancreatitis. • Monitor in neonates during 1st wk of life. • Monitor every 2-5 yrs later in life. • If persistently ↑, consider possibility of concurrent Gilbert syndrome, which ↑s risk for early development of cholelithiasis. • At least annually in those requiring frequent transfusions • In those on chelation, monitor ferritin values every 3-4 mos. • Laboratory evaluation of the phenotype (complete blood count and reticulocyte count, blood smear, osmotic fragility, or ektacytometry); • Molecular genetic testing for the ## 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 Hemoglobin Reticulocyte count Transfusion history EPB42-HS = Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Hemoglobin • Reticulocyte count • Transfusion history ## Treatment of Manifestations Detailed management guidelines for hereditary spherocytosis have been published [ Treatment of Manifestations in Individuals with Folic acid supplementation (400 µg 1x/d until age 1 yr; 1 mg 1x/d thereafter) Red blood cell transfusion as needed for hemolytic or aplastic crisis Routine immunizations (incl annual influenza vaccine) to prevent infections & precipitation of hemolytic or aplastic crisis Supplemental iron only in those w/confirmed iron deficiency Carefully monitor iron status w/ferritin & transferrin or TIBC saturation. Discontinue iron therapy after iron stores are repleted to avoid iron overload. 23-valent pneumococcal polysaccharide vaccine (PPSV23) for Meningococcal conjugate vaccine for Prevnar-13 A 2-dose primary series of MenACWY given 8-12 wks apart Prevnar-13 3 yrs after primary series if 2-dose primary series was given between ages 2-6 yrs Every 5 yrs if 2-dose primary series or booster dose was given at age 7 yrs or older In those w/signs/symptoms of cholelithiasis In those w/history of cholelithiasis undergoing splenectomy Consider in asymptomatic persons when cholelithiasis is identified on screening ultrasound to prevent complications incl obstructive jaundice &/or pancreatitis. EPB42-HS = • Folic acid supplementation (400 µg 1x/d until age 1 yr; 1 mg 1x/d thereafter) • Red blood cell transfusion as needed for hemolytic or aplastic crisis • Routine immunizations (incl annual influenza vaccine) to prevent infections & precipitation of hemolytic or aplastic crisis • Supplemental iron only in those w/confirmed iron deficiency • Carefully monitor iron status w/ferritin & transferrin or TIBC saturation. • Discontinue iron therapy after iron stores are repleted to avoid iron overload. • 23-valent pneumococcal polysaccharide vaccine (PPSV23) for • Meningococcal conjugate vaccine for • Prevnar-13 • A 2-dose primary series of MenACWY given 8-12 wks apart • Prevnar-13 • 3 yrs after primary series if 2-dose primary series was given between ages 2-6 yrs • Every 5 yrs if 2-dose primary series or booster dose was given at age 7 yrs or older • In those w/signs/symptoms of cholelithiasis • In those w/history of cholelithiasis undergoing splenectomy • Consider in asymptomatic persons when cholelithiasis is identified on screening ultrasound to prevent complications incl obstructive jaundice &/or pancreatitis. ## Surveillance Recommended Surveillance for Individuals with Monitor in neonates during 1st wk of life. Monitor every 2-5 yrs later in life. If persistently ↑, consider possibility of concurrent Gilbert syndrome, which ↑s risk for early development of cholelithiasis. At least annually in those requiring frequent transfusions In those on chelation, monitor ferritin values every 3-4 mos. • Monitor in neonates during 1st wk of life. • Monitor every 2-5 yrs later in life. • If persistently ↑, consider possibility of concurrent Gilbert syndrome, which ↑s risk for early development of cholelithiasis. • At least annually in those requiring frequent transfusions • In those on chelation, monitor ferritin values every 3-4 mos. ## Agents/Circumstances to Avoid Any preparations containing iron should be avoided except in those with iron deficiency documented with appropriate studies (see Contact sports are not advisable in those with splenomegaly; of note, acute or excessive splenomegaly is a greater risk than chronic mild splenomegaly. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs 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 include: Laboratory evaluation of the phenotype (complete blood count and reticulocyte count, blood smear, osmotic fragility, or ektacytometry); Molecular genetic testing for the Neonates require monitoring of serum bilirubin concentration during the first week of life so that treatment for hyperbilirubinemia can be instituted promptly to avoid complications such as kernicterus. Infants require monitoring in the first two to four months of life for significant anemia, which may require red blood cell transfusion. Initiation of folate supplementation should be considered in individuals with chronic hemolytic anemia with significant reticulocytosis. See • Laboratory evaluation of the phenotype (complete blood count and reticulocyte count, blood smear, osmotic fragility, or ektacytometry); • Molecular genetic testing for the ## Pregnancy Management Folic acid supplementation (800-1,000 µg daily) is recommended in pregnant women with EPB42-HS. Monitoring for exacerbation of anemia with complete blood count and reticulocyte count is recommended in pregnant women, as hemolytic crisis and persistent anemia have been reported during pregnancy in women with hemolytic anemia, especially in women who have not undergone splenectomy [ ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (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 • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (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 • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## 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 EPB42-Related Hereditary Spherocytosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EPB42-Related Hereditary Spherocytosis ( Erythrocyte membrane protein band 4.2 (also known as protein 4.2), encoded by Protein 4.2 is a part of the ankyrin-band 3 complex, connecting band 3 anion transport protein (encoded by Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Erythrocyte membrane protein band 4.2 (also known as protein 4.2), encoded by Protein 4.2 is a part of the ankyrin-band 3 complex, connecting band 3 anion transport protein (encoded by Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes The authors' work related to this review was supported by the National Institutes of Health, National Center for Advancing Translational Sciences (award 1UL1TR001425-01), and National Heart, Lung, and Blood Institute grant R01 HL152099. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Amber H Begtrup, PhD, FACMG (2014-present)Jessica A Connor, MS; Counsyl, Inc (2014-2022)Theodosia A Kalfa, MD, PhD (2014-present) 7 April 2022 (sw) Comprehensive update posted live 10 November 2016 (ma) Comprehensive update posted live 13 March 2014 (me) Review posted live 20 October 2013 (tk) Original submission • 7 April 2022 (sw) Comprehensive update posted live • 10 November 2016 (ma) Comprehensive update posted live • 13 March 2014 (me) Review posted live • 20 October 2013 (tk) Original submission ## Author Notes ## Acknowledgments The authors' work related to this review was supported by the National Institutes of Health, National Center for Advancing Translational Sciences (award 1UL1TR001425-01), and National Heart, Lung, and Blood Institute grant R01 HL152099. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ## Author History Amber H Begtrup, PhD, FACMG (2014-present)Jessica A Connor, MS; Counsyl, Inc (2014-2022)Theodosia A Kalfa, MD, PhD (2014-present) ## Revision History 7 April 2022 (sw) Comprehensive update posted live 10 November 2016 (ma) Comprehensive update posted live 13 March 2014 (me) Review posted live 20 October 2013 (tk) Original submission • 7 April 2022 (sw) Comprehensive update posted live • 10 November 2016 (ma) Comprehensive update posted live • 13 March 2014 (me) Review posted live • 20 October 2013 (tk) Original submission ## References ## Published Guidelines / Consensus Statements ## Literature Cited Ektacytometry indicating a typical curve for hereditary spherocytosis (red), characterized by increased O
[]
13/3/2014
7/4/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
epg5
epg5
[ "Vici Syndrome", "Ectopic P granules protein 5 homolog", "EPG5", "EPG5-Related Disorder" ]
Hormos Salimi Dafsari, Darius Ebrahimi-Fakhari, Afshin Saffari, Celine Deneubourg, Manolis Fanto, Heinz Jungbluth
Summary With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of The diagnosis of Of particular note, rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) should be considered for chest infections to prevent episodes of life-threatening sepsis and organ failure due to the consequences of primary immunodeficiency.
With the current widespread use of multigene panels and comprehensive genomic testing based on an unbiased (i.e., not phenotype-driven) approach, it has become apparent that the phenotypic spectrum associated with biallelic ## Diagnosis At the more severe end of the spectrum of Thymic aplasia or hypoplasia [ Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ Peripheral neuropathy with absent reflexes [ Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) Congenital structural cardiac abnormalities Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ No consensus clinical diagnostic criteria for Vici syndrome have been published; however, based on the original criteria suggested by Agenesis of corpus callosum * (Progressive) microcephaly Cataracts * Cardiomyopathy * (Severe combined) primary immunodeficiency * (Oculo-)cutaneous hypopigmentation * Failure to gain weight despite adequate caloric intake Family history is consistent with autosomal recessive inheritance (e.g., parental consanguinity and/or affected sibs). Absence of a known family history does not preclude 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. The diagnosis of This approach involves performing 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Agenesis of corpus callosum * • (Progressive) microcephaly • Cataracts * • Cardiomyopathy * • (Severe combined) primary immunodeficiency * • (Oculo-)cutaneous hypopigmentation * • Failure to gain weight despite adequate caloric intake • This approach involves performing sequence analysis of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings At the more severe end of the spectrum of Thymic aplasia or hypoplasia [ Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ Peripheral neuropathy with absent reflexes [ Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) Congenital structural cardiac abnormalities Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ No consensus clinical diagnostic criteria for Vici syndrome have been published; however, based on the original criteria suggested by Agenesis of corpus callosum * (Progressive) microcephaly Cataracts * Cardiomyopathy * (Severe combined) primary immunodeficiency * (Oculo-)cutaneous hypopigmentation * Failure to gain weight despite adequate caloric intake Family history is consistent with autosomal recessive inheritance (e.g., parental consanguinity and/or affected sibs). Absence of a known family history does not preclude the diagnosis. • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Agenesis of corpus callosum * • (Progressive) microcephaly • Cataracts * • Cardiomyopathy * • (Severe combined) primary immunodeficiency * • (Oculo-)cutaneous hypopigmentation * • Failure to gain weight despite adequate caloric intake ## Clinical Findings Thymic aplasia or hypoplasia [ Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ Peripheral neuropathy with absent reflexes [ Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) Congenital structural cardiac abnormalities Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ • Thymic aplasia or hypoplasia [ • Severe combined immunodeficiency with prominent B cell involvement, characterized by lack of memory B cells, reduced IgG2, deficient humoral response, and T4+ cell depletion [ • Increased susceptibility to infections (i.e., recurrent pulmonary and/or mucocutaneous infections) [ • Congenital myopathy with generalized hypotonia, contractures, mild-to-moderate creatine kinase elevation, and variable histologic features (fiber type disproportion, increased central nuclei, vacuoles, and/or mitochondrial abnormalities) on diagnostic muscle biopsy [ • Peripheral neuropathy with absent reflexes [ • Pyramidal and extrapyramidal movement disorders (including spastic paraplegia, dystonia, choreoathetosis, and akinetic-rigid disorders) • Congenital structural cardiac abnormalities • Acquired cardiomyopathies. Dilated cardiomyopathy is more common than hypertrophic cardiomyopathy [ ## Classic Vici Syndrome: Clinical Definition No consensus clinical diagnostic criteria for Vici syndrome have been published; however, based on the original criteria suggested by Agenesis of corpus callosum * (Progressive) microcephaly Cataracts * Cardiomyopathy * (Severe combined) primary immunodeficiency * (Oculo-)cutaneous hypopigmentation * Failure to gain weight despite adequate caloric intake • Agenesis of corpus callosum * • (Progressive) microcephaly • Cataracts * • Cardiomyopathy * • (Severe combined) primary immunodeficiency * • (Oculo-)cutaneous hypopigmentation * • Failure to gain weight despite adequate caloric intake ## Family History Family history is consistent with autosomal recessive inheritance (e.g., parental consanguinity and/or affected sibs). Absence of a known family history does not preclude the diagnosis. ## 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. The diagnosis of This approach involves performing 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • This approach involves performing sequence analysis of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of biallelic To date, around 90 individuals have been identified with biallelic The description of the phenotypic spectrum associated with Adapted from Either due to or irrespective of gastrointestinal features Note that multiple ophthalmologic features may present in a given person (e.g., cataract with retinal abnormalities). Antenatal presentation in the second trimester with agenesis of the corpus callosum, underdevelopment of the temporal lobes [ At the more severe end of the disorder spectrum, presentation is typically in the neonatal period or early infancy with callosal agenesis and (relative) hypopigmentation. (Severe) combined immunodeficiency, cardiomyopathy, and/or cataracts may or may not be present at birth but usually develop during the first year of life [ At the less severe end of the disorder spectrum, presentations ranging from hypotonia and microcephaly in infancy to nonspecific global neurodevelopmental delay with associated movement disorders (but no other signs of multisystem involvement) during early childhood have been reported [ Dysgenesis (rather than agenesis) of the corpus callosum has also been reported and may be more prominent in individuals with milder neurodevelopmental features [ About 50% of affected individuals have seizures in response to fever, while individuals at the milder end of the spectrum may show transient loss of acquired skills with febrile seizures without long-term developmental regression [ Although seizures may be well-controlled with standard anti-seizure medications, the response varies. Recurrent episodes of otherwise unexplained fever without identification of a pathogenic organism also require proactive and immediate management (see Management, Thymus aplasia or hypoplasia has been reported in around one fifth of affected individuals. Cardiomyopathy is seen in 80%-90% of individuals with cardiac involvement in Congenital heart defects including patent foramen ovale, ventricular or atrial septal defects, hypoplastic aortic arch, and mitral valve insufficiency are seen in about 10%-20% of individuals with cardiac involvement. While it may be expected that the disease course in individuals with phenotypes on the less severe end of the Precise genotype-phenotype correlations are difficult to establish because of the relatively limited number of affected individuals and the lack of long-term natural history data. Homozygosity for Bulk autophagy is at least partially impaired in fibroblasts from individuals with phenotypes on the severe end of the A milder decrease in mRNA and protein expression has been associated with a primarily neurologic phenotype without major multisystem involvement [ Classic Vici syndrome, a phenotype on the more severe end of the The birth prevalence for The variant • About 50% of affected individuals have seizures in response to fever, while individuals at the milder end of the spectrum may show transient loss of acquired skills with febrile seizures without long-term developmental regression [ • Although seizures may be well-controlled with standard anti-seizure medications, the response varies. • ## Clinical Description With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of biallelic To date, around 90 individuals have been identified with biallelic The description of the phenotypic spectrum associated with Adapted from Either due to or irrespective of gastrointestinal features Note that multiple ophthalmologic features may present in a given person (e.g., cataract with retinal abnormalities). Antenatal presentation in the second trimester with agenesis of the corpus callosum, underdevelopment of the temporal lobes [ At the more severe end of the disorder spectrum, presentation is typically in the neonatal period or early infancy with callosal agenesis and (relative) hypopigmentation. (Severe) combined immunodeficiency, cardiomyopathy, and/or cataracts may or may not be present at birth but usually develop during the first year of life [ At the less severe end of the disorder spectrum, presentations ranging from hypotonia and microcephaly in infancy to nonspecific global neurodevelopmental delay with associated movement disorders (but no other signs of multisystem involvement) during early childhood have been reported [ Dysgenesis (rather than agenesis) of the corpus callosum has also been reported and may be more prominent in individuals with milder neurodevelopmental features [ About 50% of affected individuals have seizures in response to fever, while individuals at the milder end of the spectrum may show transient loss of acquired skills with febrile seizures without long-term developmental regression [ Although seizures may be well-controlled with standard anti-seizure medications, the response varies. Recurrent episodes of otherwise unexplained fever without identification of a pathogenic organism also require proactive and immediate management (see Management, Thymus aplasia or hypoplasia has been reported in around one fifth of affected individuals. Cardiomyopathy is seen in 80%-90% of individuals with cardiac involvement in Congenital heart defects including patent foramen ovale, ventricular or atrial septal defects, hypoplastic aortic arch, and mitral valve insufficiency are seen in about 10%-20% of individuals with cardiac involvement. While it may be expected that the disease course in individuals with phenotypes on the less severe end of the • About 50% of affected individuals have seizures in response to fever, while individuals at the milder end of the spectrum may show transient loss of acquired skills with febrile seizures without long-term developmental regression [ • Although seizures may be well-controlled with standard anti-seizure medications, the response varies. • ## Genotype-Phenotype Correlations Precise genotype-phenotype correlations are difficult to establish because of the relatively limited number of affected individuals and the lack of long-term natural history data. Homozygosity for Bulk autophagy is at least partially impaired in fibroblasts from individuals with phenotypes on the severe end of the A milder decrease in mRNA and protein expression has been associated with a primarily neurologic phenotype without major multisystem involvement [ ## Nomenclature Classic Vici syndrome, a phenotype on the more severe end of the ## Prevalence The birth prevalence for The variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of Note: For more information on the immunologic abnormalities in Multisystem Disorders in the Differential Diagnosis of Primary immunodeficiency w/(oculo-)cutaneous hypopigmentation, DD, seizures, & failure to gain weight Not assoc w/ACC or cardiomyopathy Cataracts, myopathy, neuropathy, DD, brain malformation Not assoc w/cardiomyopathy, immunodeficiency, or hypopigmentation Primary immunodeficiency w/↓ of memory B cells, cutaneous hypopigmentation, coarse facies, short stature Not assoc w/neurologic features (DD, mvmt disorders) or brain malformations Primary immunodeficiency w/hemophagocytic lymphohistiocytosis, oculocutaneous albinism, failure to gain weight, delayed myelination, cortical atrophy, mvmt disorder, myopathy Not assoc w/ACC or cardiomyopathy Primary immunodeficiency w/hemophagocytic lymphohistiocytosis, cutaneous albinism, mvmt disorder Not assoc w/ACC or cardiomyopathy Dysgenesis of corpus callosum, DD, mvmt disorder, microcephaly Not assoc w/immunodeficiency or hypopigmentation DD, cataracts, myopathy, neuropathy, mvmt disorder, skeletal deformities Not assoc w/cardiomyopathy, immunodeficiency, or hypopigmentation Dysgenesis of corpus callosum, neuronal migration abnormalities, progressive microcephaly, DD, ichthyosis, palmoplantar keratoderma Not assoc w/immunodeficiency or cardiomyopathy Primary immunodeficiency w/failure to gain weight & DD Not assoc w/hypopigmentation or brain malformations Adapted from ACC = agenesis of the corpus callosum; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance • Primary immunodeficiency w/(oculo-)cutaneous hypopigmentation, DD, seizures, & failure to gain weight • Not assoc w/ACC or cardiomyopathy • Cataracts, myopathy, neuropathy, DD, brain malformation • Not assoc w/cardiomyopathy, immunodeficiency, or hypopigmentation • Primary immunodeficiency w/↓ of memory B cells, cutaneous hypopigmentation, coarse facies, short stature • Not assoc w/neurologic features (DD, mvmt disorders) or brain malformations • Primary immunodeficiency w/hemophagocytic lymphohistiocytosis, oculocutaneous albinism, failure to gain weight, delayed myelination, cortical atrophy, mvmt disorder, myopathy • Not assoc w/ACC or cardiomyopathy • Primary immunodeficiency w/hemophagocytic lymphohistiocytosis, cutaneous albinism, mvmt disorder • Not assoc w/ACC or cardiomyopathy • Dysgenesis of corpus callosum, DD, mvmt disorder, microcephaly • Not assoc w/immunodeficiency or hypopigmentation • DD, cataracts, myopathy, neuropathy, mvmt disorder, skeletal deformities • Not assoc w/cardiomyopathy, immunodeficiency, or hypopigmentation • Dysgenesis of corpus callosum, neuronal migration abnormalities, progressive microcephaly, DD, ichthyosis, palmoplantar keratoderma • Not assoc w/immunodeficiency or cardiomyopathy • Primary immunodeficiency w/failure to gain weight & DD • Not assoc w/hypopigmentation or brain malformations ## Management No comprehensive clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To evaluate development of motor, speech, & language abilities Brain MRI for agenesis/dysgenesis of corpus callosum & other brain malformations Consider EEG & ASM if seizures are a concern. Consider specific treatment for mvmt disorders (e.g., PT, botulinum toxin or baclofen for spasticity, &/or trihexyphenidyl for dystonia). To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/dysphagia &/or ↑ risk of aspiration, or poor weight gain. To evaluate for symptoms of primary immunodeficiency To arrange specific testing (i.e., immunoglobulins, T, B, & NK cell numbers & function) To assess for thymus aplasia/hypoplasia on chest x-ray To evaluate for aspiration risk & secretion mgmt Consider antibiotic prophylaxis. To check for thyroid aplasia/hypoplasia To assess thyroid function as clinically indicated Community or Social work involvement for parental support; Home nursing referral. Adapted from ADL = activities of daily living; ASM = anti-seizure medication; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Supportive care recommendations to improve quality of life, optimize function, and reduce complications are summarized in Consider rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) for chest infections to prevent episodes of life-threatening sepsis and organ failure due to the consequences of primary immunodeficiency. Treatment of Manifestations in Individuals with Nutritional supplementation as directed by dietitian Consider gastrostomy placement. Per treating immunologist Immunoglobulin infusions, vitamin D supplementation, antimicrobial prophylaxis During chest infections, rigorous antibiotic therapy, chest physiotherapy, potentially ICU treatment & ventilation Antibiotic prophylaxis Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Adapted from ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy No data are available on use of live viral vaccines in individuals with this disorder. 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 identify the multidisciplinary evaluations (and their frequency) for assessing disease progression, optimizing functional abilities and communication skills, and addressing other disease manifestations, see Recommended Surveillance for Individuals with Assess for mvmt disorders & seizure activity. Perform EEG if clinically indicated. PT/OT eval Assess for contractures, scoliosis, &/or foot deformities. Hip/spine x-rays as indicated Ophthalmologic eval for cataracts, visual acuity Assess need for support services for visually impaired. Monitor for aspiration & pulmonary complications. Polysomnography as indicated Assess for aspiration risk. Assess nutritional status. Monitor for constipation & bowel dysfunction. Assess plasma amino acid levels if clinically indicated. Adapted from See Search • To evaluate development of motor, speech, & language abilities • Brain MRI for agenesis/dysgenesis of corpus callosum & other brain malformations • Consider EEG & ASM if seizures are a concern. • Consider specific treatment for mvmt disorders (e.g., PT, botulinum toxin or baclofen for spasticity, &/or trihexyphenidyl for dystonia). • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in those w/dysphagia &/or ↑ risk of aspiration, or poor weight gain. • To evaluate for symptoms of primary immunodeficiency • To arrange specific testing (i.e., immunoglobulins, T, B, & NK cell numbers & function) • To assess for thymus aplasia/hypoplasia on chest x-ray • To evaluate for aspiration risk & secretion mgmt • Consider antibiotic prophylaxis. • To check for thyroid aplasia/hypoplasia • To assess thyroid function as clinically indicated • Community or • Social work involvement for parental support; • Home nursing referral. • Nutritional supplementation as directed by dietitian • Consider gastrostomy placement. • Per treating immunologist • Immunoglobulin infusions, vitamin D supplementation, antimicrobial prophylaxis • During chest infections, rigorous antibiotic therapy, chest physiotherapy, potentially ICU treatment & ventilation • Antibiotic prophylaxis • 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. • Assess for mvmt disorders & seizure activity. • Perform EEG if clinically indicated. • PT/OT eval • Assess for contractures, scoliosis, &/or foot deformities. • Hip/spine x-rays as indicated • Ophthalmologic eval for cataracts, visual acuity • Assess need for support services for visually impaired. • Monitor for aspiration & pulmonary complications. • Polysomnography as indicated • Assess for aspiration risk. • Assess nutritional status. • Monitor for constipation & bowel dysfunction. • Assess plasma amino acid levels if clinically indicated. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with To evaluate development of motor, speech, & language abilities Brain MRI for agenesis/dysgenesis of corpus callosum & other brain malformations Consider EEG & ASM if seizures are a concern. Consider specific treatment for mvmt disorders (e.g., PT, botulinum toxin or baclofen for spasticity, &/or trihexyphenidyl for dystonia). To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in those w/dysphagia &/or ↑ risk of aspiration, or poor weight gain. To evaluate for symptoms of primary immunodeficiency To arrange specific testing (i.e., immunoglobulins, T, B, & NK cell numbers & function) To assess for thymus aplasia/hypoplasia on chest x-ray To evaluate for aspiration risk & secretion mgmt Consider antibiotic prophylaxis. To check for thyroid aplasia/hypoplasia To assess thyroid function as clinically indicated Community or Social work involvement for parental support; Home nursing referral. Adapted from ADL = activities of daily living; ASM = anti-seizure medication; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To evaluate development of motor, speech, & language abilities • Brain MRI for agenesis/dysgenesis of corpus callosum & other brain malformations • Consider EEG & ASM if seizures are a concern. • Consider specific treatment for mvmt disorders (e.g., PT, botulinum toxin or baclofen for spasticity, &/or trihexyphenidyl for dystonia). • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in those w/dysphagia &/or ↑ risk of aspiration, or poor weight gain. • To evaluate for symptoms of primary immunodeficiency • To arrange specific testing (i.e., immunoglobulins, T, B, & NK cell numbers & function) • To assess for thymus aplasia/hypoplasia on chest x-ray • To evaluate for aspiration risk & secretion mgmt • Consider antibiotic prophylaxis. • To check for thyroid aplasia/hypoplasia • To assess thyroid function as clinically indicated • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Supportive care recommendations to improve quality of life, optimize function, and reduce complications are summarized in Consider rigorous and early antibacterial and antifungal treatment (potentially in an intensive care unit setting) for chest infections to prevent episodes of life-threatening sepsis and organ failure due to the consequences of primary immunodeficiency. Treatment of Manifestations in Individuals with Nutritional supplementation as directed by dietitian Consider gastrostomy placement. Per treating immunologist Immunoglobulin infusions, vitamin D supplementation, antimicrobial prophylaxis During chest infections, rigorous antibiotic therapy, chest physiotherapy, potentially ICU treatment & ventilation Antibiotic prophylaxis Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Adapted from ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy No data are available on use of live viral vaccines in individuals with this disorder. 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. • Nutritional supplementation as directed by dietitian • Consider gastrostomy placement. • Per treating immunologist • Immunoglobulin infusions, vitamin D supplementation, antimicrobial prophylaxis • During chest infections, rigorous antibiotic therapy, chest physiotherapy, potentially ICU treatment & ventilation • Antibiotic prophylaxis • 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. ## 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 identify the multidisciplinary evaluations (and their frequency) for assessing disease progression, optimizing functional abilities and communication skills, and addressing other disease manifestations, see Recommended Surveillance for Individuals with Assess for mvmt disorders & seizure activity. Perform EEG if clinically indicated. PT/OT eval Assess for contractures, scoliosis, &/or foot deformities. Hip/spine x-rays as indicated Ophthalmologic eval for cataracts, visual acuity Assess need for support services for visually impaired. Monitor for aspiration & pulmonary complications. Polysomnography as indicated Assess for aspiration risk. Assess nutritional status. Monitor for constipation & bowel dysfunction. Assess plasma amino acid levels if clinically indicated. Adapted from • Assess for mvmt disorders & seizure activity. • Perform EEG if clinically indicated. • PT/OT eval • Assess for contractures, scoliosis, &/or foot deformities. • Hip/spine x-rays as indicated • Ophthalmologic eval for cataracts, visual acuity • Assess need for support services for visually impaired. • Monitor for aspiration & pulmonary complications. • Polysomnography as indicated • Assess for aspiration risk. • Assess nutritional status. • Monitor for constipation & bowel dysfunction. • Assess plasma amino acid levels if clinically indicated. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Many individuals with 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 Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are not at risk of developing If both parents are known to be heterozygous for an Heterozygotes 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 for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if the reproductive partner is of the same ethnic background. An 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 • 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 • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes are not at risk of developing • A single- or multiexon • 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 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 for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if the reproductive partner is of the same ethnic background. An ## Mode of Inheritance Many individuals with ## 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 Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are not at risk of developing If both parents are known to be heterozygous for an Heterozygotes are not at risk of developing • 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 • 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 • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes are not at risk of developing • A single- or multiexon • 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 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 for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if the reproductive partner is 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 the parents of affected children and young adults who are carriers or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if the reproductive partner is of the same ethnic background. 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 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 EPG5-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EPG5-Related Disorder ( Macroautophagy (hereafter referred to as autophagy), a cellular degradation process, is pivotal for the recycling of proteins and organelles, specifically within post-mitotic cells such as neurons [ Notable Variants listed in the table have been provided by the authors. Nucleotide substitution is predicted to affect splicing between exon 2 and 5, resulting in several different isoforms [ ## Molecular Pathogenesis Macroautophagy (hereafter referred to as autophagy), a cellular degradation process, is pivotal for the recycling of proteins and organelles, specifically within post-mitotic cells such as neurons [ Notable Variants listed in the table have been provided by the authors. Nucleotide substitution is predicted to affect splicing between exon 2 and 5, resulting in several different isoforms [ ## Chapter Notes Heinz Jungbluth, Darius Ebrahimi-Fakhari, Afshin Saffari, and Hormos Dafsari are actively involved in clinical and basic research regarding individuals with Contact Heinz Jungbluth and Hormos Dafsari to inquire about review of Heinz Jungbluth, Manolis Fanto, Celine Deneubourg, and Hormos Dafsari are interested in and work on the molecular biological research in HSD was supported by the Cologne Clinician Scientist Program / Medical Faculty / University of Cologne and German Research Foundation (CCSP, DFG project no. 413543196). HJ was supported by Action Medical Research, United Kingdom, the GOSH Charity / Sparks, and a European Commission H2020-MSCA-ITN-2017 grant. 13 October 2022 (bp) Review posted live 19 April 2022 (def) Original submission • 13 October 2022 (bp) Review posted live • 19 April 2022 (def) Original submission ## Author Notes Heinz Jungbluth, Darius Ebrahimi-Fakhari, Afshin Saffari, and Hormos Dafsari are actively involved in clinical and basic research regarding individuals with Contact Heinz Jungbluth and Hormos Dafsari to inquire about review of Heinz Jungbluth, Manolis Fanto, Celine Deneubourg, and Hormos Dafsari are interested in and work on the molecular biological research in ## Acknowledgments HSD was supported by the Cologne Clinician Scientist Program / Medical Faculty / University of Cologne and German Research Foundation (CCSP, DFG project no. 413543196). HJ was supported by Action Medical Research, United Kingdom, the GOSH Charity / Sparks, and a European Commission H2020-MSCA-ITN-2017 grant. ## Revision History 13 October 2022 (bp) Review posted live 19 April 2022 (def) Original submission • 13 October 2022 (bp) Review posted live • 19 April 2022 (def) Original submission ## References ## Literature Cited Distinctive facial features in Reproduced from
[ "S Aggarwal, A Tandon, AD Bhowmik, A Dalal. Autopsy findings in EPG5-related Vici syndrome with antenatal onset: additional report of Focal cortical microdysgenesis in a second trimester fetus.. Am J Med Genet A. 2018;176:499-501", "M Al-Owain, A Al-Hashem, M Al-Muhaizea, H Humaidan, H Al-Hindi, I Al-Homoud, I Al-Mogarri. Vici syndrome associated with unilateral lung hypoplasia and myopathy.. Am J Med Genet A. 2010;152A:1849-53", "S Byrne, C Dionisi-Vici, L Smith, M Gautel, H. Jungbluth. Vici syndrome: a review.. 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Brain. 2016b;139:765-81", "T Cullup, AL Kho, C Dionisi-Vici, B Brandmeier, F Smith, Z Urry, MA Simpson, S Yau, E Bertini, V McClelland, M Al-Owain, S Koelker, C Koerner, GF Hoffmann, FA Wijburg, AE ten Hoedt, RC Rogers, D Manchester, R Miyata, M Hayashi, E Said, D Soler, PM Kroisel, C Windpassinger, FM Filloux, S Al-Kaabi, J Hertecant, M Del Campo, S Buk, I Bodi, HH Goebel, CA Sewry, S Abbs, S Mohammed, D Josifova, M Gautel, H Jungbluth. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.. Nat Genet. 2013;45:83-7", "HS Dafsari, JG Pemberton, EA Ferrer, T Yammine, C Farra, MH Mohammadi, E Ghayoor Karimiani, N Hashemi, M Souaid, S Sabbagh, P Najarzadeh Torbati, S Khan, E Roze, A Moreno-De-Luca, AM Bertoli-Avella, H Houlden, T Balla, R Maroofian. PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.. 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Two cases of Vici syndrome associated with Idiopathic Thrombocytopenic Purpura (ITP) with a review of the literature.. Am J Med Genet A. 2016;170A:1343-6", "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", "MS Kane, T Vilboux, LA Wolfe, PR Lee, Y Wang, KC Huddleston, JG Vockley, JE Niederhuber, BD Solomon. Aberrant splicing induced by the most common EPG5 mutation in an individual with Vici syndrome.. Brain. 2016;139", "MS Kane, J Zhao, J Muskett, A Diplock, S Srivastava, N Hauser, JF Deeken, JE Niederhuber, WE Smith, T Vilboux, D Ebrahimi-Fakhari. EPG5 variants with modest functional impact result in an ameliorated and primarily neurological phenotype in a 3.5-year-old patient with Vici syndrome.. Neuropediatrics. 2019;50:257-61", "V McClelland, T Cullup, I Bodi, D Ruddy, A Buj-Bello, V Biancalana, J Boehm, M Bitoun, O Miller, W Jan, E Menson, L Amaya, J Trounce, J Laporte, S Mohammed, C Sewry, J Raiman, H. Jungbluth. Vici syndrome associated with sensorineural hearing loss and evidence of neuromuscular involvement on muscle biopsy.. Am J Med Genet A. 2010;152A:741-7", "E Piano Mortari, V Folgiero, V Marcellini, P Romania, E Bellacchio, V D'Alicandro, C Bocci, R Carrozzo, D Martinelli, S Petrini, E Axiotis, C Farroni, F Locatelli, U Schara, DT Pilz, H Jungbluth, C Dionisi-Vici, R Carsetti. The Vici syndrome protein EPG5 regulates intracellular nucleic acid trafficking linking autophagy to innate and adaptive immunity.. Autophagy. 2018;14:22-37", "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", "S Shimada, K Hirasawa, A Takeshita, H Nakatsukasa, K Yamamoto-Shimojima, T Imaizumi, S Nagata, T. Yamamoto. Novel compound heterozygous EPG5 mutations consisted with a missense mutation and a microduplication in the exon 1 region identified in a Japanese patient with Vici syndrome.. Am J Med Genet A. 2018;176:2803-7", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "Y Tian, Z Li, W Hu, H Ren, E Tian, Y Zhao, Q Lu, X Huang, P Yang, X Li, X Wang, AL Kovács, L Yu, H Zhang. C. elegans screen identifies autophagy genes specific to multicellular organisms.. Cell. 2010;141:1042-55", "R Touraine, A Laquerrière, CA Petcu, F Marguet, S Byrne, R Mein, S Yau, S Mohammed, L Guibaud, M Gautel, H Jungbluth. Autopsy findings in EPG5-related Vici syndrome with antenatal onset.. Am J Med Genet A. 2017;173:2522-7", "E Verdura, A Rodríguez-Palmero, V Vélez-Santamaria, L Planas-Serra, I de la Calle, M Raspall-Chaure, A Roubertie, M Benkirane, F Saettini, L Pavinato, G Mandrile, M O'Leary, E O'Heir, E Barredo, A Chacón, V Michaud, C Goizet, M Ruiz, A Schlüter, I Rouvet, J Sala-Coromina, C Fossati, M Iascone, F Canonico, A Marcé-Grau, P de Souza, DR Adams, C Casasnovas, HL Rehm, HC Mefford, L González Gutierrez-Solana, A Brusco, M Koenig, A Macaya, A Pujol. Biallelic PI4KA variants cause a novel neurodevelopmental syndrome with hypomyelinating leukodystrophy.. Brain. 2021;144:2659-69" ]
13/10/2022
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
epm1
epm1
[ "EPM1", "Unverricht-Lundborg Disease (ULD)", "EPM1", "Unverricht-Lundborg Disease (ULD)", "Cystatin-B", "CSTB", "Progressive Myoclonic Epilepsy Type 1" ]
Progressive Myoclonic Epilepsy Type 1
Anna-Elina Lehesjoki, Reetta Kälviäinen
Summary Progressive myoclonic epilepsy type 1(EPM1) is a neurodegenerative disorder characterized by onset from age six to 15 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are cognitively mostly within the normal range, but show emotional lability and depression. The epileptic seizures are usually well controlled by anti-seizure medication, but the myoclonic jerks are progressive, action activated, and treatment resistant, and can be severely disabling. The diagnosis of EPM1 is established in a proband with suggestive findings and either biallelic abnormal CCC-CGC-CCC-GCG dodecamer repeat expansions in EPM1 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 both
## Diagnosis The diagnosis of progressive myoclonic epilepsy type 1 (EPM1) Involuntary, action-activated myoclonic jerks AND/OR generalized tonic-clonic seizures Photosensitive, generalized spike-and-wave and polyspike-and-wave paroxysms on EEG Abnormal EEG (always abnormal, even before the onset of manifestations). The background activity is labile and may be slower than normal. Photosensitivity is marked. A gradual worsening of the neurologic manifestations (myoclonus and ataxia), difficulties running, playing sports, using stairs Normal brain MRI The diagnosis of EPM1 disease Note: Pathogenic dodecamer repeat expansions in Note: The dodecamer repeat sequence is CCC-CGC-CCC-GCG. Repeats of 4-11 and 18-29 have not been observed. Molecular Genetic Testing Used in Progressive Myoclonic Epilepsy Type 1 See See Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. 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 ~99% in Finnish individuals [ • Involuntary, action-activated myoclonic jerks AND/OR generalized tonic-clonic seizures • Photosensitive, generalized spike-and-wave and polyspike-and-wave paroxysms on EEG • Abnormal EEG (always abnormal, even before the onset of manifestations). The background activity is labile and may be slower than normal. Photosensitivity is marked. • A gradual worsening of the neurologic manifestations (myoclonus and ataxia), difficulties running, playing sports, using stairs • Normal brain MRI ## Suggestive Findings The diagnosis of progressive myoclonic epilepsy type 1 (EPM1) Involuntary, action-activated myoclonic jerks AND/OR generalized tonic-clonic seizures Photosensitive, generalized spike-and-wave and polyspike-and-wave paroxysms on EEG Abnormal EEG (always abnormal, even before the onset of manifestations). The background activity is labile and may be slower than normal. Photosensitivity is marked. A gradual worsening of the neurologic manifestations (myoclonus and ataxia), difficulties running, playing sports, using stairs Normal brain MRI • Involuntary, action-activated myoclonic jerks AND/OR generalized tonic-clonic seizures • Photosensitive, generalized spike-and-wave and polyspike-and-wave paroxysms on EEG • Abnormal EEG (always abnormal, even before the onset of manifestations). The background activity is labile and may be slower than normal. Photosensitivity is marked. • A gradual worsening of the neurologic manifestations (myoclonus and ataxia), difficulties running, playing sports, using stairs • Normal brain MRI ## Establishing the Diagnosis The diagnosis of EPM1 disease Note: Pathogenic dodecamer repeat expansions in Note: The dodecamer repeat sequence is CCC-CGC-CCC-GCG. Repeats of 4-11 and 18-29 have not been observed. Molecular Genetic Testing Used in Progressive Myoclonic Epilepsy Type 1 See See Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. 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 ~99% in Finnish individuals [ ## Clinical Characteristics In more than half of individuals with progressive myoclonic epilepsy type 1 (EPM1) the first manifestation is involuntary myoclonic jerks [ During the first five to ten years, the symptoms/myoclonic jerks characteristically progress and about one third of affected individuals become severely incapacitated (wheelchair bound). Although the myoclonic jerks are disabling and resistant to therapy, the individual usually learns to tolerate them over time, if psychosocial support is good and depression not too severe. In almost half of individuals, the first manifestation is tonic-clonic seizures. There may also be absence, psychomotor, and/or focal motor seizures. Epileptic seizures, infrequent in the early stages of the disease, often increase in frequency during the ensuing three to seven years. Later they may cease entirely with appropriate anti-seizure medication. In rare cases, tonic-clonic seizures do not occur. Neurologic findings initially appear normal; however, experienced observers usually note recurrent, almost imperceptible myoclonus, especially in response to photic stimuli or other stimuli (threat, clapping of hands, nose tapping, reflexes) or to action (movements made during neurologic examination) or to cognitive stimuli (task demanding cognitive and psychomotor processing). Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Cognitive performance, especially memory, is mostly within the normal range. However, affected individuals may exhibit poor performance in time-limited tests dependent on motor functions. The disease course is inevitably progressive; however, the rate of deterioration – especially in terms of walking capacity – appears to vary even within the same family. Generalized tonic-clonic seizures are usually controlled with treatment, but myoclonic jerks may become severe, appear in series, and inhibit normal activities [ In the past, life span was shortened; many individuals died eight to 15 years after the onset of disease, usually before age 30 years. With better pharmacologic, physiotherapeutic, and psychosocial supportive treatment, life expectancy is comparable to controls up to age 40 years, but is poorer over the long term. Death occurs mainly due to respiratory infections [R Kälviäinen, personal communication]. Individuals with pathogenic variants in Moreover, EPM1 resulting from compound heterozygosity for a dodecamer repeat expansion and a sequence variant (i.e., single-nucleotide variant or indel) often presents with earlier age of onset, more severe myoclonus, and seizures that may be drug resistant [ Recently, homozygous stop-codon and frameshift pathogenic variants in Progressive myoclonic epilepsy type 1 (EPM1) was originally referred to as Baltic myoclonus (or Baltic myoclonic epilepsy) and Mediterranean myoclonus. EPM1 is known to occur worldwide, and thus these toponyms are misleading and should no longer be used. EPM1 has the highest incidence among the progressive myoclonic epilepsies (PMEs), a term that includes a large and varied group of diseases characterized by stimulus-sensitive myoclonus, epilepsy, and progressive neurologic deterioration. EPM1 occurs worldwide. Prevalence is increased in certain populations: The North African countries of Tunisia, Algeria, and Morocco, where exact prevalence figures are not available Finland, where its prevalence (2:100,000) is higher than anywhere else in the world [R Kälviäinen, personal communication]. The incidence in Finland is estimated at 1:20,000 births. • The North African countries of Tunisia, Algeria, and Morocco, where exact prevalence figures are not available • Finland, where its prevalence (2:100,000) is higher than anywhere else in the world [R Kälviäinen, personal communication]. The incidence in Finland is estimated at 1:20,000 births. ## Clinical Description In more than half of individuals with progressive myoclonic epilepsy type 1 (EPM1) the first manifestation is involuntary myoclonic jerks [ During the first five to ten years, the symptoms/myoclonic jerks characteristically progress and about one third of affected individuals become severely incapacitated (wheelchair bound). Although the myoclonic jerks are disabling and resistant to therapy, the individual usually learns to tolerate them over time, if psychosocial support is good and depression not too severe. In almost half of individuals, the first manifestation is tonic-clonic seizures. There may also be absence, psychomotor, and/or focal motor seizures. Epileptic seizures, infrequent in the early stages of the disease, often increase in frequency during the ensuing three to seven years. Later they may cease entirely with appropriate anti-seizure medication. In rare cases, tonic-clonic seizures do not occur. Neurologic findings initially appear normal; however, experienced observers usually note recurrent, almost imperceptible myoclonus, especially in response to photic stimuli or other stimuli (threat, clapping of hands, nose tapping, reflexes) or to action (movements made during neurologic examination) or to cognitive stimuli (task demanding cognitive and psychomotor processing). Some years after the onset, ataxia, incoordination, intentional tremor, and dysarthria develop. Cognitive performance, especially memory, is mostly within the normal range. However, affected individuals may exhibit poor performance in time-limited tests dependent on motor functions. The disease course is inevitably progressive; however, the rate of deterioration – especially in terms of walking capacity – appears to vary even within the same family. Generalized tonic-clonic seizures are usually controlled with treatment, but myoclonic jerks may become severe, appear in series, and inhibit normal activities [ In the past, life span was shortened; many individuals died eight to 15 years after the onset of disease, usually before age 30 years. With better pharmacologic, physiotherapeutic, and psychosocial supportive treatment, life expectancy is comparable to controls up to age 40 years, but is poorer over the long term. Death occurs mainly due to respiratory infections [R Kälviäinen, personal communication]. ## Genotype-Phenotype Correlations Individuals with pathogenic variants in Moreover, EPM1 resulting from compound heterozygosity for a dodecamer repeat expansion and a sequence variant (i.e., single-nucleotide variant or indel) often presents with earlier age of onset, more severe myoclonus, and seizures that may be drug resistant [ Recently, homozygous stop-codon and frameshift pathogenic variants in ## Nomenclature Progressive myoclonic epilepsy type 1 (EPM1) was originally referred to as Baltic myoclonus (or Baltic myoclonic epilepsy) and Mediterranean myoclonus. EPM1 is known to occur worldwide, and thus these toponyms are misleading and should no longer be used. ## Prevalence EPM1 has the highest incidence among the progressive myoclonic epilepsies (PMEs), a term that includes a large and varied group of diseases characterized by stimulus-sensitive myoclonus, epilepsy, and progressive neurologic deterioration. EPM1 occurs worldwide. Prevalence is increased in certain populations: The North African countries of Tunisia, Algeria, and Morocco, where exact prevalence figures are not available Finland, where its prevalence (2:100,000) is higher than anywhere else in the world [R Kälviäinen, personal communication]. The incidence in Finland is estimated at 1:20,000 births. • The North African countries of Tunisia, Algeria, and Morocco, where exact prevalence figures are not available • Finland, where its prevalence (2:100,000) is higher than anywhere else in the world [R Kälviäinen, personal communication]. The incidence in Finland is estimated at 1:20,000 births. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis At the onset of progressive myoclonic epilepsy type 1 (EPM1), juvenile myoclonic epilepsy (JME) (OMIM Other disorders to consider in the differential diagnosis of EPM1 are summarized in Genes of Interest in the Differential Diagnosis of Progressive Myoclonic Epilepsy Type 1 PME Focal occipital seizures & fragmentary, symmetric, or generalized myoclonus beginning in previously healthy individuals Later onset (age 8-19 yrs); rapid disease progression; death ~10 yrs after diagnosis Prior to the availability of molecular genetic testing, histologic findings on skin biopsy established the diagnosis. Early-onset ataxia (average age 2 yrs) followed by action myoclonus & seizures later in childhood Independent ambulation lost in 2nd decade Resembles EPM1 at disease onset Presents at age 6-15 yrs w/myoclonus (sometimes reported as tremor) The later disease course is characterized by moderate-to-severe incapacitating myoclonus, infrequent tonic-clonic seizures, ataxia, & mild (if any) cognitive decline. PME Onset usually in childhood, after normal early development Brain MRI often shows brain atrophy & basal ganglia calcification. Muscle biopsy typically shows RRF. AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MERRF = myoclonic epilepsy with ragged red fibers; MOI = mode of inheritance; PME = progressive myoclonic epilepsy; RRF = ragged red fibers Action myoclonus - renal failure syndrome typically comprises a continuum of two major (and ultimately fatal) manifestations: progressive myoclonic epilepsy and renal failure; however, in some instances, the kidneys are not involved. Neurologic manifestations can appear before, simultaneously, or after the renal manifestations. • PME • Focal occipital seizures & fragmentary, symmetric, or generalized myoclonus beginning in previously healthy individuals • Later onset (age 8-19 yrs); rapid disease progression; death ~10 yrs after diagnosis • Prior to the availability of molecular genetic testing, histologic findings on skin biopsy established the diagnosis. • Early-onset ataxia (average age 2 yrs) followed by action myoclonus & seizures later in childhood • Independent ambulation lost in 2nd decade • Resembles EPM1 at disease onset • Presents at age 6-15 yrs w/myoclonus (sometimes reported as tremor) • The later disease course is characterized by moderate-to-severe incapacitating myoclonus, infrequent tonic-clonic seizures, ataxia, & mild (if any) cognitive decline. • PME • Onset usually in childhood, after normal early development • Brain MRI often shows brain atrophy & basal ganglia calcification. • Muscle biopsy typically shows RRF. ## Management To establish the extent of disease and needs in an individual diagnosed with progressive myoclonic epilepsy type 1 (EPM1), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with EPM1 To incl motor, adaptive, cognitive, & speech/language eval Evaluation for special education Use of community or Need for social work involvement for parental support; Need for home nursing referral. BARS = Brief Ataxia Rating Scale; ICARS = International Cooperative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with EPM1 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) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy 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. Special education law requires that children participating in 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. Recommended Surveillance for Individuals with EPM1 Monitor BMI. Consult a nutritionist High-calorie supplementation BMI = body mass index; UMRS = Unified Myoclonus Rating Scale Search • To incl motor, adaptive, cognitive, & speech/language eval • Evaluation for special education • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function • OT to optimize ADL (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks) • Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs). • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Monitor BMI. • Consult a nutritionist • High-calorie supplementation ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with progressive myoclonic epilepsy type 1 (EPM1), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with EPM1 To incl motor, adaptive, cognitive, & speech/language eval Evaluation for special education Use of community or Need for social work involvement for parental support; Need for home nursing referral. BARS = Brief Ataxia Rating Scale; ICARS = International Cooperative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapist/therapy; PT = physical therapist/therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMRS = Unified Myoclonus Rating Scale Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech/language eval • Evaluation for special education • 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 EPM1 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) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy 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. Special education law requires that children participating in 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. • 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) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for 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. Special education law requires that children participating in 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. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 Recommended Surveillance for Individuals with EPM1 Monitor BMI. Consult a nutritionist High-calorie supplementation BMI = body mass index; UMRS = Unified Myoclonus Rating Scale • Monitor BMI. • Consult a nutritionist • High-calorie supplementation ## Agents/Circumstances to Avoid ## Evaluation of Relatives at Risk ## Therapies Under Investigation Search ## Genetic Counseling Progressive myoclonic epilepsy type 1 (EPM1) 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 each parent is heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If each parent is known to be heterozygous for a A sib who inherits biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an individual's reproductive partner has EPM1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is extremely low except in certain populations (see Carrier testing for at-risk relatives requires prior identification of the Carrier testing for the reproductive partners of a known carrier is possible. Primarily, targeted testing for the dodecamer repeat expansion should be done, and if it remains negative, sequencing 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. Once both 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 each parent is heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If each parent is known to be heterozygous for a • A sib who inherits biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an individual's reproductive partner has EPM1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is extremely low except in certain populations (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 Progressive myoclonic epilepsy type 1 (EPM1) 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 each parent is heterozygous for a Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If each parent is known to be heterozygous for a A sib who inherits biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an individual's reproductive partner has EPM1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is extremely low except in certain populations (see • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If each parent is known to be heterozygous for a • A sib who inherits biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an individual's reproductive partner has EPM1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • Because of the low carrier rate in the general population, the risk that an affected individual would have children with a carrier is extremely low except in certain populations (see ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the Carrier testing for the reproductive partners of a known carrier is possible. Primarily, targeted testing for the dodecamer repeat expansion should be done, and if it remains negative, sequencing of ## 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 both 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 Progressive Myoclonic Epilepsy Type 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Progressive Myoclonic Epilepsy Type 1 ( Impaired redox homeostasis has been reported as a pathophysiologic mechanism in Methods to Characterize Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel or capillary electrophoresis and Southern blotting. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/ or patient due to competition by the normal allele during amplification. Detection of an apparently homozygous repeat does not rule out the presence of an expanded repeat; thus, testing by expanded repeat analysis is required to detect a repeat expansion. Southern blotting [ Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated. Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Impaired redox homeostasis has been reported as a pathophysiologic mechanism in Methods to Characterize Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel or capillary electrophoresis and Southern blotting. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/ or patient due to competition by the normal allele during amplification. Detection of an apparently homozygous repeat does not rule out the presence of an expanded repeat; thus, testing by expanded repeat analysis is required to detect a repeat expansion. Southern blotting [ Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated. Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Reetta Kälviäinen, MD, PhD (2007-present) Marja-Leena Koskiniemi, MD, PhD; University of Helsinki (2004-2007) Anna-Elina Lehesjoki, MD, PhD (2004-present) 2 July 2020 (bp) Comprehensive update posted live 26 November 2014 (me) Comprehensive update posted live 18 June 2009 (me) Comprehensive update posted live 18 September 2007 (cd) Revision: sequence analysis available on a clinical basis 12 February 2007 (me) Comprehensive update posted live 24 June 2004 (me) Review posted live 6 February 2004 (ael) Original submission • 2 July 2020 (bp) Comprehensive update posted live • 26 November 2014 (me) Comprehensive update posted live • 18 June 2009 (me) Comprehensive update posted live • 18 September 2007 (cd) Revision: sequence analysis available on a clinical basis • 12 February 2007 (me) Comprehensive update posted live • 24 June 2004 (me) Review posted live • 6 February 2004 (ael) Original submission ## Author History Reetta Kälviäinen, MD, PhD (2007-present) Marja-Leena Koskiniemi, MD, PhD; University of Helsinki (2004-2007) Anna-Elina Lehesjoki, MD, PhD (2004-present) ## Revision History 2 July 2020 (bp) Comprehensive update posted live 26 November 2014 (me) Comprehensive update posted live 18 June 2009 (me) Comprehensive update posted live 18 September 2007 (cd) Revision: sequence analysis available on a clinical basis 12 February 2007 (me) Comprehensive update posted live 24 June 2004 (me) Review posted live 6 February 2004 (ael) Original submission • 2 July 2020 (bp) Comprehensive update posted live • 26 November 2014 (me) Comprehensive update posted live • 18 June 2009 (me) Comprehensive update posted live • 18 September 2007 (cd) Revision: sequence analysis available on a clinical basis • 12 February 2007 (me) Comprehensive update posted live • 24 June 2004 (me) Review posted live • 6 February 2004 (ael) Original submission ## References ## Literature Cited
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24/6/2004
2/7/2020
18/9/2007
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
epp-ar
epp-ar
[ "Ferrochelatase, mitochondrial", "FECH", "Erythropoietic Protoporphyria, Autosomal Recessive" ]
Erythropoietic Protoporphyria, Autosomal Recessive
Manisha Balwani, Joseph Bloomer, Robert Desnick
Summary Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within 30 minutes after exposure to sun or ultraviolet light and may be accompanied by swelling and redness. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias. The diagnosis of EPP is established by detection of markedly increased free erythrocyte protoporphyrin and/or by the identification of biallelic pathogenic variants in Severe liver complications are difficult to treat: cholestyramine and other porphyrin absorbents (to interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion) and plasmapheresis and intravenous hemin are sometimes beneficial. Liver transplantation may be required. EPP is inherited in an autosomal recessive manner. In about 96% of cases an affected individual inherits a loss-of-function
## Diagnosis Erythropoietic protoporphyria (EPP) Cutaneous photosensitivity, usually beginning in childhood Burning, tingling, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling Burning, itching, and intense pain; may occur without obvious skin damage Absent or sparse blisters and bullae (Note: The absence of skin damage [e.g., scarring], vesicles, and bullae often make it difficult to establish the diagnosis.) Hepatic dysfunction; may occur in 20%-30% of individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.) Note: It is important to evaluate by using an assay that distinguishes free protoporphyrin from zinc-chelated protoporphyrin, as several other conditions may lead to elevation of erythrocyte protoporphyrins (see Biochemical Characteristics of Erythropoietic Protoporphyria (EPP) Deficient activity of ferrochelatase (EC 4.99.1.1), encoded by The assay for the enzyme ferrochelatase is not widely available and is not used for diagnostic purposes. In EPP, free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin. Many assays for erythrocyte protoporphyrin or "free erythrocyte protoporphyrin" measure both zinc-chelated protoporphyrin and free protoporphyrin. Free protoporphyrin is distinguished from zinc-chelated protoporphyrin by ethanol extraction or HPLC. Protoporphyrins (usually zinc-chelated protoporphyrin) are also increased in lead poisoning, iron deficiency, anemia of chronic disease, and various hemolytic disorders, as well as in those porphyrias caused by biallelic pathogenic variants (e.g., harderoporphyria), which are more severe than the acute autosomal dominant porphyrias (e.g., In Plasma porphyrins of the III-isomer series are usually increased. Plasma total porphyrins are increased in porphyrias with cutaneous manifestations including EPP. If plasma porphyrins are increased, the fluorescence emission spectrum of plasma porphyrins at neutral pH can be characteristic and can distinguish EPP from other porphyrias. The emission maximum in EPP occurs at 632-634 nm. The diagnosis of EPP Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Erythropoietic Protoporphyria See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In addition to flanking intronic regions, sequence analysis must include deep regions of at least some introns to detect splicing or other pathogenic variant alleles (in particular, the common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. In males the phenotype of EPP is clinically indistinguishable from that of Note: Individuals with EPP have pathogenic variants in both About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression pathogenic variant (c.315-48T>C; also known as IVS3-48T>C) resulting in residual ferrochelatase activity. In populations in which a low-expression allele is quite common (see In about 4% of families with EPP, two pathogenic loss-of-function • Cutaneous photosensitivity, usually beginning in childhood • Burning, tingling, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling • Burning, itching, and intense pain; may occur without obvious skin damage • Absent or sparse blisters and bullae (Note: The absence of skin damage [e.g., scarring], vesicles, and bullae often make it difficult to establish the diagnosis.) • Hepatic dysfunction; may occur in 20%-30% of individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.) • For an introduction to multigene panels click • About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression pathogenic variant (c.315-48T>C; also known as IVS3-48T>C) resulting in residual ferrochelatase activity. • In populations in which a low-expression allele is quite common (see • In about 4% of families with EPP, two pathogenic loss-of-function ## Suggestive Findings Erythropoietic protoporphyria (EPP) Cutaneous photosensitivity, usually beginning in childhood Burning, tingling, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling Burning, itching, and intense pain; may occur without obvious skin damage Absent or sparse blisters and bullae (Note: The absence of skin damage [e.g., scarring], vesicles, and bullae often make it difficult to establish the diagnosis.) Hepatic dysfunction; may occur in 20%-30% of individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.) Note: It is important to evaluate by using an assay that distinguishes free protoporphyrin from zinc-chelated protoporphyrin, as several other conditions may lead to elevation of erythrocyte protoporphyrins (see Biochemical Characteristics of Erythropoietic Protoporphyria (EPP) Deficient activity of ferrochelatase (EC 4.99.1.1), encoded by The assay for the enzyme ferrochelatase is not widely available and is not used for diagnostic purposes. In EPP, free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin. Many assays for erythrocyte protoporphyrin or "free erythrocyte protoporphyrin" measure both zinc-chelated protoporphyrin and free protoporphyrin. Free protoporphyrin is distinguished from zinc-chelated protoporphyrin by ethanol extraction or HPLC. Protoporphyrins (usually zinc-chelated protoporphyrin) are also increased in lead poisoning, iron deficiency, anemia of chronic disease, and various hemolytic disorders, as well as in those porphyrias caused by biallelic pathogenic variants (e.g., harderoporphyria), which are more severe than the acute autosomal dominant porphyrias (e.g., In Plasma porphyrins of the III-isomer series are usually increased. Plasma total porphyrins are increased in porphyrias with cutaneous manifestations including EPP. If plasma porphyrins are increased, the fluorescence emission spectrum of plasma porphyrins at neutral pH can be characteristic and can distinguish EPP from other porphyrias. The emission maximum in EPP occurs at 632-634 nm. • Cutaneous photosensitivity, usually beginning in childhood • Burning, tingling, and itching (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling • Burning, itching, and intense pain; may occur without obvious skin damage • Absent or sparse blisters and bullae (Note: The absence of skin damage [e.g., scarring], vesicles, and bullae often make it difficult to establish the diagnosis.) • Hepatic dysfunction; may occur in 20%-30% of individuals (~2%-5% have severe liver disease that may be life threatening, necessitating liver transplantation.) ## Establishing the Diagnosis The diagnosis of EPP Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Erythropoietic Protoporphyria See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click In addition to flanking intronic regions, sequence analysis must include deep regions of at least some introns to detect splicing or other pathogenic variant alleles (in particular, the common Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. In males the phenotype of EPP is clinically indistinguishable from that of Note: Individuals with EPP have pathogenic variants in both About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression pathogenic variant (c.315-48T>C; also known as IVS3-48T>C) resulting in residual ferrochelatase activity. In populations in which a low-expression allele is quite common (see In about 4% of families with EPP, two pathogenic loss-of-function • For an introduction to multigene panels click • About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression pathogenic variant (c.315-48T>C; also known as IVS3-48T>C) resulting in residual ferrochelatase activity. • In populations in which a low-expression allele is quite common (see • In about 4% of families with EPP, two pathogenic loss-of-function ## Clinical Characteristics Most individuals with EPP develop acute cutaneous photosensitivity within 30 minutes after exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not block long-wave UVA or visible light. The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [ Severe scarring is rare, as are pigment changes, friability, and hirsutism. Blistering was reported in 26% of individuals in one large series [ Palmar keratoderma has been observed in some individuals with two loss-of-function Protoporphyric liver disease may cause severe abdominal pain (especially in the right upper quadrant) and back pain. Gallstones composed in part of protoporphyrin may be symptomatic in individuals with EPP and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation. About 20%-30% of individuals with EPP have some degree of liver dysfunction. In most cases, the hepatic manifestations are mild with slight elevations of the liver enzymes. However, up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure. In most of these individuals, underlying liver cirrhosis is already present; however, some may present with rapidly progressive cholestatic liver failure. Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in Comorbid conditions including viral hepatitis, alcohol abuse, and use of oral contraceptives (which may impair hepatic function or protoporphyrin metabolism) may contribute to hepatic disease in some [ The risk of liver disease appears to be related to higher protoporphyrin levels. The deficient activity (<30% of normal) of ferrochelatase results in EPP. Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin that is excreted in bile and feces. At times, the liver may be an important source of excess protoporphyrin, but measuring its contribution relative to that of the erythron has not been possible. Most of the excess protoporphyrin in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin leakage from these cells is proportional to their protoporphyrin content. Erythrocyte protoporphyrin in EPP is more than 90% free and not complexed with zinc. The content of free protoporphyrin in these cells declines much more rapidly when red cells age than it does in conditions in which erythrocyte zinc-chelated protoporphyrin is increased. Moreover, ultraviolet light may cause free protoporphyrin to be released from the red cell even without disruption of the red cell membrane. In this manner, free protoporphyrin may then diffuse into the plasma (where it is bound to albumin) and be taken up by the endothelium of blood vessels. The skin of persons with EPP is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called Soret band (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins). When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes. Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage. Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, acid glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease [ As noted, individuals with EPP appear to be predisposed to developing gallstones that are fluorescent and contain large quantities of protoporphyrin. In one series, approximately 22% of individuals with EPP had a known history of gallstones [ Long-term observations of patients with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces. On the other hand, severe hepatic complications, when they do occur, often follow increasing accumulation of protoporphyrin in erythrocytes, plasma, and liver. Iron deficiency and factors that impair liver function sometimes contribute. Enterohepatic circulation of protoporphyrin may favor its return and retention in the liver, especially when liver function is impaired. Liver damage probably results at least in part from protoporphyrin accumulation itself, as this porphyrin is insoluble, tends to form crystalline structures in liver cells, can impair mitochondrial functions in liver cells, and can decrease hepatic bile formation and flow [ About 96% of affected individuals are compound heterozygotes for a loss-of-function variant that markedly decreases ferrochelatase (FECH) activity and a second low-expression pathogenic variant which also decreases the FECH activity by about 50%. Persons with low residual activity may have a more severe clinical presentation. Palmar keratoderma was reported in persons with two loss-of-function Individuals with EPP with pathogenic missense variants have significantly lower median erythrocyte protoporphyrin levels than those with deletions or nonsense or consensus splice site variants. The greater the level of erythrocyte protoporphyrin, the more likely that the patient will be more severely affected, characterized by decreased sun tolerance and increased risk of liver dysfunction [ EPP appears to be 100% penetrant when there are biallelic Obsolete terms for EPP are: erythrohepatic protoporphyria, heme synthetase deficiency, and ferrochelatase deficiency EPP is the third most common porphyria, with an estimated incidence of two to five in 1,000,000; it is the most common porphyria in children. EPP is equally common in women and men. The prevalence ranges from 1:75,000 in the Netherlands (as the result of a founder effect) to 1:200,000 reported in Wales [ EPP has been described worldwide. The prevalence of EPP may vary based on the population allele frequency of the low-expression • Most individuals with EPP develop acute cutaneous photosensitivity within 30 minutes after exposure to sun or ultraviolet light. • Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region. • Affected individuals are also sensitive to sunlight that passes through window glass that does not block long-wave UVA or visible light. • The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. • Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. • Symptoms may seem out of proportion to the visible skin lesions. • Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [ • Severe scarring is rare, as are pigment changes, friability, and hirsutism. • Blistering was reported in 26% of individuals in one large series [ • Palmar keratoderma has been observed in some individuals with two loss-of-function • Protoporphyric liver disease may cause severe abdominal pain (especially in the right upper quadrant) and back pain. • Gallstones composed in part of protoporphyrin may be symptomatic in individuals with EPP and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation. • About 20%-30% of individuals with EPP have some degree of liver dysfunction. • In most cases, the hepatic manifestations are mild with slight elevations of the liver enzymes. • However, up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure. In most of these individuals, underlying liver cirrhosis is already present; however, some may present with rapidly progressive cholestatic liver failure. • Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. • End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in • Comorbid conditions including viral hepatitis, alcohol abuse, and use of oral contraceptives (which may impair hepatic function or protoporphyrin metabolism) may contribute to hepatic disease in some [ • The risk of liver disease appears to be related to higher protoporphyrin levels. ## Clinical Description Most individuals with EPP develop acute cutaneous photosensitivity within 30 minutes after exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region. Affected individuals are also sensitive to sunlight that passes through window glass that does not block long-wave UVA or visible light. The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [ Severe scarring is rare, as are pigment changes, friability, and hirsutism. Blistering was reported in 26% of individuals in one large series [ Palmar keratoderma has been observed in some individuals with two loss-of-function Protoporphyric liver disease may cause severe abdominal pain (especially in the right upper quadrant) and back pain. Gallstones composed in part of protoporphyrin may be symptomatic in individuals with EPP and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation. About 20%-30% of individuals with EPP have some degree of liver dysfunction. In most cases, the hepatic manifestations are mild with slight elevations of the liver enzymes. However, up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure. In most of these individuals, underlying liver cirrhosis is already present; however, some may present with rapidly progressive cholestatic liver failure. Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in Comorbid conditions including viral hepatitis, alcohol abuse, and use of oral contraceptives (which may impair hepatic function or protoporphyrin metabolism) may contribute to hepatic disease in some [ The risk of liver disease appears to be related to higher protoporphyrin levels. • Most individuals with EPP develop acute cutaneous photosensitivity within 30 minutes after exposure to sun or ultraviolet light. • Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band and to a lesser degree in the long-wave UV region. • Affected individuals are also sensitive to sunlight that passes through window glass that does not block long-wave UVA or visible light. • The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. • Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. • Symptoms may seem out of proportion to the visible skin lesions. • Pregnancy has been associated with decreased protoporphyrin levels and increased tolerance to sun exposure [ • Severe scarring is rare, as are pigment changes, friability, and hirsutism. • Blistering was reported in 26% of individuals in one large series [ • Palmar keratoderma has been observed in some individuals with two loss-of-function • Protoporphyric liver disease may cause severe abdominal pain (especially in the right upper quadrant) and back pain. • Gallstones composed in part of protoporphyrin may be symptomatic in individuals with EPP and need to be excluded as a cause of biliary obstruction in persons with hepatic decompensation. • About 20%-30% of individuals with EPP have some degree of liver dysfunction. • In most cases, the hepatic manifestations are mild with slight elevations of the liver enzymes. • However, up to 5% of affected individuals may develop more advanced liver disease, most notably cholestatic liver failure. In most of these individuals, underlying liver cirrhosis is already present; however, some may present with rapidly progressive cholestatic liver failure. • Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. • End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in • Comorbid conditions including viral hepatitis, alcohol abuse, and use of oral contraceptives (which may impair hepatic function or protoporphyrin metabolism) may contribute to hepatic disease in some [ • The risk of liver disease appears to be related to higher protoporphyrin levels. ## Pathophysiology The deficient activity (<30% of normal) of ferrochelatase results in EPP. Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin that is excreted in bile and feces. At times, the liver may be an important source of excess protoporphyrin, but measuring its contribution relative to that of the erythron has not been possible. Most of the excess protoporphyrin in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin leakage from these cells is proportional to their protoporphyrin content. Erythrocyte protoporphyrin in EPP is more than 90% free and not complexed with zinc. The content of free protoporphyrin in these cells declines much more rapidly when red cells age than it does in conditions in which erythrocyte zinc-chelated protoporphyrin is increased. Moreover, ultraviolet light may cause free protoporphyrin to be released from the red cell even without disruption of the red cell membrane. In this manner, free protoporphyrin may then diffuse into the plasma (where it is bound to albumin) and be taken up by the endothelium of blood vessels. The skin of persons with EPP is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called Soret band (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins). When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes. Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage. Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, acid glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease [ As noted, individuals with EPP appear to be predisposed to developing gallstones that are fluorescent and contain large quantities of protoporphyrin. In one series, approximately 22% of individuals with EPP had a known history of gallstones [ Long-term observations of patients with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces. On the other hand, severe hepatic complications, when they do occur, often follow increasing accumulation of protoporphyrin in erythrocytes, plasma, and liver. Iron deficiency and factors that impair liver function sometimes contribute. Enterohepatic circulation of protoporphyrin may favor its return and retention in the liver, especially when liver function is impaired. Liver damage probably results at least in part from protoporphyrin accumulation itself, as this porphyrin is insoluble, tends to form crystalline structures in liver cells, can impair mitochondrial functions in liver cells, and can decrease hepatic bile formation and flow [ ## Genotype-Phenotype Correlations About 96% of affected individuals are compound heterozygotes for a loss-of-function variant that markedly decreases ferrochelatase (FECH) activity and a second low-expression pathogenic variant which also decreases the FECH activity by about 50%. Persons with low residual activity may have a more severe clinical presentation. Palmar keratoderma was reported in persons with two loss-of-function Individuals with EPP with pathogenic missense variants have significantly lower median erythrocyte protoporphyrin levels than those with deletions or nonsense or consensus splice site variants. The greater the level of erythrocyte protoporphyrin, the more likely that the patient will be more severely affected, characterized by decreased sun tolerance and increased risk of liver dysfunction [ ## Penetrance EPP appears to be 100% penetrant when there are biallelic ## Nomenclature Obsolete terms for EPP are: erythrohepatic protoporphyria, heme synthetase deficiency, and ferrochelatase deficiency ## Prevalence EPP is the third most common porphyria, with an estimated incidence of two to five in 1,000,000; it is the most common porphyria in children. EPP is equally common in women and men. The prevalence ranges from 1:75,000 in the Netherlands (as the result of a founder effect) to 1:200,000 reported in Wales [ EPP has been described worldwide. The prevalence of EPP may vary based on the population allele frequency of the low-expression ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Other causes of the erythropoietic protoporphyria (EPP) phenotype include the following. Polymorphous light eruption Solar urticaria Drug-induced photosensitivity Recent natural history studies showed that 37.5% of males with XLP and 22.2% of females with XLP had abnormal serum aminotransferases compared to 13.7% of individuals with EPP [ In XLP, the ratio of free protoporphyrin to zinc-chelated protoporphyrin may range from 90:30 to 50:50 ( Biochemical Characteristics of X-Linked Protoporphyria (XLP) Increased activity due to pathogenic "gain-of-function" variants in • Polymorphous light eruption • Solar urticaria • Drug-induced photosensitivity ## Management To establish the extent of disease and needs of an individual diagnosed with erythropoietic protoporphyria (EPP), the following evaluations are recommended: Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected Consultation with a clinical geneticist and/or genetic counselor The phototoxic pain is not responsive to narcotic analgesics. Current management centers on prevention of the painful attacks by avoidance of sun/light, including the long-wave ultraviolet light sunlight that passes through window glass: Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke-colored filters provide only partial protection. Tanning products. Some tanning creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent are often effective but are not cosmetically acceptable to all. Topical sunscreens are typically not useful. β-carotene. Oral Lumitene™ (120-180 mg/dL) may improve tolerance to sunlight in some patients if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600-800 μg/dL), causing mild skin discoloration due to carotenemia. The dose of Lumitene depends on age, ranging from two to ten 30-mg capsules per day and usually started six to eight weeks before summer. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, there are currently no data to support its efficacy [ Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ Plasmapheresis and intravenous hemin are sometimes beneficial [ Liver transplantation has been performed as a life-saving measure in individuals with severe protoporphyric liver disease [ Sun avoidance is the only effective means of preventing primary manifestations. Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency as a result of to sun avoidance. Immunization for hepatitis A and B is recommended. Annual assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile is appropriate. Hepatic function should be monitored every six to 12 months. Hepatic imaging studies including abdominal sonogram are indicated if cholelithiasis is suspected. Vitamin D 25-OH levels should be monitored in all patients whether or not they are receiving supplements. The following are appropriate: Avoidance of sunlight and UV light In patients with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens) In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ It is appropriate to evaluate at-risk family members as newborns or infants in order to identify as early as possible those who would benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction. Evaluations can include the following: Molecular genetic testing if both Biochemical testing to detect markedly increased free erythrocyte protoporphyrin if the pathogenic variants in the family are not known See Pregnancy is not complicated by EPP. There may be some improvement in photosensitivity during pregnancy as well as a reduction in protoporphyrin levels [ Phase III clinical trials from the US and Europe with a subcutaneous insertion of a biodegradable, slow-released α-melanocyte-stimulating hormone analog, afamelanotide (Scenesse Scenesse In the United States, the drug is pending FDA review. Search • Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing • Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected • Consultation with a clinical geneticist and/or genetic counselor • Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats • Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke-colored filters provide only partial protection. • Tanning products. Some tanning creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent are often effective but are not cosmetically acceptable to all. Topical sunscreens are typically not useful. • β-carotene. Oral Lumitene™ (120-180 mg/dL) may improve tolerance to sunlight in some patients if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600-800 μg/dL), causing mild skin discoloration due to carotenemia. The dose of Lumitene depends on age, ranging from two to ten 30-mg capsules per day and usually started six to eight weeks before summer. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, there are currently no data to support its efficacy [ • Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ • Plasmapheresis and intravenous hemin are sometimes beneficial [ • Liver transplantation has been performed as a life-saving measure in individuals with severe protoporphyric liver disease [ • Avoidance of sunlight and UV light • In patients with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens) • In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ • Molecular genetic testing if both • Biochemical testing to detect markedly increased free erythrocyte protoporphyrin if the pathogenic variants in the family are not known • Scenesse • In the United States, the drug is pending FDA review. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with erythropoietic protoporphyria (EPP), the following evaluations are recommended: Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected Consultation with a clinical geneticist and/or genetic counselor • Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile if not performed as part of diagnostic testing • Assessment of hepatic function as well as imaging studies such as abdominal sonogram if cholelithiasis is suspected • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The phototoxic pain is not responsive to narcotic analgesics. Current management centers on prevention of the painful attacks by avoidance of sun/light, including the long-wave ultraviolet light sunlight that passes through window glass: Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke-colored filters provide only partial protection. Tanning products. Some tanning creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent are often effective but are not cosmetically acceptable to all. Topical sunscreens are typically not useful. β-carotene. Oral Lumitene™ (120-180 mg/dL) may improve tolerance to sunlight in some patients if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600-800 μg/dL), causing mild skin discoloration due to carotenemia. The dose of Lumitene depends on age, ranging from two to ten 30-mg capsules per day and usually started six to eight weeks before summer. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, there are currently no data to support its efficacy [ Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ Plasmapheresis and intravenous hemin are sometimes beneficial [ Liver transplantation has been performed as a life-saving measure in individuals with severe protoporphyric liver disease [ • Sun protection using protective clothing including long sleeves, gloves, and wide-brimmed hats • Protective tinted glass for cars and windows to prevent exposure to UV light. Grey or smoke-colored filters provide only partial protection. • Tanning products. Some tanning creams which cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent are often effective but are not cosmetically acceptable to all. Topical sunscreens are typically not useful. • β-carotene. Oral Lumitene™ (120-180 mg/dL) may improve tolerance to sunlight in some patients if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600-800 μg/dL), causing mild skin discoloration due to carotenemia. The dose of Lumitene depends on age, ranging from two to ten 30-mg capsules per day and usually started six to eight weeks before summer. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, there are currently no data to support its efficacy [ • Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ • Plasmapheresis and intravenous hemin are sometimes beneficial [ • Liver transplantation has been performed as a life-saving measure in individuals with severe protoporphyric liver disease [ ## Prevention of Primary Manifestations Sun avoidance is the only effective means of preventing primary manifestations. ## Prevention of Secondary Complications Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency as a result of to sun avoidance. Immunization for hepatitis A and B is recommended. ## Surveillance Annual assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile is appropriate. Hepatic function should be monitored every six to 12 months. Hepatic imaging studies including abdominal sonogram are indicated if cholelithiasis is suspected. Vitamin D 25-OH levels should be monitored in all patients whether or not they are receiving supplements. ## Agents/Circumstances to Avoid The following are appropriate: Avoidance of sunlight and UV light In patients with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens) In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ • Avoidance of sunlight and UV light • In patients with hepatic dysfunction, avoidance of drugs that may induce cholestasis (e.g., estrogens) • In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ ## Evaluation of Relatives at Risk It is appropriate to evaluate at-risk family members as newborns or infants in order to identify as early as possible those who would benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction. Evaluations can include the following: Molecular genetic testing if both Biochemical testing to detect markedly increased free erythrocyte protoporphyrin if the pathogenic variants in the family are not known See • Molecular genetic testing if both • Biochemical testing to detect markedly increased free erythrocyte protoporphyrin if the pathogenic variants in the family are not known ## Pregnancy Management Pregnancy is not complicated by EPP. There may be some improvement in photosensitivity during pregnancy as well as a reduction in protoporphyrin levels [ ## Therapies Under Investigation Phase III clinical trials from the US and Europe with a subcutaneous insertion of a biodegradable, slow-released α-melanocyte-stimulating hormone analog, afamelanotide (Scenesse Scenesse In the United States, the drug is pending FDA review. Search • Scenesse • In the United States, the drug is pending FDA review. ## Genetic Counseling Erythropoietic protoporphyria (EPP) is inherited in an autosomal recessive manner. Note: Because of the relatively high carrier frequency of a low-expression The parents of an affected child are obligate heterozygotes (i.e., carriers) for either a Most often one parent transmits the loss-of-function In about 4% of couples, both parents transmit a loss-of-function Heterozygotes (carriers) and individuals who inherit two low-expression alleles 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) and sibs who inherit two low-expression alleles are asymptomatic. The offspring of an individual with EPP are obligate heterozygotes (carriers) for a loss-of-function Unless an individual with EPP has children with an affected individual or a carrier of a loss-of-function Carrier testing for at-risk family members requires prior identification of the Biochemical testing is not used for carrier detection. 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 Biochemical testing is not used for prenatal diagnosis. 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) for either a • Most often one parent transmits the loss-of-function • In about 4% of couples, both parents transmit a loss-of-function • Most often one parent transmits the loss-of-function • In about 4% of couples, both parents transmit a loss-of-function • Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic and are not at risk of developing the disorder. • Most often one parent transmits the loss-of-function • In about 4% of couples, both parents transmit a loss-of-function • 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) and sibs who inherit two low-expression alleles are asymptomatic. • The offspring of an individual with EPP are obligate heterozygotes (carriers) for a loss-of-function • Unless an individual with EPP has children with an affected individual or a carrier of a loss-of-function • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Erythropoietic protoporphyria (EPP) is inherited in an autosomal recessive manner. Note: Because of the relatively high carrier frequency of a low-expression ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers) for either a Most often one parent transmits the loss-of-function In about 4% of couples, both parents transmit a loss-of-function Heterozygotes (carriers) and individuals who inherit two low-expression alleles 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) and sibs who inherit two low-expression alleles are asymptomatic. The offspring of an individual with EPP are obligate heterozygotes (carriers) for a loss-of-function Unless an individual with EPP has children with an affected individual or a carrier of a loss-of-function • The parents of an affected child are obligate heterozygotes (i.e., carriers) for either a • Most often one parent transmits the loss-of-function • In about 4% of couples, both parents transmit a loss-of-function • Most often one parent transmits the loss-of-function • In about 4% of couples, both parents transmit a loss-of-function • Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic and are not at risk of developing the disorder. • Most often one parent transmits the loss-of-function • In about 4% of couples, both parents transmit a loss-of-function • 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) and sibs who inherit two low-expression alleles are asymptomatic. • The offspring of an individual with EPP are obligate heterozygotes (carriers) for a loss-of-function • Unless an individual with EPP has children with an affected individual or a carrier of a loss-of-function ## Carrier Detection Carrier testing for at-risk family members requires prior identification of the Biochemical testing is not used for carrier detection. ## 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 Biochemical testing is not used for prenatal diagnosis. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom Canada American Porphyria Foundation Sweden • • United Kingdom • • • Canada • • • American Porphyria Foundation • • • • • • • • • • • • • Sweden • ## Molecular Genetics Erythropoietic Protoporphyria, Autosomal Recessive: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Erythropoietic Protoporphyria, Autosomal Recessive ( Selected Variants listed in the table have been provided by the authors. Conventional variant nomenclature: Human Genome Variation Society ( Variant designation that does not conform to current naming conventions About 96% of affected individuals are compound heterozygotes for a pathogenic variant resulting in markedly decreased ferrochelatase activity and a second low-expression mutated allele (c.315-48T>C) resulting in residual ferrochelatase activity. In about 4% of families with EPP, two pathogenic loss-of-function ## References ## Literature Cited ## Chapter Notes The EPP contribution to Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX Dr Montgomery Bissell, University of California, San Francisco, CA Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, NC Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT 7 September 2017 (ha) Comprehensive update posted live 16 October 2014 (me) Comprehensive updated posted live 27 September 2012 (me) Review posted live 10 April 2012 (rd) Original submission • Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX • Dr Montgomery Bissell, University of California, San Francisco, CA • Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, NC • Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT • 7 September 2017 (ha) Comprehensive update posted live • 16 October 2014 (me) Comprehensive updated posted live • 27 September 2012 (me) Review posted live • 10 April 2012 (rd) Original submission ## Acknowledgments The EPP contribution to Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX Dr Montgomery Bissell, University of California, San Francisco, CA Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, NC Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT • Dr Karl Anderson, University of Texas Medical Branch, Galveston, TX • Dr Montgomery Bissell, University of California, San Francisco, CA • Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, NC • Dr John Phillips, University of Utah School of Medicine, Salt Lake City, UT ## Revision History 7 September 2017 (ha) Comprehensive update posted live 16 October 2014 (me) Comprehensive updated posted live 27 September 2012 (me) Review posted live 10 April 2012 (rd) Original submission • 7 September 2017 (ha) Comprehensive update posted live • 16 October 2014 (me) Comprehensive updated posted live • 27 September 2012 (me) Review posted live • 10 April 2012 (rd) Original submission
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27/9/2012
7/9/2017
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
epp-xl
epp-xl
[ "5-aminolevulinate synthase, erythroid-specific, mitochondrial", "ALAS2", "X-Linked Protoporphyria" ]
X-Linked Protoporphyria
Manisha Balwani, Robert Desnick
Summary X-linked protoporphyria (XLP) is characterized in affected males by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness. Blistering lesions are uncommon. Pain, which may seem out of proportion to the visible skin lesions, may persist for hours or days after the initial phototoxic reaction. Photosensitivity is lifelong. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. An unknown proportion of individuals with XLP develop liver disease. Except for those with advanced liver disease, life expectancy is not reduced. The phenotype in heterozygous females ranges from asymptomatic to as severe as in affected males. The diagnosis of XLP is established in a male proband with markedly increased free erythrocyte protoporphyrin and zinc-chelated erythrocyte protoporphyrin by identification of a hemizygous pathogenic gain-of-function variant in The diagnosis of XLP is established in a female proband with increased free erythrocyte protoporphyrin and zinc-chelated erythrocyte protoporphyrin by identification of a heterozygous pathogenic gain-of-function variant in Severe liver complications are difficult to treat: cholestyramine and other porphyrin absorbents (to interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion) and plasmapheresis and intravenous hemin are sometimes beneficial. Liver transplantation can be a lifesaving measure in individuals with severe protoporphyric liver disease; combined bone marrow and liver transplantation is indicated in those with liver failure to prevent future damage to the allografts. By definition, XLP is inherited in an X-linked manner. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Women with an
## Diagnosis There are no established guidelines or diagnostic algorithms. X-linked protoporphyria (XLP) should be suspected in individuals with the following clinical findings and initial laboratory findings. Cutaneous photosensitivity, usually beginning in childhood Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling Painful symptoms; may occur without obvious skin damage Absent or sparse blisters and bullae Note: The absence of skin damage (e.g., scarring), vesicles, and bullae often make it difficult to suspect the diagnosis. Hepatic complications, particularly cholestatic liver disease, may develop in fewer than 5% of affected individuals. Note: It is essential to use an assay for erythrocyte protoporphyrin that distinguishes between free protoporphyrin and zinc-chelated protoporphyrin to differentiate XLP from erythropoietic protoporphyria (EPP-AR) and several other conditions that may lead to elevation of erythrocyte protoporphyrins (see Biochemical Characteristics of X-Linked Protoporphyria (XLP) Increased enzyme activity is due to Many assays for erythrocyte protoporphyrin or "free erythrocyte protoporphyrin" measure both zinc-chelated protoporphyrin and free protoporphyrin. Free protoporphyrin is distinguished from zinc-chelated protoporphyrin by ethanol extraction or HPLC. Protoporphyrins (usually zinc-chelated protoporphyrin) are also increased in lead poisoning, iron deficiency, anemia of chronic disease, and various hemolytic disorders, as well as in those porphyrias caused by biallelic pathogenic variants (e.g., harderoporphyria). In erythropoietic protoporphyria, free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin (see Plasma total porphyrins are increased in porphyrias with cutaneous manifestations including XLP. If plasma porphyrins are increased, the fluorescence emission spectrum of plasma porphyrins at neutral pH can be characteristic and can distinguish XLP and EPP-AR from other porphyrias. The emission maximum in XLP and EPP-AR occurs at 634 nm. 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 include Note: All Molecular Genetic Testing Used in X-Linked Protoporphyria 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 • Cutaneous photosensitivity, usually beginning in childhood • Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling • Painful symptoms; may occur without obvious skin damage • Absent or sparse blisters and bullae • Note: The absence of skin damage (e.g., scarring), vesicles, and bullae often make it difficult to suspect the diagnosis. • Hepatic complications, particularly cholestatic liver disease, may develop in fewer than 5% of affected individuals. ## Suggestive Findings X-linked protoporphyria (XLP) should be suspected in individuals with the following clinical findings and initial laboratory findings. Cutaneous photosensitivity, usually beginning in childhood Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling Painful symptoms; may occur without obvious skin damage Absent or sparse blisters and bullae Note: The absence of skin damage (e.g., scarring), vesicles, and bullae often make it difficult to suspect the diagnosis. Hepatic complications, particularly cholestatic liver disease, may develop in fewer than 5% of affected individuals. Note: It is essential to use an assay for erythrocyte protoporphyrin that distinguishes between free protoporphyrin and zinc-chelated protoporphyrin to differentiate XLP from erythropoietic protoporphyria (EPP-AR) and several other conditions that may lead to elevation of erythrocyte protoporphyrins (see Biochemical Characteristics of X-Linked Protoporphyria (XLP) Increased enzyme activity is due to Many assays for erythrocyte protoporphyrin or "free erythrocyte protoporphyrin" measure both zinc-chelated protoporphyrin and free protoporphyrin. Free protoporphyrin is distinguished from zinc-chelated protoporphyrin by ethanol extraction or HPLC. Protoporphyrins (usually zinc-chelated protoporphyrin) are also increased in lead poisoning, iron deficiency, anemia of chronic disease, and various hemolytic disorders, as well as in those porphyrias caused by biallelic pathogenic variants (e.g., harderoporphyria). In erythropoietic protoporphyria, free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin (see Plasma total porphyrins are increased in porphyrias with cutaneous manifestations including XLP. If plasma porphyrins are increased, the fluorescence emission spectrum of plasma porphyrins at neutral pH can be characteristic and can distinguish XLP and EPP-AR from other porphyrias. The emission maximum in XLP and EPP-AR occurs at 634 nm. • Cutaneous photosensitivity, usually beginning in childhood • Burning, tingling, pain, and itching of the skin (the most common findings); may occur within minutes of sun/light exposure, followed later by erythema and swelling • Painful symptoms; may occur without obvious skin damage • Absent or sparse blisters and bullae • Note: The absence of skin damage (e.g., scarring), vesicles, and bullae often make it difficult to suspect the diagnosis. • Hepatic complications, particularly cholestatic liver disease, may develop in fewer than 5% of affected individuals. ## 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 include Note: All Molecular Genetic Testing Used in X-Linked Protoporphyria 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 ## Molecular Genetic Testing Molecular genetic testing approaches include Note: All Molecular Genetic Testing Used in X-Linked Protoporphyria 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 ## Clinical Characteristics The natural history of X-linked protoporphyria (XLP) is not as well characterized as that of the While the cutaneous manifestations in males with XLP are similar to those of EPP, Most males with XLP develop acute cutaneous photosensitivity within five to 30 minutes following exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band, to a lesser degree in the long-wave UV region. The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Blistering lesions are uncommon. Affected males are also sensitive to sunlight that passes through window glass, which does not block long-wave UVA or visible light. Severe scarring is rare, as are hyper- or hypopigmentation, skin friability, and hirsutism. Unlike in other cutaneous porphyrias, blistering and scarring rarely occur. The information on XLP and liver disease is limited. The risk for liver dysfunction in XLP (observed in 5/31 affected individuals) is higher than the risk in EPP-AR [ Note that the information on liver involvement presented below is based on experience with liver disease in Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in The phenotype of XLP in heterozygous females, the consequence of random X-chromosome inactivation, ranges from as severe as in affected males to asymptomatic. The median age of symptom onset for females with XLP was 11 years. Following sun exposure, symptom onset ranged from within ten minutes to none [ Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin that is excreted in bile and feces. Most of the excess protoporphyrin in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin leakage from these cells is proportional to their protoporphyrin content. The skin of persons with XLP is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called "Soret band" (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins). When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes. Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage. Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease [ Long-term observations of individuals with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces [ Because of the limited number of families known to have XLP, no genotype-phenotype correlations have been identified. XLP appears to be 100% penetrant in males. In heterozygous females, clinical variability is attributed to random X-chromosome inactivation. Symptomatic females have been reported [ Although sometimes considered a synonym for XLP, the term "erythropoietic protoporphyria, X-linked dominant" is incorrect and should not be used: in all X-linked metabolic disorders the phenotype in heterozygous females can range from asymptomatic to as severe as that seen in affected male relatives. The prevalence of XLP is unknown. Based on studies from the UK, XLP appears to account for about 2% of individuals with the erythropoietic protoporphyria phenotype [ In the US, XLP accounts for about 10% of individuals with the erythropoietic protoporphyria phenotype [ • Based on studies from the UK, XLP appears to account for about 2% of individuals with the erythropoietic protoporphyria phenotype [ • In the US, XLP accounts for about 10% of individuals with the erythropoietic protoporphyria phenotype [ ## Clinical Description The natural history of X-linked protoporphyria (XLP) is not as well characterized as that of the While the cutaneous manifestations in males with XLP are similar to those of EPP, Most males with XLP develop acute cutaneous photosensitivity within five to 30 minutes following exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band, to a lesser degree in the long-wave UV region. The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Blistering lesions are uncommon. Affected males are also sensitive to sunlight that passes through window glass, which does not block long-wave UVA or visible light. Severe scarring is rare, as are hyper- or hypopigmentation, skin friability, and hirsutism. Unlike in other cutaneous porphyrias, blistering and scarring rarely occur. The information on XLP and liver disease is limited. The risk for liver dysfunction in XLP (observed in 5/31 affected individuals) is higher than the risk in EPP-AR [ Note that the information on liver involvement presented below is based on experience with liver disease in Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in The phenotype of XLP in heterozygous females, the consequence of random X-chromosome inactivation, ranges from as severe as in affected males to asymptomatic. The median age of symptom onset for females with XLP was 11 years. Following sun exposure, symptom onset ranged from within ten minutes to none [ ## XLP in Males While the cutaneous manifestations in males with XLP are similar to those of EPP, Most males with XLP develop acute cutaneous photosensitivity within five to 30 minutes following exposure to sun or ultraviolet light. Photosensitivity symptoms are provoked mainly by visible blue-violet light in the Soret band, to a lesser degree in the long-wave UV region. The initial symptoms reported are tingling, burning, and/or itching that may be accompanied by swelling and redness. Symptoms vary based on the intensity and duration of sun exposure; pain may be severe and refractory to narcotic analgesics, persisting for hours or days after the initial phototoxic reaction. Symptoms may seem out of proportion to the visible skin lesions. Blistering lesions are uncommon. Affected males are also sensitive to sunlight that passes through window glass, which does not block long-wave UVA or visible light. Severe scarring is rare, as are hyper- or hypopigmentation, skin friability, and hirsutism. Unlike in other cutaneous porphyrias, blistering and scarring rarely occur. The information on XLP and liver disease is limited. The risk for liver dysfunction in XLP (observed in 5/31 affected individuals) is higher than the risk in EPP-AR [ Note that the information on liver involvement presented below is based on experience with liver disease in Life-threatening hepatic complications are preceded by increased levels of plasma and erythrocyte protoporphyrins, worsening hepatic function tests, increased photosensitivity, and increased deposition of protoporphyrins in hepatic cells and bile canaliculi. End-stage liver disease may be accompanied by motor neuropathy, similar to that seen in ## XLP in Females The phenotype of XLP in heterozygous females, the consequence of random X-chromosome inactivation, ranges from as severe as in affected males to asymptomatic. The median age of symptom onset for females with XLP was 11 years. Following sun exposure, symptom onset ranged from within ten minutes to none [ ## Pathophysiology Bone marrow reticulocytes are thought to be the primary source of the accumulated protoporphyrin that is excreted in bile and feces. Most of the excess protoporphyrin in circulating erythrocytes is found in a small percentage of cells, and the rate of protoporphyrin leakage from these cells is proportional to their protoporphyrin content. The skin of persons with XLP is maximally sensitive to visible blue-violet light near 400 nm, which corresponds to the so-called "Soret band" (the narrow peak absorption maximum that is characteristic for protoporphyrin and other porphyrins). When porphyrins absorb light they enter an excited energy state. This energy is presumably released as fluorescence and by formation of singlet oxygen and other oxygen radicals that can produce tissue and vessel damage. This may involve lipid peroxidation, oxidation of amino acids, and cross-linking of proteins in cell membranes. Photoactivation of the complement system and release of histamine, kinins, and chemotactic factors may mediate skin damage. Histologic changes occur predominantly in the upper dermis and include deposition of amorphous material containing immunoglobulin, complement components, glycoproteins, glycosaminoglycans, and lipids around blood vessels. Damage to capillary endothelial cells in the upper dermis has been demonstrated immediately after light exposure in this disease [ Long-term observations of individuals with protoporphyria generally show little change in protoporphyrin levels in erythrocytes, plasma, and feces [ ## Genotype-Phenotype Correlations Because of the limited number of families known to have XLP, no genotype-phenotype correlations have been identified. ## Penetrance XLP appears to be 100% penetrant in males. In heterozygous females, clinical variability is attributed to random X-chromosome inactivation. Symptomatic females have been reported [ ## Nomenclature Although sometimes considered a synonym for XLP, the term "erythropoietic protoporphyria, X-linked dominant" is incorrect and should not be used: in all X-linked metabolic disorders the phenotype in heterozygous females can range from asymptomatic to as severe as that seen in affected male relatives. ## Prevalence The prevalence of XLP is unknown. Based on studies from the UK, XLP appears to account for about 2% of individuals with the erythropoietic protoporphyria phenotype [ In the US, XLP accounts for about 10% of individuals with the erythropoietic protoporphyria phenotype [ • Based on studies from the UK, XLP appears to account for about 2% of individuals with the erythropoietic protoporphyria phenotype [ • In the US, XLP accounts for about 10% of individuals with the erythropoietic protoporphyria phenotype [ ## Genetically Related (Allelic) Disorders X-linked sideroblastic anemia, the only other phenotype known to be associated with pathogenic variants in ## Differential Diagnosis Other causes of the X-linked protoporphyria (XLP) phenotype include the following: Polymorphous light eruption Solar urticaria Drug-induced photosensitivity Late-onset XLP with photosensitivity and elevated protoporphyrin levels has been reported in an instance of emerging myelodysplastic syndrome with somatic mosaicism of a nonsense In EPP-AR free protoporphyrin levels are elevated significantly as compared to zinc-chelated protoporphyrin ( Biochemical Characteristics of Autosomal Recessive Erythropoietic Protoporphyria (EPP-AR) Recently a heterozygous pathogenic variant was identified in CLPX, a heme biosynthesis modulator, in a family with elevated protoporphyrin levels and the EPP phenotype inherited in an autosomal dominant manner [ • Polymorphous light eruption • Solar urticaria • Drug-induced photosensitivity ## Management To establish the extent of disease and needs of an individual diagnosed with X-linked protoporphyria (XLP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended [ Comprehensive medical history including history of phototoxicity Complete physical examination, including thorough skin examination Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), complete blood count with indices to evaluate for anemia, and iron profile (including ferritin) to monitor iron stores Assessment for liver disease: Hepatic function panel (including serum aminotransferases) Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected Newer imaging modalities such as Fibroscan A liver biopsy may be indicated to evaluate for protoporphyric liver disease. Vitamin D studies to evaluate for deficiency as affected individuals are predisposed to vitamin D insufficiency resulting from sun avoidance Consultation with a clinical geneticist and/or genetic counselor Use of protective clothing including long sleeves, gloves, and wide-brimmed hats is indicated. Protective tinted glass for cars and windows prevents exposure to UV light. Gray or smoke-colored filters provide only partial protection. Topical sunscreens are typically not useful; however, some tanning products containing creams that cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent (e.g., zinc oxide) are often effective but are not cosmetically acceptable to all. Oral Lumitene™ (β-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C [ Afamelanotide (Scenesse Afamelanotide showed positive results in Phase III clinical trials in the US and Europe [ Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ Plasmapheresis and intravenous hemin are sometimes beneficial [ Liver transplantation has been performed as a lifesaving measure in individuals with severe protoporphyric liver disease [ Bone marrow transplantation has also been attempted without liver transplantation in some instances. A child age two years with XLP and stage IV hepatic fibrosis was treated with a hematopoietic progenitor cell transplantation that stabilized his liver disease, thus avoiding liver transplantation [ Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency resulting from sun avoidance. Immunization for hepatitis A and B is recommended. Iron supplementation may be attempted in persons with XLP who have anemia and low ferritin levels. Recommended Surveillance for Individuals with X-Linked Protoporphyria US = ultrasound The following are appropriate: Avoidance of sunlight and UV light In patients with hepatic dysfunction, avoidance of alcohol and drugs that may induce cholestasis (e.g., estrogens) In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ It is appropriate to clarify the genetic status of at-risk newborn or infant family members in order to identify as early as possible those who would benefit from early intervention (sun protection) and routine monitoring ( Evaluations include: Targeted molecular genetic testing if the Detection of markedly elevated erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin if the pathogenic variant in the family is not known. See There is no information on pregnancy management in XLP. Based on experience with A Phase II clinical trial with MT-7117, an oral small molecule that works as a melanocortin 1 receptor agonist and increases skin pigmentation, has been completed. A Phase III clinical trial for adults and children is planned for MT-7117. Search • Comprehensive medical history including history of phototoxicity • Complete physical examination, including thorough skin examination • Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), complete blood count with indices to evaluate for anemia, and iron profile (including ferritin) to monitor iron stores • Assessment for liver disease: • Hepatic function panel (including serum aminotransferases) • Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected • Newer imaging modalities such as Fibroscan • A liver biopsy may be indicated to evaluate for protoporphyric liver disease. • Hepatic function panel (including serum aminotransferases) • Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected • Newer imaging modalities such as Fibroscan • A liver biopsy may be indicated to evaluate for protoporphyric liver disease. • Vitamin D studies to evaluate for deficiency as affected individuals are predisposed to vitamin D insufficiency resulting from sun avoidance • Consultation with a clinical geneticist and/or genetic counselor • Hepatic function panel (including serum aminotransferases) • Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected • Newer imaging modalities such as Fibroscan • A liver biopsy may be indicated to evaluate for protoporphyric liver disease. • Use of protective clothing including long sleeves, gloves, and wide-brimmed hats is indicated. • Protective tinted glass for cars and windows prevents exposure to UV light. Gray or smoke-colored filters provide only partial protection. • Topical sunscreens are typically not useful; however, some tanning products containing creams that cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent (e.g., zinc oxide) are often effective but are not cosmetically acceptable to all. • Oral Lumitene™ (β-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C [ • Afamelanotide (Scenesse • Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ • Plasmapheresis and intravenous hemin are sometimes beneficial [ • Liver transplantation has been performed as a lifesaving measure in individuals with severe protoporphyric liver disease [ • Bone marrow transplantation has also been attempted without liver transplantation in some instances. A child age two years with XLP and stage IV hepatic fibrosis was treated with a hematopoietic progenitor cell transplantation that stabilized his liver disease, thus avoiding liver transplantation [ • Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency resulting from sun avoidance. • Immunization for hepatitis A and B is recommended. • Iron supplementation may be attempted in persons with XLP who have anemia and low ferritin levels. • Avoidance of sunlight and UV light • In patients with hepatic dysfunction, avoidance of alcohol and drugs that may induce cholestasis (e.g., estrogens) • In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ • Targeted molecular genetic testing if the • Detection of markedly elevated erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin if the pathogenic variant in the family is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with X-linked protoporphyria (XLP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended [ Comprehensive medical history including history of phototoxicity Complete physical examination, including thorough skin examination Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), complete blood count with indices to evaluate for anemia, and iron profile (including ferritin) to monitor iron stores Assessment for liver disease: Hepatic function panel (including serum aminotransferases) Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected Newer imaging modalities such as Fibroscan A liver biopsy may be indicated to evaluate for protoporphyric liver disease. Vitamin D studies to evaluate for deficiency as affected individuals are predisposed to vitamin D insufficiency resulting from sun avoidance Consultation with a clinical geneticist and/or genetic counselor • Comprehensive medical history including history of phototoxicity • Complete physical examination, including thorough skin examination • Assessment of erythrocyte protoporphyrin levels (free and zinc-chelated), complete blood count with indices to evaluate for anemia, and iron profile (including ferritin) to monitor iron stores • Assessment for liver disease: • Hepatic function panel (including serum aminotransferases) • Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected • Newer imaging modalities such as Fibroscan • A liver biopsy may be indicated to evaluate for protoporphyric liver disease. • Hepatic function panel (including serum aminotransferases) • Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected • Newer imaging modalities such as Fibroscan • A liver biopsy may be indicated to evaluate for protoporphyric liver disease. • Vitamin D studies to evaluate for deficiency as affected individuals are predisposed to vitamin D insufficiency resulting from sun avoidance • Consultation with a clinical geneticist and/or genetic counselor • Hepatic function panel (including serum aminotransferases) • Imaging studies such as abdominal ultrasound examination if cholelithiasis is suspected • Newer imaging modalities such as Fibroscan • A liver biopsy may be indicated to evaluate for protoporphyric liver disease. ## Treatment of Manifestations Use of protective clothing including long sleeves, gloves, and wide-brimmed hats is indicated. Protective tinted glass for cars and windows prevents exposure to UV light. Gray or smoke-colored filters provide only partial protection. Topical sunscreens are typically not useful; however, some tanning products containing creams that cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent (e.g., zinc oxide) are often effective but are not cosmetically acceptable to all. Oral Lumitene™ (β-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C [ Afamelanotide (Scenesse Afamelanotide showed positive results in Phase III clinical trials in the US and Europe [ Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ Plasmapheresis and intravenous hemin are sometimes beneficial [ Liver transplantation has been performed as a lifesaving measure in individuals with severe protoporphyric liver disease [ Bone marrow transplantation has also been attempted without liver transplantation in some instances. A child age two years with XLP and stage IV hepatic fibrosis was treated with a hematopoietic progenitor cell transplantation that stabilized his liver disease, thus avoiding liver transplantation [ Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency resulting from sun avoidance. Immunization for hepatitis A and B is recommended. Iron supplementation may be attempted in persons with XLP who have anemia and low ferritin levels. • Use of protective clothing including long sleeves, gloves, and wide-brimmed hats is indicated. • Protective tinted glass for cars and windows prevents exposure to UV light. Gray or smoke-colored filters provide only partial protection. • Topical sunscreens are typically not useful; however, some tanning products containing creams that cause increased pigmentation may be helpful. Sun creams containing a physical reflecting agent (e.g., zinc oxide) are often effective but are not cosmetically acceptable to all. • Oral Lumitene™ (β-carotene) (120–180 mg/dL) has been used to improve tolerance to sunlight if the dose is adjusted to maintain serum carotene levels in the range of 10-15 μmol/L (600–800 μg/dL), causing mild skin discoloration due to carotenemia. The beneficial effects of β-carotene may involve quenching of singlet oxygen or free radicals. However, a systematic review of about 25 studies showed that the available data are unable to prove efficacy of treatments including beta-carotene, N-acetyl cysteine, and vitamin C [ • Afamelanotide (Scenesse • Cholestyramine and other porphyrin absorbents, such as activated charcoal, may interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion, leading to some improvement [ • Plasmapheresis and intravenous hemin are sometimes beneficial [ • Liver transplantation has been performed as a lifesaving measure in individuals with severe protoporphyric liver disease [ • Bone marrow transplantation has also been attempted without liver transplantation in some instances. A child age two years with XLP and stage IV hepatic fibrosis was treated with a hematopoietic progenitor cell transplantation that stabilized his liver disease, thus avoiding liver transplantation [ • Vitamin D supplementation is advised as patients are predisposed to vitamin D insufficiency resulting from sun avoidance. • Immunization for hepatitis A and B is recommended. • Iron supplementation may be attempted in persons with XLP who have anemia and low ferritin levels. ## Surveillance Recommended Surveillance for Individuals with X-Linked Protoporphyria US = ultrasound ## Agents/Circumstances to Avoid The following are appropriate: Avoidance of sunlight and UV light In patients with hepatic dysfunction, avoidance of alcohol and drugs that may induce cholestasis (e.g., estrogens) In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ • Avoidance of sunlight and UV light • In patients with hepatic dysfunction, avoidance of alcohol and drugs that may induce cholestasis (e.g., estrogens) • In patients with cholestatic liver failure, use of protective filters for artificial lights in the operating room to prevent phototoxic damage during procedures such as endoscopy and surgery [ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of at-risk newborn or infant family members in order to identify as early as possible those who would benefit from early intervention (sun protection) and routine monitoring ( Evaluations include: Targeted molecular genetic testing if the Detection of markedly elevated erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin if the pathogenic variant in the family is not known. See • Targeted molecular genetic testing if the • Detection of markedly elevated erythrocyte protoporphyrin levels with a predominance of metal-free protoporphyrin if the pathogenic variant in the family is not known. ## Pregnancy Management There is no information on pregnancy management in XLP. Based on experience with ## Therapies Under Investigation A Phase II clinical trial with MT-7117, an oral small molecule that works as a melanocortin 1 receptor agonist and increases skin pigmentation, has been completed. A Phase III clinical trial for adults and children is planned for MT-7117. Search ## Genetic Counseling By definition, X-linked protoporphyria 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 or the affected male may have a A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a If the mother of the proband has an If a male proband represents a simplex case and if the If the mother of the proband has an If the father of the proband has an If a female proband represents a simplex case and if the All of their daughters, who will be heterozygotes and may be asymptomatic or have clinical manifestations of the disorder ranging from mild to severe depending on favorable vs nonfavorable X-chromosome inactivation (see None of their sons. Males who inherit the pathogenic variant will be affected. Note: Asymptomatic or mildly symptomatic females are at risk for having affected male children who may have early-onset, more severe symptoms. Females who inherit the pathogenic variant will be heterozygotes (see The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk. Note: Molecular genetic testing may be able to identify the family member in whom a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having the Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a • If the mother of the proband has an • If a male proband represents a simplex case and if the • If the mother of the proband has an • If the father of the proband has an • If a female proband represents a simplex case and if the • All of their daughters, who will be heterozygotes and may be asymptomatic or have clinical manifestations of the disorder ranging from mild to severe depending on favorable vs nonfavorable X-chromosome inactivation (see • None of their sons. • Males who inherit the pathogenic variant will be affected. Note: Asymptomatic or mildly symptomatic females are at risk for having affected male children who may have early-onset, more severe symptoms. • Females who inherit the pathogenic variant will be heterozygotes (see • The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk. • Note: Molecular genetic testing may be able to identify the family member in whom a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having the ## Mode of Inheritance By definition, X-linked protoporphyria 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 or the affected male may have a A female proband may have inherited the Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a If the mother of the proband has an If a male proband represents a simplex case and if the If the mother of the proband has an If the father of the proband has an If a female proband represents a simplex case and if the All of their daughters, who will be heterozygotes and may be asymptomatic or have clinical manifestations of the disorder ranging from mild to severe depending on favorable vs nonfavorable X-chromosome inactivation (see None of their sons. Males who inherit the pathogenic variant will be affected. Note: Asymptomatic or mildly symptomatic females are at risk for having affected male children who may have early-onset, more severe symptoms. Females who inherit the pathogenic variant will be heterozygotes (see The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk. Note: Molecular genetic testing may be able to identify the family member in whom a • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • A female proband may have inherited the • Detailed evaluation of the parents and review of the extended family history may help to distinguish probands with a • If the mother of the proband has an • If a male proband represents a simplex case and if the • If the mother of the proband has an • If the father of the proband has an • If a female proband represents a simplex case and if the • All of their daughters, who will be heterozygotes and may be asymptomatic or have clinical manifestations of the disorder ranging from mild to severe depending on favorable vs nonfavorable X-chromosome inactivation (see • None of their sons. • Males who inherit the pathogenic variant will be affected. Note: Asymptomatic or mildly symptomatic females are at risk for having affected male children who may have early-onset, more severe symptoms. • Females who inherit the pathogenic variant will be heterozygotes (see • The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk. • Note: Molecular genetic testing may be able to identify the family member in whom 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 of having the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having the ## 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 Sweden • • • • • • • • • • • • Sweden • ## Molecular Genetics X-Linked Protoporphyria: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for X-Linked Protoporphyria ( Disease-associated alteration of erythroid-specific 5-aminolevulinate synthase C-terminal amino acids results in increased ALAS2 enzyme activity [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Disease-associated alteration of erythroid-specific 5-aminolevulinate synthase C-terminal amino acids results in increased ALAS2 enzyme activity [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes The XLP contribution to Dr Karl Anderson, University of Texas Medical Branch, Galveston, Texas Dr Montgomery Bissell, University of California, San Francisco, California Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, North Carolina Dr John Phillips, University of Utah School of Medicine, Salt Lake City, Utah Manisha Balwani, MD, MS, FACMG (2013-present)Joseph Bloomer, MD; University of Alabama, Birmingham (2013-2019)Robert Desnick, MD, PhD, FACMG (2013-present)Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network (2013-present) 27 November 2019 (bp) Comprehensive update posted live 14 February 2013 (me) Review posted live 19 September 2012 (rd) Original submission • Dr Karl Anderson, University of Texas Medical Branch, Galveston, Texas • Dr Montgomery Bissell, University of California, San Francisco, California • Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, North Carolina • Dr John Phillips, University of Utah School of Medicine, Salt Lake City, Utah • 27 November 2019 (bp) Comprehensive update posted live • 14 February 2013 (me) Review posted live • 19 September 2012 (rd) Original submission ## Acknowledgments The XLP contribution to Dr Karl Anderson, University of Texas Medical Branch, Galveston, Texas Dr Montgomery Bissell, University of California, San Francisco, California Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, North Carolina Dr John Phillips, University of Utah School of Medicine, Salt Lake City, Utah • Dr Karl Anderson, University of Texas Medical Branch, Galveston, Texas • Dr Montgomery Bissell, University of California, San Francisco, California • Dr Herbert Bonkovsky, Carolinas Medical Center, Charlotte, North Carolina • Dr John Phillips, University of Utah School of Medicine, Salt Lake City, Utah ## Author History Manisha Balwani, MD, MS, FACMG (2013-present)Joseph Bloomer, MD; University of Alabama, Birmingham (2013-2019)Robert Desnick, MD, PhD, FACMG (2013-present)Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network (2013-present) ## Revision History 27 November 2019 (bp) Comprehensive update posted live 14 February 2013 (me) Review posted live 19 September 2012 (rd) Original submission • 27 November 2019 (bp) Comprehensive update posted live • 14 February 2013 (me) Review posted live • 19 September 2012 (rd) Original submission ## References ## Literature Cited
[ "C Aplin, SD Whatley, P Thompson, T Hoy, P Fisher, C Singer, CR Lovell, GH Elder. Late-onset erythropoietic porphyria caused by a chromosome 18q deletion in erythroid cells.. J Invest Dermatol. 2001;117:1647-9", "M Balwani, D Doheny, DF Bishop, I Nazarenko, M Yasuda, HA Dailey, KE Anderson, DM Bissell, J Bloomer, HL Bonkovsky, JD Phillips, L Liu, RJ Desnick. Loss-of-function ferrochelatase and gain-of-function erythroid 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and X-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria.. Mol Med. 2013;19:26-35", "M Balwani, H Naik, KE Anderson, DM Bissell, J Bloomer, HL Bonkovsky, JD Phillips, JR Overbey, B Wang, AK Singal, LU Liu, RJ Desnick. Clinical, biochemical, and genetic characterization of North American patients with erythropoietic protoporphyria and X-linked protoporphyria.. JAMA Dermatol. 2017;153:789-96", "G Biolcati, E Marchesini, F Sorge, L Barbieri, X Schneider-Yin, EI Minder. Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria.. Br J Dermatol 2015;172:1601-12", "DF Bishop, V Tchaikovskii, I Nazarenko, RJ Desnick. Molecular expression and characterization of erythroid-specific 5-aminolevulinate synthase gain-of-function mutations causing X-linked protoporphyria.. Mol Med. 2013;19:18-25", "D Blagojevic, T Schenk, O Haas, B Zierhofer, C Konnaris, F. Trautinger. Acquired erythropoietic protoporphyria.. Ann Hematol. 2010;89:743-4", "DF Butler, KF Ginn, JF Daniel, JR Bloomer, A Kats, N Shreve, GD Myers. Bone marrow transplant for X-linked protoporphyria with severe hepatic fibrosis.. Pediatr Transplant. 2015;19:E106-10", "E Di Pierro, V Brancaleoni, D Tavazzi, M Cappellini. C-terminal deletion in the ALAS2 gene and X-linked dominant protoporphyria.. Haematologica. 2009;94:315", "KD Do, BF Banner, E Katz, IO Szymanski, HL Bonkovsky. Benefits of chronic plasmapheresis and intravenous heme-albumin in erythropoietic protoporphyria after orthotopic liver transplantation.. Transplantation. 2002;73:469-72", "E Gou, C Weng, T Greene, KE Anderson, JD Phillips. Longitudinal analysis of erythrocyte and plasma protoporphyrin levels in patients with protoporphyria.. J Appl Lab Med. 2018;3:213-21", "JH Harms, S Lautenschlager, CE Minder, EI Minder. Mitigating photosensitivity of erythropoietic protoporphyria patients by an agonistic analog of alpha-melanocyte stimulating hormone.. Photochem Photobiol 2009;85:1434-9", "SA Holme, AV Anstey, MN Badminton, GH Elder. Serum 25-hydroxyvitamin D in erythropoietic protoporphyria.. Br J Dermatol 2008;159:211", "C Landefeld, K Kentouche, B Gruhn, T Stauch, S Rößler, D Schuppan, SD Whatley, JF Beck, U Stölzel. X-linked protoporphyria: iron supplementation improves protoporphyrin overload, liver damage and anaemia.. Br J Haematol. 2016;173:482-4", "JG Langendonk, M Balwani, KE Anderson, HL Bonkovsky, AV Anstey, DM Bissell, J Bloomer, C Edwards, NJ Neumann, C Parker, JD Phillips, HW Lim, I Hamzavi, JC Deybach, R Kauppinen, LE Rhodes, J Frank, GM Murphy, FPJ Karstens, EJG Sijbrands, FWM de Rooij, M Lebwohl, H Naik, CR Goding, JHP Wilson, RJ Desnick. Afamelanotide for erythropoietic protoporphyria.. N Engl J Med. 2015;373:48-59", "CB Livideanu, S Ducamp, L Lamant, L Gouya, OB Rauzy, JC Deybach, C Paul, H Puy, MC Marguery. Late-onset X-linked dominant protoporphyria: an etiology of photosensitivity in the elderly.. J Invest Dermatol. 2013;133:1688-90", "AJ McCullough, D Barron, KD Mullen, M Petrelli, MC Park, H Mukhtar, DR Bickers. Fecal protoporphyrin excretion in erythropoietic protoporphyria: effect of cholestyramine and bile acid feeding.. Gastroenterology. 1988;94:177-81", "BM McGuire, HL Bonkovsky, RL Carithers, RT Chung, LI Goldstein, JR Lake, AS Lok, CJ Potter, E Rand, MD Voigt, PR Davis, JR Bloomer. Liver transplantation for erythropoietic protoporphyria liver disease.. Liver Transpl 2005;11:1590-6", "EI Minder. Afamelanotide, an agonistic analog of α-melanocyte-stimulating hormone, in dermal phototoxicity of erythropoietic protoporphyria.. Expert Opin Investig Drugs 2010;19:1591-602", "EI Minder, X Schneider-Yin, J Steurer, LM Bachmann. A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria.. Cell Mol Biol (Noisy-le-grand) 2009;55:84-97", "MB Poh-Fitzpatrick. Human protoporphyria: reduced cutaneous photosensitivity and lower erythrocyte porphyrin levels during pregnancy.. J Am Acad Dermatol 1997;36:40-3", "EB Rand, N Bunin, W Cochran, E Ruchelli, KM Olthoff, JR Bloomer. Sequential liver and bone marrow transplantation for treatment of erythropoietic protoporphyria.. Pediatrics. 2006;118:e1896-9", "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", "RP Sarkany, G Ross, F Willis. Acquired erythropoietic protoporphyria as a result of myelodysplasia causing loss of chromosome 18.. Br J Dermatol. 2006;155:464-6", "X Schneider-Yin, L Gouya, A Meier-Weinand, JC Deybach, EI Minder. New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care.. Eur J Pediatr 2000;159:719-25", "JM Spelt, FW de Rooij, JH Wilson, AA Zandbergen. Vitamin D deficiency in patients with erythropoietic protoporphyria.. J Inherit Metab Dis. 2010;33:S1-4", "S Wahlin, Y Floderus, P Stål, P Harper. Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics.. J Intern Med 2011a;269:278-88", "S Wahlin, P. Harper. The role for BMT in erythropoietic protoporphyria.. Bone Marrow Transplant. 2010;45:393-4", "S Wahlin, N Srikanthan, B Hamre, P Harper, A Brun. Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria.. Liver Transpl. 2008;14:1340-6", "S Wahlin, P Stal, R Adam, V Karam, R Porte, D Seehofer, BK Gunson, J Hillingsø, JL Klempnauer, J Schmidt, G Alexander, J O'Grady, PA Clavien, M Salizzoni, A Paul, K Rolles, BG Ericzon, P Harper. Liver transplantation for erythropoietic protoporphyria in Europe.. Liver Transpl 2011b;17:1021-6", "SD Whatley, S Ducamp, L Gouya, B Grandchamp, C Beaumont, MN Badminton, GH Elder, SA Holme, AV Anstey, M Parker, AV Corrigall, PN Meissner, RJ Hift, JT Marsden, Y Ma, G Mieli-Vergani, JC Deybach, H Puy. C-terminal deletions in the alas2 gene lead to gain of function and cause X-linked dominant protoporphyria without anemia or iron overload.. Am J Hum Genet 2008;83:408-14", "SD Whatley, NG Mason, SA Holme, AV Anstey, GH Elder, MN Badminton. Molecular epidemiology of erythropoietic protoporphyria in the United Kingdom.. Br J Dermatol 2010;162:642-6", "YY Yien, S Ducamp, LN van der Vorm, JR Kardon, H Manceau, C Kannengiesser, HA Bergonia, MD Kafina, Z Karim, L Gouya, TA Baker, H Puy, JD Phillips, G Nicolas, BH Paw. Mutation in human CLPX elevates levels of delta-aminolevulinate synthase and protoporphyrin IX to promote erythropoietic protoporphyria.. Proc Natl Acad Sci U S A. 2017;114:E8045-52" ]
14/2/2013
27/11/2019
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
etha
etha
[ "SCN9A Erythromelalgia (SCN9A-EM)", "SCN9A Paroxysmal Extreme Pain Disorder (SCN9A-PEPD)", "SCN9A Small Fiber Neuropathy (SCN9A-SFN)", "Sodium channel protein type 9 subunit alpha", "SCN9A", "SCN9A Neuropathic Pain Syndromes" ]
Fuki M Hisama, Sulayman D Dib-Hajj, Stephen G Waxman
Summary The diagnosis of
For synonyms and outdated names see For other genetic causes of these phenotypes, see ## Diagnosis An Recurrent episodes of bilateral intense, burning pain; Redness, warmth, and occasionally swelling of the distal extremities; Feet more commonly affected than the hands; although in severely affected individuals, the legs, arms, face, and/or ears may be involved. Note: If manifestations are intermittent, photographs of the affected extremities during a flare can help with diagnosis (see Neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia; Later, episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes). Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). Attacks usually begin abruptly and range in duration from seconds to as long as two hours. Between episodes, constipation is common (from a reluctance to pass stool, thereby precipitating a painful attack). Adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; Autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, and bowel or bladder disturbances; Preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense); Normal nerve conduction studies; Reduced intraepidermal nerve fiber density and/or abnormal quantitative sensory testing. Note: Exogenous and systemic causes of small fiber neuropathy such as diabetes mellitus, HIV, and neurotoxic drugs (chemotherapy) must be excluded. The diagnosis 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 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 Human Gene Mutation Database [ 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. • Recurrent episodes of bilateral intense, burning pain; • Redness, warmth, and occasionally swelling of the distal extremities; • Feet more commonly affected than the hands; although in severely affected individuals, the legs, arms, face, and/or ears may be involved. • Neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia; • Later, episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes). • Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). • The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). • Attacks usually begin abruptly and range in duration from seconds to as long as two hours. • Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). • The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). • Attacks usually begin abruptly and range in duration from seconds to as long as two hours. • Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). • The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). • Attacks usually begin abruptly and range in duration from seconds to as long as two hours. • Adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; • Autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, and bowel or bladder disturbances; • Preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense); • Normal nerve conduction studies; • Reduced intraepidermal nerve fiber density and/or abnormal quantitative sensory testing. ## Suggestive Findings An Recurrent episodes of bilateral intense, burning pain; Redness, warmth, and occasionally swelling of the distal extremities; Feet more commonly affected than the hands; although in severely affected individuals, the legs, arms, face, and/or ears may be involved. Note: If manifestations are intermittent, photographs of the affected extremities during a flare can help with diagnosis (see Neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia; Later, episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes). Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). Attacks usually begin abruptly and range in duration from seconds to as long as two hours. Between episodes, constipation is common (from a reluctance to pass stool, thereby precipitating a painful attack). Adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; Autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, and bowel or bladder disturbances; Preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense); Normal nerve conduction studies; Reduced intraepidermal nerve fiber density and/or abnormal quantitative sensory testing. Note: Exogenous and systemic causes of small fiber neuropathy such as diabetes mellitus, HIV, and neurotoxic drugs (chemotherapy) must be excluded. • Recurrent episodes of bilateral intense, burning pain; • Redness, warmth, and occasionally swelling of the distal extremities; • Feet more commonly affected than the hands; although in severely affected individuals, the legs, arms, face, and/or ears may be involved. • Neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia; • Later, episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes). • Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). • The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). • Attacks usually begin abruptly and range in duration from seconds to as long as two hours. • Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). • The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). • Attacks usually begin abruptly and range in duration from seconds to as long as two hours. • Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks). • The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen). • Attacks usually begin abruptly and range in duration from seconds to as long as two hours. • Adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; • Autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, and bowel or bladder disturbances; • Preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense); • Normal nerve conduction studies; • Reduced intraepidermal nerve fiber density and/or abnormal quantitative sensory testing. ## Establishing the Diagnosis The diagnosis 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 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 Human Gene Mutation Database [ 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. ## 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 Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Pain is the predominant symptom of Onset of Initially, the symptoms involve the soles of the feet and the hands; with age, the lower legs and the arms may become involved. In individuals with advanced disease, symptoms may occur many times a day and last hours, especially at night, or become constant and unremitting. At the onset, the episodes are triggered by exposure to warmth. A pathognomonic feature is triggering of episodes by warm or hot ambient temperature and relief with cooling of the extremities. Less consistent precipitating factors include exercise, tight shoes, wearing socks, alcohol, spicy foods, and other vasodilating agents. Some individuals have allodynia (pain evoked by a normally innocuous stimulus) and hyperalgesia (increased sensitivity to a painful stimulus). The episodes may be disabling, interfere with sleep, and severely limit normal activities such as walking, participation in sports, wearing socks and shoes, and attending school or going to work. Individuals tend to limit their activities in warm weather and to stay in air-conditioned environments. Some individuals move from hot, humid climates to cooler climates. Affected individuals prefer to wear open-toed shoes and to sleep with their feet uncovered. Swimming can be helpful because it keeps the limbs cool during exercise. Neurologic examination is typically normal, although reduced ankle reflexes and decreased distal sensation can be seen. Histopathologic examination of skin biopsy in individuals with erythromelalgia shows nonspecific thickening of blood vessel basement membrane, perivascular edema and mononuclear infiltrate, and reduced density of the autonomic nerve plexuses. Older children and adults describe the pain as excruciating, and burning or sharp. The attacks are always accompanied by erythematous flushing of the skin, which usually corresponds to the affected region. In severe attacks, the pain spreads and become generalized. The number of rectal attacks can decrease with age, whereas the ocular and jaw attacks can increase with age [ In PEPD, biopsies of rectum or colon have been reported as normal or only nonspecific findings [ Pathogenic missense variants in Of note, in SFN, the intraepidermal nerve fiber density (IENFD) in a skin biopsy is quantitatively reduced compared with age- and sex-adjusted normative values [ Disease severity varies within families. In one family, an infant with Although The penetrance in families with Of note, in 2008 the Erythromelalgia Association conducted a survey of its members regarding diagnosis, symptoms, and response to medications (see Some authors prefer "erythromelalgia" for both primary EM (OMIM Primary EM may also be referred to as "erythermalgia." No accurate data on the worldwide prevalence of It is likely that ## Clinical Description Pain is the predominant symptom of Onset of Initially, the symptoms involve the soles of the feet and the hands; with age, the lower legs and the arms may become involved. In individuals with advanced disease, symptoms may occur many times a day and last hours, especially at night, or become constant and unremitting. At the onset, the episodes are triggered by exposure to warmth. A pathognomonic feature is triggering of episodes by warm or hot ambient temperature and relief with cooling of the extremities. Less consistent precipitating factors include exercise, tight shoes, wearing socks, alcohol, spicy foods, and other vasodilating agents. Some individuals have allodynia (pain evoked by a normally innocuous stimulus) and hyperalgesia (increased sensitivity to a painful stimulus). The episodes may be disabling, interfere with sleep, and severely limit normal activities such as walking, participation in sports, wearing socks and shoes, and attending school or going to work. Individuals tend to limit their activities in warm weather and to stay in air-conditioned environments. Some individuals move from hot, humid climates to cooler climates. Affected individuals prefer to wear open-toed shoes and to sleep with their feet uncovered. Swimming can be helpful because it keeps the limbs cool during exercise. Neurologic examination is typically normal, although reduced ankle reflexes and decreased distal sensation can be seen. Histopathologic examination of skin biopsy in individuals with erythromelalgia shows nonspecific thickening of blood vessel basement membrane, perivascular edema and mononuclear infiltrate, and reduced density of the autonomic nerve plexuses. Older children and adults describe the pain as excruciating, and burning or sharp. The attacks are always accompanied by erythematous flushing of the skin, which usually corresponds to the affected region. In severe attacks, the pain spreads and become generalized. The number of rectal attacks can decrease with age, whereas the ocular and jaw attacks can increase with age [ In PEPD, biopsies of rectum or colon have been reported as normal or only nonspecific findings [ Pathogenic missense variants in Of note, in SFN, the intraepidermal nerve fiber density (IENFD) in a skin biopsy is quantitatively reduced compared with age- and sex-adjusted normative values [ ## Genotype-Phenotype Correlations Disease severity varies within families. In one family, an infant with Although ## Penetrance The penetrance in families with Of note, in 2008 the Erythromelalgia Association conducted a survey of its members regarding diagnosis, symptoms, and response to medications (see ## Nomenclature Some authors prefer "erythromelalgia" for both primary EM (OMIM Primary EM may also be referred to as "erythermalgia." ## Prevalence No accurate data on the worldwide prevalence of It is likely that ## Genetically Related (Allelic) Disorders Disorders caused by germline pathogenic variants in GEFS+ = generalized epilepsy febrile seizures plus; GOF = gain of function; HSAN = hereditary sensory and autonomic neuropathy; LOF = loss of function ## Differential Diagnosis The differential diagnosis of Differential Diagnosis of Most significant cause of secondary EM (≤25% of affected persons) EM is frequently the presenting complaint & may precede diagnosis of MPD by several yrs. Ingestion of a single dose of aspirin relieves pain for up to several days. ( e.g., verapamil, nifedipine, bromocriptine, & ticlopidine Potentially reversible cause of secondary EM Inorganic mercury poisoning; produces acrodynia (erythema & edema of hands & feet) Potentially reversible cause of secondary EM Diabetes mellitus Alcoholism HIV infection Lyme disease A complex regional pain syndrome that may be indistinguishable from Usually follows injury in affected limb (e.g., wrist fracture) & evolves to incl signs such as ↓ circulation May also be assoc w/changes in nails, joints, & bone density May be assoc w/pain of distal extremities triggered by exercise (claudication); w/chronic disease, may cause change in skin color Assoc w/smoking & cardiovascular or cerebrovascular disease Vasospasm, pain, & skin color changes Typically exacerbated by exposure to cold (unlike Burning pain of distal extremities in childhood Differentiated from AD= autosomal dominant; EM = erythromelalgia; XL=X-linked Differential Diagnosis of Conditions in the Differential Diagnosis of Amyloid light chain amyloidosis is a plasma cell dyscrasia assoc w/monoclonal protein in urine or serum. Senile amyloidosis is caused by deposition of wild type transthyretin → heart failure, carpal tunnel, & spinal stenosis. Inherited amyloidoses incl: In a cohort of 921 patients with SFN, diagnostic evaluations identified immunologic conditions (19%), sodium channel gene variants (16.7%), diabetes mellitus (7.7%), vitamin B In one study, 58 of 1139 (5%) of individuals with SFN of unknown cause were found to have a heterozygous • Most significant cause of secondary EM (≤25% of affected persons) • EM is frequently the presenting complaint & may precede diagnosis of MPD by several yrs. • Ingestion of a single dose of aspirin relieves pain for up to several days. ( • e.g., verapamil, nifedipine, bromocriptine, & ticlopidine • Potentially reversible cause of secondary EM • Inorganic mercury poisoning; produces acrodynia (erythema & edema of hands & feet) • Potentially reversible cause of secondary EM • Diabetes mellitus • Alcoholism • HIV infection • Lyme disease • A complex regional pain syndrome that may be indistinguishable from • Usually follows injury in affected limb (e.g., wrist fracture) & evolves to incl signs such as ↓ circulation • May also be assoc w/changes in nails, joints, & bone density • May be assoc w/pain of distal extremities triggered by exercise (claudication); w/chronic disease, may cause change in skin color • Assoc w/smoking & cardiovascular or cerebrovascular disease • Vasospasm, pain, & skin color changes • Typically exacerbated by exposure to cold (unlike • Burning pain of distal extremities in childhood • Differentiated from • Amyloid light chain amyloidosis is a plasma cell dyscrasia assoc w/monoclonal protein in urine or serum. • Senile amyloidosis is caused by deposition of wild type transthyretin → heart failure, carpal tunnel, & spinal stenosis. • Inherited amyloidoses incl: ## Erythromelalgia The differential diagnosis of Differential Diagnosis of Most significant cause of secondary EM (≤25% of affected persons) EM is frequently the presenting complaint & may precede diagnosis of MPD by several yrs. Ingestion of a single dose of aspirin relieves pain for up to several days. ( e.g., verapamil, nifedipine, bromocriptine, & ticlopidine Potentially reversible cause of secondary EM Inorganic mercury poisoning; produces acrodynia (erythema & edema of hands & feet) Potentially reversible cause of secondary EM Diabetes mellitus Alcoholism HIV infection Lyme disease A complex regional pain syndrome that may be indistinguishable from Usually follows injury in affected limb (e.g., wrist fracture) & evolves to incl signs such as ↓ circulation May also be assoc w/changes in nails, joints, & bone density May be assoc w/pain of distal extremities triggered by exercise (claudication); w/chronic disease, may cause change in skin color Assoc w/smoking & cardiovascular or cerebrovascular disease Vasospasm, pain, & skin color changes Typically exacerbated by exposure to cold (unlike Burning pain of distal extremities in childhood Differentiated from AD= autosomal dominant; EM = erythromelalgia; XL=X-linked • Most significant cause of secondary EM (≤25% of affected persons) • EM is frequently the presenting complaint & may precede diagnosis of MPD by several yrs. • Ingestion of a single dose of aspirin relieves pain for up to several days. ( • e.g., verapamil, nifedipine, bromocriptine, & ticlopidine • Potentially reversible cause of secondary EM • Inorganic mercury poisoning; produces acrodynia (erythema & edema of hands & feet) • Potentially reversible cause of secondary EM • Diabetes mellitus • Alcoholism • HIV infection • Lyme disease • A complex regional pain syndrome that may be indistinguishable from • Usually follows injury in affected limb (e.g., wrist fracture) & evolves to incl signs such as ↓ circulation • May also be assoc w/changes in nails, joints, & bone density • May be assoc w/pain of distal extremities triggered by exercise (claudication); w/chronic disease, may cause change in skin color • Assoc w/smoking & cardiovascular or cerebrovascular disease • Vasospasm, pain, & skin color changes • Typically exacerbated by exposure to cold (unlike • Burning pain of distal extremities in childhood • Differentiated from ## Paroxysmal Extreme Pain Disorder Differential Diagnosis of Conditions in the Differential Diagnosis of Amyloid light chain amyloidosis is a plasma cell dyscrasia assoc w/monoclonal protein in urine or serum. Senile amyloidosis is caused by deposition of wild type transthyretin → heart failure, carpal tunnel, & spinal stenosis. Inherited amyloidoses incl: In a cohort of 921 patients with SFN, diagnostic evaluations identified immunologic conditions (19%), sodium channel gene variants (16.7%), diabetes mellitus (7.7%), vitamin B In one study, 58 of 1139 (5%) of individuals with SFN of unknown cause were found to have a heterozygous • Amyloid light chain amyloidosis is a plasma cell dyscrasia assoc w/monoclonal protein in urine or serum. • Senile amyloidosis is caused by deposition of wild type transthyretin → heart failure, carpal tunnel, & spinal stenosis. • Inherited amyloidoses incl: ## Management To establish the extent of disease and needs in an individual diagnosed with an Neurologic examination, including a quantitative sensory test and pain assessment Clinical assessment of Assessment of the pain management strategies used (see Consultation with a clinical geneticist and/or genetic counselor Most affected individuals are treated in dermatology, neurology, or pain clinics; or by anesthesiologists specializing in the management of chronic pain. The pain is often refractory to treatment. See Use of oxcarbazepine in treating EM has not been reported. Additional anti-seizure medications including lamotrigine, topiramate, tiagabine, and sodium valproate have been reported to have varying effectiveness. See Supplemental Table E3 in Analgesics and opiates are ineffective in the treatment of PEPD. A small randomized placebo-controlled double-blind crossover-design clinical trial of the anti-seizure drug lacosamide in 24 individuals with There are no published guidelines for surveillance for Follow up with a neurologist or neuromuscular specialist to assess for progression of the disease. It is important to monitor for known side effects of treatment of medications (e.g., Stevens-Johnson syndrome, liver toxicity, and neutropenia – associated with carbamazepine treatment). In some individuals, exercise can trigger symptoms. However, for many individuals, the benefits of mild exercise outweigh the disadvantages. Swimming is a preferred exercise because the extremities remain cool. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger relatives of an affected individual at risk for See Potential teratogenic effects of medications given for treatment of See Search • Neurologic examination, including a quantitative sensory test and pain assessment • Clinical assessment of • Assessment of the pain management strategies used (see • Consultation with a clinical geneticist and/or genetic counselor • See • Use of oxcarbazepine in treating EM has not been reported. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an Neurologic examination, including a quantitative sensory test and pain assessment Clinical assessment of Assessment of the pain management strategies used (see Consultation with a clinical geneticist and/or genetic counselor • Neurologic examination, including a quantitative sensory test and pain assessment • Clinical assessment of • Assessment of the pain management strategies used (see • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Most affected individuals are treated in dermatology, neurology, or pain clinics; or by anesthesiologists specializing in the management of chronic pain. The pain is often refractory to treatment. See Use of oxcarbazepine in treating EM has not been reported. Additional anti-seizure medications including lamotrigine, topiramate, tiagabine, and sodium valproate have been reported to have varying effectiveness. See Supplemental Table E3 in Analgesics and opiates are ineffective in the treatment of PEPD. A small randomized placebo-controlled double-blind crossover-design clinical trial of the anti-seizure drug lacosamide in 24 individuals with • See • Use of oxcarbazepine in treating EM has not been reported. The pain is often refractory to treatment. See Use of oxcarbazepine in treating EM has not been reported. • See • Use of oxcarbazepine in treating EM has not been reported. Additional anti-seizure medications including lamotrigine, topiramate, tiagabine, and sodium valproate have been reported to have varying effectiveness. See Supplemental Table E3 in Analgesics and opiates are ineffective in the treatment of PEPD. A small randomized placebo-controlled double-blind crossover-design clinical trial of the anti-seizure drug lacosamide in 24 individuals with ## Surveillance There are no published guidelines for surveillance for Follow up with a neurologist or neuromuscular specialist to assess for progression of the disease. It is important to monitor for known side effects of treatment of medications (e.g., Stevens-Johnson syndrome, liver toxicity, and neutropenia – associated with carbamazepine treatment). ## Agents/Circumstances to Avoid In some individuals, exercise can trigger symptoms. However, for many individuals, the benefits of mild exercise outweigh the disadvantages. Swimming is a preferred exercise because the extremities remain cool. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger relatives of an affected individual at risk for See ## Pregnancy Management Potential teratogenic effects of medications given for treatment of See ## Therapies Under Investigation Search ## Genetic Counseling Many individuals diagnosed with an A proband with an 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 of some individuals diagnosed with an If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance of A sib 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 and discussion of the availability of prenatal/preimplantation genetic testing is before 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 decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. • Many individuals diagnosed with an • A proband with an • 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 of some individuals diagnosed with an • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Penetrance of • A sib heterozygous for the same • Penetrance of • A sib heterozygous for the same • If the proband has a known • If the parents have not been tested for the • Penetrance of • A sib heterozygous for the same • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 an A proband with an 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 of some individuals diagnosed with an If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Penetrance of A sib heterozygous for the same If the proband has a known If the parents have not been tested for the • Many individuals diagnosed with an • A proband with an • 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 of some individuals diagnosed with an • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Penetrance of • A sib heterozygous for the same • Penetrance of • A sib heterozygous for the same • If the proband has a known • If the parents have not been tested for the • Penetrance of • A sib heterozygous for the same ## 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. ## Resources 200 Old Castle Lane Wallingford PA 19086 • • 200 Old Castle Lane • Wallingford PA 19086 • ## Molecular Genetics SCN9A Neuropathic Pain Syndromes: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SCN9A Neuropathic Pain Syndromes ( The normal product of The Na Voltage-clamp recordings have shown that these gain-of-function attributes include: A hyperpolarizing shift in activation of the channel (making it easier to open the channel; Increased amplitude of ramp current (an enhanced response to slow, small depolarizations); Slower deactivation (slower closing of the channel when the stimulus is removed); Depolarizing shifts in fast and slow inactivation (allowing more channels to be available to open). Individual pathogenic variants may manifest one or more of these attributes, but rarely all of them. When abnormal Nav1.7 channels are expressed in dorsal root ganglion (DRG) sensory neurons, they increase the excitability of these neurons (making it easier to fire) and increased firing frequency; these are the cellular underpinnings of the pain that patients experience. In contrast, Notable Variants listed in the table have been provided by the authors. • A hyperpolarizing shift in activation of the channel (making it easier to open the channel; • Increased amplitude of ramp current (an enhanced response to slow, small depolarizations); • Slower deactivation (slower closing of the channel when the stimulus is removed); • Depolarizing shifts in fast and slow inactivation (allowing more channels to be available to open). ## Molecular Pathogenesis The normal product of The Na Voltage-clamp recordings have shown that these gain-of-function attributes include: A hyperpolarizing shift in activation of the channel (making it easier to open the channel; Increased amplitude of ramp current (an enhanced response to slow, small depolarizations); Slower deactivation (slower closing of the channel when the stimulus is removed); Depolarizing shifts in fast and slow inactivation (allowing more channels to be available to open). Individual pathogenic variants may manifest one or more of these attributes, but rarely all of them. When abnormal Nav1.7 channels are expressed in dorsal root ganglion (DRG) sensory neurons, they increase the excitability of these neurons (making it easier to fire) and increased firing frequency; these are the cellular underpinnings of the pain that patients experience. In contrast, Notable Variants listed in the table have been provided by the authors. • A hyperpolarizing shift in activation of the channel (making it easier to open the channel; • Increased amplitude of ramp current (an enhanced response to slow, small depolarizations); • Slower deactivation (slower closing of the channel when the stimulus is removed); • Depolarizing shifts in fast and slow inactivation (allowing more channels to be available to open). ## References ## Literature Cited ## Chapter Notes This work is supported in part by a gift from the Erythromelalgia Association. 23 January 2020 (bp) Comprehensive update posted live 15 August 2013 (me) Comprehensive update posted live 25 September 2008 (cd) Revision: prenatal testing available 26 August 2008 (cg) Comprehensive update posted live 28 March 2007 (fmh) Revision: sequence analysis for 18 January 2007 (cd) Revision: mutations in 5 May 2006 (me) Review posted live 2 August 2005 (fmh) Original submission • 23 January 2020 (bp) Comprehensive update posted live • 15 August 2013 (me) Comprehensive update posted live • 25 September 2008 (cd) Revision: prenatal testing available • 26 August 2008 (cg) Comprehensive update posted live • 28 March 2007 (fmh) Revision: sequence analysis for • 18 January 2007 (cd) Revision: mutations in • 5 May 2006 (me) Review posted live • 2 August 2005 (fmh) Original submission ## Acknowledgments This work is supported in part by a gift from the Erythromelalgia Association. ## Revision History 23 January 2020 (bp) Comprehensive update posted live 15 August 2013 (me) Comprehensive update posted live 25 September 2008 (cd) Revision: prenatal testing available 26 August 2008 (cg) Comprehensive update posted live 28 March 2007 (fmh) Revision: sequence analysis for 18 January 2007 (cd) Revision: mutations in 5 May 2006 (me) Review posted live 2 August 2005 (fmh) Original submission • 23 January 2020 (bp) Comprehensive update posted live • 15 August 2013 (me) Comprehensive update posted live • 25 September 2008 (cd) Revision: prenatal testing available • 26 August 2008 (cg) Comprehensive update posted live • 28 March 2007 (fmh) Revision: sequence analysis for • 18 January 2007 (cd) Revision: mutations in • 5 May 2006 (me) Review posted live • 2 August 2005 (fmh) Original submission Red and swollen feet of an individual with
[ "JS Choi, X Cheng, E Foster, A Leffler, L Tyrrell, RH Te Morsche, EM Eastman, HJ Jansen, K Huehne, C Nau, SD Dib-Hajj, JP Drenth, SG Waxman. Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia.. Brain. 2010;133:1823-35", "JS Choi, L Zhang, SD Dib-Hajj, C Han, L Tyrrell, Z Lin, X Wang, Y Yang, SG Waxman. Mexiletine-responsive erythromelalgia due to a new Nav1.7 mutation showing use-dependent current fall-off.. Exp Neurol 2009;216:383-9", "JJ Cox, F Reimann, AK Nicholas, G Thornton, E Roberts, K Springell, G Karbani, H Jafri, J Mannan, Y Raashid, L Al-Gazali, H Hamamy, EM Valente, S Gorman, R Williams, DP McHale, JN Wood, FM Gribble, CG Woods. An SCN9A channelopathy causes congenital inability to experience pain.. Nature 2006;444:894-8", "R Cregg, JJ Cox, JN Wood, R Werdehausen. Mexilitine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F Nav1.7 sodium channels.. Br J Pharmacol 2014;171:4455-63", "BTA de Greef, JGJ Hoeijmakers, M Geerts, M Oakes, TJE Church, SG Waxman, SD Dib-Hajj, CG Faber, ISJ Merkies. Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: a randomized controlled trial.. Brain. 2019;142:263-75", "BTA de Greef, JGJ Hoeijmakers, CML Gorissen-Brouwers, M Geerts, CG Faber, ISJ Merkies. Associated conditions in small fiber neuropathy - a large cohort study and review of the literature.. Eur J Neurol. 2018;25:348-55", "SD Dib-Hajj, SG Waxman. Sodium channels in human pain disorders: genetics and pharmacogenomics.. Annu Rev Neurosci. 2019;42:87-106", "SD Dib-Hajj, Y Yang, JA Black, SG Waxman. The NaV1.7 sodium channel: from molecule to man.. Nat Rev Neurosci 2013;14:49-62", "JP Drenth, SG Waxman. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders.. J Clin Invest 2007;117:3603-9", "I Eijkenboom, M Sopacua, JGJ Hoeijmaker, BTA De Greef, P Lindsey, R Almomani, M Marchi, J Vanoevelen, HJM Smeets, SG Waxman, G Lauria, ISJ Merkies, CG Faber, MM Gerrits. Yield of peripheral sodium channels gene screening in pure small fibre neuropathy.. J Neurol Neurosurg Psychiatry. 2019;90:342-52", "EC Emery, AM Habib, JJ Cox, AK Nicholas, FM Gribble, CG Woods, F Reiman. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical correlations.. J Neurosci. 2015;35:7674-81", "CG Faber, JGJ Hoeijmakers, H-S Ahn, X Cheng, C Han, J-S Choi, M Estacion, G Lauria, EK Vanhoutte, MM Gerrits, S Dib-Hajj, JPH Drenth, SG Waxman, IJS Merkles. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy.. Ann Neurol 2012;71:26-39", "CR Fertleman, CD Ferrie, J Aicardi, NA Bednarek, O Eeg-Olofsson, FV Elmslie, DA Griesemer, F Goutieres, M Kirkpatrick, IN Malmros, M Pollitzer, M Rossiter, E Roulet-Perez, R Schubert, VV Smith, H Testard, V Wong, JB Stephenson. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome).. Neurology 2007;69:586-95", "TZ Fischer, ES Gilmore, M Estacion, E Eastman, S Taylor, M Melanson, SD Dib-Hajj, SG Waxman. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia.. Ann Neurol 2009;65:733-41", "BS Galer, MP Jensen. Development and preliminary validation of a pain measure specific to neuropathic pain: the Neuropathic Pain Scale.. Neurology 1997;48:332-8", "P Geha, Y Yang, M Estacion, BR Schulman, H Tokuno, AV Apkarian, SD Dib-Hajj, SG Waxman. Pharmacotherapy for pain in a family with inherited erythromelalgia guided by genomic analysis and functional profiling.. 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Clin Exp Dermatol 2009;34:e640-2", "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", "AJ Terkelsen, P Karlsson, G Lauria, R Freeman, NB Finnerup, TS Jensen. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes.. Lancet Neurol 2017;16:934-44", "SW Tham, M Giles. Current pain management strategies for patients with erythromelalgia: a critical review.. J Pain Res 2018;11:1689-98", "Y Yang, T Adi, P Effraim, L Chen, SD Dib-Hajj, SG Waxman. Reverse pharmacogenomics: carbamazepine normalizes activation and attenuates thermal-induced hyperexcitability of sensory neurons due to Nav1.7 mutation I234T.. 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6/5/2006
23/1/2020
25/9/2008
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
etv6-tpl
etv6-tpl
[ "ETV6-Linked Leukemia / Familial Thrombocytopenia Syndrome", "Thrombocytopenia 5 (THC5)", "ETV6-Linked Leukemia/Familial Thrombocytopenia Syndrome", "Thrombocytopenia 5 (THC5)", "Transcription factor ETV6", "ETV6", "ETV6-Related Thrombocytopenia and Predisposition to Leukemia" ]
Bojana Pencheva, Jorge Di Paola, Christopher C Porter
Summary Individuals with The diagnosis of
## Diagnosis Absent-to-moderate bleeding tendencies (e.g., menorrhagia, epistaxis, easy bruising, gum bleeding) Hematologic malignancies, including: B-cell acute lymphoblastic leukemia (B-ALL), which is the most common Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) Myeloproliferative neoplasms (MPN) Mixed-phenotype acute leukemia (MPAL) Multiple myeloma Possibly, benign and malignant solid tumors Persistent and unexplained mild-to-moderate thrombocytopenia (platelet counts are often >75 × 10 Normal white blood cell count Normal hemoglobin concentration, sometimes with a high mean erythrocyte corpuscular volume (MCV) Variably, abnormal bone marrow histology with small hyperchromatic megakaryocytes, disseminated toxic granulations, and dysplastic eosinophils in the absence of frank myelodysplasia 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 clinical and laboratory findings suggest the diagnosis of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Note: A diagnosis 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 missense, nonsense, and splice site variants and small 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. • Absent-to-moderate bleeding tendencies (e.g., menorrhagia, epistaxis, easy bruising, gum bleeding) • Hematologic malignancies, including: • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • Myeloproliferative neoplasms (MPN) • Mixed-phenotype acute leukemia (MPAL) • Multiple myeloma • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • Myeloproliferative neoplasms (MPN) • Mixed-phenotype acute leukemia (MPAL) • Multiple myeloma • Possibly, benign and malignant solid tumors • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • Myeloproliferative neoplasms (MPN) • Mixed-phenotype acute leukemia (MPAL) • Multiple myeloma • Persistent and unexplained mild-to-moderate thrombocytopenia (platelet counts are often >75 × 10 • Normal white blood cell count • Normal hemoglobin concentration, sometimes with a high mean erythrocyte corpuscular volume (MCV) • Variably, abnormal bone marrow histology with small hyperchromatic megakaryocytes, disseminated toxic granulations, and dysplastic eosinophils in the absence of frank myelodysplasia • For an introduction to multigene panels click ## Suggestive Findings Absent-to-moderate bleeding tendencies (e.g., menorrhagia, epistaxis, easy bruising, gum bleeding) Hematologic malignancies, including: B-cell acute lymphoblastic leukemia (B-ALL), which is the most common Acute myeloid leukemia (AML) Myelodysplastic syndrome (MDS) Myeloproliferative neoplasms (MPN) Mixed-phenotype acute leukemia (MPAL) Multiple myeloma Possibly, benign and malignant solid tumors Persistent and unexplained mild-to-moderate thrombocytopenia (platelet counts are often >75 × 10 Normal white blood cell count Normal hemoglobin concentration, sometimes with a high mean erythrocyte corpuscular volume (MCV) Variably, abnormal bone marrow histology with small hyperchromatic megakaryocytes, disseminated toxic granulations, and dysplastic eosinophils in the absence of frank myelodysplasia • Absent-to-moderate bleeding tendencies (e.g., menorrhagia, epistaxis, easy bruising, gum bleeding) • Hematologic malignancies, including: • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • Myeloproliferative neoplasms (MPN) • Mixed-phenotype acute leukemia (MPAL) • Multiple myeloma • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • Myeloproliferative neoplasms (MPN) • Mixed-phenotype acute leukemia (MPAL) • Multiple myeloma • Possibly, benign and malignant solid tumors • B-cell acute lymphoblastic leukemia (B-ALL), which is the most common • Acute myeloid leukemia (AML) • Myelodysplastic syndrome (MDS) • Myeloproliferative neoplasms (MPN) • Mixed-phenotype acute leukemia (MPAL) • Multiple myeloma • Persistent and unexplained mild-to-moderate thrombocytopenia (platelet counts are often >75 × 10 • Normal white blood cell count • Normal hemoglobin concentration, sometimes with a high mean erythrocyte corpuscular volume (MCV) • Variably, abnormal bone marrow histology with small hyperchromatic megakaryocytes, disseminated toxic granulations, and dysplastic eosinophils in the absence of frank myelodysplasia ## 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 clinical and laboratory findings suggest the diagnosis of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Note: A diagnosis 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 missense, nonsense, and splice site variants and small 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 ## Option 1 When the clinical 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 diagnosis of For an introduction to comprehensive genomic testing click Note: A diagnosis 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 missense, nonsense, and splice site variants and small 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 Individuals with Thrombocytopenia is found in more than 90% of affected individuals at the time of diagnosis. However, most affected individuals have normal hemostasis or only a mild bleeding tendency. Most affected individuals do not develop severe spontaneous bleeding episodes. Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [ Most reported platelet counts are between 100 and 150 × 10 Some affected individuals have platelet counts as low as 32 × 10 Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume. Bone marrow aspirates in those without concurrent leukemias have variably revealed dyserythropoiesis, megakaryocyte hyperplasia, and small hypolobulated megakaryocytes [ About 20%-30% of individuals with Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [ About two thirds of affected individuals who develop a hematologic malignancy have B-ALL. Other reported hematologic malignancies include the following: Other forms of acute lymphoblastic leukemia (ALL) Myelodysplastic syndrome (MDS) Acute myeloid leukemia (AML), including treatment-related AML [ Mixed-phenotype acute leukemia Diffuse large B-cell lymphoma Polycythemia vera Children with There may be an increased risk for the development of solid tumors in those with No clinically relevant genotype-phenotype correlations have been identified. The penetrance of thrombocytopenia in this disorder is thought to exceed 90%. The penetrance of malignancy, specifically lymphoid and myeloid, is estimated at 20%-30%. The prevalence of • Most affected individuals do not develop severe spontaneous bleeding episodes. • Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [ • Most reported platelet counts are between 100 and 150 × 10 • Some affected individuals have platelet counts as low as 32 × 10 • Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume. • Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [ • About two thirds of affected individuals who develop a hematologic malignancy have B-ALL. • Other reported hematologic malignancies include the following: • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera ## Clinical Description Individuals with Thrombocytopenia is found in more than 90% of affected individuals at the time of diagnosis. However, most affected individuals have normal hemostasis or only a mild bleeding tendency. Most affected individuals do not develop severe spontaneous bleeding episodes. Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [ Most reported platelet counts are between 100 and 150 × 10 Some affected individuals have platelet counts as low as 32 × 10 Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume. Bone marrow aspirates in those without concurrent leukemias have variably revealed dyserythropoiesis, megakaryocyte hyperplasia, and small hypolobulated megakaryocytes [ About 20%-30% of individuals with Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [ About two thirds of affected individuals who develop a hematologic malignancy have B-ALL. Other reported hematologic malignancies include the following: Other forms of acute lymphoblastic leukemia (ALL) Myelodysplastic syndrome (MDS) Acute myeloid leukemia (AML), including treatment-related AML [ Mixed-phenotype acute leukemia Diffuse large B-cell lymphoma Polycythemia vera Children with There may be an increased risk for the development of solid tumors in those with • Most affected individuals do not develop severe spontaneous bleeding episodes. • Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [ • Most reported platelet counts are between 100 and 150 × 10 • Some affected individuals have platelet counts as low as 32 × 10 • Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume. • Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [ • About two thirds of affected individuals who develop a hematologic malignancy have B-ALL. • Other reported hematologic malignancies include the following: • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera ## Thrombocytopenia Thrombocytopenia is found in more than 90% of affected individuals at the time of diagnosis. However, most affected individuals have normal hemostasis or only a mild bleeding tendency. Most affected individuals do not develop severe spontaneous bleeding episodes. Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [ Most reported platelet counts are between 100 and 150 × 10 Some affected individuals have platelet counts as low as 32 × 10 Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume. • Most affected individuals do not develop severe spontaneous bleeding episodes. • Reported bleeding symptoms have included menorrhagia, epistaxis, easy bruising, and gum bleeding [ • Most reported platelet counts are between 100 and 150 × 10 • Some affected individuals have platelet counts as low as 32 × 10 • Platelet size is usually normal by automated method (mean platelet volume) or microscopic analysis, although some affected individuals exhibit increased platelet volume. ## Bone Marrow Biopsy Bone marrow aspirates in those without concurrent leukemias have variably revealed dyserythropoiesis, megakaryocyte hyperplasia, and small hypolobulated megakaryocytes [ ## Lymphoid and Myeloid Malignancies About 20%-30% of individuals with Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [ About two thirds of affected individuals who develop a hematologic malignancy have B-ALL. Other reported hematologic malignancies include the following: Other forms of acute lymphoblastic leukemia (ALL) Myelodysplastic syndrome (MDS) Acute myeloid leukemia (AML), including treatment-related AML [ Mixed-phenotype acute leukemia Diffuse large B-cell lymphoma Polycythemia vera Children with • Reported age range at time of diagnosis of a hematologic malignancy is between two and 82 years, with an average and median age of onset of 22 and 11 years, respectively [ • About two thirds of affected individuals who develop a hematologic malignancy have B-ALL. • Other reported hematologic malignancies include the following: • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera • Other forms of acute lymphoblastic leukemia (ALL) • Myelodysplastic syndrome (MDS) • Acute myeloid leukemia (AML), including treatment-related AML [ • Mixed-phenotype acute leukemia • Diffuse large B-cell lymphoma • Polycythemia vera ## Solid Tumors There may be an increased risk for the development of solid tumors in those with ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified. ## Penetrance The penetrance of thrombocytopenia in this disorder is thought to exceed 90%. The penetrance of malignancy, specifically lymphoid and myeloid, is estimated at 20%-30%. ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Hereditary platelet disorders with increased leukemia risk to consider in the differential diangosis of Genes of Interest in the Differential Diagnosis of Myeloid malignancies are most common, incl acute myelogenous leukemia & myelodysplastic syndrome. T- & B-cell acute lymphoblastic leukemias & lymphomas have also been reported. AD = autosomal dominant; MOI = mode of inheritance • Myeloid malignancies are most common, incl acute myelogenous leukemia & myelodysplastic syndrome. • T- & B-cell acute lymphoblastic leukemias & lymphomas have also been reported. ## Management Expert and consensus clinical guidelines for the management of inherited thrombocytopenia and leukemia predisposition syndromes, including those with germline To establish the extent of disease and needs in an individual diagnosed with CBC = complete blood count; MOI = mode of inheritance Apparently dysplastic morphologic features may be present at baseline that may not represent myelodysplastic syndrome in the absence of other diagnostic criteria. 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 Antifibrinolytic agents Desmopressin If bleeding is moderate or severe May be considered prior to surgical procedures to ↓ bleeding complications Consider indications for stem cell transplantation, eligibility, & available donors. Confirm by targeted molecular genetic testing that potential related donors do not have Platelet transfusions should be used judiciously – particularly in women of childbearing age – to reduce the risk of alloimmunization. Individuals with CBC = complete blood count The benefit of this screening regimen is currently unknown. The frequency of such screening must be weighed against the burden of the screening protocol, particularly in young children. The frequency of CBC and bone marrow evaluations should be determined on a case-by-case basis by the physician and with consideration of patient/family preferences. If changes in the CBC with differential are persistent for two to fou weeks, particularly cytopenias, consider an additional bone marrow aspirate and biopsy. To include morphology, cytogenetics, fluorescence in situ hybridization (FISH) (e.g., for chromosomes 5q, 7q, 8, and 20q), and molecular studies (depending on morphology, cytogenetics, and/or FISH) [ For individuals with 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 clinical surveillance for malignancy and management of thrombocytopenia. See Platelet counts should be monitored during pregnancy and prior to delivery, in collaboration with a hematologist. Platelet transfusions prior to invasive procedures (e.g., epidural analgesia or cesarean section) or at the time of delivery may be considered in those with a history of bleeding or severe thrombocytopenia on a case-by-case basis. Search • Antifibrinolytic agents • Desmopressin • If bleeding is moderate or severe • May be considered prior to surgical procedures to ↓ bleeding complications • Consider indications for stem cell transplantation, eligibility, & available donors. • Confirm by targeted molecular genetic testing that potential related donors do not have ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with CBC = complete blood count; MOI = mode of inheritance Apparently dysplastic morphologic features may be present at baseline that may not represent myelodysplastic syndrome in the absence of other diagnostic criteria. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Antifibrinolytic agents Desmopressin If bleeding is moderate or severe May be considered prior to surgical procedures to ↓ bleeding complications Consider indications for stem cell transplantation, eligibility, & available donors. Confirm by targeted molecular genetic testing that potential related donors do not have Platelet transfusions should be used judiciously – particularly in women of childbearing age – to reduce the risk of alloimmunization. • Antifibrinolytic agents • Desmopressin • If bleeding is moderate or severe • May be considered prior to surgical procedures to ↓ bleeding complications • Consider indications for stem cell transplantation, eligibility, & available donors. • Confirm by targeted molecular genetic testing that potential related donors do not have ## Surveillance Individuals with CBC = complete blood count The benefit of this screening regimen is currently unknown. The frequency of such screening must be weighed against the burden of the screening protocol, particularly in young children. The frequency of CBC and bone marrow evaluations should be determined on a case-by-case basis by the physician and with consideration of patient/family preferences. If changes in the CBC with differential are persistent for two to fou weeks, particularly cytopenias, consider an additional bone marrow aspirate and biopsy. To include morphology, cytogenetics, fluorescence in situ hybridization (FISH) (e.g., for chromosomes 5q, 7q, 8, and 20q), and molecular studies (depending on morphology, cytogenetics, and/or FISH) [ ## Agents/Circumstances to Avoid For individuals with ## 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 clinical surveillance for malignancy and management of thrombocytopenia. See ## Pregnancy Management Platelet counts should be monitored during pregnancy and prior to delivery, in collaboration with a hematologist. Platelet transfusions prior to invasive procedures (e.g., epidural analgesia or cesarean section) or at the time of delivery may be considered in those with a history of bleeding or severe thrombocytopenia on a case-by-case basis. ## Therapies Under Investigation Search ## Genetic Counseling To date, most individuals diagnosed with An individual with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical surveillance for malignancy and management of thrombocytopenia. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance of malignancies, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the If the 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. • To date, most individuals diagnosed with • An individual with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical surveillance for malignancy and management of thrombocytopenia. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance of malignancies, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • If the • 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 To date, most individuals diagnosed with An individual with If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical surveillance for malignancy and management of thrombocytopenia. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance of malignancies, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the If the If the parents have not been tested for the • To date, most individuals diagnosed with • An individual with • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical surveillance for malignancy and management of thrombocytopenia. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance of malignancies, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • If the • 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 ETV6-Related Thrombocytopenia and Predisposition to Leukemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ETV6-Related Thrombocytopenia and Predisposition to Leukemia ( N-terminal pointed domain DNA-binding domain located at the C terminus Linker region ETV6 is a repressor of transcription, with critical roles in embryonic development and hematopoietic regulation [ • N-terminal pointed domain • DNA-binding domain located at the C terminus • Linker region ## Molecular Pathogenesis N-terminal pointed domain DNA-binding domain located at the C terminus Linker region ETV6 is a repressor of transcription, with critical roles in embryonic development and hematopoietic regulation [ • N-terminal pointed domain • DNA-binding domain located at the C terminus • Linker region ## Chapter Notes Bojana Pencheva is a certified genetic counselor who serves children and their families for germline genetic evaluation of suspected cancer predispositions, including bone marrow failure syndromes. Dr Di Paola is a pediatric hematologist whose research focuses on the genetics of bleeding and thrombotic disorders and mechanisms of platelet activation. Web page: Dr Porter is a pediatric hematologist-oncologist with a clinical and research interest in childhood cancer predispositions. His laboratory studies mechanisms of hematopoiesis and leukemogenesis. He is a founding co-Chair of the Consortium for Childhood Cancer Predisposition. Web page: The authors are grateful for the work of the contributors to this field cited in this chapter, as well as the many more who are not cited due to space constraints. We would like to thank the 26 June 2025 (sw) Comprehensive update posted live 19 November 2020 (ma) Review posted live 31 January 2020 (bbp) Original submission • 26 June 2025 (sw) Comprehensive update posted live • 19 November 2020 (ma) Review posted live • 31 January 2020 (bbp) Original submission ## Author Notes Bojana Pencheva is a certified genetic counselor who serves children and their families for germline genetic evaluation of suspected cancer predispositions, including bone marrow failure syndromes. Dr Di Paola is a pediatric hematologist whose research focuses on the genetics of bleeding and thrombotic disorders and mechanisms of platelet activation. Web page: Dr Porter is a pediatric hematologist-oncologist with a clinical and research interest in childhood cancer predispositions. His laboratory studies mechanisms of hematopoiesis and leukemogenesis. He is a founding co-Chair of the Consortium for Childhood Cancer Predisposition. Web page: ## Acknowledgments The authors are grateful for the work of the contributors to this field cited in this chapter, as well as the many more who are not cited due to space constraints. We would like to thank the ## Revision History 26 June 2025 (sw) Comprehensive update posted live 19 November 2020 (ma) Review posted live 31 January 2020 (bbp) Original submission • 26 June 2025 (sw) Comprehensive update posted live • 19 November 2020 (ma) Review posted live • 31 January 2020 (bbp) Original submission ## References ## Literature Cited
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19/11/2020
26/6/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
evc
evc
[ "Chondroectodermal Dysplasia (Ellis-van Creveld)", "Chondroectodermal Dysplasia (Ellis-van Creveld)", "cAMP-dependent protein kinase catalytic subunit alpha", "cAMP-dependent protein kinase catalytic subunit beta", "Cytoplasmic dynein 2 heavy chain 1", "Cytoplasmic dynein 2 light intermediate chain 1", "EvC complex member EVC", "Limbin", "Smoothened homolog", "WD repeat-containing protein 35", "Zinc finger protein GLI1", "DYNC2H1", "DYNC2LI1", "EVC", "EVC2", "GLI1", "PRKACA", "PRKACB", "SMO", "WDR35", "Ellis-van Creveld Syndrome" ]
Ellis-van Creveld Syndrome
Jorge Diogo Da Silva, Nataliya Tkachenko, Ana Rita Soares
Summary Ellis-van Creveld (EVC) syndrome is characterized by postaxial polydactyly of the hands, disproportionate short stature with short limbs, dystrophic and/or hypoplastic nails, dental and oral manifestations, congenital heart disease, and radiologic abnormalities (narrow chest, short ribs, short tubular bones, bulbous ends of the proximal ulnae and distal radii, carpal and metacarpal fusions, cone-shaped epiphyses of phalanges, small iliac crests, acetabular spur projections [trident ilia], and lateral slanting of the tibial plateau). Other less common and more variable features include postaxial polydactyly of the feet, upper lip defect, and developmental delay. The diagnosis of EVC syndrome is established in a proband with characteristic clinical and radiographic findings and biallelic pathogenic variants in EVC syndrome caused by pathogenic variants in
## Diagnosis No consensus clinical diagnostic criteria for Ellis-van Creveld (EVC) syndrome have been published. EVC syndrome Bilateral postaxial polydactyly of the hands (see Limb shortening (prenatal or postnatal) Disproportionate short stature (prenatal or postnatal onset) Dystrophic and/or hypoplastic nails (See Dental and oral anomalies (hypodontia, delayed eruption of teeth, frenulum abnormalities) Congenital heart defects (atrial septal defect, ventricular septal defect, single atrium, atrioventricular canal) Narrow chest with short ribs Short and thickened tubular bones Bulbous ends of the proximal ulnae and distal radii Carpal and metacarpal fusions (typically capitate and hamate) Cone-shaped epiphyses of phalanges Small iliac crests Acetabular spur projections (trident ilia) Lateral slanting of the tibial plateau The diagnosis of EVC syndrome is 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 For an introduction to multigene panels click Note: Targeted analysis for When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal and/or ectodermal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ellis-van Creveld Syndrome EVC = Ellis-van Creveld Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Approximately 23% of reported pathogenic copy number variants predictably affect both • Bilateral postaxial polydactyly of the hands (see • Limb shortening (prenatal or postnatal) • Disproportionate short stature (prenatal or postnatal onset) • Dystrophic and/or hypoplastic nails (See • Dental and oral anomalies (hypodontia, delayed eruption of teeth, frenulum abnormalities) • Congenital heart defects (atrial septal defect, ventricular septal defect, single atrium, atrioventricular canal) • Narrow chest with short ribs • Short and thickened tubular bones • Bulbous ends of the proximal ulnae and distal radii • Carpal and metacarpal fusions (typically capitate and hamate) • Cone-shaped epiphyses of phalanges • Small iliac crests • Acetabular spur projections (trident ilia) • Lateral slanting of the tibial plateau ## Suggestive Findings EVC syndrome Bilateral postaxial polydactyly of the hands (see Limb shortening (prenatal or postnatal) Disproportionate short stature (prenatal or postnatal onset) Dystrophic and/or hypoplastic nails (See Dental and oral anomalies (hypodontia, delayed eruption of teeth, frenulum abnormalities) Congenital heart defects (atrial septal defect, ventricular septal defect, single atrium, atrioventricular canal) Narrow chest with short ribs Short and thickened tubular bones Bulbous ends of the proximal ulnae and distal radii Carpal and metacarpal fusions (typically capitate and hamate) Cone-shaped epiphyses of phalanges Small iliac crests Acetabular spur projections (trident ilia) Lateral slanting of the tibial plateau • Bilateral postaxial polydactyly of the hands (see • Limb shortening (prenatal or postnatal) • Disproportionate short stature (prenatal or postnatal onset) • Dystrophic and/or hypoplastic nails (See • Dental and oral anomalies (hypodontia, delayed eruption of teeth, frenulum abnormalities) • Congenital heart defects (atrial septal defect, ventricular septal defect, single atrium, atrioventricular canal) • Narrow chest with short ribs • Short and thickened tubular bones • Bulbous ends of the proximal ulnae and distal radii • Carpal and metacarpal fusions (typically capitate and hamate) • Cone-shaped epiphyses of phalanges • Small iliac crests • Acetabular spur projections (trident ilia) • Lateral slanting of the tibial plateau ## Establishing the Diagnosis The diagnosis of EVC syndrome is 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 For an introduction to multigene panels click Note: Targeted analysis for When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal and/or ectodermal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ellis-van Creveld Syndrome EVC = Ellis-van Creveld Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Approximately 23% of reported pathogenic copy number variants predictably affect both ## Option 1 For an introduction to multigene panels click Note: Targeted analysis for ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by skeletal and/or ectodermal dysplasia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ellis-van Creveld Syndrome EVC = Ellis-van Creveld Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Approximately 23% of reported pathogenic copy number variants predictably affect both ## Clinical Characteristics Ellis-van Creveld (EVC) syndrome is characterized by postaxial polydactyly of the hands, disproportionate short stature, features of ectodermal dysplasia, congenital heart disease, and radiologic abnormalities (such as short ribs and short tubular bones) [ Ellis-van Creveld Syndrome: Frequency of Select Features Based on The thorax is usually long and narrow due to underdevelopment of the rib cage / short ribs, which may lead to lung hypoplasia during development or restrictive lung disease after birth. However, respiratory insufficiency is rarely severe [ Other common skeletal abnormalities include shortening of long bones, brachydactyly (see The skull and spine are usually normal [ Genitourinary abnormalities (epispadias, hypospadias, cryptorchidism, hydrometrocolpos, kidney malformations, kidney cysts) Central nervous system malformations (Dandy-Walker malformation, corpus callosum hypoplasia, cerebellar hypoplasia) Sensorineural deafness EVC syndrome caused by large intragenic deletions or duplications affecting Missense variants are associated with decreased frequency of common skeletal findings (e.g., shortening and thickening of tubular bones, small iliac crest). The coding region of No definitive genotype-phenotype correlations have been identified for In the 2023 revised Nosology of Genetic Skeletal Disorders [ The exact prevalence of EVC syndrome is unknown. To date, there have been approximately 250 individuals reported with EVC syndrome and confirmed pathogenic variants identified in one of the genes listed in EVC syndrome may have an increased prevalence in individuals of Amish descent, as there is a founder • Genitourinary abnormalities (epispadias, hypospadias, cryptorchidism, hydrometrocolpos, kidney malformations, kidney cysts) • Central nervous system malformations (Dandy-Walker malformation, corpus callosum hypoplasia, cerebellar hypoplasia) • Sensorineural deafness • Missense variants are associated with decreased frequency of common skeletal findings (e.g., shortening and thickening of tubular bones, small iliac crest). • The coding region of ## Clinical Description Ellis-van Creveld (EVC) syndrome is characterized by postaxial polydactyly of the hands, disproportionate short stature, features of ectodermal dysplasia, congenital heart disease, and radiologic abnormalities (such as short ribs and short tubular bones) [ Ellis-van Creveld Syndrome: Frequency of Select Features Based on The thorax is usually long and narrow due to underdevelopment of the rib cage / short ribs, which may lead to lung hypoplasia during development or restrictive lung disease after birth. However, respiratory insufficiency is rarely severe [ Other common skeletal abnormalities include shortening of long bones, brachydactyly (see The skull and spine are usually normal [ Genitourinary abnormalities (epispadias, hypospadias, cryptorchidism, hydrometrocolpos, kidney malformations, kidney cysts) Central nervous system malformations (Dandy-Walker malformation, corpus callosum hypoplasia, cerebellar hypoplasia) Sensorineural deafness • Genitourinary abnormalities (epispadias, hypospadias, cryptorchidism, hydrometrocolpos, kidney malformations, kidney cysts) • Central nervous system malformations (Dandy-Walker malformation, corpus callosum hypoplasia, cerebellar hypoplasia) • Sensorineural deafness ## Phenotype Correlations by Gene ## Genotype-Phenotype Correlations EVC syndrome caused by large intragenic deletions or duplications affecting Missense variants are associated with decreased frequency of common skeletal findings (e.g., shortening and thickening of tubular bones, small iliac crest). The coding region of No definitive genotype-phenotype correlations have been identified for • Missense variants are associated with decreased frequency of common skeletal findings (e.g., shortening and thickening of tubular bones, small iliac crest). • The coding region of ## Nomenclature In the 2023 revised Nosology of Genetic Skeletal Disorders [ ## Prevalence The exact prevalence of EVC syndrome is unknown. To date, there have been approximately 250 individuals reported with EVC syndrome and confirmed pathogenic variants identified in one of the genes listed in EVC syndrome may have an increased prevalence in individuals of Amish descent, as there is a founder ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance A somatic mosaic missense variant in ## Differential Diagnosis Skeletal Ciliopathies of Interest in the Differential Diagnosis of Ellis-van Creveld Syndrome Thoracic hypoplasia (wide spectrum of severity ranging from mild form to lethal condition) Handlebar clavicles Short trident pelvis/ilia Short tubular bones Brachydactyly Cone-shaped epiphyses Postaxial polydactyly (uncommon) Retinal degeneration Pulmonary hypoplasia Cystic disease (liver, pancreas, kidney) Kidney failure Liver failure Respiratory impairment (due to thoracic anomalies) is much more common & severe in SRTD than in EVC syndrome, being the hallmark of SRTD. Kidney & liver are also commonly affected in SRTD. Polydactyly is uncommon in SRTD. Severe thoracic hypoplasia Polydactyly (axis variable) Bulbous end of long bones Bowed radii & ulnae Tibial hypoplasia Hydropic appearance Lingual hamartomas Bifid tongue Malformations (heart, lung, epiglottis, kidney, pancreas, genitalia) Imperforate anus Holoprosencephaly SRPS is typically much more severe than EVC syndrome, w/high rate of perinatal mortality. Multiple malformations are common in SRPS. Polydactyly is variable in SRPS. Postaxial polydactyly Mild short stature Short hands w/mild brachydactyly Nail dystrophy Dental anomalies (conical teeth, hypodontia, delayed eruption) Multiple frenula WAD is considered a mild form of EVC syndrome (less prominent skeletal features). Postaxial polydactyly of feet is more common in WAD than in EVC syndrome. Craniosynostosis Narrow thorax Short proximal bones Severe brachydactyly Postaxial polydactyly (uncommon) Ectodermal dysplasia Characteristic facial features w/frontal bossing & low-set ears Loose skin & joint laxity Progressive kidney failure Hepatic disease Retinal dystrophy Unlike EVC syndrome, CED is assoc w/craniosynostosis, kidney failure, hepatic disease, & retinal dystrophy. Polydactyly is uncommon in CED. Craniosynostosis Short stature Cone-shaped epiphyses of phalanges Femoral dysplasia (small & flattened epiphyses, short neck) Microcephaly Dental anomalies Nystagmus Retinal pigmentary dystrophy Progressive kidney failure Hepatic disease (uncommon) MZSDS is assoc w/a less pronounced skeletal phenotype. Retinal dystrophy is invariably present in MZSDS. Kidney failure & malformation are also very common in MZSDS. EVC = Ellis-van Creveld; MZSDS = Mainzer-Saldino syndrome; SRPS = short-rib polydactyly syndrome; CED = cranioectodermal dysplasia; SRTD = short-rib thoracic dysplasia; WAD = Weyers acrofacial (acrodental) dysostosis • Thoracic hypoplasia (wide spectrum of severity ranging from mild form to lethal condition) • Handlebar clavicles • Short trident pelvis/ilia • Short tubular bones • Brachydactyly • Cone-shaped epiphyses • Postaxial polydactyly (uncommon) • Retinal degeneration • Pulmonary hypoplasia • Cystic disease (liver, pancreas, kidney) • Kidney failure • Liver failure • Respiratory impairment (due to thoracic anomalies) is much more common & severe in SRTD than in EVC syndrome, being the hallmark of SRTD. • Kidney & liver are also commonly affected in SRTD. • Polydactyly is uncommon in SRTD. • Severe thoracic hypoplasia • Polydactyly (axis variable) • Bulbous end of long bones • Bowed radii & ulnae • Tibial hypoplasia • Hydropic appearance • Lingual hamartomas • Bifid tongue • Malformations (heart, lung, epiglottis, kidney, pancreas, genitalia) • Imperforate anus • Holoprosencephaly • SRPS is typically much more severe than EVC syndrome, w/high rate of perinatal mortality. • Multiple malformations are common in SRPS. • Polydactyly is variable in SRPS. • Postaxial polydactyly • Mild short stature • Short hands w/mild brachydactyly • Nail dystrophy • Dental anomalies (conical teeth, hypodontia, delayed eruption) • Multiple frenula • WAD is considered a mild form of EVC syndrome (less prominent skeletal features). • Postaxial polydactyly of feet is more common in WAD than in EVC syndrome. • Craniosynostosis • Narrow thorax • Short proximal bones • Severe brachydactyly • Postaxial polydactyly (uncommon) • Ectodermal dysplasia • Characteristic facial features w/frontal bossing & low-set ears • Loose skin & joint laxity • Progressive kidney failure • Hepatic disease • Retinal dystrophy • Unlike EVC syndrome, CED is assoc w/craniosynostosis, kidney failure, hepatic disease, & retinal dystrophy. • Polydactyly is uncommon in CED. • Craniosynostosis • Short stature • Cone-shaped epiphyses of phalanges • Femoral dysplasia (small & flattened epiphyses, short neck) • Microcephaly • Dental anomalies • Nystagmus • Retinal pigmentary dystrophy • Progressive kidney failure • Hepatic disease (uncommon) • MZSDS is assoc w/a less pronounced skeletal phenotype. • Retinal dystrophy is invariably present in MZSDS. • Kidney failure & malformation are also very common in MZSDS. ## Management No clinical practice guidelines for Ellis-van Creveld (EVC) syndrome have been published. To establish the extent of disease and needs in an individual diagnosed with EVC syndrome, the evaluations summarized in Ellis-van Creveld Syndrome: Recommended Evaluations Following Initial Diagnosis Physical exam w/measurement of body & limb segments Complete radiographic skeletal survey Physical & rehab medicine eval to assess need for PT Community or Social work involvement for parental support Home nursing referral EVC = Ellis-van Creveld; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Ellis-van Creveld Syndrome: Treatment of Manifestations PT = physical therapy; OT = occupational therapy To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Ellis-van Creveld Syndrome: Recommended Surveillance PT = physical therapy See In pregnant women with EVC syndrome who have pelvic/hip abnormalities, cesarean delivery is recommended. See Search • Physical exam w/measurement of body & limb segments • Complete radiographic skeletal survey • Physical & rehab medicine eval to assess need for PT • Community or • Social work involvement for parental support • Home nursing referral ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with EVC syndrome, the evaluations summarized in Ellis-van Creveld Syndrome: Recommended Evaluations Following Initial Diagnosis Physical exam w/measurement of body & limb segments Complete radiographic skeletal survey Physical & rehab medicine eval to assess need for PT Community or Social work involvement for parental support Home nursing referral EVC = Ellis-van Creveld; MOI = mode of inheritance; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Physical exam w/measurement of body & limb segments • Complete radiographic skeletal survey • Physical & rehab medicine eval to assess need for PT • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Ellis-van Creveld Syndrome: Treatment of Manifestations PT = physical therapy; OT = occupational therapy ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Ellis-van Creveld Syndrome: Recommended Surveillance PT = physical therapy ## Evaluation of Relatives at Risk See ## Pregnancy Management In pregnant women with EVC syndrome who have pelvic/hip abnormalities, cesarean delivery is recommended. See ## Therapies Under Investigation Search ## Genetic Counseling Ellis-van Creveld (EVC) syndrome caused by pathogenic variants in EVC syndrome caused by pathogenic variants in The parents of an affected child are presumed to be heterozygous for an EVC syndrome-related pathogenic variant. Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EVC syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically If both parents are known to be heterozygous for a pathogenic variant in one of the genes listed in Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically Carrier testing for at-risk relatives requires prior identification of the EVC 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, 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 ancestry. An EVC founder variant has been identified in individuals of Amish ancestry (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 an EVC syndrome-related pathogenic variant. • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EVC syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 in one of the genes listed in • Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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, particularly if both partners are of the same ancestry. An EVC founder variant has been identified in individuals of Amish ancestry (see ## Mode of Inheritance Ellis-van Creveld (EVC) syndrome caused by pathogenic variants in EVC syndrome caused by pathogenic variants in ## Risk to Family Members (Autosomal Recessive Inheritance) The parents of an affected child are presumed to be heterozygous for an EVC syndrome-related pathogenic variant. Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EVC syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically If both parents are known to be heterozygous for a pathogenic variant in one of the genes listed in Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically • The parents of an affected child are presumed to be heterozygous for an EVC syndrome-related pathogenic variant. • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an EVC syndrome-related pathogenic variant and to allow reliable recurrence risk assessment. • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual 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 in one of the genes listed in • Heterozygotes (carriers) are usually asymptomatic and are not at risk of developing EVC syndrome. However, a small number of heterozygous variants (typically ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the EVC 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, 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 ancestry. An EVC founder variant has been identified in individuals of Amish 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 affected, 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 ancestry. An EVC founder variant has been identified in individuals of Amish ancestry (see ## 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 Ellis-van Creveld Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ellis-van Creveld Syndrome ( Ellis-van Creveld Syndrome: Gene-Specific Laboratory Considerations Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Ellis-van Creveld Syndrome: Gene-Specific Laboratory Considerations Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. ## Chapter Notes Jorge Diogo Da Silva, Nataliya Tkachenko, and Ana Rita Soares are actively involved in clinical research regarding individuals with Ellis-van Creveld (EVC) syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of EVC syndrome or other considerations. The authors are also interested in hearing from clinicians treating families affected by EVC syndrome 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 Jorge Diogo Da Silva ( The authors would like to acknowledge Dr Catarina Martins Silva for her valuable help regarding the photographic records of the individual with EVC syndrome presented in 26 October 2023 (sw) Review posted live 5 July 2023 (jds) Original submission • 26 October 2023 (sw) Review posted live • 5 July 2023 (jds) Original submission ## Author Notes Jorge Diogo Da Silva, Nataliya Tkachenko, and Ana Rita Soares are actively involved in clinical research regarding individuals with Ellis-van Creveld (EVC) syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of EVC syndrome or other considerations. The authors are also interested in hearing from clinicians treating families affected by EVC syndrome 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 Jorge Diogo Da Silva ( ## Acknowledgments The authors would like to acknowledge Dr Catarina Martins Silva for her valuable help regarding the photographic records of the individual with EVC syndrome presented in ## Revision History 26 October 2023 (sw) Review posted live 5 July 2023 (jds) Original submission • 26 October 2023 (sw) Review posted live • 5 July 2023 (jds) Original submission ## References ## Literature Cited Clinical and radiographic images of a male child with Ellis-van Creveld (EVC) syndrome A. Dysmorphic features at age 19 months with short broad nose and partial upper lip defect in the midline. B, C, D, E. Clinical images of hands and feet at age 19 months show bilateral postaxial polydactyly of the hands and nail dystrophy of most nails. F, G. Radiographic images of the hands at age 24 months show postaxial polydactyly with fusion of the left fifth and sixth metacarpals, brachydactyly, and cone-shaped epiphysis of the middle phalanges. H, I. Radiographic images of the feet at age 24 months show brachydactyly. J. Radiographic image of the pelvis at age three years nine months shows trident-shaped ilia and small acetabular spur (arrow). K. Radiographic image of the lower limbs at age three years nine months shows genu valgum due to underdevelopment of the lateral tibial metaphyses bilaterally (downslanted lateral tibial plateau). Unpublished photographic report of an individual with EVC syndrome previously reported in a systematic review [
[]
26/10/2023
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
exoc6b-semd
exoc6b-semd
[ "Spondyloepimetaphyseal Dysplasia with Joint Laxity, Type 3 (SEMDJL3)", "Spondyloepimetaphyseal Dysplasia with Joint Laxity, Type 3 (SEMDJL3)", "Exocyst complex component 6B", "EXOC6B", "EXOC6B-Related Spondyloepimetaphyseal Dysplasia with Joint Laxity" ]
Gandham SriLakshmi Bhavani, Swati Singh, Katta Mohan Girisha
Summary The diagnosis of
## Diagnosis Congenital dislocations of the hips and knees; may also affect elbows, wrists, and/or ankles Joint laxity affecting all joints and most evident at the wrists and fingers Postnatal-onset short stature Slender fingers (leptodactyly) Genu valgum Pes planus Delayed carpal/tarsal bone ossification Slender/gracile short tubular bones (leptodactyly) Metaphyseal dysplasia. Irregular metaphyses with short sclerotic striations at the distal radius, distal ulna, distal femora, and proximal tibia Epiphyseal dysplasia (generalized). Carpal and tarsal bones are usually smaller and irregular; epiphyses of the long bones appear flat and small. Slender ribs Irregular vertebral end plates and modest platyspondyly (Platyspondyly is seen only in younger individuals and becomes less conspicuous with age; even tall vertebral bodies are seen in older affected individuals.) Narrow interpedicular distance of the lumbar vertebrae Thoracolumbar scoliosis, kyphosis, and/or hyperlordosis 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 clinical and imaging findings suggest the diagnosis of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. An intragenic deletion of • Congenital dislocations of the hips and knees; may also affect elbows, wrists, and/or ankles • Joint laxity affecting all joints and most evident at the wrists and fingers • Postnatal-onset short stature • Slender fingers (leptodactyly) • Genu valgum • Pes planus • Delayed carpal/tarsal bone ossification • Slender/gracile short tubular bones (leptodactyly) • Metaphyseal dysplasia. Irregular metaphyses with short sclerotic striations at the distal radius, distal ulna, distal femora, and proximal tibia • Epiphyseal dysplasia (generalized). Carpal and tarsal bones are usually smaller and irregular; epiphyses of the long bones appear flat and small. • Slender ribs • Irregular vertebral end plates and modest platyspondyly (Platyspondyly is seen only in younger individuals and becomes less conspicuous with age; even tall vertebral bodies are seen in older affected individuals.) • Narrow interpedicular distance of the lumbar vertebrae • Thoracolumbar scoliosis, kyphosis, and/or hyperlordosis • For an introduction to multigene panels click ## Suggestive Findings Congenital dislocations of the hips and knees; may also affect elbows, wrists, and/or ankles Joint laxity affecting all joints and most evident at the wrists and fingers Postnatal-onset short stature Slender fingers (leptodactyly) Genu valgum Pes planus Delayed carpal/tarsal bone ossification Slender/gracile short tubular bones (leptodactyly) Metaphyseal dysplasia. Irregular metaphyses with short sclerotic striations at the distal radius, distal ulna, distal femora, and proximal tibia Epiphyseal dysplasia (generalized). Carpal and tarsal bones are usually smaller and irregular; epiphyses of the long bones appear flat and small. Slender ribs Irregular vertebral end plates and modest platyspondyly (Platyspondyly is seen only in younger individuals and becomes less conspicuous with age; even tall vertebral bodies are seen in older affected individuals.) Narrow interpedicular distance of the lumbar vertebrae Thoracolumbar scoliosis, kyphosis, and/or hyperlordosis • Congenital dislocations of the hips and knees; may also affect elbows, wrists, and/or ankles • Joint laxity affecting all joints and most evident at the wrists and fingers • Postnatal-onset short stature • Slender fingers (leptodactyly) • Genu valgum • Pes planus • Delayed carpal/tarsal bone ossification • Slender/gracile short tubular bones (leptodactyly) • Metaphyseal dysplasia. Irregular metaphyses with short sclerotic striations at the distal radius, distal ulna, distal femora, and proximal tibia • Epiphyseal dysplasia (generalized). Carpal and tarsal bones are usually smaller and irregular; epiphyses of the long bones appear flat and small. • Slender ribs • Irregular vertebral end plates and modest platyspondyly (Platyspondyly is seen only in younger individuals and becomes less conspicuous with age; even tall vertebral bodies are seen in older affected individuals.) • Narrow interpedicular distance of the lumbar vertebrae • Thoracolumbar scoliosis, kyphosis, and/or hyperlordosis ## 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 clinical and imaging findings suggest the diagnosis of For an introduction to multigene panels click When the diagnosis of For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. An intragenic deletion of • For an introduction to multigene panels click ## Option 1 When the clinical and imaging findings suggest the diagnosis of For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the 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. An intragenic deletion of ## Clinical Characteristics Height two or more standard deviations below the mean for sex and age Soft skin Developmental delay (1 individual) [ Hydrocephalus (1 individual) No clinically relevant genotype-phenotype correlations have been identified. Seven individuals from five unrelated families with • Soft skin • Developmental delay (1 individual) [ • Hydrocephalus (1 individual) ## Clinical Description Height two or more standard deviations below the mean for sex and age Soft skin Developmental delay (1 individual) [ Hydrocephalus (1 individual) • Soft skin • Developmental delay (1 individual) [ • Hydrocephalus (1 individual) ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified. ## Prevalence Seven individuals from five unrelated families with ## Genetically Related (Allelic) Disorders Intellectual disability has been reported in individuals with genetic alterations (intragenic pathogenic variants, contiguous gene deletions, and translocations) involving ## Differential Diagnosis Common Conditions with Multiple Joint Problems (Laxity, Dislocations, Restriction of Joint Movement) in the Differential Diagnosis of Prenatal-onset short stature Facial dysmorphism (oval face, prominent forehead, prominent eyes, blue sclera, micrognathia, cleft palate) Progressive kyphoscoliosis & joint dislocation Progressive kyphoscoliosis Ovoid vertebral bodies Severe platyspondyly Short, flared iliac wings Radioulnar dislocation Short stature Brachycephaly, prominent forehead Multiple joint dislocations Cardiac anomalies Scoliosis Occasionally modest platyspondyly Dislocation of radioulnar & interphalangeal joints Broad ilia Long phalanges w/relatively short metacarpals Occasionally generalized osteoporosis Short stature Broad, flat forehead Joint laxity & dislocations Long, slender fingers & toes Loose elastic skin Scoliosis Large joint dislocation Radioulnar synostosis Prenatal-onset short stature Midface hypoplasia Joint dislocations Occasionally, multiple coronal clefts of vertebral bodies Advanced carpal ossification Monkey wrench femora Hyperphalangy of index finger Short stature Joint dislocations &/or restriction of joint movement Clubfeet Kyphoscoliosis Multiple coronal clefts of vertebral bodies Increase in interpedicular distance from T12 to L1 or L2 Bifid distal humerus Accessory carpal ossification centers Short stature Severe myopia Joint dislocation & laxity Osteopenia Progressive kyphoscoliosis Short stature Knee/hip joint dislocation Midface hypoplasia Joint laxity Genu valgum Velvety skin Hypotonia Progressive scoliosis Vertebral dysplasia (modest platyspondyly in younger persons) Epimetaphyseal dysplasia (small, flat epiphyses & irregular metaphyses w/longitudinal striations) Gracile, short tubular bones Microcephaly Primordial short stature Flat facial features Joint laxity Joint dislocation Genu valgum Pes cavus Scoliosis Squared vertebral bodies Irregular vertebral end plates Slender, short tubular bones Metaphyseal striations Prenatal-onset short stature Midface hypoplasia Joint dislocations Multiple coronal clefts of vertebral bodies Advanced carpal ossification AD = autosomal dominant; AR = autosomal recessive; SEMD-JL = spondyloepimetaphyseal dysplasia with joint laxity; MOI = mode of inheritance Disorder names are from the Nosology of Genetic Skeletal Disorders: 2023 Revision [ This condition is not well characterized; only one family has been reported to date [ • Prenatal-onset short stature • Facial dysmorphism (oval face, prominent forehead, prominent eyes, blue sclera, micrognathia, cleft palate) • Progressive kyphoscoliosis & joint dislocation • Progressive kyphoscoliosis • Ovoid vertebral bodies • Severe platyspondyly • Short, flared iliac wings • Radioulnar dislocation • Short stature • Brachycephaly, prominent forehead • Multiple joint dislocations • Cardiac anomalies • Scoliosis • Occasionally modest platyspondyly • Dislocation of radioulnar & interphalangeal joints • Broad ilia • Long phalanges w/relatively short metacarpals • Occasionally generalized osteoporosis • Short stature • Broad, flat forehead • Joint laxity & dislocations • Long, slender fingers & toes • Loose elastic skin • Scoliosis • Large joint dislocation • Radioulnar synostosis • Prenatal-onset short stature • Midface hypoplasia • Joint dislocations • Occasionally, multiple coronal clefts of vertebral bodies • Advanced carpal ossification • Monkey wrench femora • Hyperphalangy of index finger • Short stature • Joint dislocations &/or restriction of joint movement • Clubfeet • Kyphoscoliosis • Multiple coronal clefts of vertebral bodies • Increase in interpedicular distance from T12 to L1 or L2 • Bifid distal humerus • Accessory carpal ossification centers • Short stature • Severe myopia • Joint dislocation & laxity • Osteopenia • Progressive kyphoscoliosis • Short stature • Knee/hip joint dislocation • Midface hypoplasia • Joint laxity • Genu valgum • Velvety skin • Hypotonia • Progressive scoliosis • Vertebral dysplasia (modest platyspondyly in younger persons) • Epimetaphyseal dysplasia (small, flat epiphyses & irregular metaphyses w/longitudinal striations) • Gracile, short tubular bones • Microcephaly • Primordial short stature • Flat facial features • Joint laxity • Joint dislocation • Genu valgum • Pes cavus • Scoliosis • Squared vertebral bodies • Irregular vertebral end plates • Slender, short tubular bones • Metaphyseal striations • Prenatal-onset short stature • Midface hypoplasia • Joint dislocations • Multiple coronal clefts of vertebral bodies • Advanced carpal ossification ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Complete skeletal survey Eval by orthopedic surgeon & PT to assess joint range of motion Community or Social work involvement for parental support; Home nursing referral. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for Surgical interventions to remedy joint dislocations & improve mobility Wheelchair &/or walking aids may be necessary. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Activities with a high impact on joints that may increase the risk of dislocation should be avoided. Obesity should be avoided to reduce the negative impact on joints. See Search • Complete skeletal survey • Eval by orthopedic surgeon & PT to assess joint range of motion • Community or • Social work involvement for parental support; • Home nursing referral. • Surgical interventions to remedy joint dislocations & improve mobility • Wheelchair &/or walking aids may be necessary. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Complete skeletal survey Eval by orthopedic surgeon & PT to assess joint range of motion Community or Social work involvement for parental support; Home nursing referral. Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Complete skeletal survey • Eval by orthopedic surgeon & PT to assess joint range of motion • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Surgical interventions to remedy joint dislocations & improve mobility Wheelchair &/or walking aids may be necessary. • Surgical interventions to remedy joint dislocations & improve mobility • Wheelchair &/or walking aids may be necessary. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in ## Agents/Circumstances to Avoid Activities with a high impact on joints that may increase the risk of dislocation should be avoided. Obesity should be avoided to reduce the negative impact on joints. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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 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 ## 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics EXOC6B-Related Spondyloepimetaphyseal Dysplasia with Joint Laxity: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EXOC6B-Related Spondyloepimetaphyseal Dysplasia with Joint Laxity ( ## Molecular Pathogenesis ## Chapter Notes Dr Katta Mohan Girisha is interested in clinical care and research in individuals with skeletal dysplasia. He is also keen to identify more individuals with Dr Katta Mohan Girisha ( Contact Dr Katta Mohan Girisha and Dr Gandham SriLakshmi Bhavani to inquire about review of The authors of this chapter serve as moderators for the We acknowledge the financial support provided by CSIR-UGC NET Junior Research Fellowship awarded by Human Resource Development Group under Council of Scientific and Industrial Research: 08/028(0002)/2019-EMR-I (to Swati Singh). 17 July 2025 (kmg) Revision: short stature clarified in 25 May 2023 (sw) Review posted live 20 March 2023 (kmg) Original submission • 17 July 2025 (kmg) Revision: short stature clarified in • 25 May 2023 (sw) Review posted live • 20 March 2023 (kmg) Original submission ## Author Notes Dr Katta Mohan Girisha is interested in clinical care and research in individuals with skeletal dysplasia. He is also keen to identify more individuals with Dr Katta Mohan Girisha ( Contact Dr Katta Mohan Girisha and Dr Gandham SriLakshmi Bhavani to inquire about review of The authors of this chapter serve as moderators for the ## Acknowledgments We acknowledge the financial support provided by CSIR-UGC NET Junior Research Fellowship awarded by Human Resource Development Group under Council of Scientific and Industrial Research: 08/028(0002)/2019-EMR-I (to Swati Singh). ## Revision History 17 July 2025 (kmg) Revision: short stature clarified in 25 May 2023 (sw) Review posted live 20 March 2023 (kmg) Original submission • 17 July 2025 (kmg) Revision: short stature clarified in • 25 May 2023 (sw) Review posted live • 20 March 2023 (kmg) Original submission ## References ## Literature Cited
[]
25/5/2023
17/7/2025
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
exosc3-pc-hypo-p
exosc3-pc-hypo-p
[ "Pontocerebellar Hypoplasia Type 1B (PCH1B)", "Pontocerebellar Hypoplasia Type 1B (PCH1B)", "Exosome complex component RRP40", "EXOSC3", "EXOSC3 Pontocerebellar Hypoplasia" ]
Frank Baas, Tessa van Dijk
Summary The diagnosis of
## Diagnosis Diagnosis of Hypotonia (onset is usually at birth, but a later onset is possible) Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations) Joint contractures (can be present at birth or develop later) Swallowing insufficiency Ophthalmologic findings of: Small or pale optic discs indicative of optic atrophy Nystagmus Strabismus Seizures Hypoplasia and/or atrophy of the cerebellum in varying degrees Hypoplasia and/or atrophy of the pons in varying degrees Cerebellar vermis and cerebellar hemispheres equally affected Intracerebellar cysts [ Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia * See Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. • Hypotonia (onset is usually at birth, but a later onset is possible) • Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes • Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival • Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations) • Joint contractures (can be present at birth or develop later) • Swallowing insufficiency • Ophthalmologic findings of: • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Seizures • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Hypoplasia and/or atrophy of the cerebellum in varying degrees • Hypoplasia and/or atrophy of the pons in varying degrees • Cerebellar vermis and cerebellar hemispheres equally affected • Intracerebellar cysts [ • Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia ## Suggestive Findings Diagnosis of Hypotonia (onset is usually at birth, but a later onset is possible) Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations) Joint contractures (can be present at birth or develop later) Swallowing insufficiency Ophthalmologic findings of: Small or pale optic discs indicative of optic atrophy Nystagmus Strabismus Seizures Hypoplasia and/or atrophy of the cerebellum in varying degrees Hypoplasia and/or atrophy of the pons in varying degrees Cerebellar vermis and cerebellar hemispheres equally affected Intracerebellar cysts [ Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia * See Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. • Hypotonia (onset is usually at birth, but a later onset is possible) • Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes • Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival • Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations) • Joint contractures (can be present at birth or develop later) • Swallowing insufficiency • Ophthalmologic findings of: • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Seizures • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Hypoplasia and/or atrophy of the cerebellum in varying degrees • Hypoplasia and/or atrophy of the pons in varying degrees • Cerebellar vermis and cerebellar hemispheres equally affected • Intracerebellar cysts [ • Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia ## Neurologic Findings Hypotonia (onset is usually at birth, but a later onset is possible) Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations) Joint contractures (can be present at birth or develop later) Swallowing insufficiency Ophthalmologic findings of: Small or pale optic discs indicative of optic atrophy Nystagmus Strabismus Seizures • Hypotonia (onset is usually at birth, but a later onset is possible) • Signs of neurogenic muscle atrophy, such as muscle atrophy and decreased tendon reflexes • Central motor neuron signs (spasticity, dystonia), especially in individuals with prolonged survival • Lower motor neuron involvement, demonstrated by EMG (abnormal EMG potentials, increased motor unit potentials, fasciculations) • Joint contractures (can be present at birth or develop later) • Swallowing insufficiency • Ophthalmologic findings of: • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus • Seizures • Small or pale optic discs indicative of optic atrophy • Nystagmus • Strabismus ## Brain MRI Findings Consistent with Pontocerebellar Hypoplasia Type 1 (PCH1) * Hypoplasia and/or atrophy of the cerebellum in varying degrees Hypoplasia and/or atrophy of the pons in varying degrees Cerebellar vermis and cerebellar hemispheres equally affected Intracerebellar cysts [ Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia * See • Hypoplasia and/or atrophy of the cerebellum in varying degrees • Hypoplasia and/or atrophy of the pons in varying degrees • Cerebellar vermis and cerebellar hemispheres equally affected • Intracerebellar cysts [ • Supratentorial abnormalities, such as widened extracerebellar CSF spaces and widened lateral ventricles due to small basal ganglia ## Family History Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis. ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. ## Option 1 For an introduction to multigene panels click ## Option 2 If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. ## Clinical Characteristics To date, 82 individuals (in 58 families) with Pregnancy is unremarkable in the majority. Fetal akinesia resulting in prenatal-onset joint contractures and polyhydramnios may occur in 1%-2% of cases [ Birth weight and length are normal; birth head circumference varies from normal to small. Hypotonia, the most common initial finding, is present at birth in most infants and not evident until age three to six months in the remainder. In relatively older individuals, central motor (pyramidal or extrapyramidal) and signs of peripheral motor involvement may coexist. Infections and respiratory failure due to muscle weakness are among the reported causes of death. In most severe cases, respiratory problems start soon after birth. In the majority of children onset of respiratory failure begins within the first year of life. In rare cases, onset is during childhood [ Joint contractures can be present at birth in the most severe cases, or can develop after a few years. Motor milestones are delayed or not achieved at all. Unsupported crawling, sitting, or walking is reported in a few [ Some infants can be bottle-fed or breast-fed in the first weeks of life [ Vision is hard to assess in young children. Many are unable to fix and follow, and many show strabismus and/or nystagmus. Possibly, the nystagmus in some children results from early-onset visual impairment, but clear evidence is lacking. Seizures mainly occur in individuals who survive beyond infancy [ Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers Clear genotype-phenotype correlations exist for certain Phenotypes associated with the pathogenic variant Children homozygous for this variant could be described as having a relatively "mild" clinical course. Some have the ability to walk or speak single words, and the disease course is prolonged with possible survival into puberty. Brain MRI shows a normal-size pons and cerebellar hypoplasia that is mild compared to that observed in children with other Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and Phenotypes associated with the pathogenic variant Individuals homozygous for this variant represent the severe end of the More recently, two sibs with this variant had severe growth retardation, fetal akinesia, microlissencephaly, and cerebellar malformations consistent with rhombencephalosynapsis [ Pontocerebellar hypoplasia 1 (PCH1) refers to the phenotype defined by brain imaging findings. Its subtypes, designated by letter (e.g., PCH1B), are identified by the gene in which causative pathogenic variants occur. The prevalence of About 50% of individuals with pontocerebellar hypoplasia 1 (PCH1) have pathogenic variants in To date, 82 individuals (in 58 families) have been described with The • • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers • Children homozygous for this variant could be described as having a relatively "mild" clinical course. Some have the ability to walk or speak single words, and the disease course is prolonged with possible survival into puberty. Brain MRI shows a normal-size pons and cerebellar hypoplasia that is mild compared to that observed in children with other • Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and • Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and • Individuals homozygous for this variant represent the severe end of the • More recently, two sibs with this variant had severe growth retardation, fetal akinesia, microlissencephaly, and cerebellar malformations consistent with rhombencephalosynapsis [ ## Clinical Description To date, 82 individuals (in 58 families) with Pregnancy is unremarkable in the majority. Fetal akinesia resulting in prenatal-onset joint contractures and polyhydramnios may occur in 1%-2% of cases [ Birth weight and length are normal; birth head circumference varies from normal to small. Hypotonia, the most common initial finding, is present at birth in most infants and not evident until age three to six months in the remainder. In relatively older individuals, central motor (pyramidal or extrapyramidal) and signs of peripheral motor involvement may coexist. Infections and respiratory failure due to muscle weakness are among the reported causes of death. In most severe cases, respiratory problems start soon after birth. In the majority of children onset of respiratory failure begins within the first year of life. In rare cases, onset is during childhood [ Joint contractures can be present at birth in the most severe cases, or can develop after a few years. Motor milestones are delayed or not achieved at all. Unsupported crawling, sitting, or walking is reported in a few [ Some infants can be bottle-fed or breast-fed in the first weeks of life [ Vision is hard to assess in young children. Many are unable to fix and follow, and many show strabismus and/or nystagmus. Possibly, the nystagmus in some children results from early-onset visual impairment, but clear evidence is lacking. Seizures mainly occur in individuals who survive beyond infancy [ Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers • • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers • Muscle. Typical findings of anterior horn involvement (i.e., neurogenic muscle atrophy): grouped atrophy, type II muscle fiber atrophy • Spinal cord. Degeneration and loss of motor neurons in the anterior spinal horn • Cerebellum. Loss of Purkinje cells, folial atrophy, degeneration of dentate nuclei, and loss of ventral pontine nuclei and transverse pontine nerve fibers ## Genotype-Phenotype Correlations Clear genotype-phenotype correlations exist for certain Phenotypes associated with the pathogenic variant Children homozygous for this variant could be described as having a relatively "mild" clinical course. Some have the ability to walk or speak single words, and the disease course is prolonged with possible survival into puberty. Brain MRI shows a normal-size pons and cerebellar hypoplasia that is mild compared to that observed in children with other Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and Phenotypes associated with the pathogenic variant Individuals homozygous for this variant represent the severe end of the More recently, two sibs with this variant had severe growth retardation, fetal akinesia, microlissencephaly, and cerebellar malformations consistent with rhombencephalosynapsis [ • Children homozygous for this variant could be described as having a relatively "mild" clinical course. Some have the ability to walk or speak single words, and the disease course is prolonged with possible survival into puberty. Brain MRI shows a normal-size pons and cerebellar hypoplasia that is mild compared to that observed in children with other • Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and • Two sibs, compound heterozygotes for the pathogenic variants c.395A>C (p.Asp132Ala) and • Individuals homozygous for this variant represent the severe end of the • More recently, two sibs with this variant had severe growth retardation, fetal akinesia, microlissencephaly, and cerebellar malformations consistent with rhombencephalosynapsis [ ## Nomenclature Pontocerebellar hypoplasia 1 (PCH1) refers to the phenotype defined by brain imaging findings. Its subtypes, designated by letter (e.g., PCH1B), are identified by the gene in which causative pathogenic variants occur. ## Prevalence The prevalence of About 50% of individuals with pontocerebellar hypoplasia 1 (PCH1) have pathogenic variants in To date, 82 individuals (in 58 families) have been described with The ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Key disorders to consider in the differential diagnosis of pontocerebellar hypoplasia type 1 (PCH1) include No abnormalities of the spinal cord (whereas in PCH1 anterior horn cells are involved); Attenuation of the pons on brain MRI (whereas in PCH1 the pons can be unaffected). Genes of Interest in the Differential Diagnosis of Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. Severe pontocerebellar hypoplasia w/relative sparing of pons Profound supratentorial atrophy in PCH4 Generalized clonus, impaired swallowing, dystonia, chorea, progressive microcephaly in PCH2 PCH4 is a severe type of PCH2, w/congenital contractures & polyhydramnios. Early-onset (birth-6 mos) disease is characterized by muscle weakness & lack of motor development. Cognitive function is normal. EMG reveals denervation; muscle biopsy shows grouped atrophy. Heterozygous females have severe or profound ID & structural brain anomalies incl mild congenital microcephaly & severe postnatal microcephaly. Hemizygous males are more severely affected. Very rare ↑ CSF lactate concentration AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PCH = pontocerebellar hypoplasia; XL = X-linked OMIM Children with OMIM PMM2-CDG ( Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [ Pontocerebellar hypoplasia in extremely premature infants (gestational age <28 weeks); an acquired phenocopy to be considered [ • No abnormalities of the spinal cord (whereas in PCH1 anterior horn cells are involved); • Attenuation of the pons on brain MRI (whereas in PCH1 the pons can be unaffected). • Lower motor neuron deficits due to loss of anterior horn cells; manifestations of peripheral denervation incl weakness & muscle hypotonia from birth • Mixed central (spastic, dystonic) & peripheral pareses may be present in those w/prolonged survival; some children w/PCH1 die at an early age. • Severe pontocerebellar hypoplasia w/relative sparing of pons • Profound supratentorial atrophy in PCH4 • Generalized clonus, impaired swallowing, dystonia, chorea, progressive microcephaly in PCH2 • PCH4 is a severe type of PCH2, w/congenital contractures & polyhydramnios. • Early-onset (birth-6 mos) disease is characterized by muscle weakness & lack of motor development. • Cognitive function is normal. • EMG reveals denervation; muscle biopsy shows grouped atrophy. • Heterozygous females have severe or profound ID & structural brain anomalies incl mild congenital microcephaly & severe postnatal microcephaly. • Hemizygous males are more severely affected. • Very rare • ↑ CSF lactate concentration • Lissencephalies without known gene defects exhibiting two-layered cortex, extreme microcephaly, and cerebellar and pontine hypoplasia [ • Pontocerebellar hypoplasia in extremely premature infants (gestational age <28 weeks); an acquired phenocopy to be considered [ ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of Evidence of severe generalized clonus; Chorea, spasticity; Seizures (to incl EEG); Impaired central vision. Assess visual acuity. Fundoscopy to assess optic nerve Contractures, clubfoot, & kyphoscoliosis Need for positioning devices Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist Medical geneticist, certified genetic counselor, or certified advanced genetic nurse No specific treatment for Ideally, each affected individual is managed by a multidisciplinary team of relevant specialists including developmental pediatricians, neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see Treatment of Manifestations in Individuals with Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. Alternative casting/splinting & stretching Manage pulmonary complications. Treatment of respiratory infections NG = nasogastric; OT = occupational therapy, PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Recommended Surveillance for Individuals with Aspiration risk & nutritional status Monitor for constipation. PT/OT eval Assess for contractures, scoliosis, foot deformities. Hip/spine x-rays Monitor those w/seizures as clinically indicated. Monitor for dystonia & choreic movements. OT = occupational therapy, PT = physical therapy See Search • Evidence of severe generalized clonus; • Chorea, spasticity; • Seizures (to incl EEG); • Impaired central vision. • Assess visual acuity. • Fundoscopy to assess optic nerve • Contractures, clubfoot, & kyphoscoliosis • Need for positioning devices • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. • Alternative casting/splinting & stretching • Manage pulmonary complications. • Treatment of respiratory infections • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Aspiration risk & nutritional status • Monitor for constipation. • PT/OT eval • Assess for contractures, scoliosis, foot deformities. • Hip/spine x-rays • Monitor those w/seizures as clinically indicated. • Monitor for dystonia & choreic movements. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis of Evidence of severe generalized clonus; Chorea, spasticity; Seizures (to incl EEG); Impaired central vision. Assess visual acuity. Fundoscopy to assess optic nerve Contractures, clubfoot, & kyphoscoliosis Need for positioning devices Use of community or Need for social work involvement for parental support; Need for home nursing referral. MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Evidence of severe generalized clonus; • Chorea, spasticity; • Seizures (to incl EEG); • Impaired central vision. • Assess visual acuity. • Fundoscopy to assess optic nerve • Contractures, clubfoot, & kyphoscoliosis • Need for positioning devices • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations No specific treatment for Ideally, each affected individual is managed by a multidisciplinary team of relevant specialists including developmental pediatricians, neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see Treatment of Manifestations in Individuals with Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. Alternative casting/splinting & stretching Manage pulmonary complications. Treatment of respiratory infections NG = nasogastric; OT = occupational therapy, PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Maximize gross motor & fine motor skills through PT/OT & use of adaptive devices. • Alternative casting/splinting & stretching • Manage pulmonary complications. • Treatment of respiratory infections • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 participatin in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance Recommended Surveillance for Individuals with Aspiration risk & nutritional status Monitor for constipation. PT/OT eval Assess for contractures, scoliosis, foot deformities. Hip/spine x-rays Monitor those w/seizures as clinically indicated. Monitor for dystonia & choreic movements. OT = occupational therapy, PT = physical therapy • Aspiration risk & nutritional status • Monitor for constipation. • PT/OT eval • Assess for contractures, scoliosis, foot deformities. • Hip/spine x-rays • Monitor those w/seizures as clinically indicated. • Monitor for dystonia & choreic movements. ## 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 Although some intrafamilial variability has been described, sibs who inherit biallelic Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the 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 carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for an • Although some intrafamilial variability has been described, sibs who inherit biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Although some intrafamilial variability has been described, sibs who inherit biallelic 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 • Although some intrafamilial variability has been described, sibs who inherit biallelic • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the See ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics EXOSC3 Pontocerebellar Hypoplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for EXOSC3 Pontocerebellar Hypoplasia ( Notable Most prevalent pathogenic variant w/ancestral origin (allele frequency of 0.1% in European Americans) [ Milder clinical course [ 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 ( • Most prevalent pathogenic variant w/ancestral origin (allele frequency of 0.1% in European Americans) [ • Milder clinical course [ ## Molecular Pathogenesis Notable Most prevalent pathogenic variant w/ancestral origin (allele frequency of 0.1% in European Americans) [ Milder clinical course [ 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 ( • Most prevalent pathogenic variant w/ancestral origin (allele frequency of 0.1% in European Americans) [ • Milder clinical course [ ## Chapter Notes We thank the patients and families and their doctors for their support and sharing of clinical information. Frank Baas, MD, PhD (2014-present)Peter G Barth, MD, PhD; University of Amsterdam (2014-2020)Veerle RC Eggens, MSc; University of Amsterdam (2014-2020)Tessa van Dijk, MD, PhD (2020-present) 24 September 2020 (bp) Comprehensive update posted live 21 August 2014 (me) Review posted live 11 February 2014 (vrce) Original submission • 24 September 2020 (bp) Comprehensive update posted live • 21 August 2014 (me) Review posted live • 11 February 2014 (vrce) Original submission ## Acknowledgments We thank the patients and families and their doctors for their support and sharing of clinical information. ## Author History Frank Baas, MD, PhD (2014-present)Peter G Barth, MD, PhD; University of Amsterdam (2014-2020)Veerle RC Eggens, MSc; University of Amsterdam (2014-2020)Tessa van Dijk, MD, PhD (2020-present) ## Revision History 24 September 2020 (bp) Comprehensive update posted live 21 August 2014 (me) Review posted live 11 February 2014 (vrce) Original submission • 24 September 2020 (bp) Comprehensive update posted live • 21 August 2014 (me) Review posted live • 11 February 2014 (vrce) Original submission ## References ## Literature Cited
[ "R Biancheri, D Cassandrini, F Pinto, R Trovato, M Di Rocco, M Mirabelli-Badenier, M Pedemonte, C Panicucci, H Trucks, T Sander, F Zara, A Rossi, P Striano, C Minetti, FM Santorelli. EXOSC3 mutations in isolated cerebellar hypoplasia and spinal anterior horn involvement.. J Neurol. 2013;260:1866-70", "AP Di Giovambattista, I Jácome Querejeta, P Ventura Faci, G Rodríguez Martínez, F Ramos Fuentes. Familial EXOSC3-related pontocerebellar hypoplasia.. An Pediatr (Barc) 2017;86:284-6", "VRC Eggens, PG Barth, JF Niermeijer, JN Berg, N Darin, A Dixit, J Fluss, N Foulds, D Fowler, T Hortobágyi, T Jacques, MD King, P Makrythanasis, A Máté. Nicoll JAR4, O’Rourke D, Price S, Williams AN, Wilson L, Suri M, Sztriha L, Dijns-de Wissel MB, van Meegen MT, van Ruissen F, Aronica E, Troost D, Majoie CBLM, Marquering HA, Poll-Thé BT, Baas F. EXOSC3 mutations in pontocerebellar hypoplasia type 1: novel mutations and genotype-phenotype correlations.. Orphanet J Rare Dis. 2014;9:23", "MS Forman, W Squier, WB Dobyns, JA Golden. Genotypically defined lissencephalies show distinct pathologies.. J Neuropathol Exp Neurol. 2005;64:847-57", "A Halevy, I Lerer, R Cohen, L Kornreich, A Shuper, M Gamliel, BE Zimerman, I Korabi, V Meiner, R Straussberg, A Lossos. Novel EXOSC3 mutation causes complicated hereditary spastic paraplegia.. J Neurol. 2014;261:2165-9", "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", "I Ivanov, D Atkinson, I Litvinenko, L Angelova, S Andonova, H Mumdjiev, I Pacheva, M Panova, R Yordanova, V Belovejdov, A Petrova, M Bosheva, T Shmilev, A Savov, A. Jordanova. Pontocerebellar hypoplasia type 1 for the neuropediatrician: genotypeephenotype correlations and diagnostic guidelines based on new cases and overview of the literature.. Eur J Paediatr Neurol. 2018;22:674-81", "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", "D Le Duc, S Horn, RA Jamra, J Schaper, D Wieczorek, S Redler. Novel. Eur J Med Genet. 2020;63", "CR Pierson, F Al Sufiani. Preterm birth and cerebellar neuropathology.. Semin Fetal Neonatal Med. 2016;21:305-11", "S Richards, N Aziz, S Bale, D Bick, S Das, J Gastier-Foster, WW Grody, M Hegde, E Lyon, E Spector, K Voelkerding, HL Rehm. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.. Genet Med. 2015;17:405-24", "S Rudnik-Schöneborn, PG Barth, K Zerres. Pontocerebellar hypoplasia.. Am J Med Genet C Semin Med Genet. 2014;166C:173-83", "S Rudnik-Schöneborn, J Senderek, JC Jen, G Houge, P Seeman, A Puchmajerová, L Graul-Neumann, U Seidel, R Korinthenberg, J Kirschner, J Seeger, MM Ryan, F Muntoni, M Steinlin, L Sztriha, J Colomer, C Hübner, K Brockmann, L Van Maldergem, M Schiff, A Holzinger, P Barth, W Reardon, M Yourshaw, SF Nelson, T Eggermann, K Zerres. Pontocerebellar hypoplasia type 1: clinical spectrum and relevance of EXOSC3 mutations.. Neurology. 2013;80:438-46", "P Saugier-Veber, F Marguet, M Vezain, M Bucourt, P Letard, A Delahaye, E Pipiras, T Frébourg, B Gonzalez, A Laquerrière. Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B.. Eur J Med Genet. 2020;63", "G Schottmann, S Picker-Minh, JM Schwarz, E Gill, RJT Rodenburg, W Stenzel, AM Kaindl, M Schuelke. Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia.. Mitochondrion. 2017;37:46-54", "J Schwabova, DS Brozkova, B Petrak, M Mojzisova, K Pavlickova, J Haberlova, L Mrazkova, P Hedvicakova, L Hornofova, M Kaluzova, F Fencl, M Krutova, J Zamecnik, P Seeman. Homozygous EXOSC3 mutation c.92G→C, p.G31A is a founder mutation causing severe pontocerebellar hypoplasia type 1 among the Czech Roma.. J Neurogenet. 2013;27:163-9", "T van Dijk, F Baas, PG Barth, BT Poll-The. What's new in pontocerebellar hypoplasia? An update on genes and subtypes.. Orphanet J Rare Dis. 2018;13:92", "JJ Volpe. Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances.. Lancet Neurol. 2009;8:110-24", "J Wan, M Yourshaw, H Mamsa, S Rudnik-Schöneborn, MP Menezes, JE Hong, DW Leong, J Senderek, MS Salman, D Chitayat, P Seeman, A von Moers, L Graul-Neumann, AJ Kornberg, M Castro-Gago, MJ Sobrido, M Sanefuji, PB Shieh, N Salamon, RC Kim, HV Vinters, Z Chen, K Zerres, MM Ryan, SF Nelson, JC Jen. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration.. Nat Genet. 2012;44:704-8", "G Zanni, C Scotton, C Passarelli, M Fang, S Barresi, B Dallapiccola, B Wu, F Gualandi, A Ferlini, E Bertini, W Wei. Exome sequencing in a family with intellectual disability, early onset spasticity, and cerebellar atrophy detects a novel mutation in EXOSC3.. Neurogenetics. 2013;14:247-50" ]
21/8/2014
24/9/2020
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]
ext
ext
[ "Diaphyseal Aclasis", "Hereditary Multiple Exostoses", "Multiple Cartilaginous Exostoses", "Multiple Cartilaginous Exostoses", "Diaphyseal Aclasis", "Hereditary Multiple Exostoses", "Exostosin-1", "Exostosin-2", "EXT1", "EXT2", "Hereditary Multiple Osteochondromas" ]
Hereditary Multiple Osteochondromas
Wim Wuyts, Gregory A Schmale, Howard A Chansky, Wendy H Raskind
Summary Hereditary multiple osteochondromas (HMO), previously called hereditary multiple exostoses (HME), is characterized by growths of multiple osteochondromas, benign cartilage-capped bone tumors that grow outward from the metaphyses of long bones. Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature, premature osteoarthrosis, and compression of peripheral nerves. The median age of diagnosis is three years; nearly all affected individuals are diagnosed by age 12 years. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk for malignant degeneration is low (~2%-5%). The diagnosis of HMO is established in a proband with characteristic radiographic findings of multiple osteochondromas and/or a heterozygous pathogenic variant in HMO is inherited in an autosomal dominant manner. Penetrance is approximately 96% in females and 100% in males. In 10% of affected individuals HMO is the result of a
## Diagnosis No consensus clinical diagnostic criteria for hereditary multiple osteochondromas (HMO) have been published. Hereditary multiple osteochondromas (HMO) Multiple osteochondromas (cartilage-capped bony growths) arising from the area of the growth plate in the juxtaphyseal region of long bones or from the surface of flat bones (e.g., the scapula) The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. Family history consistent with autosomal dominant inheritance (~10% of affected individuals have no family history of multiple osteochondromas.) Note regarding terminology: Osteochondromas were previously called exostoses; however, the term "exostosis" is no longer used to describe the lesions in HMO because the term "osteochondroma" specifies that these lesions are cartilaginous processes that ossify and not simply outgrowths of bone. The updated terminology has been adopted by the World Health Organization (WHO). The clinical diagnosis of HMO can be 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 HMO is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HMO, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of HMO is doubtful because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Multiple Osteochondromas 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 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Whole-gene, partial-gene, and single-exon deletions have been described but there are no recurrent break points [ It is suspected that simplex cases of HMO harbor a somatic • Multiple osteochondromas (cartilage-capped bony growths) arising from the area of the growth plate in the juxtaphyseal region of long bones or from the surface of flat bones (e.g., the scapula) • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. • Family history consistent with autosomal dominant inheritance (~10% of affected individuals have no family history of multiple osteochondromas.) • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. • For an introduction to multigene panels click ## Suggestive Findings Hereditary multiple osteochondromas (HMO) Multiple osteochondromas (cartilage-capped bony growths) arising from the area of the growth plate in the juxtaphyseal region of long bones or from the surface of flat bones (e.g., the scapula) The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. Family history consistent with autosomal dominant inheritance (~10% of affected individuals have no family history of multiple osteochondromas.) Note regarding terminology: Osteochondromas were previously called exostoses; however, the term "exostosis" is no longer used to describe the lesions in HMO because the term "osteochondroma" specifies that these lesions are cartilaginous processes that ossify and not simply outgrowths of bone. The updated terminology has been adopted by the World Health Organization (WHO). • Multiple osteochondromas (cartilage-capped bony growths) arising from the area of the growth plate in the juxtaphyseal region of long bones or from the surface of flat bones (e.g., the scapula) • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. • Family history consistent with autosomal dominant inheritance (~10% of affected individuals have no family history of multiple osteochondromas.) • The key radiographic and anatomic feature of an osteochondroma is the uninterrupted flow of cortex and medullary bone from the host bone into the osteochondroma. • Osteochondromas possess the equivalent of a growth plate that ossifies and closes with the onset of skeletal maturity. • Approximately 70% of affected individuals have a clinically apparent osteochondroma about the knee, suggesting that radiographs of the knees to detect non-palpable osteochondromas may be a sensitive way to detect mildly affected individuals. ## Establishing the Diagnosis The clinical diagnosis of HMO can be 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 HMO is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of HMO, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the diagnosis of HMO is doubtful because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Multiple Osteochondromas 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 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Whole-gene, partial-gene, and single-exon deletions have been described but there are no recurrent break points [ It is suspected that simplex cases of HMO harbor a somatic • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of HMO, molecular genetic testing approaches can include use of a For an introduction to multigene panels click • For an introduction to multigene panels click ## Option 2 When the diagnosis of HMO is doubtful because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Hereditary Multiple Osteochondromas 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 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Whole-gene, partial-gene, and single-exon deletions have been described but there are no recurrent break points [ It is suspected that simplex cases of HMO harbor a somatic ## Clinical Characteristics To date, more than 1,000 individuals with a pathogenic variant in Select Features of Hereditary Multiple Osteochondromas (HMO) 67% <50th centile 46% of The number of osteochondromas, number and location of involved bones, and degree of deformity vary. Osteochondromas grow in size and gradually ossify during skeletal development and stop growing with skeletal maturity, after which no new osteochondromas develop. The proportion of individuals with hereditary multiple osteochondromas (HMO) who have clinical findings increases from approximately 5% at birth to 96% at age 12 years [ The number of osteochondromas that develop in an affected person varies widely even within families. Involvement is usually symmetric. Most commonly involved bones are the femur (30%), radius and ulna (13%), tibia (20%), and fibula (13%). Hand deformity resulting from shortened metacarpals is common. Abnormal bone remodeling may result in shortening and bowing with widened metaphyses [ Abnormal growth and development of the forearm and leg in untreated individuals with HMO is common, including both proportionate and disproportionate shortening of the two bones of the forearm or leg, producing shortened and angulated limbs, respectively. In a study of 46 kindreds in Washington State, 39% of individuals had a deformity of the forearm, 10% had an inequality in limb length, 8% had an angular deformity of the knee, and 2% had a deformity of the ankle [ Hip dysplasia frequently results from osteochondromas of the proximal femur and from coxa valga. Decreased center-edge angles and increased uncovering of the femoral heads may lead to early thigh pain and abductor weakness and late arthritis [ It has been stated that 40% of individuals with HMO have "shortened stature." Although interference with the linear growth of the long bones of the leg often results in reduction of predicted adult height, the height of most adults with Note: "Shortened stature" is used to indicate that although stature is often shorter than predicted based on the heights of unaffected parents and sibs, it is usually within the normal range. Osteochondromas typically arise in the juxtaphyseal region of long bones and from the surface of flat bones (pelvis, scapula). An osteochondroma may be sessile or pedunculated. Sessile osteochondromas have a broad-based attachment to the cortex. The pedunculated variants have a pedicle arising from the cortex that is usually directed away from the adjacent growth plate. The pedunculated form is more likely to irritate overlying soft tissue, such as tendons, and compress peripheral nerves or vessels. The marrow and cancellous bone of the host bone are continuous with the osteochondroma. Symptoms may also arise secondary to mass effect. Compression or stretching of peripheral nerves usually causes pain but may also cause sensory or motor deficits [ The most serious complication of HMO is sarcomatous degeneration of an osteochondroma. Axial sites, such as the pelvis, scapula, ribs, and spine, are more commonly the location of degeneration of osteochondromas to chondrosarcoma [ A bulky cartilage cap (best visualized with MRI or CT) thicker than 2.0 to 3.0 cm is highly suggestive of chondrosarcoma [ After skeletal maturity, increased radionucleotide uptake on serial technetium bone scans may also be evidence of malignancy. High metabolic activity in the cartilage as evidenced by uptake of gadolinum on T FDG-PET imaging may be useful in the workup for malignant transformation in HMO. An SUV The incidence of malignant degeneration to chondrosarcoma, or less commonly to other sarcomas, is estimated at 2%-5%. In a large cohort of 529 affected individuals, the rate of malignant transformation was calculated to be 5% [ Malignant degeneration can occur during childhood or adolescence, but the risk increases with age. Based on a study of HMO in Washington State (USA), it was estimated that HMO may increase the risk of developing a chondrosarcoma by a factor of 1,000 to 2,500 over the risk for individuals without HMO. Most studies have identified a higher burden of disease in persons with No genotype-phenotype correlations for The penetrance is estimated to be 96% in females and 100% in males [ "Multiple osteocartilaginous exostoses" was used to convey the observation that the growths are composed primarily of cartilage in the child and ossify as skeletal maturity is reached. In the United States, the terms "exostosis" and "hereditary multiple exostoses" have been used to denote the growths and the disorder, but the World Health Organization (WHO) has selected the nomenclature "osteochondromas" for exostoses and "multiple osteochondromas" for the disorder [ The reported prevalence of HMO ranges from as high as one in 100 in a small population in Guam to approximately one in 100,000 in European populations [ • 67% <50th centile • 46% of • A bulky cartilage cap (best visualized with MRI or CT) thicker than 2.0 to 3.0 cm is highly suggestive of chondrosarcoma [ • After skeletal maturity, increased radionucleotide uptake on serial technetium bone scans may also be evidence of malignancy. • High metabolic activity in the cartilage as evidenced by uptake of gadolinum on T • FDG-PET imaging may be useful in the workup for malignant transformation in HMO. An SUV ## Clinical Description To date, more than 1,000 individuals with a pathogenic variant in Select Features of Hereditary Multiple Osteochondromas (HMO) 67% <50th centile 46% of The number of osteochondromas, number and location of involved bones, and degree of deformity vary. Osteochondromas grow in size and gradually ossify during skeletal development and stop growing with skeletal maturity, after which no new osteochondromas develop. The proportion of individuals with hereditary multiple osteochondromas (HMO) who have clinical findings increases from approximately 5% at birth to 96% at age 12 years [ The number of osteochondromas that develop in an affected person varies widely even within families. Involvement is usually symmetric. Most commonly involved bones are the femur (30%), radius and ulna (13%), tibia (20%), and fibula (13%). Hand deformity resulting from shortened metacarpals is common. Abnormal bone remodeling may result in shortening and bowing with widened metaphyses [ Abnormal growth and development of the forearm and leg in untreated individuals with HMO is common, including both proportionate and disproportionate shortening of the two bones of the forearm or leg, producing shortened and angulated limbs, respectively. In a study of 46 kindreds in Washington State, 39% of individuals had a deformity of the forearm, 10% had an inequality in limb length, 8% had an angular deformity of the knee, and 2% had a deformity of the ankle [ Hip dysplasia frequently results from osteochondromas of the proximal femur and from coxa valga. Decreased center-edge angles and increased uncovering of the femoral heads may lead to early thigh pain and abductor weakness and late arthritis [ It has been stated that 40% of individuals with HMO have "shortened stature." Although interference with the linear growth of the long bones of the leg often results in reduction of predicted adult height, the height of most adults with Note: "Shortened stature" is used to indicate that although stature is often shorter than predicted based on the heights of unaffected parents and sibs, it is usually within the normal range. Osteochondromas typically arise in the juxtaphyseal region of long bones and from the surface of flat bones (pelvis, scapula). An osteochondroma may be sessile or pedunculated. Sessile osteochondromas have a broad-based attachment to the cortex. The pedunculated variants have a pedicle arising from the cortex that is usually directed away from the adjacent growth plate. The pedunculated form is more likely to irritate overlying soft tissue, such as tendons, and compress peripheral nerves or vessels. The marrow and cancellous bone of the host bone are continuous with the osteochondroma. Symptoms may also arise secondary to mass effect. Compression or stretching of peripheral nerves usually causes pain but may also cause sensory or motor deficits [ The most serious complication of HMO is sarcomatous degeneration of an osteochondroma. Axial sites, such as the pelvis, scapula, ribs, and spine, are more commonly the location of degeneration of osteochondromas to chondrosarcoma [ A bulky cartilage cap (best visualized with MRI or CT) thicker than 2.0 to 3.0 cm is highly suggestive of chondrosarcoma [ After skeletal maturity, increased radionucleotide uptake on serial technetium bone scans may also be evidence of malignancy. High metabolic activity in the cartilage as evidenced by uptake of gadolinum on T FDG-PET imaging may be useful in the workup for malignant transformation in HMO. An SUV The incidence of malignant degeneration to chondrosarcoma, or less commonly to other sarcomas, is estimated at 2%-5%. In a large cohort of 529 affected individuals, the rate of malignant transformation was calculated to be 5% [ Malignant degeneration can occur during childhood or adolescence, but the risk increases with age. Based on a study of HMO in Washington State (USA), it was estimated that HMO may increase the risk of developing a chondrosarcoma by a factor of 1,000 to 2,500 over the risk for individuals without HMO. • 67% <50th centile • 46% of • A bulky cartilage cap (best visualized with MRI or CT) thicker than 2.0 to 3.0 cm is highly suggestive of chondrosarcoma [ • After skeletal maturity, increased radionucleotide uptake on serial technetium bone scans may also be evidence of malignancy. • High metabolic activity in the cartilage as evidenced by uptake of gadolinum on T • FDG-PET imaging may be useful in the workup for malignant transformation in HMO. An SUV ## Phenotype Correlations by Gene Most studies have identified a higher burden of disease in persons with ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Penetrance The penetrance is estimated to be 96% in females and 100% in males [ ## Nomenclature "Multiple osteocartilaginous exostoses" was used to convey the observation that the growths are composed primarily of cartilage in the child and ossify as skeletal maturity is reached. In the United States, the terms "exostosis" and "hereditary multiple exostoses" have been used to denote the growths and the disorder, but the World Health Organization (WHO) has selected the nomenclature "osteochondromas" for exostoses and "multiple osteochondromas" for the disorder [ ## Prevalence The reported prevalence of HMO ranges from as high as one in 100 in a small population in Guam to approximately one in 100,000 in European populations [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Inherited Conditions with Multiple Osteochondromas in the Differential Diagnosis of Hereditary Multiple Osteochondromas Parietal foramina & ossification defects of the skull (See Craniofacial abnormalities, syndactyly, & ID in some affected persons ID Characteristic craniofacial & digital anomalies Assoc w/both osteochondromas & intraosseous enchondromas Tumors occur predominantly in digits, point toward nearby joint, & do not cause shortening or bowing of long bone, joint deformity, or subluxation. AD = autosomal dominant; ID = intellectual disability; MOI = mode of inheritance Deletion events invariably remove • Parietal foramina & ossification defects of the skull (See • Craniofacial abnormalities, syndactyly, & ID in some affected persons • ID • Characteristic craniofacial & digital anomalies • Assoc w/both osteochondromas & intraosseous enchondromas • Tumors occur predominantly in digits, point toward nearby joint, & do not cause shortening or bowing of long bone, joint deformity, or subluxation. ## Management To establish the extent of disease and needs in an individual diagnosed with hereditary multiple osteochondromas (HMO), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Multiple Osteochondromas Detailed history of symptoms from osteochondromas Physical exam to document location of osteochondromas, functional limitations, & deformity (shortness of stature, forearm bowing & shortening, knee & ankle angular deformities) HMO = hereditary multiple osteochondromas; MOI = mode of inheritance Although spinal osteochrondromas are common in HMO and can cause neurologic impairment, intervention is reserved for symptomatic cases and in almost all cases there was complete recovery [ Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Treatment of Manifestations in Individuals with Hereditary Multiple Osteochondromas May incl excision of osteochondromas, corrective osteotomies, &/or ulnar lengthening procedures to improve pronation, supination, & forearm alignment Adults w/untreated forearm deformities describe few functional limitations. Recommended Surveillance for Individuals with Hereditary Multiple Osteochondromas It is not known whether the benefits outweigh the risks of irradiation and the potential for false positive results that lead to unnecessary interventions. There is insufficient data to support routine interval spine surveillance in asymptomatic individuals, as surgical interventions are reserved for those with intractable pain or functional impairment [ Asymptomatic, predictive testing is not warranted because the clinical diagnosis is evident at an early age and because no precipitants, protective strategies, or specific nonsurgical interventions are known. See A clinical trial of the RARγ agonist palovarotene for patients younger than age 14 years with HMO was paused in January 2020, based on results of a futility analysis. Search • Detailed history of symptoms from osteochondromas • Physical exam to document location of osteochondromas, functional limitations, & deformity (shortness of stature, forearm bowing & shortening, knee & ankle angular deformities) • May incl excision of osteochondromas, corrective osteotomies, &/or ulnar lengthening procedures to improve pronation, supination, & forearm alignment • Adults w/untreated forearm deformities describe few functional limitations. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hereditary multiple osteochondromas (HMO), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Multiple Osteochondromas Detailed history of symptoms from osteochondromas Physical exam to document location of osteochondromas, functional limitations, & deformity (shortness of stature, forearm bowing & shortening, knee & ankle angular deformities) HMO = hereditary multiple osteochondromas; MOI = mode of inheritance Although spinal osteochrondromas are common in HMO and can cause neurologic impairment, intervention is reserved for symptomatic cases and in almost all cases there was complete recovery [ Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Detailed history of symptoms from osteochondromas • Physical exam to document location of osteochondromas, functional limitations, & deformity (shortness of stature, forearm bowing & shortening, knee & ankle angular deformities) ## Treatment of Manifestations Treatment of Manifestations in Individuals with Hereditary Multiple Osteochondromas May incl excision of osteochondromas, corrective osteotomies, &/or ulnar lengthening procedures to improve pronation, supination, & forearm alignment Adults w/untreated forearm deformities describe few functional limitations. • May incl excision of osteochondromas, corrective osteotomies, &/or ulnar lengthening procedures to improve pronation, supination, & forearm alignment • Adults w/untreated forearm deformities describe few functional limitations. ## Surveillance Recommended Surveillance for Individuals with Hereditary Multiple Osteochondromas It is not known whether the benefits outweigh the risks of irradiation and the potential for false positive results that lead to unnecessary interventions. There is insufficient data to support routine interval spine surveillance in asymptomatic individuals, as surgical interventions are reserved for those with intractable pain or functional impairment [ ## Evaluation of Relatives at Risk Asymptomatic, predictive testing is not warranted because the clinical diagnosis is evident at an early age and because no precipitants, protective strategies, or specific nonsurgical interventions are known. See ## Therapies Under Investigation A clinical trial of the RARγ agonist palovarotene for patients younger than age 14 years with HMO was paused in January 2020, based on results of a futility analysis. Search ## Genetic Counseling The disorder hereditary multiple osteochondromas (HMO) is inherited in an autosomal dominant manner. Approximately 90% of individuals with HMO have an affected parent. Approximately 10% of individuals diagnosed with HMO have the disorder as the result of a If the proband is the only family member known to have HMO, recommendations for the evaluation of the parents of the proband include physical examination, radiographs, and/or molecular genetic testing (if the causative pathogenic variant has been identified in the proband). If the proband has a known * Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals diagnosed with HMO may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: If the parent is the individual in whom the pathogenic variant first occurred, they may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. If the proband has a known HMO-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 undergone molecular genetic testing but are clinically unaffected, sibs are still presumed to be at increased risk for HMO 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. Once the HMO-causing pathogenic variant has 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 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 90% of individuals with HMO have an affected parent. • Approximately 10% of individuals diagnosed with HMO have the disorder as the result of a • If the proband is the only family member known to have HMO, recommendations for the evaluation of the parents of the proband include physical examination, radiographs, and/or molecular genetic testing (if the causative pathogenic variant has been identified in the proband). • If the proband has a known • * Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals diagnosed with HMO may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • 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 HMO-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 undergone molecular genetic testing but are clinically unaffected, sibs are still presumed to be at increased risk for HMO 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. ## Mode of Inheritance The disorder hereditary multiple osteochondromas (HMO) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 90% of individuals with HMO have an affected parent. Approximately 10% of individuals diagnosed with HMO have the disorder as the result of a If the proband is the only family member known to have HMO, recommendations for the evaluation of the parents of the proband include physical examination, radiographs, and/or molecular genetic testing (if the causative pathogenic variant has been identified in the proband). If the proband has a known * Misattributed parentage can also be explored as an alternative explanation for an apparent The family history of some individuals diagnosed with HMO may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: If the parent is the individual in whom the pathogenic variant first occurred, they may have somatic mosaicism for the variant and may be mildly/minimally affected. If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. If the proband has a known HMO-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 undergone molecular genetic testing but are clinically unaffected, sibs are still presumed to be at increased risk for HMO because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism [ • Approximately 90% of individuals with HMO have an affected parent. • Approximately 10% of individuals diagnosed with HMO have the disorder as the result of a • If the proband is the only family member known to have HMO, recommendations for the evaluation of the parents of the proband include physical examination, radiographs, and/or molecular genetic testing (if the causative pathogenic variant has been identified in the proband). • If the proband has a known • * Misattributed parentage can also be explored as an alternative explanation for an apparent • The family history of some individuals diagnosed with HMO may appear to be negative because of failure to recognize the disorder in family members and/or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • 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 HMO-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 undergone molecular genetic testing but are clinically unaffected, sibs are still presumed to be at increased risk for HMO because of the possibility of reduced penetrance in a heterozygous parent or 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. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 HMO-causing pathogenic variant has 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 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 Hereditary Multiple Osteochondromas: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Multiple Osteochondromas ( Both Osteochondroma mouse models have shown that complete inactivation of both Not only do Hereditary Multiple Osteochondromas: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Exon, multiexon, and whole-gene deletions ## Molecular Pathogenesis Both Osteochondroma mouse models have shown that complete inactivation of both Not only do Hereditary Multiple Osteochondromas: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Exon, multiexon, and whole-gene deletions ## References ## Literature Cited ## Chapter Notes 6 August 2020 (sw) Comprehensive updated posted live 21 November 2013 (me) Comprehensive update posted live 5 September 2008 (me) Comprehensive update posted live 20 September 2005 (me) Comprehensive update posted live 2 July 2003 (me) Comprehensive update posted live 3 August 2000 (me) Review posted live 22 March 2000 (hc) Original submission • 6 August 2020 (sw) Comprehensive updated posted live • 21 November 2013 (me) Comprehensive update posted live • 5 September 2008 (me) Comprehensive update posted live • 20 September 2005 (me) Comprehensive update posted live • 2 July 2003 (me) Comprehensive update posted live • 3 August 2000 (me) Review posted live • 22 March 2000 (hc) Original submission ## Revision History 6 August 2020 (sw) Comprehensive updated posted live 21 November 2013 (me) Comprehensive update posted live 5 September 2008 (me) Comprehensive update posted live 20 September 2005 (me) Comprehensive update posted live 2 July 2003 (me) Comprehensive update posted live 3 August 2000 (me) Review posted live 22 March 2000 (hc) Original submission • 6 August 2020 (sw) Comprehensive updated posted live • 21 November 2013 (me) Comprehensive update posted live • 5 September 2008 (me) Comprehensive update posted live • 20 September 2005 (me) Comprehensive update posted live • 2 July 2003 (me) Comprehensive update posted live • 3 August 2000 (me) Review posted live • 22 March 2000 (hc) Original submission
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3/8/2000
6/8/2020
GeneReviews®
https://www.ncbi.nlm.nih.gov/books/NBK1116/
[ "Review", "Clinical Review" ]